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Clinical Trial Results:
A Phase 1b/2 Study to Evaluate the Safety and Efficacy Of PF-04449913, An Oral Hedgehog Inhibitor, in Combination With Intensive Chemotherapy, Low Dose Ara-C or Decitabine In Patients With Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome

Summary
EudraCT number	2012-000684-24
Trial protocol	PL ES IT
Global end of trial date	04 Mar 2019

Results information
Results version number	v2(current)
This version publication date	07 Mar 2020
First version publication date	29 Dec 2017
Other versions	v1
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

B1371003

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer, Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States, NY 10017

Public contact

Pfizer Clinical Trials.gov Call Center, Pfizer, Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

04 Mar 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

03 Jan 2017

Global end of trial reached?

Yes

Global end of trial date

04 Mar 2019

Was the trial ended prematurely?

Main objective of the trial

The main objective of this study was to evaluate the safety and efficacy of glasdegib (PF-04449913) when administered in combination with first line treatment regimens for Acute Myeloid Leukemia (AML) and High Risk Myelodysplastic Syndrome (MDS).

Protection of trial subjects

This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial subjects.

Background therapy

Evidence for comparator

Actual start date of recruitment

27 Jun 2012

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy

Long term follow-up duration

2 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 147

Country: Number of subjects enrolled

Italy: 14

Country: Number of subjects enrolled

Germany: 43

Country: Number of subjects enrolled

Poland: 20

Country: Number of subjects enrolled

Spain: 22

Country: Number of subjects enrolled

Canada: 9

Worldwide total number of subjects

255

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

190

85 years and over

Subject disposition

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Recruitment details

Screening details

Phase 1B:Unfit(unfit for intensive chemotherapy)subjects with prior decitabine or azacitidine for high risk MDS or AHD(antecedent hematologic disease)were eligible for the LDAC arm only;with prior cytarabine were eligible for decitabine arm only.Phase 2:Subject's treatment arm assignment was based on the fit or unfit status at screening.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1B: Glasdegib 100 mg + LDAC

Arm description

Subjects received oral doses of glasdegib (PF-04449913) tablets 100 milligram (mg) starting on Day 3 of Cycle 1 for pharmacokinetic (PK) assessment purposes and thereafter once daily (QD) and continuously for 28-day cycles (starting on Day 1 for all other cycles). Low dose Ara-C (LDAC) was given at a dose of 20 mg subcutaneously twice daily (BID) on Days 1-10 of the 28-day cycles.

Arm type

Experimental

Investigational medicinal product name

Glasdegib (PF-04449913)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Glasdegib (PF-04449913) tablets 100 mg were taken orally QD starting on Day 3 of Cycle 1 and continuously for 28-day cycles (starting on Day 1 for all other cycles). Tablets were taken in the morning at approximately the same time each day. Dosing occurred with plenty of water (without adjustment for body size). Study medication were swallowed whole and not chewed, with or without food.

Investigational medicinal product name

LDAC (low dose Ara-C)

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solution for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

LDAC was given at a dose of 20 mg (not adjusted for the subjects weight) subcutaneously (SC) twice daily (morning and evening; approximately 12 hrs apart) on Days 1-10 days of the 28 day cycles.

Phase 1B: Glasdegib 200 mg + LDAC

Arm description

Subjects received oral doses of glasdegib tablets 200 mg starting on Day 3 of Cycle 1 for PK assessment purposes and thereafter QD and continuously for 28-day cycles (starting on Day 1 for all other cycles). LDAC was given at a dose of 20 mg subcutaneously BID on Days 1-10 of the 28-day cycles. In March 2013, all active subjects receiving glasdegib 200 mg were required to reduce dose to 100 mg. Subjects who had glasdegib dose reduction were reported as the starting glasdegib dose level received. Two (2) subjects in this cohort had dose reduction to 100 mg starting from Cycle 2/Day 1 and Cycle 2/Day 16, respectively.

Arm type

Experimental

Investigational medicinal product name

LDAC (low dose Ara-C)

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solution for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

LDAC was given at a dose of 20 mg (not adjusted for the subjects weight) subcutaneously (SC) twice daily (morning and evening; approximately 12 hrs apart) on Days 1-10 days of the 28 day cycles.

Investigational medicinal product name

Glasdegib (PF-04449913)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Glasdegib (PF-04449913) tablets 200 mg were taken orally QD starting on Day 3 of Cycle 1 and continuously for 28-day cycles (starting on Day 1 for all other cycles). Tablets were taken in the morning at approximately the same time each day. Dosing occurred with plenty of water (without adjustment for body size). Study medication were swallowed whole and not chewed, with or without food.In March 2013, all active subjects receiving glasdegib 200 mg were required to reduce dose to 100 mg. Subjects who had glasdegib dose reduction were reported as the starting glasdegib dose level received. Two (2) subjects in this cohort had dose reduction to 100 mg starting from Cycle 2/Day 1 and Cycle 2/Day 16, respectively.

Phase 1B: Glasdegib 100 mg + Decitabine

Arm description

Subjects received oral doses of glasdegib tablets 100 mg starting on Day 2 of Cycle 1 for PK assessment purposes and thereafter QD and continuously for 28-day cycles (starting on Day 1 for all other cycles). Decitabine was given at a dose of 20 mg/m^2 as an intravenous (IV) infusion over 1 hour on Days 1-5 of the 28-day cycles.

Arm type

Experimental

Investigational medicinal product name

Decitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

Decitabine was given at a dose of 20 mg/m^2 over a 1 hour IV infusion on Days 1-5 of a 28 day cycle. Dose was recalculated when the weight changes >10%.

Investigational medicinal product name

Glasdegib (PF-04449913)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Glasdegib (PF-04449913) tablets 100 mg were taken orally QD starting on Day 2 of Cycle 1 and continuously for 28-day cycles (starting on Day 1 for all other cycles). Tablets were taken in the morning at approximately the same time each day. Dosing occurred with plenty of water (without adjustment for body size). Study medication were swallowed whole and not chewed, with or without food.

Phase 1B: Glasdegib 200 mg + Decitabine

Arm description

Subjects received oral doses of glasdegib tablets 200 mg starting on Day 2 of Cycle 1 for PK assessment purposes and thereafter QD and continuously for 28-day cycles (starting on Day 1 for all other cycles). Decitabine was given at a dose of 20 mg/m^2 as an IV infusion over 1 hour on Days 1-5 of the 28-day cycles.In March 2013, all active subjects receiving glasdegib 200 mg were required to reduce dose to 100 mg. Subjects who had glasdegib dose reduction were reported as the starting glasdegib dose level received. Two (2) subjects in this cohort had dose reduction to 100 mg starting from Cycle 1/Day 24 and Cycle 5/Day 1, respectively.

Arm type

Experimental

Investigational medicinal product name

Decitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

Decitabine was given at a dose of 20 mg/m^2 over a 1 hour IV infusion on Days 1-5 of a 28 day cycle. Dose was recalculated when the weight changes >10%.

Investigational medicinal product name

Glasdegib (PF-04449913)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Glasdegib (PF-04449913) tablets 200 mg were taken orally QD starting on Day 2 of Cycle 1 and continuously for 28-day cycles (starting on Day 1 for all other cycles). Tablets were taken in the morning at approximately the same time each day. Dosing occurred with plenty of water (without adjustment for body size). Study medication were swallowed whole and not chewed, with or without food.In March 2013, all active subjects receiving glasdegib 200 mg were required to reduce dose to 100 mg. Subjects who had glasdegib dose reduction were reported as the starting glasdegib dose level received. Two (2) subjects in this cohort had dose reduction to 100 mg starting from Cycle 1/Day 24 and Cycle 5/Day 1, respectively.

Phase 1B: Glasdegib 100 mg + Cytarabine/Daunorubicin

Arm description

Subjects received 1-2 cycles of induction (glasdegib and daunorubicin/cytarabine), followed by 2-4 cycles of consolidation (glasdegib and high dose cytarabine) and a maximum of 6 cycles of maintenance (glasdegib alone). Daunorubicin was given on Days 1-3 QD at a dose of 60 mg/m^2/day by IV together with cytarabine on Days 1-7 at a dose of 100 mg/m^2/day by continuous IV infusion for each cycle of induction. Cytarabine was given on Days 1, 3, and 5 at a dose of 1 g/m^2 administered as a 3-hour IV infusion every 12 hours (2 g/m^2/day) for each cycle of consolidation. Glasdegib tablets 100 mg QD was started on induction Cycle 1/Day -3 and administered continuously QD thereafter for the duration of the study. A cycle was defined as 28 days.

Arm type

Experimental

Investigational medicinal product name

Glasdegib (PF-04449913)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Glasdegib (PF-04449913) tablets 100 mg were taken orally QD on induction Cycle 1/Day -3 and administered continuously QD thereafter for the duration of the study. A cycle was defined as 28 days. Tablets were taken in the morning at approximately the same time each day. Dosing occurred with plenty of water (without adjustment for body size). Study medication were swallowed whole and not chewed, with or without food.

Investigational medicinal product name

Daunorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

Daunorubicin was given on Days 1-3 QD at a dose of 60 mg/m^2/day by IV for each cycle. Daunorubicin was given as close as possible to the administration of glasdegib.

Investigational medicinal product name

Cytarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cytarabine was given on Days 1 through 7 at a dose of 100 mg/m^2/day by continuous intravenous infusion (CIV) for each cycle of induction, and given on Days 1, 3, and 5 at a dose of 1 g/m^2 administered as a 3-hour IV infusion every 12 hours (2 g/m^2/day) for each cycle of consolidation.

Phase 1B: Glasdegib 200 mg + Cytarabine/Daunorubicin

Arm description

Subjects received 1-2 cycles of induction (glasdegib and daunorubicin/cytarabine), followed by 2-4 cycles of consolidation (glasdegib and high dose cytarabine) and a maximum of 6 cycles of maintenance (glasdegib alone). Daunorubicin was given on Days 1-3 QD at a dose of 60 mg/m^2/day by IV together with cytarabine on Days 1-7 at a dose of 100 mg/m^2/day by continuous IV infusion for each cycle of induction. Cytarabine was given on Days 1, 3, and 5 at a dose of 1 g/m^2 administered as a 3-hour IV infusion every 12 hours (2 g/m^2/day) for each cycle of consolidation. Glasdegib tablets 200 mg QD was started on induction Cycle 1/Day -3 and administered continuously QD thereafter for the duration of the study. A cycle was defined as 28 days.In March 2013, all active subjects receiving glasdegib 200 mg were required to reduce dose to 100 mg.One (1) subject in this cohort had dose reduction to 100 mg starting from Consolidation Cycle 1/Day 21.

Arm type

Experimental

Investigational medicinal product name

Glasdegib (PF-04449913)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Glasdegib (PF-04449913) tablets 200 mg were taken orally QD on induction Cycle 1/Day -3 and administered continuously QD thereafter for the duration of the study. A cycle was defined as 28 days.Tablets were taken in the morning at approximately the same time each day. Dosing occurred with plenty of water (without adjustment for body size). Study medication were swallowed whole and not chewed, with or without food.In March 2013, all active subjects receiving glasdegib 200 mg were required to reduce dose to 100 mg. Subjects who had glasdegib dose reduction were reported as the starting glasdegib dose level received. One (1) subject in this cohort had dose reduction to 100 mg starting from Consolidation Cycle 1/Day 21.

Investigational medicinal product name

Daunorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

Daunorubicin was given on Days 1-3 QD at a dose of 60 mg/m^2/day by IV for each cycle. Daunorubicin was given as close as possible to the administration of glasdegib.

Investigational medicinal product name

Cytarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin

Arm description

Arm type

Experimental

Investigational medicinal product name

Glasdegib (PF-04449913)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Daunorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for injection

Routes of administration

Intravenous use

Dosage and administration details

Daunorubicin was given on Days 1-3 QD at a dose of 60 mg/m^2/day by IV for each cycle. Daunorubicin was given as close as possible to the administration of glasdegib.

Investigational medicinal product name

Cytarabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Phase 2 Unfit: Glasdegib 100 mg + LDAC

Arm description

Subjects received oral doses of glasdegib tablets 100 mg QD in 28-day cycles on a continuous basis, starting on Day 1 of Cycle 1. LDAC was given at a dose of 20 mg subcutaneously BID on Days 1-10 of the 28 day cycles.

Arm type

Experimental

Investigational medicinal product name

LDAC (low dose Ara-C)

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solution for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

LDAC was given at a dose of 20 mg (not adjusted for the subjects weight) subcutaneously (SC) twice daily (morning and evening; approximately 12 hrs apart) on Days 1-10 days of the 28 day cycles.

Investigational medicinal product name

Glasdegib (PF-04449913)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Glasdegib (PF-04449913) tablets 100 mg were taken orally QD starting on Day 1 of Cycle 1 and continuously for 28-day cycles. Tablets were taken in the morning at approximately the same time each day. Dosing occurred with plenty of water (without adjustment for body size). Study medication were swallowed whole and not chewed, with or without food.

Phase 2 Unfit: LDAC alone

Arm description

Subjects received LDAC subcutaneously at a dose of 20 mg BID on Days 1-10 of the 28 day cycles.

Arm type

Active comparator

Investigational medicinal product name

LDAC (low dose Ara-C)

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solution for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

LDAC was given at a dose of 20 mg (not adjusted for the subjects weight) subcutaneously (SC) twice daily (morning and evening; approximately 12 hrs apart) on Days 1-10 days of the 28 day cycles.

Number of subjects in period 1	Phase 1B: Glasdegib 100 mg + LDAC	Phase 1B: Glasdegib 200 mg + LDAC	Phase 1B: Glasdegib 100 mg + Decitabine	Phase 1B: Glasdegib 200 mg + Decitabine	Phase 1B: Glasdegib 100 mg + Cytarabine/Daunorubicin	Phase 1B: Glasdegib 200 mg + Cytarabine/Daunorubicin	Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin	Phase 2 Unfit: Glasdegib 100 mg + LDAC	Phase 2 Unfit: LDAC alone
Started	17	6	4	3	16	6	71	88	44
Received treatment	17	6	4	3	16	6	69	84	41
Completed	1	0	0	0	6	2	18	4	1
Not completed	16	6	4	3	10	4	53	84	43
Adverse event, serious fatal	15	6	4	2	9	3	46	76	39
Consent withdrawn by subject	1	-	-	1	-	1	3	3	1
: Randomized, not treated	-	-	-	-	-	-	2	4	3
Lost to follow-up	-	-	-	-	1	-	2	1	-

Baseline characteristics

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Reporting group title

Phase 1B: Glasdegib 100 mg + LDAC

Reporting group description

Reporting group title

Phase 1B: Glasdegib 200 mg + LDAC

Reporting group description

Reporting group title

Phase 1B: Glasdegib 100 mg + Decitabine

Reporting group description

Reporting group title

Phase 1B: Glasdegib 200 mg + Decitabine

Reporting group description

Reporting group title

Phase 1B: Glasdegib 100 mg + Cytarabine/Daunorubicin

Reporting group description

Reporting group title

Phase 1B: Glasdegib 200 mg + Cytarabine/Daunorubicin

Reporting group description

Subjects received 1-2 cycles of induction (glasdegib and daunorubicin/cytarabine), followed by 2-4 cycles of consolidation (glasdegib and high dose cytarabine) and a maximum of 6 cycles of maintenance (glasdegib alone). Daunorubicin was given on Days 1-3 QD at a dose of 60 mg/m^2/day by IV together with cytarabine on Days 1-7 at a dose of 100 mg/m^2/day by continuous IV infusion for each cycle of induction. Cytarabine was given on Days 1, 3, and 5 at a dose of 1 g/m^2 administered as a 3-hour IV infusion every 12 hours (2 g/m^2/day) for each cycle of consolidation. Glasdegib tablets 200 mg QD was started on induction Cycle 1/Day -3 and administered continuously QD thereafter for the duration of the study. A cycle was defined as 28 days.In March 2013, all active subjects receiving glasdegib 200 mg were required to reduce dose to 100 mg.One (1) subject in this cohort had dose reduction to 100 mg starting from Consolidation Cycle 1/Day 21.

Reporting group title

Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin

Reporting group description

Reporting group title

Phase 2 Unfit: Glasdegib 100 mg + LDAC

Reporting group description

Reporting group title

Phase 2 Unfit: LDAC alone

Reporting group description

Subjects received LDAC subcutaneously at a dose of 20 mg BID on Days 1-10 of the 28 day cycles.

Reporting group values	Phase 1B: Glasdegib 100 mg + LDAC	Phase 1B: Glasdegib 200 mg + LDAC	Phase 1B: Glasdegib 100 mg + Decitabine	Phase 1B: Glasdegib 200 mg + Decitabine	Phase 1B: Glasdegib 100 mg + Cytarabine/Daunorubicin	Phase 1B: Glasdegib 200 mg + Cytarabine/Daunorubicin	Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin	Phase 2 Unfit: Glasdegib 100 mg + LDAC	Phase 2 Unfit: LDAC alone	Total
Number of subjects	17	6	4	3	16	6	71	88	44	255
Age categorical
Units: Subjects
< 18 years	0	0	0	0	0	0	0	0	0	0
18 to 44 years	0	0	0	0	3	1	5	0	0	9
45 to 64 years	0	1	0	0	9	2	33	2	1	48
>=65 years	17	5	4	3	4	3	33	86	43	198
Age Continuous
Units: Years
arithmetic mean (standard deviation)	76.2 ± 5.7	74.5 ± 8.8	75.3 ± 5.7	74.7 ± 2.9	54.2 ± 12.6	56.7 ± 13.9	61.9 ± 9.6	76.2 ± 6.2	74.5 ± 4.9	-
Gender, Male/Female
Units: Subjects
Female	5	3	1	1	8	2	28	19	18	85
Male	12	3	3	2	8	4	43	69	26	170

Subject analysis set title

Phase 1B: Glasdegib + LDAC

Subject analysis set type

Full analysis

Subject analysis set description

Included all subjects who received oral glasdegib in combination with LDAC in phase 1B portion.

Subject analysis set title

Phase 1B: Glasdegib + Decitabine

Subject analysis set type

Full analysis

Subject analysis set description

Included all subjects who received oral glasdegib in combination with decitabine in phase 1B portion.

Subject analysis set title

Phase 1B: Glasdegib + Cytarabine/Daunorubicin

Subject analysis set type

Full analysis

Subject analysis set description

Included all subjects who received oral glasdegib in combination with cytarabine/daunorubicin in phase 1B portion.

Subject analysis set title

Phase 1B: Glasdegib + LDAC (Biomarker, Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

AML subjects who achieved CR, CRi, MLFS, PR, or PRi (AML investigator reported best overall response), and MDS subjects who achieved CR, mCR, PR, or SD (MDS investigator reported best overall response).

Subject analysis set title

Phase 1B: Glasdegib + LDAC (Biomarker, non-Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

AML subjects who did not achieve CR, CRi, MLFS, PR, or PRi; and MDS subjects who did not achieve CR, mCR, PR or SD were defined as non-responders for best overall response.

Subject analysis set title

Phase 1B: Glasdegib + Decitabine (Biomarker, Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Phase 1B: Glasdegib + Decitabine (Biomarker, non-Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

AML subjects who did not achieve CR, CRi, MLFS, PR, or PRi; and MDS subjects who did not achieve CR, mCR, PR or SD were defined as non-responders for best overall response.

Subject analysis set title

Phase 1B: Glasdegib + Cytarabine/Dauno (Biomarker, Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Phase 1B: Glasdegib+Cytarabine/Dauno(Biomarker,non-Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

AML subjects who did not achieve CR, CRi, MLFS, PR, or PRi; and MDS subjects who did not achieve CR, mCR, PR or SD were defined as non-responders for best overall response. Dauno is short for daunorubicin.

Subject analysis set title

Phase 2 Fit (Biomarker, Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Phase 2 Fit (Biomarker, non-Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

AML subjects who did not achieve CR, CRi, MLFS, PR, or PRi; and MDS subjects who did not achieve CR, mCR, PR or SD were defined as non-responders for best overall response.

Subject analysis set title

Phase 2 Unfit: Glasdegib 100 mg + LDAC (Biomarker, Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Phase 2 Unfit: Glasdegib 100 mg+LDAC(Biomarker, non-Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

AML subjects who did not achieve CR, CRi, MLFS, PR, or PRi; and MDS subjects who did not achieve CR, mCR, PR or SD were defined as non-responders for best overall response.

Subject analysis set title

Phase 2 Unfit: LDAC alone (Biomarker, Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Phase 2 Unfit: LDAC alone (Biomarker, non-Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

AML subjects who did not achieve CR, CRi, MLFS, PR, or PRi; and MDS subjects who did not achieve CR, mCR, PR or SD were defined as non-responders for best overall response.

