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Clinical Trial Results:
A Phase 1 Trial of PF-03084014 in Patients With Advanced Solid Tumor Malignancy and T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma

Summary
EudraCT number	2010-022036-36
Trial protocol	IT
Global end of trial date	22 Nov 2016

Results information
Results version number	v1(current)
This version publication date	10 Nov 2017
First version publication date	10 Nov 2017
Other versions

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

A8641014

ISRCTN number

US NCT number

NCT00878189

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer, Inc.

Sponsor organisation address

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

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer ClinicalTrials.gov Call Center, 001 800781021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 8007181021, 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

25 May 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

10 Jan 2013

Global end of trial reached?

Yes

Global end of trial date

22 Nov 2016

Was the trial ended prematurely?

Main objective of the trial

The primary objectives of this trial were: 1. To determine the maximum tolerated dose (MTD); and 2. To define the recommended phase 2 dose (RP2D) of PF-03084014 when administered twice daily (BID) for 21 days alone in patients with advanced malignancies.

Protection of trial subjects

The study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (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

25 Jun 2009

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Italy: 4

Country: Number of subjects enrolled

United States: 68

Worldwide total number of subjects

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

85 years and over

Subject disposition

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Recruitment details

This study originally planned to give PF-03084014 in combination with dexamethasone in subjects with solid tumors and with T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma, including a drug-drug-interaction test of PF-03084014 and dexamethasone in solid tumor participants. But these parts were removed per protocol amendments.

Screening details

This study was conducted in male or female with age greater than or equal to 16, and with advanced malignancies (encompassing solid tumors and refractory/ relapsed T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma [T-ALL/ LBL]). Female who were pregnant or giving breast feeding had been excluded.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

PF-03084014 20 mg BID in Solid Tumor Subjects

Arm description

PF-03084014 20 mg was administered BID, beginning on Day 1 of each cycle, for 21 days. In Cycle 1 only, subjects with advanced solid tumor malignancies received PF-03084014 BID for 21 days (on Cycle 1 Day 21 only the morning dose was administered) followed by 7 days' off-treatment for the purpose of pharmacokinetic (PK) assessments. In Cycle 2 and beyond, PF-03084014 was administered BID continuously.

Arm type

Experimental

Investigational medicinal product name

PF-03084014

Investigational medicinal product code

PF-03081014

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-03084014 20 mg was administered orally BID, beginning on Day 1 of each cycle, for 21 days. In Cycle 1 only, subjects with advanced solid tumor malignancies received PF-03084014 BID for 21 days (on Cycle 1 Day 21 only the morning dose was administered) followed by 7 days' off-treatment for the purpose of PK assessments. In Cycle 2 and beyond, PF-03084014 was administered BID continuously.

PF-03084014 40 mg BID in Solid Tumor Subjects

Arm description

PF-03084014 40 mg was administered orally BID, beginning on Day 1 of each cycle, for 21 days. In Cycle 1 only, subjects with advanced solid tumor malignancies received PF-03084014 BID for 21 days (on Cycle 1 Day 21 only the morning dose was administered) followed by 7 days' off-treatment for the purpose of PK assessments. In Cycle 2 and beyond, PF-03084014 was administered BID continuously.

Arm type

Experimental

Investigational medicinal product name

PF-03084014

Investigational medicinal product code

PF-03084014

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-03084014 80 mg BID in Solid Tumor Subjects

Arm description

PF-03084014 80 mg was administered orally BID, beginning on Day 1 of each cycle, for 21 days. In Cycle 1 only, subjects with advanced solid tumor malignancies received PF-03084014 BID for 21 days (on Cycle 1 Day 21 only the morning dose was administered) followed by 7 days' off-treatment for the purpose of PK assessments. In Cycle 2 and beyond, PF-03084014 was administered BID continuously.

Arm type

Experimental

Investigational medicinal product name

PF-03084014

Investigational medicinal product code

PF-03084014

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-03084014 100 mg BID in Solid Tumor Subjects

Arm description

PF-03084014 100 mg was administered orally BID, beginning on Day 1 of each cycle, for 21 days. In Cycle 1 only, subjects with advanced solid tumor malignancies received PF-03084014 BID for 21 days (on Cycle 1 Day 21 only the morning dose was administered) followed by 7 days' off-treatment for the purpose of PK assessments. In Cycle 2 and beyond, PF-03084014 was administered BID continuously..

Arm type

Experimental

Investigational medicinal product name

PF-03084014

Investigational medicinal product code

PF-03084014

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-03084014 130 mg BID in Solid Tumor Subjects

Arm description

PF-03084014 130 mg was administered orally BID, beginning on Day 1 of each cycle, for 21 days. In Cycle 1 only, subjects with advanced solid tumor malignancies received PF-03084014 BID for 21 days (on Cycle 1 Day 21 only the morning dose was administered) followed by 7 days' off-treatment for the purpose of PK assessments. In Cycle 2 and beyond, PF-03084014 was administered BID continuously..

Arm type

Experimental

Investigational medicinal product name

PF-03084014

Investigational medicinal product code

PF-03084014

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-03084014 150 mg BID in Solid Tumor Subjects

Arm description

PF-03084014 150 mg was administered orally BID, beginning on Day 1 of each cycle, for 21 days. In Cycle 1 only, subjects with advanced solid tumor malignancies received PF-03084014 BID for 21 days (on Cycle 1 Day 21 only the morning dose was administered) followed by 7 days' off-treatment for the purpose of PK assessments. In Cycle 2 and beyond, PF-03084014 was administered BID continuously.

Arm type

Experimental

Investigational medicinal product name

PF-03084014

Investigational medicinal product code

PF-03084014

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-03084014 220 mg BID in Solid Tumor Subjects

Arm description

PF-03084014 220 mg was administered orally BID, beginning on Day 1 of each cycle, for 21 days. In Cycle 1 only, subjects with advanced solid tumor malignancies received PF-03084014 BID for 21 days (on Cycle 1 Day 21 only the morning dose was administered) followed by 7 days' off-treatment for the purpose of PK assessments. In Cycle 2 and beyond, PF-03084014 was administered BID continuously.

Arm type

Experimental

Investigational medicinal product name

PF-03084014

Investigational medicinal product code

PF-03084014

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-03084014 330 mg BID in Solid Tumor Subjects

Arm description

PF-03084014 330 mg was administered orally BID, beginning on Day 1 of each cycle, for 21 days. In Cycle 1 only, subjects with advanced solid tumor malignancies received PF-03084014 BID for 21 days (on Cycle 1 Day 21 only the morning dose was administered) followed by 7 days' off-treatment for the purpose of PK assessments. In Cycle 2 and beyond, PF-03084014 was administered BID continuously.

Arm type

Experimental

Investigational medicinal product name

PF-03084014

Investigational medicinal product code

PF-03084014

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-03084014 in T-ALL/LBL Subjects

Arm description

PF-03084014 150 mg was administered orally BID to subjects with T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LBL) as single agent for 21 days per cycle continuously (except for Cycle 1). On Cycle 1 Day 21, only the morning dose was administered, followed by a 7-day washout interval.

Arm type

Experimental

Investigational medicinal product name

PF-03081014

Investigational medicinal product code

PF-03081014

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-03084014 150 mg was administered orally BID to subjects with T-ALL/LBL as single agent for 21 days per cycle continuously (except for Cycle 1). On Cycle 1 Day 21, only the morning dose was administered, followed by a 7-day washout interval.