Subject analysis sets values	Phase 1B: Glasdegib + LDAC	Phase 1B: Glasdegib + Decitabine	Phase 1B: Glasdegib + Cytarabine/Daunorubicin	Phase 1B: Glasdegib + LDAC (Biomarker, Responder)	Phase 1B: Glasdegib + LDAC (Biomarker, non-Responder)	Phase 1B: Glasdegib + Decitabine (Biomarker, Responder)	Phase 1B: Glasdegib + Decitabine (Biomarker, non-Responder)	Phase 1B: Glasdegib + Cytarabine/Dauno (Biomarker, Responder)	Phase 1B: Glasdegib+Cytarabine/Dauno(Biomarker,non-Responder)	Phase 2 Fit (Biomarker, Responder)	Phase 2 Fit (Biomarker, non-Responder)	Phase 2 Unfit: Glasdegib 100 mg + LDAC (Biomarker, Responder)	Phase 2 Unfit: Glasdegib 100 mg+LDAC(Biomarker, non-Responder)	Phase 2 Unfit: LDAC alone (Biomarker, Responder)	Phase 2 Unfit: LDAC alone (Biomarker, non-Responder)
Number of subjects	23	7	22	4	19	5	2	14	8	45	26	33	55	4	40
Age categorical
Units: Subjects
< 18 years	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
18 to 44 years	0	0	4	0	0	0	0	3	1	4	1	0	0	0	0
45 to 64 years	1	0	11	0	1	0	0	7	4	21	12	1	1	0	1
>=65 years	22	7	7	4	18	5	2	4	3	20	13	32	54	4	39
Age Continuous
Units: Years
arithmetic mean (standard deviation)	75.8 ± 6.5	75.0 ± 4.4	54.9 ± 12.7	75.8 ± 6.1	75.8 ± 6.7	74.4 ± 5.1	76.5 ± 2.1	53.0 ± 13.8	58.1 ± 10.7	61.2 ± 10.7	62.9 ± 7.5	75.2 ± 6.0	76.7 ± 6.3	77.8 ± 4.2	74.2 ± 4.9
Gender, Male/Female
Units: Subjects
Female	8	2	10	1	7	2	0	8	2	17	11	8	11	2	16
Male	15	5	12	3	12	3	2	6	6	28	15	25	44	2	24

End points

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Reporting group title

Phase 1B: Glasdegib 100 mg + LDAC

Reporting group description

Reporting group title

Phase 1B: Glasdegib 200 mg + LDAC

Reporting group description

Reporting group title

Phase 1B: Glasdegib 100 mg + Decitabine

Reporting group description

Reporting group title

Phase 1B: Glasdegib 200 mg + Decitabine

Reporting group description

Reporting group title

Phase 1B: Glasdegib 100 mg + Cytarabine/Daunorubicin

Reporting group description

Reporting group title

Phase 1B: Glasdegib 200 mg + Cytarabine/Daunorubicin

Reporting group description

Subjects received 1-2 cycles of induction (glasdegib and daunorubicin/cytarabine), followed by 2-4 cycles of consolidation (glasdegib and high dose cytarabine) and a maximum of 6 cycles of maintenance (glasdegib alone). Daunorubicin was given on Days 1-3 QD at a dose of 60 mg/m^2/day by IV together with cytarabine on Days 1-7 at a dose of 100 mg/m^2/day by continuous IV infusion for each cycle of induction. Cytarabine was given on Days 1, 3, and 5 at a dose of 1 g/m^2 administered as a 3-hour IV infusion every 12 hours (2 g/m^2/day) for each cycle of consolidation. Glasdegib tablets 200 mg QD was started on induction Cycle 1/Day -3 and administered continuously QD thereafter for the duration of the study. A cycle was defined as 28 days.In March 2013, all active subjects receiving glasdegib 200 mg were required to reduce dose to 100 mg.One (1) subject in this cohort had dose reduction to 100 mg starting from Consolidation Cycle 1/Day 21.

Reporting group title

Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin

Reporting group description

Reporting group title

Phase 2 Unfit: Glasdegib 100 mg + LDAC

Reporting group description

Reporting group title

Phase 2 Unfit: LDAC alone

Reporting group description

Subjects received LDAC subcutaneously at a dose of 20 mg BID on Days 1-10 of the 28 day cycles.

Subject analysis set title

Phase 1B: Glasdegib + LDAC

Subject analysis set type

Full analysis

Subject analysis set description

Included all subjects who received oral glasdegib in combination with LDAC in phase 1B portion.

Subject analysis set title

Phase 1B: Glasdegib + Decitabine

Subject analysis set type

Full analysis

Subject analysis set description

Included all subjects who received oral glasdegib in combination with decitabine in phase 1B portion.

Subject analysis set title

Phase 1B: Glasdegib + Cytarabine/Daunorubicin

Subject analysis set type

Full analysis

Subject analysis set description

Included all subjects who received oral glasdegib in combination with cytarabine/daunorubicin in phase 1B portion.

Subject analysis set title

Phase 1B: Glasdegib + LDAC (Biomarker, Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Phase 1B: Glasdegib + LDAC (Biomarker, non-Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

AML subjects who did not achieve CR, CRi, MLFS, PR, or PRi; and MDS subjects who did not achieve CR, mCR, PR or SD were defined as non-responders for best overall response.

Subject analysis set title

Phase 1B: Glasdegib + Decitabine (Biomarker, Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Phase 1B: Glasdegib + Decitabine (Biomarker, non-Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

AML subjects who did not achieve CR, CRi, MLFS, PR, or PRi; and MDS subjects who did not achieve CR, mCR, PR or SD were defined as non-responders for best overall response.

Subject analysis set title

Phase 1B: Glasdegib + Cytarabine/Dauno (Biomarker, Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Phase 1B: Glasdegib+Cytarabine/Dauno(Biomarker,non-Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Phase 2 Fit (Biomarker, Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Phase 2 Fit (Biomarker, non-Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

AML subjects who did not achieve CR, CRi, MLFS, PR, or PRi; and MDS subjects who did not achieve CR, mCR, PR or SD were defined as non-responders for best overall response.

Subject analysis set title

Phase 2 Unfit: Glasdegib 100 mg + LDAC (Biomarker, Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Phase 2 Unfit: Glasdegib 100 mg+LDAC(Biomarker, non-Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

AML subjects who did not achieve CR, CRi, MLFS, PR, or PRi; and MDS subjects who did not achieve CR, mCR, PR or SD were defined as non-responders for best overall response.

Subject analysis set title

Phase 2 Unfit: LDAC alone (Biomarker, Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Phase 2 Unfit: LDAC alone (Biomarker, non-Responder)

Subject analysis set type

Sub-group analysis

Subject analysis set description

AML subjects who did not achieve CR, CRi, MLFS, PR, or PRi; and MDS subjects who did not achieve CR, mCR, PR or SD were defined as non-responders for best overall response.

Primary: Number of subjects with dose-limiting toxicities (DLTs) at Phase 1B

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End point title

Number of subjects with dose-limiting toxicities (DLTs) at Phase 1B ^[1] ^[2]

End point description

A DLT was any of the following adverse events(AEs) in Cycle 1,considered by investigator possibly related to glasdegib in combination with chemotherapy:(1)Grade>=3 non-hematologic toxicity,excluding Grade>=3 infection,fever,infusion related AEs,electrolyte abnormalities and ALT/AST elevation that returned to Grade<=1 or baseline within 7 days;(2)prolonged myelosuppression lasted longer than 42 days from the point of detection,defined as absolute neutrophil count<500/mL or platelet count<10*10^9/L with a normal bone marrow;(3)inability to deliver at least 80% planned study doses for all agents in a combination due to non-hematologic toxicities;(4)Delay of >28 days in receiving next scheduled cycle due to persisting non-hematologic toxicities.Per protocol analysis set was used,including all enrolled subjects in the dose escalation component who received at least 1 dose of glasdegib, co-administered chemotherapeutics,did not have major treatment deviations during DLT monitoring period.

End point type

Primary

End point timeframe

Glasdegib+LDAC, Glasdegib+Decitabine: Cycle 1, Day 1 to Day 28; Glasdegib+Cytarabine/Daunorubicin: Cycle 1, Day -3 to Day 21 or to Day 28 depending on when the next chemotherapy cycle was started

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: statistical analyses were not planned for this endpoint
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 1B: Glasdegib 100 mg + LDAC	Phase 1B: Glasdegib 200 mg + LDAC	Phase 1B: Glasdegib 100 mg + Decitabine	Phase 1B: Glasdegib 200 mg + Decitabine	Phase 1B: Glasdegib 100 mg + Cytarabine/Daunorubicin	Phase 1B: Glasdegib 200 mg + Cytarabine/Daunorubicin
Number of subjects analysed	3 ^[3]	5 ^[4]	4 ^[5]	2 ^[6]	6 ^[7]	6 ^[8]
Units: Subjects	0	0	0	0	1	0

Notes
[3] - Actual number of subjects that started the Arm: 3
[4] - Actual number of subjects that started the Arm: 6
[5] - Actual number of subjects that started the Arm: 4
[6] - Actual number of subjects that started the Arm: 3
[7] - Actual number of subjects that started the Arm: 6
[8] - Actual number of subjects that started the Arm: 6

No statistical analyses for this end point

Primary: Percentage of subjects with complete response (CR) at Phase 2 Fit

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End point title

Percentage of subjects with complete response (CR) at Phase 2 Fit ^[9] ^[10]

End point description

For AML subjects:CR were those with repeat bone marrow showing <5% myeloblasts,spicules present and no Auer rods, peripheral blood showing neutrophils>=1000/mcL and platelets>=100,000/mcL, transfusion independent and no extramedullary disease. For MDS subjects:CR were those with repeat bone marrow showing <=5% myeloblasts, peripheral blood showing neutrophils>=1000/mcL, platelets>=100,000/mcL, 0% blast and hemoglobin (Hgb)>= 11 g/dL, normal maturation of all cell lines. End of treatment: maximum of 12 cycles from start of therapy or until disease progression or relapse, subject refusal or unacceptable toxicity occurred, whichever came first. Full analysis set was used to analyze this end point, including all enrolled subjects of Phase 2 Fit arm who received at least 1 dose of study medication. Number of subjects analyzed is number of subjects in the treatment group. ‘n’ in the categories is number of subjects contributing to the summary statistics.

End point type

Primary

End point timeframe

Screening (within 28 days Prior to Dosing), Day 21 of each Induction Cycles and final Consolidation Cycle, Day 1 of every third Maintenance Cycles, End of Treatment

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: statistical analyses were not planned for this endpoint
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin
Number of subjects analysed	69
Units: Percentage of subjects
number (confidence interval 80%)
Total subjects	42.0 (34.4 to 49.6)
Subject >= 55 years old (n = 60)	36.7 (28.7 to 44.6)
Subjects < 55 years old (n = 9)	77.8 (60.0 to 95.5)

No statistical analyses for this end point

Primary: Overall survival (OS) at Phase 2 Unfit

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End point title

Overall survival (OS) at Phase 2 Unfit ^[11]

End point description

OS was defined as duration from the date of randomization to the date of death from any cause. Subjects not known to have died at the last follow-up were censored on the date they were last known to be alive. Survival status were collected every month for the first two months after discontinuation of study treatment and thereafter every 2 months until death or 4 years from time of randomization for each subject. Full analysis set was used to analyze this end point, including all randomized subjects of Phase 2 Unfit arm.

End point type

Primary

End point timeframe

Randomization to Follow-up (4 years)

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Unfit: Glasdegib 100 mg + LDAC	Phase 2 Unfit: LDAC alone
Number of subjects analysed	88	44
Units: Months
median (confidence interval 80%)	8.8 (6.9 to 9.9)	4.9 (3.5 to 6.0)

Difference between groups in overall survival

Comparison groups

Phase 2 Unfit: Glasdegib 100 mg + LDAC v Phase 2 Unfit: LDAC alone

Number of subjects included in analysis

132

Analysis specification

Pre-specified

Analysis type

P-value

= 0.002 ^[12]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.569

Confidence interval

level

80%

sides

2-sided

lower limit

0.441

upper limit

0.734

Notes
[12] - 1-sided p-value from the log-rank test stratified by prognosis stratum according to Interactive Voice Response System (IVRS).

Secondary: Overall survival (OS) at Phase 1B

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End point title

Overall survival (OS) at Phase 1B

End point description

OS was defined as duration from the date of the first dose of any of the study medications to the date of death from any cause. Subjects not known to have died at the last follow up were censored on the date they were last known to be alive. Survival status were collected every month for the first two months after discontinuation of study treatment and thereafter every 2 months until death or 4 years from each subject's first dose for each subject. Full analysis set was used to analyze this end point, including all enrolled subjects of Phase 1B portion who received at least 1 dose of study medication. 99999 represents data not estimable (NE) when the number of subjects analyzed is less than or equal to 3.

End point type

Secondary

End point timeframe

First dose to Follow-up (4 years)

End point values	Phase 1B: Glasdegib + LDAC	Phase 1B: Glasdegib + Decitabine	Phase 1B: Glasdegib + Cytarabine/Daunorubicin
Number of subjects analysed	23	7	22
Units: Months
median (confidence interval 80%)	4.4 (2.5 to 6.6)	11.5 (4.5 to 17.4)	37.8 (14.5 to 99999)

No statistical analyses for this end point

Secondary: Overall survival (OS) at Phase 2 Fit

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End point title

Overall survival (OS) at Phase 2 Fit ^[13]

End point description

OS was defined as duration from the date of the first dose of any of the study medications to the date of death from any cause. Subjects not known to have died at the last follow up were censored on the date they were last known to be alive. Survival status were collected every month for the first two months after discontinuation of study treatment and thereafter every 2 months until death or 4 years from each subject's first dose for each subject. Full analysis set was used to analyze this endpoint, including all enrolled subjects of Phase 2 Fit arm who received at least 1 dose of study medication. Number of subjects analyzed is number of subjects in the treatment group. ‘n’ in the categories is number of subjects contributing to the summary statistics. 99999 represents data not estimable (NE) when the number of subjects analyzed is less than 3.

End point type

Secondary

End point timeframe

First dose to Follow-up (4 years)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin
Number of subjects analysed	69
Units: Months
median (confidence interval 80%)
Total subjects	14.9 (13.4 to 19.3)
Subjects >= 55 years old (n = 60)	14.7 (13.1 to 17.7)
Subjects < 55 years old (n = 9)	99999 (11.0 to 99999)

No statistical analyses for this end point

Secondary: Percentage of subjects with CR / complete response with incomplete blood count recovery (CRi) at Phase 1B

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End point title

Percentage of subjects with CR / complete response with incomplete blood count recovery (CRi) at Phase 1B

End point description

For AML subjects:CR were those with repeat bone marrow showing <5% myeloblasts,spicules present and no Auer rods, peripheral blood showing neutrophils>=1000/mcL and platelets>=100,000/mcL, transfusion independent and no extramedullary disease. For MDS subjects:CR were those with repeat bone marrow showing <=5% myeloblasts, peripheral blood showing neutrophils>=1000/mcL, platelets>=100,000/mcL, 0% blast and hemoglobin (Hgb)>= 11 g/dL, normal maturation of all cell lines.For AML and MDS subjects,complete response with incomplete blood count recovery(CRi)were those with repeat bone marrow showing <5% myeloblasts with platelets <100,000/mcL or neutrophils <1000/mcL.End of treatment:maximum of 12 cycles from start of therapy or until disease progression or relapse, subject refusal or unacceptable toxicity occurred, whichever came first.Full analysis set was used to analyze this endpoint, defined as all enrolled subjects of Phase 1B portion who received at least 1 dose of study medication.

End point type

Secondary

End point timeframe

Arm A and Arm B: Screening (within 28 days prior to Dosing), Day 1 of every third cycles, End of Treatment; Arm C: Screening, Day 21 of each Induction cycles and final Consolidation Cycle, Day 1 of every third Maintenance Cycles, End of Treatment

End point values	Phase 1B: Glasdegib + LDAC	Phase 1B: Glasdegib + Decitabine	Phase 1B: Glasdegib + Cytarabine/Daunorubicin
Number of subjects analysed	23	7	22
Units: Percentage of subjects
number (confidence interval 80%)
Percentage of subjects with CR/CRi	8.7 (2.3 to 21.5)	28.6 (7.9 to 59.6)	54.5 (38.9 to 69.5)

No statistical analyses for this end point

Secondary: Percentage of subjects with complete response (CR) at Phase 2 Unfit

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End point title

Percentage of subjects with complete response (CR) at Phase 2 Unfit ^[14]

End point description

End point type

Secondary

End point timeframe

Screening (within 28 days prior to Dosing), Day 1 of every third cycles, End of Treatment.

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Unfit: Glasdegib 100 mg + LDAC	Phase 2 Unfit: LDAC alone
Number of subjects analysed	88	44
Units: Percentage of subjects
number (confidence interval 80%)
Percentage of subjects with CR	18.2 (12.9 to 23.5)	2.3 (0.0 to 5.2)

Difference between groups in CR rate

Comparison groups

Phase 2 Unfit: Glasdegib 100 mg + LDAC v Phase 2 Unfit: LDAC alone

Number of subjects included in analysis

132

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.0112

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

4.2755

Confidence interval

level

80%

sides

2-sided

lower limit

1.3057

upper limit

13.9994

Secondary: Percentage of subjects with disease-specific efficacy for Acute Myeloid Leukemia (AML) at Phase 2 Fit and Unfit

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End point title

Percentage of subjects with disease-specific efficacy for Acute Myeloid Leukemia (AML) at Phase 2 Fit and Unfit ^[15]

End point description

AML subjects,disease specific efficacy measures included:CRi;Morphologic Leukemia Free State(MLFS)(bone marrow<5%myeloblasts with spicules and no auer rods,neutrophils<1000/mcL and platelets<100,000/mcL);partial remission(PR)(bone marrow myeloblasts decrease to 5–25&>=50%decrease from start, neutrophils>=1000/mcL, platelets>=100,000/mcL);PR with incomplete blood count recovery(PRi)(bone marrow myeloblasts decrease to 5–25&>=50%decrease from start,neutrophils<1000/mcL or platelets<100,000/mcL);minor response(MR)(bone marrow myeloblasts decrease to>=25% from start);stable disease(SD)(bone marrow myeloblasts stable+/-25% from screening value);cytogenetic complete response(CRc)(bone marrow<5%myeloblasts, neutrophils>1000/mcL,platelets>100,000/mcL,normal cytogenetics),molecular complete response(CRm)(bone marrow<5%myeloblasts, neutrophils>1000/mcL, platelets>100,000/mcL and molecular-negative).AML subjects in Full analysis set were analyzed.

End point type

Secondary

End point timeframe

Phase 2 Fit: Screening (within 28 days prior to Dosing), Day 21 of each Induction cycles and final Consolidation Cycle, Day 1 of every third Maintenance Cycles, End of Treatment. Phase 2 Unfit: Screening, Day 1 of every third cycles, End of Treatment.

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin	Phase 2 Unfit: Glasdegib 100 mg + LDAC	Phase 2 Unfit: LDAC alone
Number of subjects analysed	64	78	38
Units: Percentage of subjects
number (confidence interval 80%)
CRi	10.9 (6.2 to 17.7)	5.1 (2.3 to 10.0)	2.6 (0.3 to 9.9)
MLFS	7.8 (3.8 to 14.0)	2.6 (0.7 to 6.7)	0.0 (0.0 to 5.9)
PR	1.6 (0.2 to 5.9)	6.4 (3.2 to 11.6)	2.6 (0.3 to 9.9)
PRi	1.6 (0.2 to 5.9)	1.3 (0.1 to 4.9)	0.0 (0.0 to 5.9)
MR	10.9 (6.2 to 17.7)	6.4 (3.2 to 11.6)	10.5 (4.7 to 19.9)
SD	6.3 (2.8 to 12.1)	16.7 (11.3 to 23.4)	21.1 (12.7 to 31.9)
CRc	35.9 (27.9 to 44.7)	11.5 (7.1 to 17.6)	0.0 (0.0 to 5.9)
CRm	37.5 (29.4 to 46.2)	16.7 (11.3 to 23.4)	2.6 (0.3 to 9.9)

No statistical analyses for this end point

Secondary: Percentage of subjects with disease-specific efficacy for Myelodysplastic Syndrome (MDS) at Phase 2 Fit and Unfit

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End point title

Percentage of subjects with disease-specific efficacy for Myelodysplastic Syndrome (MDS) at Phase 2 Fit and Unfit ^[16]

End point description

MDS subjects,disease specific efficacy measures included:CRi(bone marrow showing <5% myeloblasts with platelets <100,000/mcL or neutrophils <1000/mcL, include confirmed and unconfirmed responses);PR(repeat bone marrow myeloblasts showing decreased by >= 50% decrease but still >5%, peripheral blood showing neutrophils >= 1,000/mcL, platelets >= 100,000/mcL and Hgb>=11g/dL; include confirmed and unconfirmed responses); SD(include confirmed and unconfirmed responses, failure to achieve PR and no evidence of progression for >8 weeks); marrow complete response(mCR)(bone marrow showing <=5% myeloblasts and decreased by >= 50%),partial cytogenetic response(>=50% reduction of chromosomal abnormality) and complete cytogenetic response(CRc)(disappearance of chromosomal abnormality with no appearance of now ones).MDS subjects in Full analysis set were analyzed: all enrolled subjects of Phase 2 Fit arm who received at least 1 dose of study medication,all randomized subjects of Phase 2 Unfit arm.

End point type

Secondary

End point timeframe

Phase 2 Fit: Screening (within 28 days Prior to Dosing), Day 21 of each Induction cycles and final Consolidation Cycle, Day 1 of every third Maintenance Cycles, End of Treatment. Phase 2 Unfit: Screening, Day 1 of every third cycles, End of Treatment.

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin	Phase 2 Unfit: Glasdegib 100 mg + LDAC	Phase 2 Unfit: LDAC alone
Number of subjects analysed	5	10	6
Units: Percentage of subjects
number (confidence interval 80%)
mCR	0.0 (0.0 to 36.9)	10.0 (1.0 to 33.7)	0.0 (0.0 to 31.9)
PR	0.0 (0.0 to 36.9)	0.0 (0.0 to 20.6)	0.0 (0.0 to 31.9)
SD	0.0 (0.0 to 36.9)	0.0 (0.0 to 20.6)	33.3 (9.3 to 66.7)
CRi	20.0 (2.1 to 58.4)	10.0 (1.0 to 33.7)	0.0 (0.0 to 31.9)
Unconfirmed SD	0.0 (0.0 to 36.9)	10.0 (1.0 to 33.7)	0.0 (0.0 to 31.9)
Unconfirmed CRi	0.0 (0.0 to 36.9)	10.0 (1.0 to 33.7)	0.0 (0.0 to 31.9)
mCR (CRi not included)	0.0 (0.0 to 36.9)	10.0 (1.0 to 33.7)	0.0 (0.0 to 31.9)
CRc	60.0 (24.7 to 88.8)	10.0 (1.0 to 33.7)	0.0 (0.0 to 31.9)

No statistical analyses for this end point

Secondary: Time to maximum observed plasma concentration (Tmax) of glasdegib in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 10 and Cycle 2/Day 1

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End point title

Time to maximum observed plasma concentration (Tmax) of glasdegib in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 10 and Cycle 2/Day 1 ^[17]

End point description

Dose compliant group were used to analyze this end point: subjects who had at least 4 days of uninterrupted dosing for a multiple dose PK assessment were considered to be at steady state,part of the “dose compliant” group. Number of subjects analyzed:numbers of subjects in the treatment group.‘n’ in categories:number of subjects contributing to the summary statistics. 99999 represents data not estimable (NE) as fewer than 3 subjects had reportable parameter values.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post-dose on Cycle 1/Day 10; pre-dose, 0.5, 1, 2, 6 and 24 hours post-dose on Cycle 2/Day 1

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 1B: Glasdegib 100 mg + Decitabine	Phase 1B: Glasdegib 200 mg + Decitabine
Number of subjects analysed	4	3
Units: Hours
median (full range (min-max))
Cycle 1/Day 10 (n = 3, 3)	2.00 (0.500 to 24.0)	2.05 (1.00 to 5.97)
Cycle 2/Day 1 (n = 3)	1.03 (0.567 to 2.00)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Area under the plasma concentration-time profile from time 0 to dosing interval (AUCtau) of glasdegib in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 10 and Cycle 2/Day 1

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End point title

Area under the plasma concentration-time profile from time 0 to dosing interval (AUCtau) of glasdegib in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 10 and Cycle 2/Day 1 ^[18]

End point description

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post-dose on Cycle 1/Day 10; pre-dose, 0.5, 1, 2, 6 and 24 hours post-dose on Cycle 2/Day 1

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 1B: Glasdegib 100 mg + Decitabine	Phase 1B: Glasdegib 200 mg + Decitabine
Number of subjects analysed	4	3
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Cycle 1/Day 10 (n = 2, 3)	99999 ± 99999	28380 ± 11
Cycle 2/Day 1 (n = 3)	17060 ± 29	99999 ± 99999

No statistical analyses for this end point

Secondary: Maximum observed plasma concentration (Cmax) of glasdegib in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3 and Day 10

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End point title

Maximum observed plasma concentration (Cmax) of glasdegib in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3 and Day 10 ^[19]

End point description

Dose compliant group was used to analyze this end point. Subjects who had at least 4 days of uninterrupted dosing for a multiple dose PK assessment were considered to be at steady state and part of the “dose compliant” group. Number of subjects analyzed is number of subjects in the treatment group. ‘n’ in categories is number of subjects contributing to the summary statistics.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 6 and 24 hours post-dose on Induction Cycle 1/Day 3; pre-dose, 0.5, 1, 4, 6 and 24 hours post-dose on Induction Cycle 1/Day 10

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 1B: Glasdegib 100 mg + Cytarabine/Daunorubicin	Phase 1B: Glasdegib 200 mg + Cytarabine/Daunorubicin
Number of subjects analysed	14	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
Induction Cycle 1/Day 3 (n = 14, 6)	674.2 ± 45	1622 ± 25
Induction Cycle 1/Day 10 (n = 15, 6)	1135 ± 43	2371 ± 43

No statistical analyses for this end point

Secondary: Tmax of glasdegib in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3 and Day 10

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End point title

Tmax of glasdegib in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3 and Day 10 ^[20]

End point description

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 6 and 24 hours post-dose on Induction Cycle 1/Day 3; pre-dose, 0.5, 1, 4, 6 and 24 hours post-dose on Induction Cycle 1/Day 10

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 1B: Glasdegib 100 mg + Cytarabine/Daunorubicin	Phase 1B: Glasdegib 200 mg + Cytarabine/Daunorubicin
Number of subjects analysed	16	6
Units: Hours
median (full range (min-max))
Induction Cycle 1/Day 3 (n = 14, 6)	5.99 (0.467 to 25.2)	6.00 (1.00 to 6.07)
Induction Cycle 1/Day 10 (n = 15, 6)	4.08 (0.500 to 24.7)	1.04 (0.583 to 4.12)

No statistical analyses for this end point

Secondary: AUCtau of glasdegib in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3 and Day 10

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End point title

AUCtau of glasdegib in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3 and Day 10 ^[21]

End point description

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 6 and 24 hours post-dose on Induction Cycle 1/Day 3; pre-dose, 0.5, 1, 4, 6 and 24 hours post-dose on Induction Cycle 1/Day 10

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 1B: Glasdegib 100 mg + Cytarabine/Daunorubicin	Phase 1B: Glasdegib 200 mg + Cytarabine/Daunorubicin
Number of subjects analysed	16	6
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Induction Cycle 1/Day 3 (n = 12, 5)	9332 ± 56	22840 ± 43
Induction Cycle 1/Day 10 (n = 13, 5)	16300 ± 46	26370 ± 39

No statistical analyses for this end point

Secondary: Cmax of LDAC and Ara-U in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 2 and Cycle 1/Day 10

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End point title

Cmax of LDAC and Ara-U in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 2 and Cycle 1/Day 10 ^[22]

End point description

Ara-U is the major metabolite of cytarabine. LDAC (low dose cytarabine) is rapidly degraded to the stable metabolite Ara-U. PK concentration population were analyzed: all treated participants who had at least 1 concentration of any of the study drugs. Number of subjects analyzed is number of subjects in the treatment group. ‘n’ in categories is number of subjects contributing to the summary statistics.

End point type

Secondary

End point timeframe

Pre-dose, 0.25, 0.5, 1, 2, 4 and 6 hours post-dose on Cycle 1/Day 2 and Cycle 1/Day 10

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 1B: Glasdegib 100 mg + LDAC	Phase 1B: Glasdegib 200 mg + LDAC
Number of subjects analysed	17	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
LDAC Cycle 1/Day 2 (n = 16, 6)	58.50 ± 58	100.1 ± 29
LDAC Cycle 1/Day 10 (n = 12, 6)	63.01 ± 88	132.5 ± 39
Ara-U Cycle 1/Day 2 (n = 17, 6)	379.5 ± 34	569.7 ± 29
Ara-U Cycle 1/Day 10 (n = 12, 6)	452.2 ± 36	652.0 ± 27

No statistical analyses for this end point

Secondary: Tmax of LDAC and Ara-U in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 2 and Cycle 1/Day 10

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End point title

Tmax of LDAC and Ara-U in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 2 and Cycle 1/Day 10 ^[23]

End point description

Ara-U is the major metabolite of cytarabine. LDAC (low dose cytarabine) is rapidly degraded to the stable metabolite Ara-U. PK parameter analysis set was used to analyze this end point, including all treated subjects who had at least 1 of the PK parameters of interest for any of the study drugs. Number of subjects analyzed is number of subjects in the treatment group. ‘n’ in categories is number of subjects contributing to the summary statistics.

End point type

Secondary

End point timeframe

Pre-dose, 0.25, 0.5, 1, 2, 4 and 6 hours post-dose on Cycle 1/Day 2 and Cycle 1/Day 10

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 1B: Glasdegib 100 mg + LDAC	Phase 1B: Glasdegib 200 mg + LDAC
Number of subjects analysed	17	6
Units: Hours
median (full range (min-max))
LDAC Cycle 1/Day 2 (n = 16, 6)	0.250 (0.233 to 1.00)	0.250 (0.250 to 0.500)
LDAC Cycle 1/Day 10 (n = 12, 6)	0.325 (0.233 to 1.00)	0.250 (0.233 to 0.500)
Ara-U Cycle 1/Day 2 (n = 17, 6)	3.97 (1.00 to 6.05)	4.00 (1.00 to 6.00)
Ara-U Cycle 1/Day 10 (n = 12, 6)	2.00 (0.000 to 6.00)	1.99 (1.02 to 4.08)

No statistical analyses for this end point

Secondary: Area under the plasma concentration-time profile from time 0 to infinity (AUCinf) of LDAC in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 2 and Cycle 1/Day 10

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End point title

Area under the plasma concentration-time profile from time 0 to infinity (AUCinf) of LDAC in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 2 and Cycle 1/Day 10 ^[24]

End point description

PK parameter analysis set was used to analyze this end point, including all treated subjects who had at least 1 of the PK parameters of interest for any of the study drugs. Number of subjects analyzed is number of subjects in the treatment group. ‘n’ in categories is number of subjects contributing to the summary statistics.

End point type

Secondary

End point timeframe

Pre-dose, 0.25, 0.5, 1, 2, 4 and 6 hours post-dose on Cycle 1/Day 2 and Cycle 1/Day 10

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 1B: Glasdegib 100 mg + LDAC	Phase 1B: Glasdegib 200 mg + LDAC
Number of subjects analysed	17	6
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
LDAC Cycle 1/Day 2 (n = 14, 6)	71.10 ± 28	89.35 ± 28
LDAC Cycle 1/Day 10 (n = 9, 5)	92.28 ± 25	143.9 ± 24

No statistical analyses for this end point

Secondary: Area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration (AUClast) of LDAC and Ara-U in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 2 and Cycle 1/Day 10

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End point title

Area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration (AUClast) of LDAC and Ara-U in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 2 and Cycle 1/Day 10 ^[25]

End point description

End point type

Secondary

End point timeframe

Pre-dose, 0.25, 0.5, 1, 2, 4 and 6 hours post-dose on Cycle 1/Day 2 and Cycle 1/Day 10

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 1B: Glasdegib 100 mg + LDAC	Phase 1B: Glasdegib 200 mg + LDAC
Number of subjects analysed	17	6
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
LDAC Cycle 1/Day 2 (n = 16, 6)	62.55 ± 41	87.49 ± 29
LDAC Cycle 1/Day 10 (n = 12, 6)	65.56 ± 76	134.8 ± 26
Ara-U Cycle 1/Day 2 (n = 17, 6)	2036 ± 36	3050 ± 29
Ara-U Cycle 1/Day 10 (n = 12, 6)	2283 ± 43	3528 ± 29

No statistical analyses for this end point

Secondary: Cmax of decitabine in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 1 and Cycle 1/Day 2

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End point title

Cmax of decitabine in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 1 and Cycle 1/Day 2 ^[26]

End point description

PK concentration population: all treated subjects who had at least 1 concentration of any of the study drugs.

End point type

Secondary

End point timeframe

Pre-dose, 0.5 hour from start of infusion, 1 hour (at end of infusion) and 2, 3 and 4 hours from start of infusion on Cycle 1/Day 1 and Cycle 1/Day 2

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 1B: Glasdegib 100 mg + Decitabine	Phase 1B: Glasdegib 200 mg + Decitabine
Number of subjects analysed	3	3
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1/Day 1	113.4 ± 59	174.2 ± 113
Cycle 1/Day 2	127.9 ± 43	121.7 ± 37

No statistical analyses for this end point

Secondary: Tmax of decitabine in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 1 and Cycle 1/Day 2

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End point title

Tmax of decitabine in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 1 and Cycle 1/Day 2 ^[27]

End point description

PK parameter analysis set was used to analyze this end point, including all treated subjects who had at least 1 of the PK parameters of interest for any of the study drugs.

End point type

Secondary

End point timeframe

Pre-dose, 0.5 hour from start of infusion, 1 hour (at end of infusion) and 2, 3 and 4 hours from start of infusion on Cycle 1/Day 1 and Cycle 1/Day 2

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 1B: Glasdegib 100 mg + Decitabine	Phase 1B: Glasdegib 200 mg + Decitabine
Number of subjects analysed	3	3
Units: Hours
median (full range (min-max))
Cycle 1/Day 1	0.75 (0.50 to 1.0)	0.53 (0.52 to 0.75)
Cycle 1/Day 2	0.58 (0.53 to 0.95)	0.53 (0.52 to 1.3)

No statistical analyses for this end point

Secondary: AUCinf of decitabine in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 1 and Cycle 1/Day 2

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End point title

AUCinf of decitabine in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 1 and Cycle 1/Day 2 ^[28]

End point description

End point type

Secondary

End point timeframe

Pre-dose, 0.5 hour from start of infusion, 1 hour (at end of infusion) and 2, 3 and 4 hours from start of infusion on Cycle 1/Day 1 and Cycle 1/Day 2

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 1B: Glasdegib 100 mg + Decitabine	Phase 1B: Glasdegib 200 mg + Decitabine
Number of subjects analysed	4	3
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Cycle 1/Day 1 (n = 3, 3)	133.4 ± 71	251.5 ± 140
Cycle 1/Day 2 (n = 2, 2)	99999 ± 99999	99999 ± 99999

No statistical analyses for this end point

Secondary: AUCtau of cytarabine and Ara-U in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3

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End point title

AUCtau of cytarabine and Ara-U in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3 ^[29]

End point description

Ara-U is the major metabolite of cytarabine. PK parameter analysis set was used to analyze this end point, including all treated subjects who had at least 1 of the PK parameters of interest for any of the study drugs. 99999 represents data not estimable (NE) as fewer than 3 subjects had reportable parameter values.

End point type

Secondary

End point timeframe

Pre-dose, 6 and 24 hours post start of cytarabine infusion on Induction Cycle 1/Day 3

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 1B: Glasdegib 100 mg + Cytarabine/Daunorubicin	Phase 1B: Glasdegib 200 mg + Cytarabine/Daunorubicin
Number of subjects analysed	9	2
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Cytarabine	1070 ± 211	99999 ± 99999
Ara-U	28420 ± 32	99999 ± 99999

No statistical analyses for this end point

Secondary: Cmax of daunorubicin and daunorubicinol in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3

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End point title

Cmax of daunorubicin and daunorubicinol in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3 ^[30]

End point description

Daunorubicinol is the major metabolite of daunorubicin, which has anti-neoplastic activity.PK concentration population were analyzed: all treated participants who had at least 1 concentration of any of the study drugs.

End point type

Secondary

End point timeframe

Pre-dose, 0.25, 0.5, 1, 4, 6, 24 hours post administration of daunorubicin on Induction Cycle 1/Day 3

Notes
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 1B: Glasdegib 100 mg + Cytarabine/Daunorubicin	Phase 1B: Glasdegib 200 mg + Cytarabine/Daunorubicin
Number of subjects analysed	15	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
Daunorubicin	275.3 ± 153	341.0 ± 82
Daunorubicinol	195.4 ± 139	233.4 ± 46

No statistical analyses for this end point

Secondary: Tmax of daunorubicin and daunorubicinol in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3

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End point title

Tmax of daunorubicin and daunorubicinol in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3 ^[31]

End point description

End point type

Secondary

End point timeframe

Pre-dose, 0.25, 0.5, 1, 4, 6, 24 hours post administration of daunorubicin on Induction Cycle 1/Day 3

Notes
[31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 1B: Glasdegib 100 mg + Cytarabine/Daunorubicin	Phase 1B: Glasdegib 200 mg + Cytarabine/Daunorubicin
Number of subjects analysed	15	6
Units: Hours
median (full range (min-max))
Daunorubicin	0.500 (0.217 to 1.72)	0.492 (0.250 to 0.600)
Daunorubicinol	1.00 (0.217 to 5.90)	0.642 (0.283 to 4.00)

No statistical analyses for this end point

Secondary: AUCtau of daunorubicin and daunorubicinol in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3

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End point title

AUCtau of daunorubicin and daunorubicinol in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3 ^[32]

End point description

Daunorubicinol is the major metabolite of daunorubicin, which has anti-neoplastic activity. PK parameter analysis set was used to analyze this end point, including all treated subjects who had at least 1 of the PK parameters of interest for any of the study drugs. Number of subjects analyzed is number of subjects in the treatment group. ‘n’ in categories is number of subjects contributing to the summary statistics.

End point type

Secondary

End point timeframe

Pre-dose, 0.25, 0.5, 1, 4, 6, 24 hours post administration of daunorubicin on Induction Cycle 1/Day 3

Notes
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 1B: Glasdegib 100 mg + Cytarabine/Daunorubicin	Phase 1B: Glasdegib 200 mg + Cytarabine/Daunorubicin
Number of subjects analysed	16	6
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Daunorubicin (n = 14, 4)	499.3 ± 61	424.9 ± 38
Daunorubicinol (n = 15, 5)	2152 ± 24	2712 ± 33

No statistical analyses for this end point

Secondary: Cmax of glasdegib in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 10 and Cycle 1/Day 21

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End point title

Cmax of glasdegib in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 10 and Cycle 1/Day 21 ^[33]

End point description

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post-dose on Cycle 1/Day 10 and Cycle 1/Day 21

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 1B: Glasdegib 100 mg + LDAC	Phase 1B: Glasdegib 200 mg + LDAC
Number of subjects analysed	17	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1/Day 10 (n = 13, 6)	1074 ± 63	1942 ± 75
Cycle 1/Day 21 (n = 8, 5)	1242 ± 56	2577 ± 104

No statistical analyses for this end point

Secondary: Tmax of glasdegib in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 10 and Cycle 1/Day 21

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End point title

Tmax of glasdegib in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 10 and Cycle 1/Day 21 ^[34]

End point description

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post-dose on Cycle 1/Day 10 and Cycle 1/Day 21

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 1B: Glasdegib 100 mg + LDAC	Phase 1B: Glasdegib 200 mg + LDAC
Number of subjects analysed	17	6
Units: Hours
median (full range (min-max))
Cycle 1/Day 10 (n = 13, 6)	1.75 (0.750 to 24.0)	4.00 (1.02 to 24.0)
Cycle 1/Day 21 (n = 8, 5)	1.34 (0.533 to 2.00)	4.00 (1.00 to 6.00)

No statistical analyses for this end point

Secondary: AUCtau of glasdegib in subjects receiving glasdegib and LDAC at phase 1B on Cycle 1/Day 10 and Cycle 1/Day 21

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End point title

AUCtau of glasdegib in subjects receiving glasdegib and LDAC at phase 1B on Cycle 1/Day 10 and Cycle 1/Day 21 ^[35]

End point description

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post-dose on Cycle 1/Day 10 and Cycle 1/Day 21

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 1B: Glasdegib 100 mg + LDAC	Phase 1B: Glasdegib 200 mg + LDAC
Number of subjects analysed	17	6
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Cycle 1/Day 10 (n = 10, 4)	15020 ± 49	28600 ± 17
Cycle 1/Day 21 (n = 8, 4)	16660 ± 43	31400 ± 119

No statistical analyses for this end point

Secondary: Cmax of glasdegib in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 10 and Cycle 2/Day 1

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End point title

Cmax of glasdegib in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 10 and Cycle 2/Day 1 ^[36]

End point description

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post-dose on Cycle 1/Day 10; pre-dose, 0.5, 1, 2, 6 and 24 hours post-dose on Cycle 2/Day 1

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 1B: Glasdegib 100 mg + Decitabine	Phase 1B: Glasdegib 200 mg + Decitabine
Number of subjects analysed	4	3
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1/Day 10 (n = 3, 3)	1718 ± 28	2381 ± 28
Cycle 2/Day 1 (n = 3)	1826 ± 44	99999 ± 99999

No statistical analyses for this end point

Secondary: Pre-dose plasma concentration (Ctrough) of glasdegib in Phase 2 Fit on Induction Cycle 1/Day 10

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End point title

Pre-dose plasma concentration (Ctrough) of glasdegib in Phase 2 Fit on Induction Cycle 1/Day 10 ^[37]

End point description

Dose compliant, non CYP3A4 group was used to analyze this end point, defined as dose compliant group subjects who did not have administration of any strong or moderate CYP3A4 inhibitors.

End point type

Secondary

End point timeframe

Pre-dose, 1 and 4 hours post-dose on Induction Cycle 1/Day 10

Notes
[37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin
Number of subjects analysed	42
Units: ng/mL
geometric mean (geometric coefficient of variation)	308.7 ± 74

No statistical analyses for this end point

Secondary: Cmax of glasdegib in subjects receiving glasdegib and LDAC at Phase 2 Unfit on Cycle 1/Day 10

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End point title

Cmax of glasdegib in subjects receiving glasdegib and LDAC at Phase 2 Unfit on Cycle 1/Day 10 ^[38]

End point description

Dose compliant, non CYP3A4 group was used to analyze this end point, defined as dose compliant group subjects who did not have administration of any strong or moderate CYP3A4 inhibitors.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 4, and 6 hour post-dose on Cycle 1/Day 10

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Unfit: Glasdegib 100 mg + LDAC
Number of subjects analysed	41
Units: ng/mL
geometric mean (geometric coefficient of variation)	1525 ± 44

No statistical analyses for this end point

Secondary: Tmax of glasdegib in subjects receiving glasdegib and LDAC at Phase 2 Unfit on Cycle 1/Day 10

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End point title

Tmax of glasdegib in subjects receiving glasdegib and LDAC at Phase 2 Unfit on Cycle 1/Day 10 ^[39]

End point description

Dose compliant, non CYP3A4 group was used to analyze this end point, defined as dose compliant group subjects who did not have administration of any strong or moderate CYP3A4 inhibitors.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 4, and 6 hour post-dose on Cycle 1/Day 10

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Unfit: Glasdegib 100 mg + LDAC
Number of subjects analysed	41
Units: Hours
median (full range (min-max))
Tmax	1.67 (0.667 to 5.83)

No statistical analyses for this end point

Secondary: AUCtau of glasdegib in subjects receiving glasdegib and LDAC at Phase 2 Unfit on Cycle 1/Day 10

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End point title

AUCtau of glasdegib in subjects receiving glasdegib and LDAC at Phase 2 Unfit on Cycle 1/Day 10 ^[40]

End point description

Dose compliant, non CYP3A4 group was used to analyze this end point, defined as dose compliant group subjects who did not have administration of any strong or moderate CYP3A4 inhibitors.