Number of subjects in period 1	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 330 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Started	3	3	4	8	4	23	16	3	8
Completed	0	0	0	0	0	0	0	0	0
Not completed	3	3	4	8	4	23	16	3	8
Adverse event, serious fatal	-	1	-	1	-	-	-	-	1
Subject Refused Further Follow-up	-	-	4	-	-	4	-	-	-
Unspecified	3	2	-	7	4	18	15	3	4
Lost to follow-up	-	-	-	-	-	1	1	-	-
Objective progression or relapse	-	-	-	-	-	-	-	-	3

Baseline characteristics

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Reporting group title

Overall Study

Reporting group description

Reporting group values	Overall Study	Total
Number of subjects	72	72
Age categorical
Units: Subjects
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	51	51
From 65-84 years	21	21
85 years and over	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	52.9 ± 16.1	-
Gender, Male/Female
Units: Subjects
Female	35	35
Male	37	37

Subject analysis set title

PF-03084014 in T-ALL/LBL Subjects

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

PF-03084014 in Solid Tumor Subjects

Subject analysis set type

Sub-group analysis

Subject analysis set description

PF-03084014 20, 40, 80, 100, 130, 150, 220 and 330 mg was administered orally BID to subjects with advanced solid tumor malignancies as single agent for 21 days per cycle continuously (except for Cycle 1). On Cycle 1 Day 21, only the morning dose was administered, followed by a 7-day washout interval.

Subject analysis sets values	PF-03084014 in T-ALL/LBL Subjects	PF-03084014 in Solid Tumor Subjects
Number of subjects	8	64
Age categorical
Units: Subjects
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	8	43
From 65-84 years	0	21
85 years and over	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	30.8 ± 9.0	55.6 ± 14.7
Gender, Male/Female
Units: Subjects
Female	2	33
Male	6	31

End points

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Reporting group title

PF-03084014 20 mg BID in Solid Tumor Subjects

Reporting group description

Reporting group title

PF-03084014 40 mg BID in Solid Tumor Subjects

Reporting group description

Reporting group title

PF-03084014 80 mg BID in Solid Tumor Subjects

Reporting group description

Reporting group title

PF-03084014 100 mg BID in Solid Tumor Subjects

Reporting group description

Reporting group title

PF-03084014 130 mg BID in Solid Tumor Subjects

Reporting group description

Reporting group title

PF-03084014 150 mg BID in Solid Tumor Subjects

Reporting group description

Reporting group title

PF-03084014 220 mg BID in Solid Tumor Subjects

Reporting group description

Reporting group title

PF-03084014 330 mg BID in Solid Tumor Subjects

Reporting group description

Reporting group title

PF-03084014 in T-ALL/LBL Subjects

Reporting group description

Subject analysis set title

PF-03084014 in T-ALL/LBL Subjects

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

PF-03084014 in Solid Tumor Subjects

Subject analysis set type

Sub-group analysis

Subject analysis set description

Primary: Number of Solid Tumor Subjects With First-Cycle Dose-Limiting Toxicity (DLT)

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End point title

Number of Solid Tumor Subjects With First-Cycle Dose-Limiting Toxicity (DLT) ^[1] ^[2]

End point description

Any DLT event attributable to PF-03084014 during Cycle 1: non-hematologic toxicities >= Grade 3 despite optimal care; treatment delay >=7 days or unable to deliver at least 80% of planned dose due to treatment-related toxicities; Grade 4 neutropenia >7 days; febrile neutropenia; neutropenic infection; Grade >=3 thrombocytopenia with bleeding. Analysis population included solid tumor subjects enrolled for dose-escalation who started treatment and who did not have first cycle major treatment deviations (including less than 80% of the planned dose of PF-03084014 in Cycle 1 for reasons other than treatment-related toxicities) were evaluable for DLTs.

End point type

Primary

End point timeframe

Baseline to the end of Cycle 1 (Week 4)

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: This endpoint only applies to solid tumor subjects.
[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: This endpoint only applies to solid tumor subjects.

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 330 mg BID in Solid Tumor Subjects
Number of subjects analysed	3	3	3	6	3	6	6	2
Units: subjects	0	0	0	1	0	1	1	2

No statistical analyses for this end point

Primary: Number of T-ALL/LBL Subjects With First-Cycle DLT

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End point title

Number of T-ALL/LBL Subjects With First-Cycle DLT ^[3] ^[4]

End point description

Any dose-limiting toxicity (DLT) attributable to PF-03084014 at 1st Cycle: non-hematologic toxicities >= Grade 3 despite optimal care; treatment delay >=7 days; unable to deliver at least 80% of planned dose; absolute neutrophil count (ANC) <1000/microliter (uL), or platelet count <30,000/uL, or hemoglobin <8 gram/deciliter (g/dL) in a bone marrow with <5% blasts and no evidence of leukemia or abnormal dysplasia for >42 days. Analysis population included T-ALL/LBL subjects enrolled for dose-escalation who started treatment and who did not have first cycle major treatment deviations (including less than 80% of the planned dose of PF-03084014 in Cycle 1 for reasons other than treatment-related toxicities) were evaluable for DLTs.

End point type

Primary

End point timeframe

Baseline to the end of Cycle 1 (Week 4)

Notes
[3] - 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: This endpoint only applies to T-ALL/LBL subjects
[4] - 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: This endpoint only applies to T-ALL/LBL subjects

End point values	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	5
Units: subjects	1

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) (All Causality)

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End point title

Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) (All Causality)

End point description

An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of casual relationship. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. A 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), and resulted in congenital anomaly/birth defect. Analysis population included all subjects who received at least 1 dose of study medication.

End point type

Secondary

End point timeframe

Baseline to the end of study (28 days after last dose of study drug)

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 330 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	3	3	4	8	4	23	16	3	8
Units: subjects
No. of Subjects With AEs	3	3	4	6	4	23	16	3	8
No. of Subjects With SAEs	1	1	2	4	2	8	7	1	4
No. of Subjects Discontinued PF-03084014	0	1	0	2	1	1	4	2	3
No. of Subjects Temp. Discontinued Treatment	1	1	2	1	1	9	5	1	0

No statistical analyses for this end point

Secondary: Number of Subjects With TEAEs (Treatment-Related)

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End point title

Number of Subjects With TEAEs (Treatment-Related)

End point description

An AE was any untoward medical occurrence in a subject who received study drug. Treatment-related events were those assessed by the investigator as related to study medication. An 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), and resulted in congenital anomaly/birth defect. Analysis population included all subjects who received at least 1 dose of study medication.

End point type

Secondary

End point timeframe

Baseline to the end of study (28 days after last dose of study drug).

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 330 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	3	3	4	8	4	23	16	3	8
Units: subjects
No. of Subjects With AEs	2	1	2	6	4	20	16	3	5
No. of Subjects With SAEs	0	0	0	1	1	0	1	0	1
No. of Subjects Discontinued PF-03084014	0	0	0	1	0	1	1	1	0
No. of Subjects Temp. Discontinued Treatment	0	0	0	0	1	7	4	1	0
No.of Subjects With Dose Reduction Due to AEs	0	0	0	0	1	4	3	1	1

No statistical analyses for this end point

Secondary: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) (All Causality) by maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade

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End point title

Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) (All Causality) by maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade

End point description

An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. CTCAE version 3.0 was used for AE grading: Grade 1 mild AE; Grade 2 moderate AE; Grade 3 severe AE; Grade 4 life-threatening or disabling AE; Grade 5 death related to AE. Analysis population included all subjects who received at least 1 dose of study medication.