End point type

Secondary

End point timeframe

Pre-dose, 1, 2, 4, and 6 hour post-dose on Cycle 1/Day 10

Notes
[40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Unfit: Glasdegib 100 mg + LDAC
Number of subjects analysed	37
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
AUCtau	17210 ± 54

No statistical analyses for this end point

Secondary: Number of subjects with disease-related gene mutations at Phase 1B

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End point title

Number of subjects with disease-related gene mutations at Phase 1B

End point description

Peripheral blood and bone marrow aspirate were collected for baseline mutational analyses. Genetic abnormalities frequently associated with AML were analyzed. These genetic abnormalities included known mutations in the genes NPM1, CEBPA, FLT3, RUNX1, IDH1, IDH2, KIT, K Ras, N Ras and WT1. Additional genes with mutations known to be associated with AML and MDS such as TET2 and DNMT3A were also evaluated. Pharmacodynamic (PD) analysis set was used to analyze this end point, defined as all enrolled subjects in the Phase 1B portion who received at least 1 dose of glasdegib, and had at least 1 PD parameter from the corresponding assay sample with a baseline and an adequate post treatment assessment.

End point type

Secondary

End point timeframe

Baseline (Cycle 1/Day 1 pre-dose for Glasdegib + LDAC and Glasdegib + Decitabine Arms; Induction Cycle 1/Day -3 pre-dose for Glasdegib +Cytarabine/Daunorubicin Arm)

End point values	Phase 1B: Glasdegib + LDAC (Biomarker, Responder)	Phase 1B: Glasdegib + LDAC (Biomarker, non-Responder)	Phase 1B: Glasdegib + Decitabine (Biomarker, Responder)	Phase 1B: Glasdegib + Decitabine (Biomarker, non-Responder)	Phase 1B: Glasdegib + Cytarabine/Dauno (Biomarker, Responder)	Phase 1B: Glasdegib+Cytarabine/Dauno(Biomarker,non-Responder)
Number of subjects analysed	0 ^[41]	9	0 ^[42]	1	11	1
Units: Subjects
CEBPA (CCAAT/enhancer-binding protein alpha)		3		0	2	0
DNMT3A (DNA [cytosine-5]-methyltransferase 3A)		2		0	0	0
FLT3 (Fms-like tyrosine kinase 3)		1		0	2	0
FLT3-ITD (FLT3 internal tandem duplications)		0		0	1	0
IDH1 (Isocitrate dehydrogenase 1)		1		0	0	0
IDH2 (Isocitrate dehydrogenase 2)		0		0	2	0
KIT(Tyrosine-protein kinase Kit)		0		1	0	0
KRAS(Kirsten rat sarcoma 2 viral oncogene homolog)		1		0	0	0
NPM1 (Nucleophosmin)		0		0	4	0
NRAS(Neuroblastoma RAS viral oncogene homolog)		5		0	1	0
RUNX1 (Runt related transcription factor 1)		1		0	1	0
TET2 (Tet methylcytosine dioxygenase 2)		3		0	1	0
WT1 (Wilm's tumour tumor suppressor gene1)		0		0	0	0

Notes
[41] - Sample non-collection/availability, blast count being too low for reliable mutation detection.
[42] - Sample non-collection/availability, blast count being too low for reliable mutation detection.

No statistical analyses for this end point

Secondary: Serum levels of circulating protein analytes at Phase 1B - Baseline

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End point title

Serum levels of circulating protein analytes at Phase 1B - Baseline

End point description

Blood samples were collected at pre-dose on Cycle 1/Day 1(baseline), 1 hour post-dose on Cycle 1/Day 2 and Day 10, pre-dose on Cycle 1/Day 21 and end of treatment for Glasdegib+LADC arm; Cycle 1/Day 1(baseline), 1 hour post-dose on Cycle 1/Day 1 and Day 2 and pre-dose on Cycle 1/Day 10 for Glasdegib+Decitabine arm; pre-dose on Induction Cycle 1/Day -3(baseline), 1 hour post-dose on Induction Cycle 1/Lead-in,Day 3 and Day 10, 1 hour post-dose on Consolidation Cycle 1/Day 1, pre-dose on Consolidation Cycle 1/Day 10, and at end of treatment for Glasdegib+Cytarabine/Daunorubicin arm. Serum levels were determined for 38 circulating proteins. Only the values showing statistically significant change from baseline are reported here. Pharmacodynamic(PD) analysis set was analyzed: all enrolled subjects in the Phase 1B portion who received at least 1 dose of glasdegib, and had at least 1 PD parameter from the corresponding assay sample with a baseline and an adequate post treatment assessment.

End point type

Secondary

End point timeframe

Baseline (Induction Cycle 1/Day -3 pre-dose)

End point values	Phase 1B: Glasdegib + Cytarabine/Daunorubicin
Number of subjects analysed	22
Units: pg/mL
median (full range (min-max))
MMP-3 (Matrix metalloproteinase-3)	10200 (1700 to 44000)
IL-8 (Interleukin-8)	10.7 (0.00 to 71.00)
BDNF (Brain-derived neurotrophic factor)	1200 (0.00 to 22000)
IL-5 (Interleukin-5)	0.00 (0.00 to 0.00)
VEGF (Vascular endothelial growth factor)	88.00 (32.00 to 2000.00)
MCP-1 (Monocyte chemotactic protein-1)	180.5 (0.00 to 1850.00)
ITAC:Interferon-inducible T-cell α chemoattractant	0.00 (0.00 to 1900.00)

No statistical analyses for this end point

Secondary: Serum levels of circulating protein analytes at Phase 1B - Induction Cycle 1/Day 3: MMP-3 (Matrix metalloproteinase-3)

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End point title

Serum levels of circulating protein analytes at Phase 1B - Induction Cycle 1/Day 3: MMP-3 (Matrix metalloproteinase-3)

End point description

End point type

Secondary

End point timeframe

Induction Cycle 1/Day 3, 1 Hour Post dose

End point values	Phase 1B: Glasdegib + Cytarabine/Daunorubicin
Number of subjects analysed	21
Units: pg/mL
median (full range (min-max))	20000 (1600 to 111000)

No statistical analyses for this end point

Secondary: Serum levels of circulating protein analytes at Phase 1B - Induction Cycle 1/Day 10

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End point title

Serum levels of circulating protein analytes at Phase 1B - Induction Cycle 1/Day 10

End point description

End point type

Secondary

End point timeframe

Induction Cycle 1/Day 10, 1 Hour Post dose

End point values	Phase 1B: Glasdegib + Cytarabine/Daunorubicin
Number of subjects analysed	21
Units: pg/mL
median (full range (min-max))
IL-8	37.00 (7.90 to 128.00)
BDNF	200 (0.00 to 2800)
IL-5	99.00 (0.00 to 2440.00)
VEGF	51.00 (0.00 to 149.00)
MCP-1	684.00 (368.00 to 9780.00)
ITAC	0.00 (0.00 to 218.00)

No statistical analyses for this end point

Secondary: Baseline levels of serum circulating protein analytes associated with best overall response at Phase 1B

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End point title

Baseline levels of serum circulating protein analytes associated with best overall response at Phase 1B

End point description

Blood samples were collected at pre-dose on Cycle 1/Day 1 (baseline), 1 hour post-dose on Cycle 1/Day 2 and Day 10, pre-dose on Cycle 1/Day 21 and end of treatment for Glasdegib+LADC arm; Cycle 1/Day 1 (baseline), 1 hour post-dose on Cycle 1/Day 1 and Day 2 and pre-dose on Cycle 1/Day 10 for Glasdegib+Decitabine arm; pre-dose on Induction Cycle 1/Day -3 (baseline), 1 hour post-dose on Induction Cycle 1/Lead-in,Day 3 and Day 10, 1 hour post-dose on Consolidation Cycle 1/Day 1, pre-dose on Consolidation Cycle 1/Day 10, and at end of treatment for Glasdegib+Cytarabine/Daunorubicin arm. Responders were AML subjects who achieved CR, CRi, MLFS, PR or PRi and MDS subjects who achieved CR, mCR, PR or SD based on investigator-reported best overall response. A total of 38 proteins were analyzed. Serum level showed statistically significant correlation with clinical response are reported. PD analysis set was used to analyze this end point.

End point type

Secondary

End point timeframe

Baseline (Cycle 1/Day 1 pre-dose for Glasdegib + LDAC and Glasdegib + Decitabine Arms; Induction Cycle 1/Day -3 pre-dose for Glasdegib +Cytarabine/Daunorubicin Arm)

End point values	Phase 1B: Glasdegib + LDAC (Biomarker, Responder)	Phase 1B: Glasdegib + LDAC (Biomarker, non-Responder)	Phase 1B: Glasdegib + Decitabine (Biomarker, Responder)	Phase 1B: Glasdegib + Decitabine (Biomarker, non-Responder)	Phase 1B: Glasdegib + Cytarabine/Dauno (Biomarker, Responder)	Phase 1B: Glasdegib+Cytarabine/Dauno(Biomarker,non-Responder)
Number of subjects analysed	4	19	5	2	14	8
Units: pg/mL
median (full range (min-max))
IL-6 (Interleukin-6)	3.2 (0.00 to 11.00)	0.00 (0.00 to 232.00)	0.00 (0.00 to 7.00)	8.50 (0.00 to 17.00)	6.90 (0.00 to 25.00)	0.00 (0.00 to 14.00)
SDF-1 (Stromal cell-derived factor 1)	2895.00 (2370.00 to 3330.00)	2480.00 (1170.00 to 4280.00)	1720.00 (1440.00 to 3190.00)	4045.00 (2860.00 to 5230.00)	2275.00 (1600.00 to 3700.00)	3275.00 (1950.00 to 4730.00)

No statistical analyses for this end point

Secondary: Post-baseline levels of serum circulating protein analytes associated with best overall response at Phase 1B - Induction Cycle 1/Lead-In: MMP-3 (Matrix metalloproteinase-3)

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End point title

Post-baseline levels of serum circulating protein analytes associated with best overall response at Phase 1B - Induction Cycle 1/Lead-In: MMP-3 (Matrix metalloproteinase-3)

End point description

Blood samples were collected at pre-dose on Cycle 1/Day 1 (baseline), 1 hour post-dose on Cycle 1/Day 2 and Day 10, pre-dose on Cycle 1/Day 21 and end of treatment for Glasdegib+LADC arm; Cycle 1/Day 1 (baseline), 1 hour post-dose on Cycle 1/Day 1 and Day 2 and pre-dose on Cycle 1/Day 10 for Glasdegib+Decitabine arm; pre-dose on Induction Cycle 1/Day -3 (baseline), 1 hour post-dose on Induction Cycle 1/Lead-in,Day 3 and Day 10, 1 hour post-dose on Consolidation Cycle 1/Day 1, pre-dose on Consolidation Cycle 1/Day 10, and at end of treatment for Glasdegib+Cytarabine/Daunorubicin arm. Responders were AML subjects who achieved CR, CRi, MLFS, PR or PRi and MDS subjects who achieved CR, mCR, PR or SD based on investigator-reported best overall response. A total of 38 proteins were analyzed. Serum level showed statistically significant correlation with clinical response are reported. PD analysis set was used to analyze this end point.

End point type

Secondary

End point timeframe

Induction Cycle 1/Lead-in, 1 Hour Post dose

End point values	Phase 1B: Glasdegib + Cytarabine/Dauno (Biomarker, Responder)	Phase 1B: Glasdegib+Cytarabine/Dauno(Biomarker,non-Responder)
Number of subjects analysed	14	8
Units: ng/mL
median (full range (min-max))	8.90 (2.20 to 51.00)	10.50 (6.50 to 19.00)

No statistical analyses for this end point

Secondary: Post-baseline levels of serum circulating protein analytes associated with best overall response at Phase 1B - Induction Cycle 1/Day 3: SDF-1 (Stromal cell-derived factor 1)

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End point title

Post-baseline levels of serum circulating protein analytes associated with best overall response at Phase 1B - Induction Cycle 1/Day 3: SDF-1 (Stromal cell-derived factor 1)

End point description

Blood samples were collected at pre-dose on Cycle 1/Day 1 (baseline), 1 hour post-dose on Cycle 1/Day 2 and Day 10, pre-dose on Cycle 1/Day 21 and end of treatment for Glasdegib+LADC arm; Cycle 1/Day 1 (baseline), 1 hour post-dose on Cycle 1/Day 1 and Day 2 and pre-dose on Cycle 1/Day 10 for Glasdegib+Decitabine arm; pre-dose on Induction Cycle 1/Day -3 (baseline), 1 hour post-dose on Induction Cycle 1/Lead-in,Day 3 and Day 10, 1 hour post-dose on Consolidation Cycle 1/Day 1, pre-dose on Consolidation Cycle 1/Day 10, and at end of treatment for Glasdegib+Cytarabine/Daunorubicin arm. Responders were AML subjects who achieved CR, CRi, MLFS, PR or PRi and MDS subjects who achieved CR, mCR, PR or SD based on investigator-reported best overall response. A total of 38 proteins were analyzed. Serum level showed statistically significant correlation with clinical response are reported. PD analysis set was used to analyze this end point.

End point type

Secondary

End point timeframe

Induction Cycle 1/Day 3, 1 Hour Post dose

End point values	Phase 1B: Glasdegib + Cytarabine/Dauno (Biomarker, Responder)	Phase 1B: Glasdegib+Cytarabine/Dauno(Biomarker,non-Responder)
Number of subjects analysed	13	8
Units: pg/mL
median (full range (min-max))	2510.00 (1530.00 to 3520.00)	3260.00 (1350.00 to 4430.00)

No statistical analyses for this end point

Secondary: Number of subjects with disease-related gene mutations at Phase 2 Fit and Unfit

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End point title

Number of subjects with disease-related gene mutations at Phase 2 Fit and Unfit

End point description

Peripheral blood and bone marrow aspirate were collected for baseline mutational analyses. Genetic abnormalities frequently associated with AML were analyzed. These genetic abnormalities included known mutations in the genes NPM1, CEBPA, FLT3, RUNX1, IDH1, IDH2, KIT, K Ras, N Ras and WT1. Additional genes with mutations known to be associated with AML and MDS such as TET2 and DNMT3A were also evaluated. PD analysis set was used to analyze this end point, defined as all enrolled subjects in the Phase 1B portion who received at least 1 dose of glasdegib, and had at least 1 PD parameter from the corresponding assay sample with a baseline and an adequate post treatment assessment.

End point type

Secondary

End point timeframe

Baseline (Induction Cycle 1/Day -3 pre-dose for Phase 2 Fit; Cycle 1/Day 1 pre-dose for Phase 2 Unfit)

End point values	Phase 2 Fit (Biomarker, Responder)	Phase 2 Fit (Biomarker, non-Responder)	Phase 2 Unfit: Glasdegib 100 mg + LDAC (Biomarker, Responder)	Phase 2 Unfit: Glasdegib 100 mg+LDAC(Biomarker, non-Responder)	Phase 2 Unfit: LDAC alone (Biomarker, Responder)	Phase 2 Unfit: LDAC alone (Biomarker, non-Responder)
Number of subjects analysed	32	18	21	40	1	26
Units: Subjects
CEBPA	6	3	3	5	0	3
DNMT3A	12	6	2	13	0	6
FLT3	3	2	1	4	0	0
FLT3-ITD	2	1	1	2	0	2
IDH1	2	1	5	5	0	2
IDH2	5	4	2	10	0	5
KIT	2	1	1	2	0	1
KRAS	0	1	0	2	0	2
NPM1	12	3	2	3	0	1
NRAS	5	1	1	4	0	3
RUNX1	7	7	10	18	0	7
TET2	7	5	7	8	1	8
WT1	0	1	1	2	0	1

No statistical analyses for this end point

Secondary: Serum levels of circulating protein analytes at Phase 2 Fit - Induction Cycle 1/Day 3

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End point title

Serum levels of circulating protein analytes at Phase 2 Fit - Induction Cycle 1/Day 3 ^[43]

End point description

Blood samples were collected at pre-dose on Induction Cycle 1/Day -3 (baseline), 1 hour post-dose on Induction Cycle 1/Day 3 and Day 10, 1 hour post-dose on Consolidation Cycle 1/Day 1, pre-dose on Consolidation Cycle 1/Day 10, and at end of treatment treatment (maximum of 12 cycles from start of therapy or until disease progression or relapse, subjects refusal or unacceptable toxicity occurred, whichever came first). Serum levels were determined for 38 circulating proteins. Only the values showing statistically significant change from baseline are reported here. PD analysis set was used to analyze this end point, defined as all enrolled subjects in the Phase 2 Fit portion who received at least 1 dose of glasdegib, and had at least 1 PD parameter from the corresponding assay sample with a baseline and an adequate post treatment assessment.

End point type

Secondary

End point timeframe

Induction Cycle 1/Day 3, 1 Hour Post dose

Notes
[43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin
Number of subjects analysed	57
Units: pg/mL
median (full range (min-max))
Factor VII(activated blood coagulation factor VII)	318000 (56000 to 620000)
BDNF	700 (0 to 6200)
MMP-3	21000 (1700 to 107000)
IL-8	28.00 (0.00 to 139.00)
ITAC	14.00 (0.00 to 535.00)

No statistical analyses for this end point

Secondary: Serum levels of circulating protein analytes at Phase 2 Fit - Induction Cycle 1/Day 10

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End point title

Serum levels of circulating protein analytes at Phase 2 Fit - Induction Cycle 1/Day 10 ^[44]

End point description

End point type

Secondary

End point timeframe

Induction Cycle 1/Day 10, 1 Hour Post dose

Notes
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin
Number of subjects analysed	62
Units: pg/mL
median (full range (min-max))
IL-1β (Interleukin-1β)	8.50 (0.00 to 15.00)
IL-6	17.00 (0.00 to 7320.00)
Factor VII	292500 (45000 to 641000)
BDNF	300 (0 to 15000)
VEGF	69.00 (0.00 to 140.00)
MCP-1	594.00 (126.00 to 21200.00)
MMP-3	12000 (3000 to 93000)
IL-8	55.00 (0.00 to 8930.00)
IL-5	85.00 (0.00 to 2240.00)
ITAC	0.00 (0.00 to 46.00)

No statistical analyses for this end point

Secondary: Serum levels of circulating protein analytes at Phase 2 Fit - Consolidation Cycle 1/Day 1

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End point title

Serum levels of circulating protein analytes at Phase 2 Fit - Consolidation Cycle 1/Day 1 ^[45]

End point description

End point type

Secondary

End point timeframe

Consolidation Cycle 1/Day 1, 1 Hour Post dose

Notes
[45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin
Number of subjects analysed	24
Units: pg/mL
median (full range (min-max))
MIP-1β (Macrophage Inflammatory Protein-1β)	226.00 (0.00 to 6160.00)
BDNF	7000 (370 to 38000)
VEGF	232.50 (41.00 to 834.00)
IL-8	9.90 (0.00 to 514.00)
ITAC	41.50 (10.00 to 117.00)

No statistical analyses for this end point

Secondary: Serum levels of circulating protein analytes at Phase 2 Fit - Consolidation Cycle 1/Day 10

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End point title

Serum levels of circulating protein analytes at Phase 2 Fit - Consolidation Cycle 1/Day 10 ^[46]

End point description

End point type

Secondary

End point timeframe

Consolidation Cycle 1/Day 10, Pre-dose

Notes
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin
Number of subjects analysed	20
Units: pg/mL
median (full range (min-max))
MIP-1β	239.50 (0.00 to 6560.00)
MCP-1	581.00 (192.00 to 3880.00)
MMP-3	12000 (2700 to 48000)
IL-8	11.00 (0.00 to 74.00)
ITAC	4.10 (0.00 to 27.00)

No statistical analyses for this end point

Secondary: Serum levels of circulating protein analytes at Phase 2 Fit - End of Treatment

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End point title

Serum levels of circulating protein analytes at Phase 2 Fit - End of Treatment ^[47]

End point description

End point type

Secondary

End point timeframe

End of Treatment (maximum of 12 cycles from start of therapy or until disease progression or relapse, subject refusal or unacceptable toxicity occurred, whichever came first), Hours not specified

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin
Number of subjects analysed	42
Units: pg/mL
median (full range (min-max))
MIP-1β	338.00 (0.00 to 4480.00)
VEGF	133.00 (0.00 to 2880.00)
MCP-1	277.00 (0.00 to 7450.00)

No statistical analyses for this end point

Secondary: Baseline levels of serum circulating protein analytes associated with best overall response at Phase 2 Fit: 6CKINE (C-C motif chemokine 21)

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End point title

Baseline levels of serum circulating protein analytes associated with best overall response at Phase 2 Fit: 6CKINE (C-C motif chemokine 21)

End point description

Blood samples were collected at pre-dose on Induction Cycle 1/Day -3 (baseline), 1 hour post-dose on Induction Cycle 1/Day 3 and Day 10, 1 hour post-dose on Consolidation Cycle 1/Day 1, pre-dose on Consolidation Cycle 1/Day 10, and at end of treatment. Responders were AML subjects who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS subjects who achieved CR, mCR, PR or SD based on investigator-reported best overall response. A total of 38 proteins were analyzed. The data of analytes for which the serum level showed statistically significant correlation with clinical response are reported. PD analysis set was used to analyze this end point, defined as all enrolled subjects in the Phase 2 Fit portion who received at least 1 dose of glasdegib, and had at least 1 PD parameter from the corresponding assay sample with a baseline and an adequate post treatment assessment.

End point type

Secondary

End point timeframe

Baseline (Induction Cycle 1/Day -3 pre-dose)

End point values	Phase 2 Fit (Biomarker, Responder)	Phase 2 Fit (Biomarker, non-Responder)
Number of subjects analysed	43	22
Units: pg/mL
median (full range (min-max))
6CKINE (C-C motif chemokine 21)	323.00 (158.00 to 419.00)	362.00 (225.00 to 758.00)

No statistical analyses for this end point

Secondary: Post-baseline levels of serum circulating protein analytes associated with best overall response at Phase 2 Fit - Induction Cycle 1/Day 3: TNFα (Tumor necrosis factor α)

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End point title

Post-baseline levels of serum circulating protein analytes associated with best overall response at Phase 2 Fit - Induction Cycle 1/Day 3: TNFα (Tumor necrosis factor α)

End point description

Blood samples were collected at pre-dose on Induction Cycle 1/Day -3 (baseline), 1 hour post-dose on Induction Cycle 1/Day 3 and Day 10, 1 hour post-dose on Consolidation Cycle 1/Day 1, pre-dose on Consolidation Cycle 1/Day 10, and at end of treatment treatment. Responders were AML subjects who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS subjects who achieved CR, mCR, PR or SD based on investigator-reported best overall response. A total of 38 proteins were analyzed. The data of analytes for which the serum level showed statistically significant correlation with clinical response are reported. PD analysis set was used to analyze this end point, defined as all enrolled subjects in the Phase 2 Fit portion who received at least 1 dose of glasdegib, and had at least 1 PD parameter from the corresponding assay sample with a baseline and an adequate post treatment assessment.

End point type

Secondary

End point timeframe

Induction Cycle 1/Day 3, 1 Hour Post dose

End point values	Phase 2 Fit (Biomarker, Responder)	Phase 2 Fit (Biomarker, non-Responder)
Number of subjects analysed	37	20
Units: pg/mL
arithmetic mean (full range (min-max))	3.20 (0.00 to 26.00)	10.90 (0.00 to 63.00)

No statistical analyses for this end point

Secondary: Post-baseline levels of serum circulating protein analytes associated with best overall response at Phase 2 Fit - Induction Cycle 1/Day 10: TNFα (Tumor necrosis factor α)

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End point title

Post-baseline levels of serum circulating protein analytes associated with best overall response at Phase 2 Fit - Induction Cycle 1/Day 10: TNFα (Tumor necrosis factor α)

End point description

Blood samples were collected at pre-dose on Induction Cycle 1/Day -3 (baseline), 1 hour post-dose on Induction Cycle 1/Day 3 and Day 10, 1 hour post-dose on Consolidation Cycle 1/Day 1, pre-dose on Consolidation Cycle 1/Day 10, and at end of treatment treatment. Responders were AML subjects who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS subjects who achieved CR, mCR, PR or SD based on investigator-reported best overall response. A total of 38 proteins were analyzed. The data of analytes for which the serum level showed statistically significant correlation with clinical response are reported. PD analysis set was used to analyze this end point, defined as all enrolled subjects in the Phase 2 Fit portion who received at least 1 dose of glasdegib, and had at least 1 PD parameter from the corresponding assay sample with a baseline and an adequate post treatment assessment.

End point type

Secondary

End point timeframe

Induction Cycle 1/Day 10, 1 Hour Post dose

End point values	Phase 2 Fit (Biomarker, Responder)	Phase 2 Fit (Biomarker, non-Responder)
Number of subjects analysed	42	20
Units: pg/mL
arithmetic mean (full range (min-max))	1.20 (0.00 to 18.00)	6.60 (0.00 to 88.00)

No statistical analyses for this end point

Secondary: Post-baseline levels of serum circulating protein analytes associated with best overall response at Phase 2 Fit - End of Treatment

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End point title

Post-baseline levels of serum circulating protein analytes associated with best overall response at Phase 2 Fit - End of Treatment

End point description

Blood samples were collected at pre-dose on Induction Cycle 1/Day -3 (baseline), 1 hour post-dose on Induction Cycle 1/Day 3 and Day 10, 1 hour post-dose on Consolidation Cycle 1/Day 1, pre-dose on Consolidation Cycle 1/Day 10, and at end of treatment treatment. Responders were AML subjects who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS subjects who achieved CR, mCR, PR or SD based on investigator-reported best overall response. A total of 38 proteins were analyzed. The data of analytes for which the serum level showed statistically significant correlation with clinical response are reported. PD analysis set was used to analyze this end point, defined as all enrolled subjects in the Phase 2 Fit portion who received at least 1 dose of glasdegib, and had at least 1 PD parameter from the corresponding assay sample with a baseline and an adequate post treatment assessment.

End point type

Secondary

End point timeframe

End of Treatment (maximum of 12 cycles from start of therapy or until disease progression or relapse, subject refusal or unacceptable toxicity occurred, whichever came first), Hours not specified

End point values	Phase 2 Fit (Biomarker, Responder)	Phase 2 Fit (Biomarker, non-Responder)
Number of subjects analysed	27	15
Units: pg/mL
median (full range (min-max))
IL-1β	9.70 (0.00 to 20.00)	6.70 (0.00 to 20.00)
IL-15 (Interleukin-15)	700 (0 to 1300)	600 (0 to 850)

No statistical analyses for this end point

Secondary: Serum levels of circulating protein analytes at Phase 2 Unfit - Cycle 1/Day 1: IL-18 (Interleukin-18)

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End point title

Serum levels of circulating protein analytes at Phase 2 Unfit - Cycle 1/Day 1: IL-18 (Interleukin-18) ^[48]

End point description

Blood samples were collected at pre-dose on Cycle 1/Day 1 (baseline), 1 hour post-dose on Cycle 1/Day 1 and pre-dose on Cycle 1/Day 10 and end of treatment (maximum of 12 cycles from start of therapy or until disease progression or relapse, subjects refusal or unacceptable toxicity occurred, whichever came first). Serum levels were determined for 38 circulating proteins. Only the values showing statistically significant change from baseline are reported here. PD analysis set was used to analyze this end point, defined as all enrolled subjects in the Phase 2 Unfit portion who received at least 1 dose of glasdegib, and had at least 1 PD parameter from the corresponding assay sample with a baseline and an adequate post treatment assessment.

End point type

Secondary

End point timeframe

Cycle 1/Day 1, 1 Hour Post dose

Notes
[48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Unfit: Glasdegib 100 mg + LDAC
Number of subjects analysed	18
Units: pg/mL
median (full range (min-max))	483.00 (40.00 to 1230.00)

No statistical analyses for this end point

Secondary: Serum levels of circulating protein analytes at Phase 2 Unfit - Cycle 1/Day 10

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End point title

Serum levels of circulating protein analytes at Phase 2 Unfit - Cycle 1/Day 10 ^[49]

End point description

End point type

Secondary

End point timeframe

Cycle 1/Day 10, Pre-dose

Notes
[49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Unfit: Glasdegib 100 mg + LDAC	Phase 2 Unfit: LDAC alone
Number of subjects analysed	66	24
Units: pg/mL
median (full range (min-max))
BDNF	500 (0 to 7200)	200 (0 to 5100)
ITAC	7.5 (0.00 to 226.00)	0.00 (0.00 to 71.00)

No statistical analyses for this end point

Secondary: Baseline levels of serum circulating protein analytes associated with best overall response at Phase 2 Unfit

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End point title

Baseline levels of serum circulating protein analytes associated with best overall response at Phase 2 Unfit

End point description

Blood samples were collected at pre-dose on Cycle 1/Day 1 (baseline), 1 hour post-dose on Cycle 1/Day 1 and pre-dose on Cycle 1/Day 10 and end of treatment (maximum of 12 cycles from start of therapy or until disease progression or relapse, subjects refusal or unacceptable toxicity occurred, whichever came first). Responders were AML subjects who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS subjects who achieved CR, mCR, PR or SD based on investigator-reported best overall response. A total of 38 proteins were analyzed. The data of analytes for which the serum level showed statistically significant correlation with clinical response are reported. PD analysis set was used to analyze this end point, defined as all enrolled subjects in the Phase 2 Unfit portion who received at least 1 dose of glasdegib, and had at least 1 PD parameter from the corresponding assay sample with a baseline and an adequate post treatment assessment.

End point type

Secondary

End point timeframe

Baseline (Cycle 1/Day 1 pre-dose)

End point values	Phase 2 Unfit: Glasdegib 100 mg + LDAC (Biomarker, Responder)	Phase 2 Unfit: Glasdegib 100 mg+LDAC(Biomarker, non-Responder)
Number of subjects analysed	28	44
Units: pg/mL
median (full range (min-max))
BDNF	2000 (170 to 22000)	900 (0 to 12000)
ICAM-1 (Intercellular cell adhesion molecule-1)	128000 (37000 to 287000)	161000 (82000 to 580000)
6CKINE	223.50 (53.00 to 679.00)	318.00 (128.00 to 911.00)
BAFF (B-cell activating factor)	704.50 (116.00 to 3000.00)	1295.00 (199.00 to 6190.00)
MIP-3β	275.00 (86.00 to 2060.00)	414.50 (109.00 to 2130.00)
Eotaxin-1 (C-C motif chemokine 11)	169.00 (0.00 to 333.00)	0.00 (0.00 to 260.00)

No statistical analyses for this end point

Secondary: Post-baseline levels of serum circulating protein analytes associated with best overall response at Phase 2 Unfit - Cycle 1/Day 1

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End point title

Post-baseline levels of serum circulating protein analytes associated with best overall response at Phase 2 Unfit - Cycle 1/Day 1

End point description

Blood samples were collected at pre-dose on Cycle 1/Day 1 (baseline), 1 hour post-dose on Cycle 1/Day 1 and pre-dose on Cycle 1/Day 10 and end of treatment (maximum of 12 cycles from start of therapy or until disease progression or relapse, subjects refusal or unacceptable toxicity occurred, whichever came first). Responders were AML subjects who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS subjects who achieved CR, mCR, PR or SD based on investigator-reported best overall response. A total of 38 proteins were analyzed. The data of analytes for which the serum level showed statistically significant correlation with clinical response are reported. PD analysis set was used to analyze this end point, defined as all enrolled subjects in the Phase 2 Unfit portion who received at least 1 dose of glasdegib, and had at least 1 PD parameter from the corresponding assay sample with a baseline and an adequate post treatment assessment.

End point type

Secondary

End point timeframe

Cycle 1/Day 1, 1 Hour Post dose

End point values	Phase 2 Unfit: Glasdegib 100 mg + LDAC (Biomarker, Responder)	Phase 2 Unfit: Glasdegib 100 mg+LDAC(Biomarker, non-Responder)
Number of subjects analysed	6	12
Units: pg/mL
median (full range (min-max))
Factor VII:activated blood coagulation factor VII	311500 (48000 to 661000)	234500 (147000 to 676000)
IL-6 (Interleukin-6)	0.00 (0.00 to 3.50)	6.80 (0.00 to 62.00)

No statistical analyses for this end point

Secondary: Post-baseline levels of serum circulating protein analytes associated with best overall response at Phase 2 Unfit - End of Treatment: IL-6 (Interleukin-6)

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End point title

Post-baseline levels of serum circulating protein analytes associated with best overall response at Phase 2 Unfit - End of Treatment: IL-6 (Interleukin-6)

End point description

Blood samples were collected at pre-dose on Cycle 1/Day 1 (baseline), 1 hour post-dose on Cycle 1/Day 1 and pre-dose on Cycle 1/Day 10 and end of treatment (maximum of 12 cycles from start of therapy or until disease progression or relapse, subjects refusal or unacceptable toxicity occurred, whichever came first). Responders were AML subjects who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS subjects who achieved CR, mCR, PR or SD based on investigator-reported best overall response. A total of 38 proteins were analyzed. The data of analytes for which the serum level showed statistically significant correlation with clinical response are reported. PD analysis set was used to analyze this end point, defined as all enrolled subjects in the Phase 2 Unfit portion who received at least 1 dose of glasdegib, and had at least 1 PD parameter from the corresponding assay sample with a baseline and an adequate post treatment assessment.

End point type

Secondary

End point timeframe

End of Treatment (maximum of 12 cycles from start of therapy or until disease progression or relapse, subject refusal or unacceptable toxicity occurred, whichever came first), Hours not specified

End point values	Phase 2 Unfit: Glasdegib 100 mg + LDAC (Biomarker, Responder)	Phase 2 Unfit: Glasdegib 100 mg+LDAC(Biomarker, non-Responder)
Number of subjects analysed	17	18
Units: pg/mL
median (full range (min-max))	0.00 (0.00 to 45.00)	9.40 (0.00 to 52.00)

No statistical analyses for this end point

Secondary: Ratios of mRNA levels to baseline at Phase 2 Fit - Induction Cycle 1/Day 3

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End point title

Ratios of mRNA levels to baseline at Phase 2 Fit - Induction Cycle 1/Day 3 ^[50]

End point description

Blood samples were collected at pre-dose on Induction Cycle 1/Day -3(baseline),1 hour post-dose on Induction Cycle 1/Day 3 and end of treatment (maximum of 12 cycles from start of therapy or until disease progression or relapse, subjects refusal or unacceptable toxicity occurred, whichever came first).Whole blood mRNA analyses were performed on 21 mRNA candidates. Only the values showing statistically significant change from baseline are reported here. CDKN1A: cyclin-dependent kinase inhibitor 1A; SMO: mRNA encoding the glasdegib target Smoothened. PD analysis set was used to analyze this end point: all enrolled subjects in the Phase 2 Fit portion who received at least 1 dose of glasdegib, and had at least 1 PD parameter from the corresponding assay sample with a baseline and an adequate post treatment assessment. Number of subjects analyzed is number of subjects in the treatment group. ‘n’ in categories is number of subjects contributing to the summary statistics.

End point type

Secondary

End point timeframe

Induction Cycle 1/Day 3, 1 Hour Post dose

Notes
[50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin
Number of subjects analysed	62
Units: Not Applicable
median (full range (min-max))
CDKN1A (n = 54)	2.40 (0.08 to 53.17)
SMO (n = 18)	4.80 (0.06 to 51.22)

No statistical analyses for this end point

Secondary: Ratios of mRNA levels to baseline at Phase 2 Fit - End of Treatment

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End point title

Ratios of mRNA levels to baseline at Phase 2 Fit - End of Treatment ^[51]

End point description

Blood samples were collected at pre-dose on Induction Cycle 1/Day -3 (baseline), 1 hour post-dose on Induction Cycle 1/Day 3 and end of treatment. Whole blood mRNA analyses were performed on 21 mRNA candidates. Only the values showing statistically significant change from baseline are reported here. CCND2:G1/S-Specific Cyclin D2; MSI2: Musashi RNA Binding Protein 2; PTCH2: Patched 2. PD analysis set was used to analyze this end point, defined as all enrolled subjects in the Phase 2 Fit portion who received at least 1 dose of glasdegib, and had at least 1 PD parameter from the corresponding assay sample with a baseline and an adequate post treatment assessment. Number of subjects analyzed is number of subjects in the treatment group. ‘n’ in categories is number of subjects contributing to the summary statistics.

End point type

Secondary

End point timeframe

End of Treatment (maximum of 12 cycles from start of therapy or until disease progression or relapse, subject refusal or unacceptable toxicity occurred, whichever came first), Hours not specified

Notes
[51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin
Number of subjects analysed	62
Units: Not Applicable
median (full range (min-max))
CCND2 (n = 42)	0.80 (0.23 to 3.23)
MSI2 (n = 42)	0.80 (0.31 to 4.58)
PTCH2 (n = 12)	0.70 (0.29 to 1.90)

No statistical analyses for this end point

Secondary: Ratios of mRNA levels to baseline at Phase 2 Unfit - End of Treatment

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End point title

Ratios of mRNA levels to baseline at Phase 2 Unfit - End of Treatment ^[52]

End point description

Blood samples were collected at pre-dose on Cycle 1/Day1 (baseline), 1 hour post-dose on Cycle 1/Day 1 and end of treatment (maximum of 12 cycles from start of therapy or until disease progression or relapse, subjects refusal or unacceptable toxicity occurred, whichever came first). Whole blood mRNA analyses were performed on 21 mRNA candidates. Only the values showing statistically significant change from baseline are reported here. PD analysis set was used to analyze this end point, defined as all enrolled subjects in the Phase 2 Unfit portion who received at least 1 dose of glasdegib, and had at least 1 PD parameter from the corresponding assay sample with a baseline and an adequate post treatment assessment. Number of subjects analyzed is number of subjects in the treatment group. ‘n’ in categories is number of subjects contributing to the summary statistics.

End point type

Secondary

End point timeframe

End of Treatment (maximum of 12 cycles from start of therapy or until disease progression or relapse, subject refusal or unacceptable toxicity occurred, whichever came first), Hours not specified

Notes
[52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Unfit: Glasdegib 100 mg + LDAC
Number of subjects analysed	47
Units: Not Applicable
median (full range (min-max))
CCND2 (n = 30)	0.70 (0.06 to 2.35)
SMO (n = 20)	0.40 (0.09 to 8.09)
CCND1 (n = 17)	0.40 (0.10 to 13.33)

No statistical analyses for this end point

Secondary: Baseline mRNA levels associated with best overall response at Phase 2 Fit: CCND2 (G1/S-Specific Cyclin D2)

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End point title

Baseline mRNA levels associated with best overall response at Phase 2 Fit: CCND2 (G1/S-Specific Cyclin D2)

End point description

Blood samples were collected at pre-dose on Induction Cycle 1/Day -3 (baseline), 1 hour post-dose on Induction Cycle 1/Day 3 and end of treatment (maximum of 12 cycles from start of therapy or until disease progression or relapse, subjects refusal or unacceptable toxicity occurred, whichever came first). Responders were AML subjects who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS subjects who achieved CR, mCR, PR or SD based on investigator-reported best overall response. Whole blood mRNA analyses were performed on 21 mRNA candidates. Baseline mRNA level showing statistically significant correlation with clinical response are reported. PD analysis set was used to analyze this end point, defined as all enrolled subjects in the Phase 2 Fit portion who received at least 1 dose of glasdegib, and had at least 1 PD parameter from the corresponding assay sample with a baseline and an adequate post treatment assessment.

End point type

Secondary

End point timeframe

Baseline (Induction Cycle 1/Day -3 pre-dose)

End point values	Phase 2 Fit (Biomarker, Responder)	Phase 2 Fit (Biomarker, non-Responder)
Number of subjects analysed	39	22
Units: Not Applicable
median (full range (min-max))	10.9 (1.61 to 25.26)	14.80 (5.03 to 23.74)

No statistical analyses for this end point

Secondary: Baseline mRNA levels associated with best overall response at Phase 2 Unfit

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End point title

Baseline mRNA levels associated with best overall response at Phase 2 Unfit

End point description

Blood samples were collected at pre-dose on Cycle 1/Day 1 (baseline), 1 hour post-dose on Cycle 1/Day 1 and end of treatment. Responders were AML subjects who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS subjects who achieved CR, mCR, PR or SD based on investigator-reported best overall response. Whole blood mRNA analyses were performed on 21 mRNA candidates. Baseline mRNA level showing statistically significant correlation with clinical response are reported. FOXM1: Forkhead box M1; PTCH1: Patched 1. PD analysis set was used to analyze this end point, defined as all enrolled subjects in the Phase 2 Unfit portion who received at least 1 dose of glasdegib, and had at least 1 PD parameter from the corresponding assay sample with a baseline and an adequate post treatment assessment. Number of subjects analyzed is number of subjects in the treatment group. ‘n’ in categories is number of subjects contributing to the summary statistics.

End point type

Secondary

End point timeframe

Baseline (Cycle 1/Day 1 pre-dose)

End point values	Phase 2 Unfit: Glasdegib 100 mg + LDAC (Biomarker, Responder)	Phase 2 Unfit: Glasdegib 100 mg+LDAC(Biomarker, non-Responder)
Number of subjects analysed	33	55
Units: Not Applicable
median (full range (min-max))
FOXM1 (n = 15, 28)	0.20 (0.05 to 0.77)	0.40 (0.09 to 1.86)
PTCH1 (n = 14, 27)	0.20 (0.07 to 0.58)	0.10 (0.01 to 0.42)

No statistical analyses for this end point

Secondary: Ratios of mRNA levels to baseline associated with best overall response at Phase 2 Fit

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End point title

Ratios of mRNA levels to baseline associated with best overall response at Phase 2 Fit

End point description

Blood samples were collected at pre-dose on Induction Cycle 1/Day -3 (baseline), 1 hour post-dose on Induction Cycle 1/Day 3 and end of treatment (maximum of 12 cycles from start of therapy or until disease progression or relapse, subjects refusal or unacceptable toxicity occurred, whichever came first). Responders were AML subjects who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS subjects who achieved CR, mCR, PR or SD based on investigator-reported best overall response. Whole blood mRNA analyses were performed on 21 mRNA candidates. Ratios of mRNA level to baseline showing statistically significant correlation with clinical response are reported. PD analysis set was used to analyze this end point, defined as all enrolled subjects in the Phase 2 Fit portion who received at least 1 dose of glasdegib, and had at least 1 PD parameter from the corresponding assay sample with a baseline and an adequate post treatment assessment.