End point type

Secondary

End point timeframe

Baseline to the end of study (28 days after last dose of study drug)

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 330 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	3	3	4	8	4	23	16	3	8
Units: subjects
Any AEs, Grade 1	0	0	1	0	0	1	1	0	1
Any AEs, Grade 2	2	1	0	1	2	8	3	0	1
Any AEs, Grade 3	1	1	2	2	2	12	9	2	4
Any AEs, Grade 4	0	0	1	2	0	2	1	1	1
Any AEs, Grade 5	0	1	0	1	0	0	2	0	1

No statistical analyses for this end point

Secondary: Number of Subjects with TEAEs (Treatment-Related) by Maximum CTCAE Grade

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End point title

Number of Subjects with TEAEs (Treatment-Related) by Maximum CTCAE Grade

End point description

An AE was any untoward medical occurrence attributed to study drug in a subject who received study drug. Treatment-related events were those assessed by the investigator as related to study medication. CTCAE version 3.0 was used for AE grading: Grade 1 mild AE; Grade 2 moderate AE; Grade 3 severe AE; Grade 4 life-threatening or disabling AE; Grade 5 death related to AE. Analysis population included all subjects who received at least 1 dose of study medication.

End point type

Secondary

End point timeframe

Baseline to the end of study (28 days after last dose of study drug)

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 330 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	3	3	4	8	4	23	16	3	8
Units: Subjects
Any AEs, Grade 1	1	0	1	1	1	6	2	0	3
Any AEs, Grade 2	1	1	0	3	2	6	4	1	0
Any AEs, Grade 3	0	0	1	1	1	8	10	2	1
Any AEs, Grade 4	0	0	0	1	0	0	0	0	0
Any AEs, Grade 5	0	0	0	0	0	0	0	0	0
Missing or Unknown	0	0	0	0	0	0	0	0	1

No statistical analyses for this end point

Secondary: Number of Subjects With Potentially Clinical Significant Categorical Changes From Baseline in Electrocardiogram (ECG) Findings in QTc Interval

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End point title

Number of Subjects With Potentially Clinical Significant Categorical Changes From Baseline in Electrocardiogram (ECG) Findings in QTc Interval

End point description

Criteria for potentially important changes in ECG were defined as: maximum (max.) post-dose (post-baseline) time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole (QT interval) corrected for heart rate using Fridericia's formular (QTcF), or QT interval corrected for heart rate using Bazett's formula (QTcB): <450, 450 -<480, 480-<500, and >=500 msec. Maximum increase (inc.) from baseline in QTcF or QTcB: change (chg) <30, 30=<chg<60, and chg >=60 msec. Analysis population included all subjects who received at least 1 dose of study medication.

End point type

Secondary

End point timeframe

Baseline to end of study treatment (Day 28).

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 330 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	3	3	4	8	4	23	16	3	8
Units: subjects
Max. QTcB interval <450	0	3	2	4	2	11	5	2	8
Max. QTcB interval 450-<480	3	0	1	3	2	8	9	1	0
Max. QTcB interval 480-<500	0	0	0	1	0	4	0	0	0
Max. QTcB interval >=500	0	0	1	0	0	0	2	0	0
Max. QTcF interval <450	3	3	2	7	3	13	12	3	8
Max. QTcF interval 450-<480	0	0	1	0	1	9	2	0	0
Max. QTcF interval 480-<500	0	0	0	1	0	1	0	0	0
Max. QTcF interval >=500	0	0	1	0	0	0	2	0	0
Max. QTcB interval inc. from baseline chg<30	1	2	1	7	3	21	7	3	7
Max. QTcB interval inc. from baseline 30=<chg<60	2	1	2	1	1	2	7	0	1
Max. QTcB interval inc. from baseline chg>=60	0	0	1	0	0	0	2	0	0
Max. QTcF interval inc. from baseline chg<30	3	2	1	7	3	22	12	3	8
Max. QTcF interval inc. from baseline 30=<chg<60	0	1	2	1	1	1	2	0	0
Max. QTcF interval inc. from baseline chg>=60	0	0	1	0	0	0	2	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With Laboratory Tests Abnormalities Meeting the Criteria of Potential Clinical Concern (Hematology and Chemistries, All Cycles)

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End point title

Number of Subjects With Laboratory Tests Abnormalities Meeting the Criteria of Potential Clinical Concern (Hematology and Chemistries, All Cycles)

End point description

Parameters analyzed included: White blood cell (WBC) count plus differential, absolute (Abs) neutrophil count, platelets, hemoglobin, sodium, potassium, bicarbonate, chloride, blood urea nitrogen, creatinine, glucose, uric acid, calcium, phosphate, magnesium, total protein, albumin, total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), partial prothrombin time/international normalized ratio (PTT/INR). Urinalysis: pH, specific gravity, protein, glucose, ketones, blood, leukocyte esterase, and nitrites. Pregnancy test: Serum or urine pregnancy test for women of childbearing potential. There were no changes in urine protein among the solid tumor and T-ALL/LBL subjects that were clinically significant. Clinical significance was judged by the investigator. Analysis population included all subjects who received at least 1 dose of study medication.

End point type

Secondary

End point timeframe

Baseline to the end of study (28 days after last dose of study drug).

End point values	PF-03084014 in T-ALL/LBL Subjects	PF-03084014 in Solid Tumor Subjects
Number of subjects analysed	8	64
Units: subjects
Hemoglobin	8	45
Lymphocytes (abs)	8	40
Neutrophils (abs)	5	4
Platelets	6	13
WBC	5	4
ALT	4	22
ALP	3	24
AST	4	32
Bicarbonate	1	15
Bilirubin	2	10
Creatinine	1	17
Hypercalcaemia	0	2
Hyperglycaemia	6	55
Hyperkalaemia	0	4
Hypermagnesaemia	0	1
Hypernatraemia	0	4
Hypoalbuminaemia	6	43
Hypocalcaemia	6	18
Hypoglycaemia	0	6
Hypokalaemia	4	23
Hypomagnesaemia	1	8
Hyponatraemia	3	19
Hypophosphataemia	4	54

No statistical analyses for this end point

Secondary: Maximum Observed Serum Concentration (Cmax) After a Single Dose on Cycle 1 Day 1

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End point title

Maximum Observed Serum Concentration (Cmax) After a Single Dose on Cycle 1 Day 1

End point description

Cmax was the maximum observed serum concentration. Analysis population included all treated subjects who had at least 1 of the pharmacokinetic (PK) parameters of interest. N=number of subjects evaluable for this endpoint

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (predose and 0.5, 1, 2, 4, and 10 hours [hr] postdose)

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 330 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	3	3	4	8	4	22	16	3	8
Units: nanogram/milliliter (ng/mL)
geometric mean (geometric coefficient of variation)	163 ± 62	368 ± 48	230 ± 193	691 ± 37	536 ± 72	943 ± 100	861 ± 63	1892 ± 54	1604 ± 85

No statistical analyses for this end point

Secondary: Time to Reach Cmax (Tmax) After a Single Dose on Cycle 1 Day 1

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End point title

Time to Reach Cmax (Tmax) After a Single Dose on Cycle 1 Day 1

End point description

Tmax was the time to reach maximum serum concentration (Cmax). Analysis population included all treated subjects who had at least 1 of the PK parameters of interest. N=number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, and 10 hr post-dose)

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 330 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	3	3	4	8	4	22	16	3	8
Units: hr
median (full range (min-max))	1.0 (0.9 to 1.0)	1.0 (1.0 to 1.3)	2.0 (1.0 to 8.0)	1.0 (1.0 to 2.0)	2.5 (1.0 to 4.0)	1.1 (0.5 to 4.1)	2.0 (1.0 to 4.1)	1.2 (1.0 to 2.0)	1.1 (0.9 to 4.0)

No statistical analyses for this end point

Secondary: Area Under the Time-Concentration Curve From Time 0 to the Dosing Interval (AUCtau) After a Single Dose on Cycle 1 Day 1

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End point title

Area Under the Time-Concentration Curve From Time 0 to the Dosing Interval (AUCtau) After a Single Dose on Cycle 1 Day 1

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, and 10 hr post-dose)

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 330 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	3	3	3	7	3	21	16	2 ^[5]	4
Units: nanogramhour/milliliter (nghr/mL)
geometric mean (geometric coefficient of variation)	409 ± 83	1329 ± 87	1649 ± 98	2204 ± 37	2924 ± 81	3677 ± 86	3593 ± 58	8014 ± 99999	6412 ± 80

Notes
[5] - Geometric %CV was NE when No. of subjects analyzed is <3, hence data was not calculated.

No statistical analyses for this end point

Secondary: Cmax After Multiple Dose on Cycle 1 Day 21

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End point title

Cmax After Multiple Dose on Cycle 1 Day 21 ^[6]

End point description

Cmax was the maximum observed serum concentration. 99999 represents data not estimable (NE) when the number (No.) of subjects analyzed is less than (<) 3. Analysis population included all subjects who had at least 6 days of uninterrupted dosing prior to the Cycle 1 Day 21 PK assessment. The 6-day duration was chosen based on the observed terminal half-life of PF-03084014. N=number of subjects evaluable for this endpoint. Cycle 1 Day 21 PK parameter summaries are presented only for subjects who were considered to be dose compliant.

End point type

Secondary

End point timeframe

Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)

Notes
[6] - 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: No data was available for the 330 mg BID in solid tumor subjects arm

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	2 ^[7]	2 ^[8]	3	5	3	12	8	4
Units: ng/mL
geometric mean (geometric coefficient of variation)	64.5 ± 99999	381 ± 99999	313 ± 29	867 ± 44	421 ± 130	1246 ± 79	1894 ± 76	1828 ± 42

Notes
[7] - Geometric %CV was NE when No. of subjects analyzed is <3, hence data was not calculated.
[8] - Geometric %CV was NE when No. of subjects analyzed is <3, hence data was not calculated.

No statistical analyses for this end point

Secondary: Time to Reach Cmax (Tmax) after multiple dose on Cycle 1 Day 21

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End point title

Time to Reach Cmax (Tmax) after multiple dose on Cycle 1 Day 21 ^[9]

End point description

Tmax was the time to reach maximum serum concentration (Cmax). Analysis population included all subjects who had at least 6 days of uninterrupted dosing prior to the Cycle 1 Day 21 PK assessment. The 6-day duration was chosen based on the observed terminal half-life of PF-03084014. N=number of subjects evaluable for this endpoint. Cycle 1 Day 21 PK parameter summaries are presented only for subjects who were considered to be dose compliant.

End point type

Secondary

End point timeframe

Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)

Notes
[9] - 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: No data was available for the 330 mg BID in solid tumor subjects arm

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	2	2	3	5	3	12	8	4
Units: hr
median (full range (min-max))	1.1 (1.0 to 1.1)	1.0 (1.0 to 1.0)	1.0 (1.0 to 4.0)	1.1 (1.0 to 2.7)	3.7 (1.0 to 8.0)	1.1 (1.0 to 4.0)	1.0 (0.5 to 2.0)	1.6 (1.0 to 2.0)

No statistical analyses for this end point

Secondary: AUCtau After Multiple Dose on Cycle 1 Day 21

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End point title

AUCtau After Multiple Dose on Cycle 1 Day 21 ^[10]

End point description

AUCtau was area under the serum concentration-time profile from time 0 to tau (dosing interval). 99999 represents data not estimable (NE) when the number (No.) of subjects analyzed is less than (<) 3. Analysis population included all subjects who had at least 6 days of uninterrupted dosing prior to the Cycle 1 Day 21 PK assessment. The 6-day duration was chosen based on the observed terminal half-life of PF-03084014. N=number of subjects evaluable for this endpoint. Cycle 1 Day 21 PK parameter summaries are presented only for subjects who were considered to be dose compliant.

End point type

Secondary

End point timeframe

Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)

Notes
[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: No data was available for the 330 mg BID in solid tumor subjects arm

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	2 ^[11]	2 ^[12]	3	5	3	12	8	4
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)	309 ± 99999	2521 ± 99999	1572 ± 42	4741 ± 70	3155 ± 59	6430 ± 89	10520 ± 89	9161 ± 30

Notes
[11] - Geometric %CV was NE when No. of subjects analyzed is <3, hence data was not calculated.
[12] - Geometric %CV was NE when No. of subjects analyzed is <3, hence data was not calculated.

No statistical analyses for this end point

Secondary: Apparent Volume of Distribution (Vz/F) on Cycle 1 Day 21

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End point title

Apparent Volume of Distribution (Vz/F) on Cycle 1 Day 21 ^[13]

End point description

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired concentration of a drug. 99999 represents data not estimable (NE) when the number (No.) of subjects analyzed is less than (<) 3. Analysis population included all subjects who had at least 6 days of uninterrupted dosing prior to the Cycle 1 Day 21 PK assessment. The 6-day duration was chosen based on the observed terminal half-life of PF-03084014. N=number of subjects evaluable for this endpoint. Cycle 1 Day 21 PK parameter summaries are presented only for subjects who were considered to be dose compliant.

End point type

Secondary

End point timeframe

Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)

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: No data was available for the 330 mg BID in solid tumor subjects arm

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	2 ^[14]	2 ^[15]	2 ^[16]	5	3	12	8	3
Units: liter (L)
geometric mean (geometric coefficient of variation)	2810 ± 99999	516 ± 99999	3353 ± 99999	986 ± 52	2048 ± 49	801 ± 144	852 ± 120	424 ± 61

Notes
[14] - Geometric %CV was NE when No. of subjects analyzed is <3, hence data was not calculated.
[15] - Geometric %CV was NE when No. of subjects analyzed is <3, hence data was not calculated.
[16] - Geometric %CV was NE when No. of subjects analyzed is <3, hence data was not calculated.

No statistical analyses for this end point

Secondary: Serum Decay Half-Life (t1/2) After Multiple Dose on Cycle 1 Day 21

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End point title

Serum Decay Half-Life (t1/2) After Multiple Dose on Cycle 1 Day 21 ^[17]

End point description

Serum decay half-life is the time measured for the serum concentration to decrease by one half. 99999 represents data not estimable (NE) when the number (No.) of subjects analyzed is less than (<) 3. Analysis population included all subjects who had at least 6 days of uninterrupted dosing prior to the Cycle 1 Day 21 PK assessment. The 6-day duration was chosen based on the observed terminal half-life of PF-03084014. N=number of subjects evaluable for this endpoint. Cycle 1 Day 21 PK parameter summaries are presented only for subjects who were considered to be dose compliant.