End point type

Secondary

End point timeframe

End of Treatment (maximum of 12 cycles from start of therapy or until disease progression or relapse, subject refusal or unacceptable toxicity occurred, whichever came first), Hours not specified

End point values	Phase 2 Fit (Biomarker, Responder)	Phase 2 Fit (Biomarker, non-Responder)
Number of subjects analysed	45	26
Units: Not Applicable
median (full range (min-max))
CCNE1 (n = 26, 13)	0.60 (0.21 to 1.65)	1.10 (0.28 to 3.82)
MSI2 (n = 28, 14)	0.90 (0.31 to 4.58)	0.50 (0.33 to 1.86)

No statistical analyses for this end point

Secondary: Ratios of mRNA levels to baseline associated with best overall response at Phase 2 Unfit: MYCN (Neuroblastoma Myc oncogene)

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End point title

Ratios of mRNA levels to baseline associated with best overall response at Phase 2 Unfit: MYCN (Neuroblastoma Myc oncogene)

End point description

Blood samples were collected at pre-dose on Cycle 1/Day 1 (baseline), 1 hour post-dose on Cycle 1/Day 1 and end of treatment (maximum of 12 cycles from start of therapy or until disease progression or relapse, subjects refusal or unacceptable toxicity occurred, whichever came first). Responders were AML subjets who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS subjects who achieved CR, mCR, PR or SD based on investigator-reported best overall response. Whole blood mRNA analyses were performed on 21 mRNA candidates. Ratios of mRNA level to baseline showing statistically significant correlation with clinical response are reported. PD analysis set was used to analyze this end point, defined as all enrolled subjects in the Phase 2 Unfit portion who received at least 1 dose of glasdegib, and had at least 1 PD parameter from the corresponding assay sample with a baseline and an adequate post treatment assessment.

End point type

Secondary

End point timeframe

Cycle 1/Day 1, 1 Hour Post dose

End point values	Phase 2 Unfit: Glasdegib 100 mg + LDAC (Biomarker, Responder)	Phase 2 Unfit: Glasdegib 100 mg+LDAC(Biomarker, non-Responder)
Number of subjects analysed	7	12
Units: Not Applicable
median (full range (min-max))	1.60 (0.50 to 40.25)	0.50 (0.03 to 20.60)

No statistical analyses for this end point

Secondary: Number of subjects with corrected QT interval using Fridericia's formula (QTcF) values meeting predefined criteria at Phase 1B

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End point title

Number of subjects with corrected QT interval using Fridericia's formula (QTcF) values meeting predefined criteria at Phase 1B

End point description

Maximum absolute values and increases from baseline were summarized for QTcF interval (time from the beginning of Q wave to the end of T wave corresponding to electrical systole corrected for heart rate using Fridericia’s formula). Number of subjects with QTcF meeting the following criteria is presented:QTcF interval:<450 msec; QTcF interval: 450 to <480 msec; QTcF interval: 480 to <500 msec; QTcF interval >=500 msec; QTcF interval increase from baseline: <30 msec; QTcF interval increase from baseline: 30 to <60 msec; QTcF interval increase from baseline >=60 msec. End of treatment in the time frame were defined as: maximum of 12 cycles from start of therapy or until disease progression or relapse, subject refusal or unacceptable toxicity occurred, whichever came first. QTc analysis set was analyzed:all subjects enrolled in study having at least 1 ECG assessment after receiving at least 1 dose of glasdegib.

End point type

Secondary

End point timeframe

All Arms: Screening (within 28 days prior to Dosing), Day 1 of each cycle, Cycle 1/Day 10, End of Treatment. Additions: Cycle 1/Day 3, Day 21 in Arm A; Cycle 1/Day 2 in Arm B;Lead-in Day -3, Day 10 of Induction and Consolidation Cycles in Arm C.

End point values	Phase 1B: Glasdegib + LDAC	Phase 1B: Glasdegib + Decitabine	Phase 1B: Glasdegib + Cytarabine/Daunorubicin
Number of subjects analysed	21	7	22
Units: Subjects
QTcF interval increase < 30 msec	16	2	14
QTcF interval increase: 30 to < 60 msec	5	3	6
QTcF interval increase >= 60 msec	0	2	2
Maximum QTcF interval < 450 msec	10	4	10
Maximum QTcF interval: 450 to < 480 msec	11	2	10
Maximum QTcF interval: 480 to < 500 msec	0	0	1
Maximum QTcF interval >= 500 msec	0	1	1

No statistical analyses for this end point

Secondary: Number of subjects with corrected QT interval using Fridericia's formula (QTcF) values meeting predefined criteria at Phase 2 Fit and Unfit

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End point title

Number of subjects with corrected QT interval using Fridericia's formula (QTcF) values meeting predefined criteria at Phase 2 Fit and Unfit ^[53]

End point description

Maximum absolute values and increases from baseline were summarized for QTcF interval (time from the beginning of Q wave to the end of T wave corresponding to electrical systole corrected for heart rate using Fridericia’s formula). Number of subjects with QTcF meeting the following criteria is presented:QTcF interval:<450 msec; QTcF interval: 450 to <480 msec; QTcF interval: 480 to <500 msec; QTcF interval >=500 msec; QTcF interval increase from baseline: <30 msec; QTcF interval increase from baseline: 30 to <60 msec; QTcF interval increase from baseline >=60 msec. End of treatment in the time frame were defined as: maximum of 12 cycles from start of therapy or until disease progression or relapse, subject refusal or unacceptable toxicity occurred, whichever came first. QTc analysis set was used to analyze this end point, defined as all subjects enrolled in the study having at least 1 ECG assessment after receiving at least 1 dose of glasdegib.

End point type

Secondary

End point timeframe

All Arms: Screening, Day 1 of each cycle, Cycle 1/Day 10, End of Treatment. Additions: Lead-in Day -3, Day 10 of Induction and Consolidation Cycles in Phase 2 Fit Arm.

Notes
[53] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin	Phase 2 Unfit: Glasdegib 100 mg + LDAC	Phase 2 Unfit: LDAC alone
Number of subjects analysed	68	83	17
Units: Subjects
QTcF interval increase < 30 msec	41	60	12
QTcF interval increase: 30 to < 60 msec	21	19	4
QTcF interval increase >= 60 msec	6	4	1
Maximum QTcF interval < 450 msec	46	46	8
Maximum QTcF interval: 450 to < 480 msec	18	29	4
Maximum QTcF interval: 480 to < 500 msec	3	3	3
Maximum QTcF interval >= 500 msec	1	5	2

No statistical analyses for this end point

Secondary: Number of subjects with treatment-emergent adverse events (AEs) at Phase 1B (All Causality)

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End point title

Number of subjects with treatment-emergent adverse events (AEs) at Phase 1B (All Causality)

End point description

An adverse event (AE) was any untoward medical occurrence in a clinical investigation subject administered a product or medical device; the event did not necessarily had a causal relationship with the treatment or usage. Treatment Emergent AEs were those with initial onset or increasing in severity after the first dose of study medication，and occurred within 28 days post last dose. AEs were graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 : Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated; Grade 5: death related to AE. Safety analysis set was used to analyze this end point, defined as all enrolled subjects who received at least 1 dose of any of the study medications for each drug combination.

End point type

Secondary

End point timeframe

From the time subjects took at least 1 dose of investigational product to Follow-up (at least 28 days and no more than 35 days after discontinuation of treatment)

End point values	Phase 1B: Glasdegib + LDAC	Phase 1B: Glasdegib + Decitabine	Phase 1B: Glasdegib + Cytarabine/Daunorubicin
Number of subjects analysed	23	7	22
Units: Subjects
Grade 1 AEs	1	1	0
Grade 2 AEs	2	0	3
Grade 3 AEs	3	1	8
Grade 4 AEs	10	4	10
Grade 5 AEs	7	1	1
Missing or unknown AEs	0	0	0

No statistical analyses for this end point

Secondary: Number of subjects with treatment-emergent adverse events (AEs) at Phase 1B (Treatment-related)

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End point title

Number of subjects with treatment-emergent adverse events (AEs) at Phase 1B (Treatment-related)

End point description

An adverse event (AE) was any untoward medical occurrence in a clinical investigation subject administered a product or medical device; the event did not necessarily had a causal relationship with the treatment or usage. Treatment Emergent AEs were those with initial onset or increasing in severity after the first dose of study medication and occurred within 28 days post last dose. Treatment-related AEs were AEs related to glasdegib and/or backbone chemotherapy. AEs were graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 : Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated; Grade 5: death related to AE. Safety analysis set was used to analyze this end point, defined as all enrolled subjects who received at least 1 dose of any of the study medications for each drug combination.

End point type

Secondary

End point timeframe

From the time subjects took at least 1 dose of investigational product to Follow-up (at least 28 days and no more than 35 days after discontinuation of treatment)

End point values	Phase 1B: Glasdegib + LDAC	Phase 1B: Glasdegib + Decitabine	Phase 1B: Glasdegib + Cytarabine/Daunorubicin
Number of subjects analysed	23	7	22
Units: Subjects
Grade 1 AEs	3	2	2
Grade 2 AEs	2	0	7
Grade 3 AEs	7	0	3
Grade 4 AEs	6	4	10
Grade 5 AEs	3	0	0
Missing or unknown AEs	0	0	0

No statistical analyses for this end point

Secondary: Number of subjects with treatment-emergent AEs categorized by seriousness at Phase 1B

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End point title

Number of subjects with treatment-emergent AEs categorized by seriousness at Phase 1B ^[54]

End point description

An adverse event (AE) was any untoward medical occurrence in a clinical investigation subject administered a product or medical device; the event did not necessarily had a causal relationship with the treatment or usage. Treatment Emergent AEs were those with initial onset or increasing in severity after the first dose of study medication and occurred within 28 days post last dose. An serious adverse event (SAE) was any untoward medical occurrence at any dose that: resulted in death; was life threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); resulted in congenital anomaly/birth defect. Safety analysis set was used to analyze this end point, defined as all enrolled subjects who received at least 1 dose of any of the study medications for each drug combination.

End point type

Secondary

End point timeframe

From the time subjects took at least 1 dose of investigational product to Follow-up (at least 28 days and no more than 35 days after discontinuation of treatment)

Notes
[54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 1B: Glasdegib 100 mg + LDAC	Phase 1B: Glasdegib 200 mg + LDAC	Phase 1B: Glasdegib 100 mg + Decitabine	Phase 1B: Glasdegib 200 mg + Decitabine	Phase 1B: Glasdegib 100 mg + Cytarabine/Daunorubicin	Phase 1B: Glasdegib 200 mg + Cytarabine/Daunorubicin
Number of subjects analysed	17	6	4	3	16	6
Units: Subjects
AEs	17	6	4	3	16	6
SAEs	13	5	4	2	10	3

No statistical analyses for this end point

Secondary: Number of subjects with treatment-emergent AEs at Phase 2 Fit and Unfit (All Causality)

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End point title

Number of subjects with treatment-emergent AEs at Phase 2 Fit and Unfit (All Causality) ^[55]

End point description

An adverse event (AE) was any untoward medical occurrence in a clinical investigation subject administered a product or medical device; the event did not necessarily had a causal relationship with the treatment or usage. Treatment Emergent AEs were those with initial onset or increasing in severity after the first dose of study medication and occurred within 28 days post last dose. AEs were graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 : Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated; Grade 5: death related to AE. Safety analysis set was used to analyze this end point, defined as all enrolled subjects who received at least 1 dose of any of the study medications for each drug combination.

End point type

Secondary

End point timeframe

From the time subjects took at least 1 dose of investigational product to Follow-up (at least 28 days and no more than 35 days after discontinuation of treatment)

Notes
[55] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin	Phase 2 Unfit: Glasdegib 100 mg + LDAC	Phase 2 Unfit: LDAC alone
Number of subjects analysed	69	84	41
Units: Subjects
Grade 1 AEs	0	2	0
Grade 2 AEs	1	4	1
Grade 3 AEs	11	15	8
Grade 4 AEs	52	39	15
Grade 5 AEs	5	24	17
Missing or unknown AEs	0	0	0

No statistical analyses for this end point

Secondary: Number of subjects with treatment-emergent AEs at Phase 2 Fit and Unfit (Treatment-related)

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End point title

Number of subjects with treatment-emergent AEs at Phase 2 Fit and Unfit (Treatment-related) ^[56]

End point description

An adverse event (AE) was any untoward medical occurrence in a clinical investigation subject administered a product or medical device; the event did not necessarily had a causal relationship with the treatment or usage. Treatment Emergent AEs were those with initial onset or increasing in severity after the first dose of study medication and occurred within 28 days post last dose. Treatment-related AEs were AEs related to glasdegib and/or backbone chemotherapy. AEs were graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 : Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated; Grade 5: death related to AE. Safety analysis set was used to analyze this end point, defined as all enrolled subjects who received at least 1 dose of any of the study medications for each drug combination.

End point type

Secondary

End point timeframe

From the time subjects took at least 1 dose of investigational product to Follow-up (at least 28 days and no more than 35 days after discontinuation of treatment)

Notes
[56] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin	Phase 2 Unfit: Glasdegib 100 mg + LDAC	Phase 2 Unfit: LDAC alone
Number of subjects analysed	69	84	41
Units: Subjects
Grade 1 AEs	0	4	4
Grade 2 AEs	4	9	6
Grade 3 AEs	15	20	3
Grade 4 AEs	46	34	10
Grade 5 AEs	1	1	1
Missing or unknown AEs	0	0	0

No statistical analyses for this end point

Secondary: Number of subjects with treatment-emergent AEs categorized by seriousness at Phase 2 Fit and Unfit

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End point title

Number of subjects with treatment-emergent AEs categorized by seriousness at Phase 2 Fit and Unfit ^[57]

End point description

An adverse event (AE) was any untoward medical occurrence in a clinical investigation subject administered a product or medical device; the event did not necessarily had a causal relationship with the treatment or usage. Treatment Emergent AEs were those with initial onset or increasing in severity after the first dose of study medication and occurred within 28 days post last dose. AEs were graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 : Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated; Grade 5: death related to AE. Safety analysis set was used to analyze this end point, defined as all enrolled subjects who received at least 1 dose of any of the study medications for each drug combination.

End point type

Secondary

End point timeframe

From the time subjects took at least 1 dose of investigational product to Follow-up (at least 28 days and no more than 35 days after discontinuation of treatment)

Notes
[57] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not every reporting arm is required for reporting this endpoint of the study.

End point values	Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin	Phase 2 Unfit: Glasdegib 100 mg + LDAC	Phase 2 Unfit: LDAC alone
Number of subjects analysed	69	84	41
Units: Subjects
AEs	69	84	41
SAEs	35	68	32

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From the time subjects took at least 1 dose of investigational product to Follow-up (at least 28 days and no more than 35 days after discontinuation of treatment)

Adverse event reporting additional description

MedDRA 21.1 coding dictionary was applied for all AE tables.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

21.1

Reporting group title

Phase 1B: Glasdegib 100 mg + LDAC

Reporting group description

Reporting group title

Phase 1B: Glasdegib 200 mg + LDAC

Reporting group description

Reporting group title

Phase 1B: Glasdegib 100 mg + Decitabine

Reporting group description

Reporting group title

Phase 1B: Glasdegib 200 mg + Decitabine

Reporting group description

Reporting group title

Phase 1B: Glasdegib 200 mg + Cytarabine/Daunorubicin

Reporting group description

Subjects received 1-2 cycles of induction (glasdegib and daunorubicin/cytarabine), followed by 2-4 cycles of consolidation (glasdegib and high dose cytarabine) and a maximum of 6 cycles of maintenance (glasdegib alone). Daunorubicin was given on Days 1-3 QD at a dose of 60 mg/m^2/day by IV together with cytarabine on Days 1-7 at a dose of 100 mg/m^2/day by continuous IV infusion for each cycle of induction. Cytarabine was given on Days 1, 3, and 5 at a dose of 1 g/m^2 administered as a 3-hour IV infusion every 12 hours (2 g/m^2/day) for each cycle of consolidation. Glasdegib tablets 200 mg QD was started on induction Cycle 1/Day -3 and administered continuously QD thereafter for the duration of the study. A cycle was defined as 28 days.In March 2013, all active subjects receiving glasdegib 200 mg were required to reduce dose to 100 mg.One (1) subject in this cohort had dose reduction to 100 mg starting from Consolidation Cycle 1/Day 21.

Reporting group title

Phase 1B: Glasdegib 100 mg + Cytarabine/Daunorubicin

Reporting group description

Reporting group title

Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin

Reporting group description

Reporting group title

Phase 2 Unfit: Glasdegib 100 mg + LDAC

Reporting group description

Reporting group title

Phase 2 Unfit: LDAC alone

Reporting group description

Subjects received LDAC subcutaneously at a dose of 20 mg BID on Days 1-10 of the 28 day cycles.