End point type

Secondary

End point timeframe

Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)

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: No data was available for the 330 mg BID in solid tumor subjects arm

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	2 ^[18]	2 ^[19]	2 ^[20]	5	3	12	8	3
Units: hr
arithmetic mean (standard deviation)	30.3 ± 99999	22.6 ± 99999	38.6 ± 99999	34.2 ± 11.7	34.7 ± 5.3	25.3 ± 9.2	29.3 ± 9.3	18.0 ± 3.6

Notes
[18] - Geometric %CV was NE when No. of subjects analyzed is <3, hence data was not calculated.
[19] - Geometric %CV was NE when No. of subjects analyzed is <3, hence data was not calculated.
[20] - Geometric %CV was NE when No. of subjects analyzed is <3, hence data was not calculated.

No statistical analyses for this end point

Secondary: Apparent Oral Clearance (CL/F) on Cycle 1 Day 21

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End point title

Apparent Oral Clearance (CL/F) on Cycle 1 Day 21 ^[21]

End point description

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. 99999 represents data not estimable (NE) when the number (No.) of subjects analyzed is less than (<) 3 Analysis population included all subjects who had at least 6 days of uninterrupted dosing prior to the Cycle 1 Day 21 PK assessment. The 6-day duration was chosen based on the observed terminal half-life of PF-03084014. N=number of subjects evaluable for this endpoint. Cycle 1 Day 21 PK parameter summaries are presented only for subjects who were considered to be dose compliant.

End point type

Secondary

End point timeframe

Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)

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: No data was available for the 330 mg BID in solid tumor subjects arm

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	2 ^[22]	2 ^[23]	3	5	3	12	8	4
Units: liter/hour (L/hr)
geometric mean (geometric coefficient of variation)	64.8 ± 99999	15.9 ± 99999	50.9 ± 42	21.1 ± 70	41.2 ± 59	23.4 ± 88	20.9 ± 89	16.4 ± 30

Notes
[22] - Geometric %CV was NE when No. of subjects analyzed is <3, hence data was not calculated.
[23] - Geometric %CV was NE when No. of subjects analyzed is <3, hence data was not calculated.

No statistical analyses for this end point

Secondary: Minimum Observed Serum Concentration (Cmin) After Multiple Dose on Cycle 1 Day 21

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End point title

Minimum Observed Serum Concentration (Cmin) After Multiple Dose on Cycle 1 Day 21 ^[24]

End point description

Cmin was the minimum observed serum concentration. 99999 represents data not estimable (NE) when the number (No.) of subjects analyzed is less than (<) 3. Analysis population included all subjects who had at least 6 days of uninterrupted dosing prior to the Cycle 1 Day 21 PK assessment. The 6-day duration was chosen based on the observed terminal half-life of PF-03084014. N=number of subjects evaluable for this endpoint. Cycle 1 Day 21 PK parameter summaries are presented only for subjects who were considered to be dose compliant.

End point type

Secondary

End point timeframe

Cycle 1 Day 21 (predose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr postdose)

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: No data was available for the 330 mg BID in solid tumor subjects arm

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	2 ^[25]	2 ^[26]	3	5	3	12	8	4
Units: ng/mL
geometric mean (geometric coefficient of variation)	10.7 ± 99999	126 ± 99999	59.2 ± 103	232 ± 118	206 ± 40	266 ± 102	469 ± 118	420 ± 81

Notes
[25] - Geometric %CV was NE when No. of subjects analyzed is <3, hence data was not calculated.
[26] - Geometric %CV was NE when No. of subjects analyzed is <3, hence data was not calculated.

No statistical analyses for this end point

Secondary: Average Serum Concentration (Cavg) at Steady State on Cycle 1 Day 21

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End point title

Average Serum Concentration (Cavg) at Steady State on Cycle 1 Day 21 ^[27]

End point description

Cavg was the average serum concentration at steady state.99999 represents data not estimable (NE) when the number (No.) of subjects analyzed is less than (<) 3.Analysis population included all subjects who had at least 6 days of uninterrupted dosing prior to the Cycle 1 Day 21 PK assessment. The 6-day duration was chosen based on the observed terminal half-life of PF-03084014. N=number of subjects evaluable for this endpoint. Cycle 1 Day 21 PK parameter summaries are presented only for subjects who were considered to be dose compliant.

End point type

Secondary

End point timeframe

Cycle 1 Day 21 (predose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr postdose)

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: No data was available for the 330 mg BID in solid tumor subjects arm

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	2 ^[28]	2 ^[29]	3	5	3	12	8	4
Units: ng/mL
geometric mean (geometric coefficient of variation)	25.7 ± 99999	210 ± 99999	131 ± 42	395 ± 69	263 ± 59	536 ± 89	877 ± 89	763 ± 30

Notes
[28] - Geometric %CV was NE when No. of subjects analyzed is <3, hence data was not calculated.
[29] - Geometric %CV was NE when No. of subjects analyzed is <3, hence data was not calculated.

No statistical analyses for this end point

Secondary: Accumulation ratio (Rac) on Cycle 1 Day 21

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End point title

Accumulation ratio (Rac) on Cycle 1 Day 21 ^[30]

End point description

Accumulation was calculated as AUCtau at steady state (Cycle 1 Day 21) divided by AUCtau after a single dose on Cycle 1 Day 1. 99999 signifies data not estimable. Analysis population included all subjects who had at least 6 days of uninterrupted dosing prior to the Cycle 1 Day 21 PK assessment. The 6-day duration was chosen based on the observed terminal half-life of PF-03084014. N=number of subjects evaluable for this endpoint. Cycle 1 Day 21 PK parameter summaries are presented only for subjects who were considered to be dose compliant.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (predose and 0.5, 1, 2, 4, and 10 hr postdose), Cycle 1 Day 21 (predose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr postdose)

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: No data was available for the 330 mg BID in solid tumor subjects arm

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	2	2	2	5	3	12	8	1 ^[31]
Units: ratio
median (full range (min-max))	1.18 (0.72 to 1.63)	1.60 (1.45 to 1.74)	1.36 (0.93 to 1.79)	2.49 (1.23 to 2.86)	1.98 (1.81 to 2.15)	2.29 (0.95 to 4.90)	2.84 (1.14 to 5.80)	0.97 (00000 to 99999)

Notes
[31] - Unable to calculate median and range as only 1 subject provided value.

No statistical analyses for this end point

Secondary: Dose-normalized AUCtau [AUCtau(dn)] in the Fasted State for Solid Tumor Subjects

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End point title

Dose-normalized AUCtau [AUCtau(dn)] in the Fasted State for Solid Tumor Subjects

End point description

AUCtau(dn) was calculated by area under the serum concentration-time profile from time 0 to tau (dosing interval) (AUCtau) divided by administered dose. Analysis population included solid tumor subjects who were enrolled in the food-effect sub-study, were treated and had evaluable PK data under both fed and fasted states.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (predose and 0.5, 1, 2, 4, 10 and 24 hr post-dose) or Cycle 2 Day 1 (predose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)

End point values	PF-03084014 in Solid Tumor Subjects
Number of subjects analysed	11
Units: (ng*hr/mL)/mg
geometric mean (geometric coefficient of variation)	23.71 ± 115

No statistical analyses for this end point

Secondary: Dose-normalized AUCtau [AUCtau(dn)] in the Fed State for Solid Tumor Subjects

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End point title

Dose-normalized AUCtau [AUCtau(dn)] in the Fed State for Solid Tumor Subjects

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose) or Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)

End point values	PF-03084014 in Solid Tumor Subjects
Number of subjects analysed	11
Units: (ng*hr/mL)/mg
geometric mean (geometric coefficient of variation)	22.54 ± 67

No statistical analyses for this end point

Secondary: Dose-normalized Cmax [Cmax(dn)] in the Fasted State for Solid Tumor Subjects

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End point title

Dose-normalized Cmax [Cmax(dn)] in the Fasted State for Solid Tumor Subjects

End point description

Cmax(dn) was calculated by maximum observed serum concentration (Cmax) divided by administered dose. Analysis population included solid tumor subjects who were enrolled in the food-effect sub-study, were treated and had evaluable PK data under both fed and fasted states.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose) or Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)

End point values	PF-03084014 in Solid Tumor Subjects
Number of subjects analysed	13
Units: (ng/mL)/milligram (ng/mL)/mg
geometric mean (geometric coefficient of variation)	6.56 ± 106

No statistical analyses for this end point

Secondary: Dose-normalized Cmax(dn) in the Fed State for Solid Tumor Subjects

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End point title

Dose-normalized Cmax(dn) in the Fed State for Solid Tumor Subjects

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose) or Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose) and Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)

End point values	PF-03084014 in Solid Tumor Subjects
Number of subjects analysed	13
Units: (ng/mL)/mg
geometric mean (geometric coefficient of variation)	5.22 ± 64

No statistical analyses for this end point

Secondary: Percentage of Solid Tumor Subjects With Objective Response (OR)

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End point title

Percentage of Solid Tumor Subjects With Objective Response (OR) ^[32]

End point description

OR was defined as confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0). Confirmed CR defined as disappearance of all target lesions. Confirmed PR defined as >=30% decrease in sum of the longest dimensions (LD) of the target lesions taking as a reference the baseline sum LD according to RECIST. Confirmed responses are those that persist on repeat imaging study >=4 weeks after initial documentation of response.

End point type

Secondary

End point timeframe

Baseline, Cycle 2 Day 1, Cycle 3 Day 1 and then Day 1 (plus [+] or minus [-] 5 days) of every odd cycle or as clinically indicated, up to Cycle 9; afterwards assessed on Day 1 (+ or -5 days) every 4 cycles

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: This endpoint applies to solid tumor subjects only

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 330 mg BID in Solid Tumor Subjects
Number of subjects analysed	3	3	3	5	3	18	10	1
Units: percentage of subjects
number (confidence interval 95%)	33.3 (0.8 to 90.6)	0 (0.0 to 70.8)	66.7 (9.4 to 99.2)	0 (0.0 to 52.2)	0 (0.0 to 70.8)	5.6 (0.1 to 27.3)	10.0 (0.3 to 44.5)	100 (2.5 to 100.0)

No statistical analyses for this end point

Secondary: Time to Progression (TTP) for Solid Tumor Subjects

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End point title

Time to Progression (TTP) for Solid Tumor Subjects ^[33]

End point description

Time from Cycle 1 Day 1 to first documentation of disease progression. Progression was defined as per RECIST version 1.0, as a 20% increase in the sum of the longest diameter of target lesions, or target lesions over nadir, uneuivocal progression of non-target disease, or the appearance of new lesions. TTP (months) was calculated as (first event date minus the date of first dose of study medication plus 1) divided by 30. 99999 signifies data not estimable.

End point type

Secondary

End point timeframe

Baseline, Cycle 2 Day 1, Cycle 3 Day 1 and then Day 1 (+ or - 5 days) of every odd cycle or as clinically indicated, up to Cycle 9; afterwards assessed on Day 1 (+ or -5 days) every 4 cycles

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: This endpoint applies to solid tumor subjects only

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 330 mg BID in Solid Tumor Subjects
Number of subjects analysed	3 ^[34]	3	4 ^[35]	8 ^[36]	4	23	16	3 ^[37]
Units: months
median (confidence interval 95%)	99999 (0.8 to 99999)	1.2 (1.0 to 2.8)	99999 (1.7 to 99999)	3.1 (1.0 to 99999)	4.3 (1.6 to 19.5)	1.6 (1.4 to 6.0)	1.5 (1.1 to 4.2)	99999 (99999 to 99999)

Notes
[34] - As 2 subjects were censored and only 1 subject was evaluable
[35] - Unable to calculate as 3 subjects were censored and only 1 subject was evaluable
[36] - The upper 95% confidence limit can not be calculated due to limited number of subjects
[37] - Unable to calculate as all 3 subjects were censored

No statistical analyses for this end point

Secondary: Duration of Response (DR) for Solid Tumor Subjects

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End point title

Duration of Response (DR) for Solid Tumor Subjects ^[38]

End point description

Time from the first documentation of OR to objective disease progression or death due to any cause. DR was only calculated for subjects with an OR. DR (months) was calculated as (date of first documentation of objective progression or death minus date of first documentation of PR or CR plus 1) divided by 30. 99999 signifies data not estimable.

End point type

Secondary

End point timeframe

Baseline, Cycle 2 Day 1, Cycle 3 Day 1 and then Day 1 (+ or -5 days) of every odd cycle or as clinically indicated, up to Cycle 9. Afterwards, assessed on Day 1 (+ or -5 days) every 4 cycles.

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: This endpoint applies to solid tumor subjects only

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 330 mg BID in Solid Tumor Subjects
Number of subjects analysed	1 ^[39]	2 ^[40]	1 ^[41]	1 ^[42]	1 ^[43]
Units: months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)

Notes
[39] - Unable to calculate as the subject was censored.
[40] - Unable to calculate as the subject was censored.
[41] - Unable to calculate as the subject was censored.
[42] - Unable to calculate as the subject was censored.
[43] - Unable to calculate as the subject was censored.

No statistical analyses for this end point

Secondary: Progression-Free Survival (PFS) for Solid Tumor Subjects

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End point title

Progression-Free Survival (PFS) for Solid Tumor Subjects ^[44]

End point description

PFS was defined as the time from Cycle 1 Day 1 to date of first documentation of progression or death due to any cause. Progression was defined as per RECIST version 1.0, as a 20% increase in the sum of the longest diameter of target lesions, or target lesions over nadir, unequivocal progression of non-target disease, or the appearance of new lesions. PFS (months) was calculated as (the first event date minus the date of first dose of study medication plus 1) divided by 30. 99999 signifies data not applicable.

End point type

Secondary

End point timeframe

Baseline, Cycle 2 Day 1, Cycle 3 Day 1 and then Day 1 (+ or - 5 days) of every odd cycle or as clinically indicated, up to Cycle 9; afterwards assessed on Day 1 (+ or -5 days) every 4 cycles

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: This endpoint applies to solid tumor subjects only

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 330 mg BID in Solid Tumor Subjects
Number of subjects analysed	3 ^[45]	3	4 ^[46]	8 ^[47]	4	23	16	3 ^[48]
Units: months
median (confidence interval 95%)	99999 (0.8 to 99999)	1.2 (1.0 to 2.8)	99999 (1.7 to 99999)	2.3 (0.4 to 99999)	4.3 (1.6 to 19.5)	1.6 (1.4 to 6.0)	1.5 (1.1 to 4.2)	99999 (99999 to 99999)

Notes
[45] - Unable to calculate as 2 subjects were censored and only 1 subject was evaluable.
[46] - Unable to calculate as 3 subjects were censored and only 1 subject was evaluable.
[47] - The upper 95% confidence limit can not be determined due to limited number of subjects with PFS.
[48] - Unable to calculate as all 3 subjects were censored.