Serious adverse events	Phase 1B: Glasdegib 100 mg + LDAC	Phase 1B: Glasdegib 200 mg + LDAC	Phase 1B: Glasdegib 100 mg + Decitabine	Phase 1B: Glasdegib 200 mg + Decitabine	Phase 1B: Glasdegib 200 mg + Cytarabine/Daunorubicin	Phase 1B: Glasdegib 100 mg + Cytarabine/Daunorubicin	Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin	Phase 2 Unfit: Glasdegib 100 mg + LDAC	Phase 2 Unfit: LDAC alone
Total subjects affected by serious adverse events
subjects affected / exposed	13 / 17 (76.47%)	5 / 6 (83.33%)	4 / 4 (100.00%)	2 / 3 (66.67%)	3 / 6 (50.00%)	10 / 16 (62.50%)	35 / 69 (50.72%)	68 / 84 (80.95%)	32 / 41 (78.05%)
number of deaths (all causes)	6	1	1	0	1	0	5	26	17
number of deaths resulting from adverse events	6	1	1	0	1	0	5	26	17
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of skin
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Disease progression
subjects affected / exposed	3 / 17 (17.65%)	1 / 6 (16.67%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	2 / 69 (2.90%)	10 / 84 (11.90%)	5 / 41 (12.20%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 1	0 / 0	0 / 1	0 / 0	0 / 2	0 / 10	0 / 5
deaths causally related to treatment / all	3 / 3	1 / 1	1 / 1	0 / 0	1 / 1	0 / 0	2 / 2	8 / 8	5 / 5
Fatigue
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	3 / 84 (3.57%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nodule
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	3 / 84 (3.57%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oedema
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	2 / 84 (2.38%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Respiratory failure
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleuritic pain
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Respiratory arrest
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
Respiratory distress
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Bipolar II disorder
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Lumbar puncture abnormal
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Alanine aminotransferase increased
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Laboratory test abnormal
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 17 (0.00%)	2 / 6 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	2 / 84 (2.38%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin abrasion
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	2 / 69 (2.90%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Splenic rupture
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
Thoracic vertebral fracture
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	0 / 84 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	2 / 84 (2.38%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Cardiac failure
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	2 / 84 (2.38%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiogenic shock
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
Myocardial infarction
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	2 / 84 (2.38%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
Tachyarrhythmia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocarditis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Autonomic nervous system imbalance
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neurotoxicity
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Polyneuropathy
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyskinesia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	4 / 84 (4.76%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	1 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	3 / 84 (3.57%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	1 / 1
Peripheral sensorimotor neuropathy
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	3 / 17 (17.65%)	3 / 6 (50.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	1 / 16 (6.25%)	14 / 69 (20.29%)	24 / 84 (28.57%)	7 / 41 (17.07%)
occurrences causally related to treatment / all	2 / 3	1 / 3	0 / 0	1 / 1	0 / 1	1 / 1	10 / 16	10 / 27	3 / 8
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
Neutropenia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	2 / 69 (2.90%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	3 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	0 / 84 (0.00%)	2 / 41 (4.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	6 / 84 (7.14%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	6 / 8	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
Granulocytopenia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymphadenitis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytosis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Mydriasis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	2 / 84 (2.38%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Impaired gastric emptying
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenic colitis
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	2 / 69 (2.90%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	0 / 84 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Retroperitoneal haematoma
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	2 / 69 (2.90%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash generalised
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin toxicity
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	3 / 84 (3.57%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Muscle spasms
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	2 / 84 (2.38%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	2 / 69 (2.90%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	2 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile sepsis
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterobacter sepsis
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis infectious
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 16 (12.50%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection bacterial
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	2 / 17 (11.76%)	0 / 6 (0.00%)	2 / 4 (50.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	4 / 69 (5.80%)	19 / 84 (22.62%)	7 / 41 (17.07%)
occurrences causally related to treatment / all	0 / 2	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0	2 / 5	6 / 26	1 / 12
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	9 / 9	3 / 3
Sepsis
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	6 / 69 (8.70%)	3 / 84 (3.57%)	5 / 41 (12.20%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	5 / 7	2 / 3	1 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1	5 / 5
Skin infection
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	1 / 69 (1.45%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	2 / 84 (2.38%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1	1 / 1
Abscess
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspergillus infection
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device related infections
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infected dermal cyst
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media chronic
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia fungal
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pseudomembranous colitis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic encephalopathy
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urogenital infection bacterial
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Adenovirus infection
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mycobacterium avium complex infection
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pseudomonal sepsis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tooth abscess
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridial sepsis
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal infection
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gout
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperuricaemia
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	1 / 69 (1.45%)	2 / 84 (2.38%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	1 / 1	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour lysis syndrome
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Phase 1B: Glasdegib 100 mg + LDAC	Phase 1B: Glasdegib 200 mg + LDAC	Phase 1B: Glasdegib 100 mg + Decitabine	Phase 1B: Glasdegib 200 mg + Decitabine	Phase 1B: Glasdegib 200 mg + Cytarabine/Daunorubicin	Phase 1B: Glasdegib 100 mg + Cytarabine/Daunorubicin	Phase 2 Fit: Glasdegib 100 mg + Cytarabine/Daunorubicin	Phase 2 Unfit: Glasdegib 100 mg + LDAC	Phase 2 Unfit: LDAC alone
Total subjects affected by non serious adverse events
subjects affected / exposed	16 / 17 (94.12%)	6 / 6 (100.00%)	4 / 4 (100.00%)	3 / 3 (100.00%)	6 / 6 (100.00%)	16 / 16 (100.00%)	69 / 69 (100.00%)	82 / 84 (97.62%)	39 / 41 (95.12%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	3 / 16 (18.75%)	12 / 69 (17.39%)	6 / 84 (7.14%)	1 / 41 (2.44%)
occurrences all number	0	1	0	1	1	3	14	7	1
Hypotension
subjects affected / exposed	1 / 17 (5.88%)	2 / 6 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 16 (25.00%)	14 / 69 (20.29%)	12 / 84 (14.29%)	4 / 41 (9.76%)
occurrences all number	2	3	0	0	0	5	15	13	4
Ischaemia
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Phlebitis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Thrombophlebitis
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Venous thrombosis
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Pallor
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	1 / 84 (1.19%)	3 / 41 (7.32%)
occurrences all number	0	0	0	0	0	0	0	1	3
Haematoma
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	5 / 84 (5.95%)	2 / 41 (4.88%)
occurrences all number	0	0	0	0	0	0	0	7	2
General disorders and administration site conditions
Asthenia
subjects affected / exposed	3 / 17 (17.65%)	1 / 6 (16.67%)	1 / 4 (25.00%)	2 / 3 (66.67%)	0 / 6 (0.00%)	1 / 16 (6.25%)	8 / 69 (11.59%)	10 / 84 (11.90%)	8 / 41 (19.51%)
occurrences all number	3	2	1	2	0	1	10	16	20
Catheter site pain
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Catheter site swelling
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Chest discomfort
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Chest pain
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	0 / 16 (0.00%)	9 / 69 (13.04%)	9 / 84 (10.71%)	1 / 41 (2.44%)
occurrences all number	0	0	0	0	2	0	9	9	1
Chills
subjects affected / exposed	1 / 17 (5.88%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	5 / 16 (31.25%)	21 / 69 (30.43%)	5 / 84 (5.95%)	1 / 41 (2.44%)
occurrences all number	1	1	0	1	0	7	30	5	1
Fatigue
subjects affected / exposed	6 / 17 (35.29%)	1 / 6 (16.67%)	1 / 4 (25.00%)	2 / 3 (66.67%)	2 / 6 (33.33%)	6 / 16 (37.50%)	25 / 69 (36.23%)	26 / 84 (30.95%)	8 / 41 (19.51%)
occurrences all number	8	1	1	5	3	10	37	71	11
Gait disturbance
subjects affected / exposed	0 / 17 (0.00%)	2 / 6 (33.33%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	2	1	0	0	0	0	0	0
Generalised oedema
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Hernia
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Influenza like illness
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Injection site pain
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Localised oedema
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Mucosal inflammation
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 16 (6.25%)	8 / 69 (11.59%)	6 / 84 (7.14%)	2 / 41 (4.88%)
occurrences all number	0	0	0	0	1	1	8	10	3
Nodule
subjects affected / exposed	2 / 17 (11.76%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0
Non-cardiac chest pain
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 16 (18.75%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	1	0	0	4	0	0	0
Oedema
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 16 (6.25%)	6 / 69 (8.70%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	1	1	9	0	0
Oedema peripheral
subjects affected / exposed	5 / 17 (29.41%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 3 (33.33%)	2 / 6 (33.33%)	7 / 16 (43.75%)	22 / 69 (31.88%)	22 / 84 (26.19%)	7 / 41 (17.07%)
occurrences all number	6	1	0	1	4	8	37	35	7
Pain
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 16 (18.75%)	6 / 69 (8.70%)	4 / 84 (4.76%)	3 / 41 (7.32%)
occurrences all number	1	0	0	0	0	4	6	5	3
Performance status decreased
subjects affected / exposed	2 / 17 (11.76%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0
Pyrexia
subjects affected / exposed	5 / 17 (29.41%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	10 / 16 (62.50%)	34 / 69 (49.28%)	23 / 84 (27.38%)	9 / 41 (21.95%)
occurrences all number	5	0	2	0	3	15	52	44	11
Thirst
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Catheter site erythema
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	6 / 69 (8.70%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	0	6	0	0
Catheter site haemorrhage
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	4 / 69 (5.80%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	0	4	0	0
Immune system disorders
Hypersensitivity
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	3	0	0	0	0	0	0	0	0
Reproductive system and breast disorders
Pelvic pain
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Vaginal haemorrhage
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Vulvovaginal pruritus
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 16 (12.50%)	5 / 69 (7.25%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	1	2	5	0	0
Cough
subjects affected / exposed	4 / 17 (23.53%)	1 / 6 (16.67%)	1 / 4 (25.00%)	1 / 3 (33.33%)	2 / 6 (33.33%)	1 / 16 (6.25%)	14 / 69 (20.29%)	18 / 84 (21.43%)	7 / 41 (17.07%)
occurrences all number	4	1	1	1	2	1	18	20	7
Dysphonia
subjects affected / exposed	1 / 17 (5.88%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0	0
Dyspnoea
subjects affected / exposed	2 / 17 (11.76%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 3 (33.33%)	2 / 6 (33.33%)	3 / 16 (18.75%)	13 / 69 (18.84%)	21 / 84 (25.00%)	11 / 41 (26.83%)
occurrences all number	2	0	2	3	2	5	14	36	11
Dyspnoea exertional
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Epistaxis
subjects affected / exposed	1 / 17 (5.88%)	1 / 6 (16.67%)	1 / 4 (25.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	3 / 16 (18.75%)	11 / 69 (15.94%)	7 / 84 (8.33%)	6 / 41 (14.63%)
occurrences all number	1	1	2	1	1	3	13	11	7
Hypoxia
subjects affected / exposed	2 / 17 (11.76%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	8 / 69 (11.59%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	2	0	1	0	0	1	8	0	0
Lung infiltration
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Nasal congestion
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	7 / 69 (10.14%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	7	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	1 / 16 (6.25%)	12 / 69 (17.39%)	9 / 84 (10.71%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	3	2	12	9	0
Pleural effusion
subjects affected / exposed	2 / 17 (11.76%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	9 / 69 (13.04%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	2	0	0	0	0	1	10	0	0
Pleuritic pain
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Pulmonary fibrosis
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Pulmonary oedema
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0	0
Respiratory failure
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Rhinitis allergic
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 16 (12.50%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Rhinorrhoea
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	5 / 69 (7.25%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	1	0	5	0	0
Sinus congestion
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Wheezing
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	7 / 69 (10.14%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	7	0	0
Hiccups
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	5 / 69 (7.25%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	0	5	0	0
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	3 / 84 (3.57%)	3 / 41 (7.32%)
occurrences all number	0	1	0	0	0	0	0	5	3
Anxiety
subjects affected / exposed	1 / 17 (5.88%)	2 / 6 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	3 / 16 (18.75%)	15 / 69 (21.74%)	3 / 84 (3.57%)	4 / 41 (9.76%)
occurrences all number	1	2	0	0	1	3	17	3	4
Apathy
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Confusional state
subjects affected / exposed	1 / 17 (5.88%)	1 / 6 (16.67%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	4 / 69 (5.80%)	7 / 84 (8.33%)	0 / 41 (0.00%)
occurrences all number	2	1	1	0	0	0	4	7	0
Depressed mood
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Depression
subjects affected / exposed	2 / 17 (11.76%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	1 / 16 (6.25%)	4 / 69 (5.80%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	2	1	0	0	2	1	4	0	0
Disorientation
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Insomnia
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	2 / 4 (50.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	5 / 16 (31.25%)	19 / 69 (27.54%)	10 / 84 (11.90%)	2 / 41 (4.88%)
occurrences all number	2	0	2	0	0	5	21	11	3
Panic attack
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Delirium
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	4 / 69 (5.80%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	0	4	0	0
Hallucination
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	5 / 69 (7.25%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	0	5	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	4 / 16 (25.00%)	21 / 69 (30.43%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	1	0	1	5	26	0	0
Amylase increased
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 16 (12.50%)	17 / 69 (24.64%)	6 / 84 (7.14%)	1 / 41 (2.44%)
occurrences all number	0	0	0	0	1	3	23	15	1
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 16 (6.25%)	13 / 69 (18.84%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	1	1	16	0	0
Blood bilirubin increased
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 16 (12.50%)	19 / 69 (27.54%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	2	35	0	0
Blood creatinine increased
subjects affected / exposed	2 / 17 (11.76%)	2 / 6 (33.33%)	1 / 4 (25.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	0 / 16 (0.00%)	14 / 69 (20.29%)	9 / 84 (10.71%)	3 / 41 (7.32%)
occurrences all number	2	2	1	1	1	0	16	13	4
Blood fibrinogen decreased
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Blood uric acid increased
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Chest X-ray abnormal
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Eastern Cooperative Oncology Group performance status worsened
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	7 / 69 (10.14%)	7 / 84 (8.33%)	1 / 41 (2.44%)
occurrences all number	0	0	0	0	1	0	15	11	1
International normalised ratio increased
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 16 (12.50%)	7 / 69 (10.14%)	3 / 84 (3.57%)	5 / 41 (12.20%)
occurrences all number	0	0	0	0	0	2	8	3	5
Karnofsky scale worsened
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Lipase increased
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0	0
Liver function test increased
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Lymphocyte count decreased
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 16 (18.75%)	6 / 69 (8.70%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	3	9	0	0
Neutrophil count decreased
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	12 / 69 (17.39%)	11 / 84 (13.10%)	1 / 41 (2.44%)
occurrences all number	0	0	0	0	0	1	14	45	1
Platelet count decreased
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 16 (12.50%)	18 / 69 (26.09%)	14 / 84 (16.67%)	4 / 41 (9.76%)
occurrences all number	0	0	0	0	0	6	47	148	24
Weight decreased
subjects affected / exposed	1 / 17 (5.88%)	1 / 6 (16.67%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 16 (6.25%)	9 / 69 (13.04%)	17 / 84 (20.24%)	1 / 41 (2.44%)
occurrences all number	1	1	1	0	1	1	12	28	1
White blood cell count decreased
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 16 (25.00%)	20 / 69 (28.99%)	13 / 84 (15.48%)	2 / 41 (4.88%)
occurrences all number	0	0	0	0	0	7	54	55	2
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	5 / 69 (7.25%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	0	5	0	0
Weight increased
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	4 / 69 (5.80%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	0	4	0	0
C-reactive protein increased
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	6 / 84 (7.14%)	6 / 41 (14.63%)
occurrences all number	0	0	0	0	0	0	0	10	9
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 17 (5.88%)	2 / 6 (33.33%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	6 / 69 (8.70%)	5 / 84 (5.95%)	2 / 41 (4.88%)
occurrences all number	1	2	1	0	0	0	7	10	2
Fall
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 16 (6.25%)	0 / 69 (0.00%)	9 / 84 (10.71%)	1 / 41 (2.44%)
occurrences all number	0	2	0	0	1	1	0	15	1
Infusion related reaction
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Post procedural haemorrhage
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Procedural headache
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Skin abrasion
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Vascular access complication
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Cardiac disorders
Angina pectoris
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0	0
Atrial fibrillation
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	5 / 69 (7.25%)	7 / 84 (8.33%)	1 / 41 (2.44%)
occurrences all number	1	0	0	0	0	0	6	10	1
Diastolic dysfunction
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Palpitations
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	4 / 69 (5.80%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	2	4	0	0
Sinus bradycardia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Sinus tachycardia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	7 / 69 (10.14%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	1	0	0	1	7	0	0
Tachycardia
subjects affected / exposed	1 / 17 (5.88%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	0 / 16 (0.00%)	5 / 69 (7.25%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	1	0	1	1	0	5	0	0
Ventricular tachycardia
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Pericardial effusion
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	4 / 69 (5.80%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	0	4	0	0
Nervous system disorders
Ageusia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0
Amnesia
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Central nervous system lesion
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Cognitive disorder
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Dizziness
subjects affected / exposed	1 / 17 (5.88%)	2 / 6 (33.33%)	1 / 4 (25.00%)	1 / 3 (33.33%)	2 / 6 (33.33%)	1 / 16 (6.25%)	12 / 69 (17.39%)	18 / 84 (21.43%)	4 / 41 (9.76%)
occurrences all number	1	2	1	1	2	1	15	25	5
Dysgeusia
subjects affected / exposed	4 / 17 (23.53%)	4 / 6 (66.67%)	1 / 4 (25.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	7 / 16 (43.75%)	19 / 69 (27.54%)	21 / 84 (25.00%)	1 / 41 (2.44%)
occurrences all number	4	4	2	1	1	7	22	27	1
Headache
subjects affected / exposed	3 / 17 (17.65%)	1 / 6 (16.67%)	1 / 4 (25.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	9 / 16 (56.25%)	22 / 69 (31.88%)	11 / 84 (13.10%)	5 / 41 (12.20%)
occurrences all number	3	1	1	0	2	11	34	13	5
Lethargy
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Memory impairment
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	1	0	0	1	0	0	0
Mental impairment
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Paraesthesia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Peroneal nerve palsy
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Presyncope
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0	0
Sedation
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Syncope
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Hypoaesthesia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	5 / 69 (7.25%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	0	5	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	3 / 17 (17.65%)	1 / 6 (16.67%)	2 / 4 (50.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	4 / 16 (25.00%)	28 / 69 (40.58%)	37 / 84 (44.05%)	17 / 41 (41.46%)
occurrences all number	9	2	3	5	1	9	54	318	62
Febrile neutropenia
subjects affected / exposed	3 / 17 (17.65%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	8 / 16 (50.00%)	38 / 69 (55.07%)	8 / 84 (9.52%)	4 / 41 (9.76%)
occurrences all number	3	0	0	0	2	9	44	8	7
Leukocytosis
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	6 / 84 (7.14%)	2 / 41 (4.88%)
occurrences all number	1	0	1	0	0	0	0	6	2
Leukopenia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 16 (12.50%)	9 / 69 (13.04%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	1	0	1	3	11	0	0
Lymphadenitis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Neutropenia
subjects affected / exposed	7 / 17 (41.18%)	0 / 6 (0.00%)	2 / 4 (50.00%)	2 / 3 (66.67%)	1 / 6 (16.67%)	4 / 16 (25.00%)	15 / 69 (21.74%)	13 / 84 (15.48%)	8 / 41 (19.51%)
occurrences all number	11	0	3	7	1	8	32	38	13
Spleen disorder
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Splenomegaly
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Thrombocytopenia
subjects affected / exposed	6 / 17 (35.29%)	1 / 6 (16.67%)	2 / 4 (50.00%)	1 / 3 (33.33%)	2 / 6 (33.33%)	3 / 16 (18.75%)	23 / 69 (33.33%)	26 / 84 (30.95%)	11 / 41 (26.83%)
occurrences all number	9	1	2	2	4	4	46	110	53
Lymphadenopathy
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	4 / 69 (5.80%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	0	4	0	0
Eye disorders
Diplopia
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Eye haemorrhage
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Ocular hyperaemia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Photophobia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Scleral pigmentation
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Vision blurred
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 16 (12.50%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	2	0	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Abdominal distension
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 16 (12.50%)	10 / 69 (14.49%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	2	10	0	0
Abdominal pain
subjects affected / exposed	4 / 17 (23.53%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	6 / 16 (37.50%)	20 / 69 (28.99%)	15 / 84 (17.86%)	4 / 41 (9.76%)
occurrences all number	4	0	1	1	0	7	24	17	4
Abdominal pain upper
subjects affected / exposed	2 / 17 (11.76%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	7 / 84 (8.33%)	1 / 41 (2.44%)
occurrences all number	2	0	1	0	0	1	0	8	1
Anal fissure
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Anal haemorrhage
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Angina bullosa haemorrhagica
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Ascites
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Constipation
subjects affected / exposed	7 / 17 (41.18%)	3 / 6 (50.00%)	2 / 4 (50.00%)	1 / 3 (33.33%)	3 / 6 (50.00%)	10 / 16 (62.50%)	32 / 69 (46.38%)	21 / 84 (25.00%)	6 / 41 (14.63%)
occurrences all number	7	3	2	1	3	14	39	28	7
Diarrhoea
subjects affected / exposed	8 / 17 (47.06%)	2 / 6 (33.33%)	2 / 4 (50.00%)	0 / 3 (0.00%)	6 / 6 (100.00%)	10 / 16 (62.50%)	49 / 69 (71.01%)	24 / 84 (28.57%)	9 / 41 (21.95%)
occurrences all number	10	2	4	0	8	18	62	49	10
Diverticulum
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Dry mouth
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	2 / 16 (12.50%)	10 / 69 (14.49%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	1	1	2	10	0	0
Dyspepsia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	2 / 4 (50.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	4 / 16 (25.00%)	12 / 69 (17.39%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	3	0	1	4	13	0	0
Dysphagia
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	1	0	0	1	0	0	0
Faeces discoloured
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Flatulence
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	4 / 69 (5.80%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	2	4	0	0
Gastritis
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	1 / 16 (6.25%)	6 / 69 (8.70%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	2	1	6	0	0
Gingival bleeding
subjects affected / exposed	2 / 17 (11.76%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 16 (6.25%)	4 / 69 (5.80%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	2	0	0	0	1	1	4	0	0
Gingival pain
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 16 (12.50%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	1	0	0	2	0	0	0
Haematemesis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0
Haematochezia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 16 (12.50%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Haemorrhoids
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	4 / 16 (25.00%)	5 / 69 (7.25%)	7 / 84 (8.33%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	2	5	5	7	0
Hiatus hernia
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Megacolon
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Mouth haemorrhage
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	5 / 69 (7.25%)	2 / 84 (2.38%)	4 / 41 (9.76%)
occurrences all number	0	0	0	0	0	1	6	2	4
Nausea
subjects affected / exposed	6 / 17 (35.29%)	4 / 6 (66.67%)	4 / 4 (100.00%)	1 / 3 (33.33%)	3 / 6 (50.00%)	14 / 16 (87.50%)	40 / 69 (57.97%)	30 / 84 (35.71%)	5 / 41 (12.20%)
occurrences all number	10	5	6	2	4	25	70	46	6
Oral disorder
subjects affected / exposed	1 / 17 (5.88%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 16 (12.50%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	1	0	0	0	2	0	0	0
Oral mucosal blistering
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Oral pain
subjects affected / exposed	1 / 17 (5.88%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	1	0	0	0	3	0	0	0
Pancreatitis
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Proctalgia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 16 (12.50%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Retching
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Stomatitis
subjects affected / exposed	2 / 17 (11.76%)	0 / 6 (0.00%)	0 / 4 (0.00%)	2 / 3 (66.67%)	0 / 6 (0.00%)	5 / 16 (31.25%)	17 / 69 (24.64%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	4	0	0	2	0	11	20	0	0
Tongue disorder
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Tooth loss
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Toothache
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 16 (12.50%)	5 / 69 (7.25%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	1	0	0	2	5	0	0
Vomiting
subjects affected / exposed	1 / 17 (5.88%)	2 / 6 (33.33%)	1 / 4 (25.00%)	1 / 3 (33.33%)	4 / 6 (66.67%)	5 / 16 (31.25%)	25 / 69 (36.23%)	18 / 84 (21.43%)	4 / 41 (9.76%)
occurrences all number	4	3	2	1	5	11	36	29	4
Mouth ulceration
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	3 / 41 (7.32%)
occurrences all number	0	0	0	0	0	0	0	0	3
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	1 / 17 (5.88%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0	0
Hyperbilirubinaemia
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	4 / 69 (5.80%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	4	0	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	1 / 17 (5.88%)	1 / 6 (16.67%)	1 / 4 (25.00%)	2 / 3 (66.67%)	2 / 6 (33.33%)	4 / 16 (25.00%)	16 / 69 (23.19%)	9 / 84 (10.71%)	0 / 41 (0.00%)
occurrences all number	1	1	1	2	2	4	19	9	0
Decubitus ulcer
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0	0
Dermatitis acneiform
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	1	0	0	1	0	0	0
Dry skin
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 16 (12.50%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	1	2	0	0	0
Ecchymosis
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Erythema
subjects affected / exposed	0 / 17 (0.00%)	2 / 6 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 16 (12.50%)	0 / 69 (0.00%)	7 / 84 (8.33%)	2 / 41 (4.88%)
occurrences all number	0	2	0	0	0	2	0	9	3
Macule
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Night sweats
subjects affected / exposed	2 / 17 (11.76%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 16 (6.25%)	4 / 69 (5.80%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	2	0	0	0	1	1	4	0	0
Pain of skin
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Palmar erythema
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Panniculitis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Petechiae
subjects affected / exposed	2 / 17 (11.76%)	2 / 6 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 16 (6.25%)	11 / 69 (15.94%)	7 / 84 (8.33%)	4 / 41 (9.76%)
occurrences all number	2	4	0	0	1	1	13	7	5
Plantar erythema
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Pruritus
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	4 / 16 (25.00%)	10 / 69 (14.49%)	6 / 84 (7.14%)	1 / 41 (2.44%)
occurrences all number	0	0	0	0	1	4	11	9	1
Pruritus allergic
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Purpura
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Rash
subjects affected / exposed	2 / 17 (11.76%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	3 / 16 (18.75%)	14 / 69 (20.29%)	11 / 84 (13.10%)	1 / 41 (2.44%)
occurrences all number	2	0	0	0	1	4	18	11	1
Rash macular
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0
Rash maculo-papular
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 16 (18.75%)	9 / 69 (13.04%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	4	10	0	0
Rash papular
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Skin disorder
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Skin lesion
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Skin ulcer
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Urticaria
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Hyperhidrosis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	9 / 69 (13.04%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	0	9	0	0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	2 / 17 (11.76%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	3 / 16 (18.75%)	8 / 69 (11.59%)	7 / 84 (8.33%)	1 / 41 (2.44%)
occurrences all number	2	0	1	0	2	3	10	8	1
Dysuria
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	4 / 69 (5.80%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	1	0	0	1	5	0	0
Haematuria
subjects affected / exposed	1 / 17 (5.88%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	5 / 69 (7.25%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	1	0	0	0	1	5	0	0
Pollakiuria
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	4 / 69 (5.80%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	1	0	0	0	4	0	0
Proteinuria
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	4 / 69 (5.80%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	4	0	0
Renal cyst
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Renal failure
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Urinary retention
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0	0
Urinary incontinence
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	7 / 84 (8.33%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	0	0	7	0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Hypothyroidism
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 17 (5.88%)	2 / 6 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	11 / 69 (15.94%)	10 / 84 (11.90%)	0 / 41 (0.00%)
occurrences all number	1	3	0	0	1	0	13	14	0
Back pain
subjects affected / exposed	2 / 17 (11.76%)	1 / 6 (16.67%)	2 / 4 (50.00%)	2 / 3 (66.67%)	1 / 6 (16.67%)	4 / 16 (25.00%)	12 / 69 (17.39%)	9 / 84 (10.71%)	3 / 41 (7.32%)
occurrences all number	2	1	3	2	1	4	14	12	3
Bone pain
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 16 (25.00%)	0 / 69 (0.00%)	2 / 84 (2.38%)	3 / 41 (7.32%)
occurrences all number	0	0	0	0	0	4	0	4	5
Joint effusion
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Muscle spasms
subjects affected / exposed	5 / 17 (29.41%)	1 / 6 (16.67%)	0 / 4 (0.00%)	2 / 3 (66.67%)	2 / 6 (33.33%)	10 / 16 (62.50%)	11 / 69 (15.94%)	19 / 84 (22.62%)	2 / 41 (4.88%)
occurrences all number	6	3	0	4	4	12	14	46	2
Muscular weakness
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	6 / 84 (7.14%)	0 / 41 (0.00%)
occurrences all number	0	0	0	1	0	1	0	6	0
Musculoskeletal pain
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 16 (18.75%)	7 / 69 (10.14%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	4	8	0	0
Musculoskeletal stiffness
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Myalgia
subjects affected / exposed	1 / 17 (5.88%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	3 / 16 (18.75%)	5 / 69 (7.25%)	5 / 84 (5.95%)	0 / 41 (0.00%)
occurrences all number	1	1	0	0	1	3	5	6	0
Neck pain
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	4 / 69 (5.80%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	1	4	0	0
Osteoarthritis
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0	0
Pain in extremity
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 3 (33.33%)	3 / 6 (50.00%)	4 / 16 (25.00%)	9 / 69 (13.04%)	15 / 84 (17.86%)	2 / 41 (4.88%)
occurrences all number	2	0	1	1	3	4	12	20	2
Pain in jaw
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	1	1	0	0	0
Periarthritis
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Plantar fasciitis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Spinal pain
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Infections and infestations
Arthritis bacterial
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Bacteraemia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0
Bronchiolitis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Candida infection
subjects affected / exposed	1 / 17 (5.88%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	1	0	0	0	1	0	0	0
Cellulitis
subjects affected / exposed	1 / 17 (5.88%)	1 / 6 (16.67%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	2	2	0	1	0	0	0	0
Clostridium difficile colitis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0
Clostridium difficile infection
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 16 (12.50%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	1	2	0	0	0
Device related infection
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Enterobacter bacteraemia
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Enterocolitis bacterial
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Enterocolitis infectious
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Folliculitis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Fungal infection
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Genital infection viral
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Nasopharyngitis
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Onychomycosis
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Otitis media
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Pneumonia
subjects affected / exposed	1 / 17 (5.88%)	1 / 6 (16.67%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 16 (12.50%)	6 / 69 (8.70%)	9 / 84 (10.71%)	3 / 41 (7.32%)
occurrences all number	1	1	1	0	1	2	6	10	3
Pneumonia fungal
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	1 / 16 (6.25%)	4 / 69 (5.80%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	2	1	4	0	0
Pulmonary mycosis
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Sepsis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0
Skin infection
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Staphylococcal bacteraemia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Staphylococcal infection
subjects affected / exposed	2 / 17 (11.76%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	2	1	0	0	0	0	0	0	0
Subcutaneous abscess
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Urinary tract infection
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	0 / 16 (0.00%)	8 / 69 (11.59%)	5 / 84 (5.95%)	5 / 41 (12.20%)
occurrences all number	0	0	2	1	1	0	8	6	5
Viral infection
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Oral herpes
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	3 / 84 (3.57%)	3 / 41 (7.32%)
occurrences all number	0	0	0	0	0	0	0	5	3
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 17 (5.88%)	2 / 6 (33.33%)	1 / 4 (25.00%)	2 / 3 (66.67%)	2 / 6 (33.33%)	2 / 16 (12.50%)	26 / 69 (37.68%)	29 / 84 (34.52%)	5 / 41 (12.20%)
occurrences all number	1	2	1	5	2	2	33	44	9
Dehydration
subjects affected / exposed	1 / 17 (5.88%)	1 / 6 (16.67%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 16 (12.50%)	6 / 69 (8.70%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	1	1	0	0	2	6	0	0
Gout
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	5 / 84 (5.95%)	2 / 41 (4.88%)
occurrences all number	1	0	0	0	0	0	0	6	2
Hyperkalaemia
subjects affected / exposed	1 / 17 (5.88%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	6 / 69 (8.70%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	2	1	0	0	0	0	9	0	0
Hypermagnesaemia
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	4 / 69 (5.80%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	1	0	0	0	1	4	0	0
Hypernatraemia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	5 / 69 (7.25%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	5	0	0
Hyperphosphataemia
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	2 / 16 (12.50%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0	1	1	2	0	0	0
Hyperuricaemia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 16 (12.50%)	0 / 69 (0.00%)	7 / 84 (8.33%)	1 / 41 (2.44%)
occurrences all number	0	0	0	0	1	2	0	8	1
Hypoalbuminaemia
subjects affected / exposed	2 / 17 (11.76%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	3 / 16 (18.75%)	18 / 69 (26.09%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	2	0	0	0	2	3	24	0	0
Hypocalcaemia
subjects affected / exposed	2 / 17 (11.76%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	5 / 16 (31.25%)	22 / 69 (31.88%)	5 / 84 (5.95%)	1 / 41 (2.44%)
occurrences all number	2	0	1	0	4	10	32	5	1
Hypoglycaemia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Hypokalaemia
subjects affected / exposed	2 / 17 (11.76%)	3 / 6 (50.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	6 / 16 (37.50%)	37 / 69 (53.62%)	13 / 84 (15.48%)	6 / 41 (14.63%)
occurrences all number	2	5	1	0	3	6	64	19	7
Hypomagnesaemia
subjects affected / exposed	0 / 17 (0.00%)	1 / 6 (16.67%)	1 / 4 (25.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	4 / 16 (25.00%)	20 / 69 (28.99%)	8 / 84 (9.52%)	2 / 41 (4.88%)
occurrences all number	0	2	1	0	2	4	23	11	2
Hyponatraemia
subjects affected / exposed	2 / 17 (11.76%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	5 / 16 (31.25%)	23 / 69 (33.33%)	10 / 84 (11.90%)	0 / 41 (0.00%)
occurrences all number	2	0	4	2	1	6	35	36	0
Hypophagia
subjects affected / exposed	1 / 17 (5.88%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	1	0	0	0	0	0	0
Hypophosphataemia
subjects affected / exposed	1 / 17 (5.88%)	1 / 6 (16.67%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 16 (18.75%)	15 / 69 (21.74%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	1	3	0	0	4	21	0	0
Hypovolaemia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Metabolic acidosis
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 16 (6.25%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Tumour lysis syndrome
subjects affected / exposed	1 / 17 (5.88%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0	0
Vitamin D deficiency
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 16 (0.00%)	0 / 69 (0.00%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Hyperglycaemia
subjects affected / exposed	0 / 17 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 16 (0.00%)	13 / 69 (18.84%)	0 / 84 (0.00%)	0 / 41 (0.00%)
occurrences all number	0	0	0	0	0	0	16	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