No statistical analyses for this end point

Secondary: Percentage of T-ALL/LBL subjects with OR

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End point title

Percentage of T-ALL/LBL subjects with OR ^[49]

End point description

OR was adapted from International Working Group Response Criteria for Acute Myeloid Leukemia (AML). The response categories of interest were CR, complete response with incomplete hematopoietic recovery (CRi), and PR. CR: ANC >1500/microliter (uL), no circulating blasts. Platelets >100,000/uL, <5% marrow blast cells, no extramedullary disease, bone marrow cellularity >20% with tri-lineage hematopoiesis and <5% marrow blast cells, none of which were neoplastic; CRi: same as CR but ANC may be >1500/uL or platelet count >100,000/uL, no requirement on bone marrow cellularity; PR: same as CR but bone marrow with >= 50% reduction of leukemia blast cells and an absolute blast count between 5% and 25%.

End point type

Secondary

End point timeframe

Baseline, Cycle 2 Day 1, Cycle 3 Day 1 and then Day 1 (+ or - 5 days) of every odd cycle or as clinically indicated, up to Cycle 9.

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: This endpoint applies to T-ALL/LBL subjects only

End point values	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	8
Units: percentage of subjects
number (confidence interval 95%)	12.5 (0.3 to 52.7)

No statistical analyses for this end point

Secondary: Relapse Free Survival (RFS) for T-ALL/LBL subjects

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End point title

Relapse Free Survival (RFS) for T-ALL/LBL subjects ^[50]

End point description

The RFS of CR was defined as the time from the date of first attaining CR to the date of relapse or death from any cause, whichever occurred first. Similarly, the RFS of CR + CRi (or RFS of CR + CRi + partial response [PR]) was defined as the time from the date of first attaining CR + CRi (or CR + CRi + PR) to the date of relapse or death from any cause, whichever occurred first.

End point type

Secondary

End point timeframe

Baseline, Cycle 2 Day 1, Cycle 3 Day 1 and then Day 1 (+ or - 5 days) of every odd cycle or as clinically indicated, up to Cycle 9.

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: This endpoint applies to T-ALL/LBL subjects only

End point values	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	0 ^[51]
Units: months
median (confidence interval 95%)	( to )

Notes
[51] - Data not analyzed due to halting of T-ALL/LBL subject enrollment and the limited No. of subjects.

No statistical analyses for this end point

Secondary: Peripheral Blast Count Reduction (PBR) for T-ALL/LBL Subjects

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End point title

Peripheral Blast Count Reduction (PBR) for T-ALL/LBL Subjects ^[52]

End point description

PBR was the maximum percentage of peripheral blast count reduction for each subject who received at least one dose of study medication. PBR was derived by the Sponsor from percentage of peripheral blood Blast Count reported by sites.

End point type

Secondary

End point timeframe

Baseline, Cycle 2 Day 1, Cycle 3 Day 1 and then Day 1 (+ or - 5 days) of every odd cycle or as clinically indicated, up to Cycle 9.

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: This endpoint applies to T-ALL/LBL subjects only

End point values	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	0 ^[53]
Units: percentage of PBR
number (confidence interval 95%)	( to )

Notes
[53] - Data not analyzed due to halting of T-ALL/LBL subject enrollment and the limited No. of subjects.

No statistical analyses for this end point

Secondary: Changes in Expression Levels of Notch 1 Target Genes in Tumor Biopsies for Solid Tumor Subjects: Hes4 Gene Expression Levels on Cycle 1 Day 21 Relative to That at Baseline

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End point title

Changes in Expression Levels of Notch 1 Target Genes in Tumor Biopsies for Solid Tumor Subjects: Hes4 Gene Expression Levels on Cycle 1 Day 21 Relative to That at Baseline ^[54]

End point description

Gene expression analysis in tumor biopsies was done using cDNA prepared from ribonucleic acid (RNA) extracted from tumor biopsies. Gene expression was measured by custom Taqman low density array (TLDA) cards run on Applied Biosystems 7900HT Fast Real-Time polymerase chain reaction (PCR) system. Changes from baseline were calculated as ratios to baseline. Only Hes4 gene showed consistent down modulation across dosing cohorts (150 mg and 220 mg BID) and therefore results were reported for Hes4 only.

End point type

Secondary

End point timeframe

Baseline, Cycle 1 Day 21 (-5 days)

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: This endpoint applies to 150 mg BID and 220 mg BID in solid tumor subjects arms only

End point values	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects
Number of subjects analysed	3	2
Units: ratio
arithmetic mean (standard deviation)	0.9 ± 0.57	0.5 ± 0.50

No statistical analyses for this end point

Secondary: Changes From Baseline in Expression Levels of Notch 1 Target Genes in Peripheral Blood for T-ALL/LBL Subjects: Hes4 Gene Expression Levels on Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 21 Relative to That at Baseline

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End point title

Changes From Baseline in Expression Levels of Notch 1 Target Genes in Peripheral Blood for T-ALL/LBL Subjects: Hes4 Gene Expression Levels on Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 21 Relative to That at Baseline

End point description

RNA was extracted from peripheral blood and used as a template to synthesize complementary deoxyribonucleic acid (cDNA). Gene expression in cDNA was measured by custom Taqman low density array (TLDA) cards run on Applied Biosystems 7900HT Fast Real-Time PCR system. Changes from baseline were calculated as ratios to baseline. Results were reported Only for Hes4 as this was the only gene to show consistent down modulation across dosing cohorts (150 mg and 220 mg).

End point type

Secondary

End point timeframe

Baseline (morning), Cycle 1 Days 8, 15 and 21 (morning, matched with the first PK sample of the particular day), Cycle 1 Day 21 (24, 48, and 120 hr postdose) and at end of treatment (EoT)

End point values	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	8 ^[55]
Units: ratio
arithmetic mean (standard deviation)
Cycle 1 Day 8, n=7	0.7 ± 0.65
Cycle 1 Day 15, n=4	0.3 ± 0.41
Cycle 1 Day 21, n=4	0.4 ± 0.27
EOT, n=1	2.0 ± 99999

Notes
[55] - Data for standard deviation at EOT was not estimable since only 1 participant was analyzed.

No statistical analyses for this end point

Secondary: Changes in Expression Levels of Notch 1 Target Genes in Peripheral Blood for Solid Tumor Subjects: Hairy and Enhancer of Split-4 (Hes4) Gene Expression Level on Cycle 1 Day 8 and Cycle 1 Day 21 Relative to That at Baseline

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End point title

Changes in Expression Levels of Notch 1 Target Genes in Peripheral Blood for Solid Tumor Subjects: Hairy and Enhancer of Split-4 (Hes4) Gene Expression Level on Cycle 1 Day 8 and Cycle 1 Day 21 Relative to That at Baseline ^[56]

End point description

RNA was extracted from peripheral blood and used as a template to synthesize DNA. Gene expression in cDNA was measured by custom TLDA cards run on Applied Biosystems 7900HT Fast Real-Time PCR system. Changes from baseline were calculated as ratios to baseline. Results were reported Only for Hes4 as this was the only gene to show consistent down modulation across dosing cohorts (150 mg and 220 mg).

End point type

Secondary

End point timeframe

Baseline (morning), Cycle 1 Days 8 and 21 (predose)

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: This endpoint applies to 150 mg BID and 220 mg BID in solid tumor subjects arms only

End point values	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects
Number of subjects analysed	11	7
Units: ratio
arithmetic mean (standard deviation)
Cycle 1 Day 8, n=11, 7	0.3 ± 0.24	0.1 ± 0.14
Cycle 1 Day 21, n=6, 5	0.3 ± 0.33	0.0 ± 0.02

No statistical analyses for this end point

Secondary: Changes From Baseline in Notch Intracellular Domain (NICD) Levels in Peripheral Blood for T-ALL/LBL Subjects

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End point title

Changes From Baseline in Notch Intracellular Domain (NICD) Levels in Peripheral Blood for T-ALL/LBL Subjects ^[57]

End point description

NICD was measured in peripheral blood mononuclear cell (PBMC) pellets using a validated enzyme-linked immunosorbent assay (ELISA). LOQ is the lower limit of quantitation.

End point type

Secondary

End point timeframe

Baseline, Cycle 1 Days 8 and 15 (predose AM), Cycle 1 Day 21 (predose AM and 24, 48 and 120 hr postdose) and EOT

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: This endpoint applies to T-ALL/LBL subjects only

End point values	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	0 ^[58]
Units: optical density
arithmetic mean (standard deviation)	±

Notes
[58] - As NICD levels fell below the LOQ of the assay in most cases, No data were reported.

No statistical analyses for this end point

Secondary: Changes From Baseline in Notch Intracellular Domain (NICD) Levels in Bone Marrow for T-ALL/LBL Subjects

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End point title

Changes From Baseline in Notch Intracellular Domain (NICD) Levels in Bone Marrow for T-ALL/LBL Subjects ^[59]

End point description

NICD was to be measured in bone marrow mononuclear cell (BMMC) cell pellets using a validated ELISA.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 and Cycles 2 Day 1

Notes
[59] - 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: This endpoint applies to T-ALL/LBL subjects only

End point values	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	0 ^[60]
Units: microgram/milliliter
arithmetic mean (standard deviation)	±

Notes
[60] - No. of bone marrow samples received was insufficient and analyses were not mandatory per protocol.

No statistical analyses for this end point

Secondary: Dose-normalized Cmax [Cmax (dn)] After a Single Dose on Cycle 1 Day 1

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End point title

Dose-normalized Cmax [Cmax (dn)] After a Single Dose on Cycle 1 Day 1

End point description

Cmax(dn) was calculated by maximum observed serum concentration (Cmax) divided by administered dose. Analysis population included all treated subjects who had at least 1 of the PK parameters of interest. N=number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, and 10 hr post-dose)

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 330 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	3	3	4	8	4	22	16	3	8
Units: ng/mL/mg
geometric mean (geometric coefficient of variation)	8.1 ± 63	9.2 ± 48	2.9 ± 193	6.9 ± 37	4.1 ± 72	6.3 ± 100	3.9 ± 63	5.7 ± 54	10.7 ± 85

No statistical analyses for this end point

Secondary: Dose-normalized AUCtau [AUCtau (dn) ] After a single dose on Cycle 1 Day 1

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End point title

Dose-normalized AUCtau [AUCtau (dn) ] After a single dose on Cycle 1 Day 1

End point description

AUCtau (dn) was calculated by area under the serum concentration-time profile from time 0 to tau (dosing interval) (AUCtau) divided by administered dose. Analysis population included all treated subjects who had at least 1 of the PK parameters of interest. N=number of subjects evaluable for this endpoint. 99999 signifies data that are not estimable.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, and 10 hr post-dose)

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 330 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	3	3	3	7	3	21	16	2	4
Units: (ng*hr/mL)/mg
geometric mean (geometric coefficient of variation)	20.4 ± 83	33.2 ± 87	20.6 ± 98	22.0 ± 37	22.5 ± 81	24.5 ± 86	16.3 ± 58	24.3 ± 99999	42.7 ± 80

No statistical analyses for this end point

Secondary: Dose-normalized AUCtau [AUCtau (dn)] After Multiple Dose on Cycle 1 Day 21

Top of page

End point title

Dose-normalized AUCtau [AUCtau (dn)] After Multiple Dose on Cycle 1 Day 21 ^[61]

End point description

AUCtau (dn) was calculated by area under the serum concentration-time profile from time 0 to tau (dosing interval) (AUCtau) divided by administered dose. 99999 represents data not estimable (NE) when the number (No.) of subjects analyzed is less than (<) 3.Analysis population included all subjects who had at least 6 days of uninterrupted dosing prior to the Cycle 1 Day 21 PK assessment. The 6-day duration was chosen based on the observed terminal half-life of PF-03084014. N=number of subjects evaluable for this endpoint. Cycle 1 Day 21 PK parameter summaries are presented only for subjects who were considered to be dose compliant.

End point type

Secondary

End point timeframe

Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)

Notes
[61] - 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: No data was available for the 330 mg BID in solid tumor subjects arm

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	2	2	3	5	3	12	8	4
Units: (ng*hr/mL)/mg
geometric mean (geometric coefficient of variation)	15.4 ± 99999	63.0 ± 99999	19.7 ± 41	47.4 ± 70	24.3 ± 59	42.9 ± 88	47.9 ± 89	61.1 ± 30

No statistical analyses for this end point

Secondary: Dose-normalized Cmax [Cmax (dn)] After Multiple Dose on Cycle 1 Day 21

Top of page

End point title

Dose-normalized Cmax [Cmax (dn)] After Multiple Dose on Cycle 1 Day 21 ^[62]

End point description

Cmax(dn) was calculated by maximum observed serum concentration (Cmax) divided by administered dose. 99999 represents data not estimable (NE) when the number (No.) of subjects analyzed is less than (<) 3.Analysis population included all subjects who had at least 6 days of uninterrupted dosing prior to the Cycle 1 Day 21 PK assessment. The 6-day duration was chosen based on the observed terminal half-life of PF-03084014. N=number of subjects evaluable for this endpoint. Cycle 1 Day 21 PK parameter summaries are presented only for subjects who were considered to be dose compliant.

End point type

Secondary

End point timeframe

Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)

Notes
[62] - 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: No data was available for the 330 mg BID in solid tumor subjects arm

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Number of subjects analysed	2	2	3	5	3	12	8	4
Units: ng/mL/mg
geometric mean (geometric coefficient of variation)	3.2 ± 99999	9.6 ± 99999	3.9 ± 29	8.7 ± 44	3.2 ± 130	8.3 ± 79	8.5 ± 76	12.2 ± 42

No statistical analyses for this end point

Secondary: AUCtau in the Fasted State for Solid Tumor Subjects

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End point title

AUCtau in the Fasted State for Solid Tumor Subjects ^[63]

End point description

AUCtau was area under the serum concentration-time profile from time 0 to tau (dosing interval). Analysis population included solid tumor subjects who were enrolled in the food-effect sub-study, were treated and had evaluable PK data under both fed and fasted states.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr postdose) or Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)

Notes
[63] - 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: This endpoint apples to only solid tumor subjects who participated in food effects study

End point values	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects
Number of subjects analysed	7	4
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)	2547 ± 101	9353 ± 100

No statistical analyses for this end point

Secondary: AUCtau in the Fed State for Solid Tumor Subjects

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End point title

AUCtau in the Fed State for Solid Tumor Subjects ^[64]

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr postdose) or Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)

Notes
[64] - 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: This endpoint apples to only solid tumor subjects who participated in food effects study

End point values	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects
Number of subjects analysed	7	4
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)	3163 ± 83	5573 ± 39

No statistical analyses for this end point

Secondary: Cmax in the Fasted State for Solid Tumor Subjects

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End point title