15 May 2012

Inclusion criteria had been modified to provide clarification for the ECOG performance status requirement, age, and gender. The starting dose of PF 04449913 for the safety cohorts was 100 mg daily based on the data from the ongoing Phase 1 study in hematologic malignancies, and the potential dose levels were modified accordingly. For the Safety Cohorts, cumulative incidence of relapse (CIR), relapse free survival (RFS), event free survival (EFS), and cumulative incidence of death (CID) had been removed as secondary endpoints. For the Efficacy Expansion Cohorts, the following had been added as secondary endpoints: disease specific efficacy endpoints such as Morphologic Leukemia Free State, Partial Remission (PR), Partial Remission with incomplete blood count recovery (PRi), Minor Response (MR), Stable Disease (SD), Cytogenetic Complete Response (CRc), and Molecular Complete Response (CRm) for AML, and Hematologic Improvement (HI), marrow CR, Partial Remission (PR), Stable Disease (SD), and Partial or Complete Cytogenetic Response for MDS. Approximately 30 evaluable subjects from treatment arms PF 04449913 in combination with LDAC or decitabine were undergo additional ECG assessments as outlined in the Schedule of Activities. The schedule of PF 04449913 pharmacokinetic sample collection had also been modified. The Adverse Event reporting section had been updated due to alignment with the US Food and Drug Administration Final Rule (21 CFR Parts 312 and 320) and the European Union CT 3 Guidance (2011/C 172/01). Guidance on tumor lysis syndrome prophylaxis had been added. Clarification that subjects who received prior azacitidine treatment for their high risk MDS or AHD were eligible for Arm A only had been provided.

01 Nov 2012

The study design was modified and B1371003 had been a phase 1B/2 study. Requirement for safety and efficacy review of study results by an internal review committee (IOBU SDMC) had been introduced. The expansion cohort for the evaluation of PF 04449913 at the RP2D in combination with decitabine had been removed. Unfit subjects in phase 2 portion were randomized 2:1 (LDAC + PF 04449913: LDAC alone) and stratified based on prognosis (poor vs good/intermediate). Study objectives and endpoints had been updated and aligned with the Phase 1B/2 study design. The inclusion/exclusion criteria had been updated as followed: restriction of enrollment to subjects ≥55 years old in the phase 2 portion for unfit subjects, as the efficacy of the PF 04449913 + LDAC combination was evaluated in this subject population; requirement of known cytogenetic profile at study entry for enrollment in the phase 2 portion for unfit subjects; requirement of 2 negative pregnancy tests before starting study treatments for women of childbearing potential; clarification that no prior treatment with investigational agents for antecedent hematologic disease was allowed; explicit exclusion of subjects who showed recent or active suicidal ideation or behavior from enrollment. The number of required consolidation cycles for fit subjects had been updated from 4 to 2 4 depending on disease response. The dose modification criteria for PF 04449913 and backbone chemotherapy agents had been updated. Allowed concominant medications (antimicrobial agents and doses) had been added. The treatment duration and withdrawal criteria for unfit subjects had been modified. The Adverse Event reporting section had been updated to clarify the expection for reporting SAEs after the active safety reporting period.

26 Mar 2014

The RP2D for Phase 2 Fit and Phase 2 Unfit was confirmed as PF-04449913 100 mg QD. Exclusion criteria for prohibited concomitant medications (CYP3A4 inhibitors, narrow therapeutic index CYP3A4 substrates and P glycoprotein inhibitors/inducers) were removed. Transplant exclusion critiera were removed. A Prep B1 plasma sample was added at screening to be used for pharmcogenomic assessments. The schedule of events added creatine kinase at select timepoints. The bone marrow assesement schedule has clarified aspirate collection requirements, changed initial hematologic recovery bone marrow collection from 7 days to 14 days, and for Unfit subjects changed the timepoints to Cycle 3 Day 1 and every third cycle to better align with standard of care and removed the treatment duration criteria. For fit subjects Maintenance Day 15 visit was removed. Continuous PF 04449913 dosing during induction and/or consolidation cycles >28 days was clarified. Extended contraception use to 180 days after last dose of investigational products to align with the Summary of Product Characteristics (SPC) for cytarabine and daunorubicin. Concomitant medication restrictions were minimized and/or removed. The independent bone marrow pathology review was removed. The MDS response timeframe for Hematologic Improvement, and the AML response definitions for Minor Response and Treatment Failure, were clarified. Appendix 6 containing list of drugs with known risk of Torsade de Pointes was added. Appendix 7 containing list of strong and moderate CYP3A4/5 inhibitors was added. Appendix 8 containing list of strong and moderate CYP3A4/5 inducers was added.

20 Apr 2015

Eligibility criteria corrected an inconsistency for inclusion criteria #2 (Acute Promyelocytic Leukemia (APL) subjects with t(15;17) are excluded) and clarified prior treatments for exclusion criteria #14. Sections 5.3.7 and 7.1.6: Revised dosing modification guidelines for treatment-related QTcF prolongation. Phase 2 Unfit Schedule of Activities, Sections 7.5.1 and 7.6.1: Removed requirement for bone marrow biopsies, if this evaluation was not performed as standard of care (the requirement for bone marrow aspirates remains unchanged). Section 8 Adverse Event Reporting: text updated to align with revised protocol template. Section 15.1 Communication of Results by Pfizer: text updated to align with revised protocol template. Modified AML response criteria for CRi requirements.

08 Feb 2016

Phase 2 secondary endpoints cumulative incidence of relapse (CIR), relapse free survival (RFS), event free survival (EFS), cumulative incidence of death (CID), and hematologic improvement (MDS subjects only) were removed. Table 2 Schedule of Activities and sections 3 and 5 for Phase 2 Unfit subjects updated to include survival follow up requirement for randomized subjects that did not start treatment. Section 1.2.8.5 Summary of Benefit-Risk Assessment updated with information concerning QTc interval prolongation. Section 5.3.7.1 QTcF Interval Monitoring and Management added for monitoring of potential cardiovascular symptoms and guidance on the use of moderate/strong CYP3A4/5 inhibitors or drugs with a known risk of Torsade de pointes as concomitant therapy. Section 5.5 Concomitant Medications updated for consistency with the new safety monitoring guidance provided in Section 7.1.6 and Table 8. Section 7.1.6 Triplicate (12-Lead) added new safety guidance when moderate/strong CYP3A4/5 inhibitors or drugs with a known risk of Torsade de pointes were administered as concomitant therapy. Section 8.6.1 Protocol-Specified Serious Adverse Events updated to include SAE reporting of all cases of > Grade 2 mQTcF prolongation regardless of causality for up to 28 calendar days after the last dose of study drug administered. Section 9.3.2 removed secondary endpoints CIR, RFS, EFS, CID, and independent central review of bone marrow samples. Appendix 6, 7 and 8 replaced with new tables and updated source references.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase 1b/2 Study to Evaluate the Safety and Efficacy Of PF-04449913, An Oral Hedgehog Inhibitor, in Combination With Intensive Chemotherapy, Low Dose Ara-C or Decitabine In Patients With Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of subjects with dose-limiting toxicities (DLTs) at Phase 1B

Primary: Number of subjects with dose-limiting toxicities (DLTs) at Phase 1B

Primary: Percentage of subjects with complete response (CR) at Phase 2 Fit

Primary: Percentage of subjects with complete response (CR) at Phase 2 Fit

Primary: Overall survival (OS) at Phase 2 Unfit

Primary: Overall survival (OS) at Phase 2 Unfit

Secondary: Overall survival (OS) at Phase 1B

Secondary: Overall survival (OS) at Phase 1B

Secondary: Overall survival (OS) at Phase 2 Fit

Secondary: Overall survival (OS) at Phase 2 Fit

Secondary: Percentage of subjects with CR / complete response with incomplete blood count recovery (CRi) at Phase 1B

Secondary: Percentage of subjects with CR / complete response with incomplete blood count recovery (CRi) at Phase 1B

Secondary: Percentage of subjects with complete response (CR) at Phase 2 Unfit

Secondary: Percentage of subjects with complete response (CR) at Phase 2 Unfit

Secondary: Percentage of subjects with disease-specific efficacy for Acute Myeloid Leukemia (AML) at Phase 2 Fit and Unfit

Secondary: Percentage of subjects with disease-specific efficacy for Acute Myeloid Leukemia (AML) at Phase 2 Fit and Unfit

Secondary: Percentage of subjects with disease-specific efficacy for Myelodysplastic Syndrome (MDS) at Phase 2 Fit and Unfit

Secondary: Percentage of subjects with disease-specific efficacy for Myelodysplastic Syndrome (MDS) at Phase 2 Fit and Unfit

Secondary: Time to maximum observed plasma concentration (Tmax) of glasdegib in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 10 and Cycle 2/Day 1

Secondary: Time to maximum observed plasma concentration (Tmax) of glasdegib in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 10 and Cycle 2/Day 1

Secondary: Area under the plasma concentration-time profile from time 0 to dosing interval (AUCtau) of glasdegib in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 10 and Cycle 2/Day 1

Secondary: Area under the plasma concentration-time profile from time 0 to dosing interval (AUCtau) of glasdegib in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 10 and Cycle 2/Day 1

Secondary: Maximum observed plasma concentration (Cmax) of glasdegib in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3 and Day 10

Secondary: Maximum observed plasma concentration (Cmax) of glasdegib in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3 and Day 10

Secondary: Tmax of glasdegib in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3 and Day 10

Secondary: Tmax of glasdegib in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3 and Day 10

Secondary: AUCtau of glasdegib in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3 and Day 10

Secondary: AUCtau of glasdegib in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3 and Day 10

Secondary: Cmax of LDAC and Ara-U in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 2 and Cycle 1/Day 10

Secondary: Cmax of LDAC and Ara-U in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 2 and Cycle 1/Day 10

Secondary: Tmax of LDAC and Ara-U in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 2 and Cycle 1/Day 10

Secondary: Tmax of LDAC and Ara-U in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 2 and Cycle 1/Day 10

Secondary: Area under the plasma concentration-time profile from time 0 to infinity (AUCinf) of LDAC in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 2 and Cycle 1/Day 10

Secondary: Area under the plasma concentration-time profile from time 0 to infinity (AUCinf) of LDAC in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 2 and Cycle 1/Day 10

Secondary: Area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration (AUClast) of LDAC and Ara-U in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 2 and Cycle 1/Day 10

Secondary: Area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration (AUClast) of LDAC and Ara-U in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 2 and Cycle 1/Day 10

Secondary: Cmax of decitabine in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 1 and Cycle 1/Day 2

Secondary: Cmax of decitabine in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 1 and Cycle 1/Day 2

Secondary: Tmax of decitabine in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 1 and Cycle 1/Day 2

Secondary: Tmax of decitabine in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 1 and Cycle 1/Day 2

Secondary: AUCinf of decitabine in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 1 and Cycle 1/Day 2

Secondary: AUCinf of decitabine in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 1 and Cycle 1/Day 2

Secondary: AUCtau of cytarabine and Ara-U in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3

Secondary: AUCtau of cytarabine and Ara-U in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3

Secondary: Cmax of daunorubicin and daunorubicinol in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3

Secondary: Cmax of daunorubicin and daunorubicinol in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3

Secondary: Tmax of daunorubicin and daunorubicinol in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3

Secondary: Tmax of daunorubicin and daunorubicinol in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3

Secondary: AUCtau of daunorubicin and daunorubicinol in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3

Secondary: AUCtau of daunorubicin and daunorubicinol in subjects receiving glasdegib and cytarabine/daunorubicin at Phase 1B on Induction Cycle 1/Day 3

Secondary: Cmax of glasdegib in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 10 and Cycle 1/Day 21

Secondary: Cmax of glasdegib in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 10 and Cycle 1/Day 21

Secondary: Tmax of glasdegib in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 10 and Cycle 1/Day 21

Secondary: Tmax of glasdegib in subjects receiving glasdegib and LDAC at Phase 1B on Cycle 1/Day 10 and Cycle 1/Day 21

Secondary: AUCtau of glasdegib in subjects receiving glasdegib and LDAC at phase 1B on Cycle 1/Day 10 and Cycle 1/Day 21

Secondary: AUCtau of glasdegib in subjects receiving glasdegib and LDAC at phase 1B on Cycle 1/Day 10 and Cycle 1/Day 21

Secondary: Cmax of glasdegib in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 10 and Cycle 2/Day 1

Secondary: Cmax of glasdegib in subjects receiving glasdegib and decitabine at Phase 1B on Cycle 1/Day 10 and Cycle 2/Day 1

Secondary: Pre-dose plasma concentration (Ctrough) of glasdegib in Phase 2 Fit on Induction Cycle 1/Day 10

Secondary: Pre-dose plasma concentration (Ctrough) of glasdegib in Phase 2 Fit on Induction Cycle 1/Day 10

Secondary: Cmax of glasdegib in subjects receiving glasdegib and LDAC at Phase 2 Unfit on Cycle 1/Day 10

Secondary: Cmax of glasdegib in subjects receiving glasdegib and LDAC at Phase 2 Unfit on Cycle 1/Day 10

Secondary: Tmax of glasdegib in subjects receiving glasdegib and LDAC at Phase 2 Unfit on Cycle 1/Day 10

Secondary: Tmax of glasdegib in subjects receiving glasdegib and LDAC at Phase 2 Unfit on Cycle 1/Day 10

Secondary: AUCtau of glasdegib in subjects receiving glasdegib and LDAC at Phase 2 Unfit on Cycle 1/Day 10

Secondary: AUCtau of glasdegib in subjects receiving glasdegib and LDAC at Phase 2 Unfit on Cycle 1/Day 10

Secondary: Number of subjects with disease-related gene mutations at Phase 1B

Secondary: Number of subjects with disease-related gene mutations at Phase 1B

Secondary: Serum levels of circulating protein analytes at Phase 1B - Baseline

Secondary: Serum levels of circulating protein analytes at Phase 1B - Baseline

Clinical Trial Results:
A Phase 1b/2 Study to Evaluate the Safety and Efficacy Of PF-04449913, An Oral Hedgehog Inhibitor, in Combination With Intensive Chemotherapy, Low Dose Ara-C or Decitabine In Patients With Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome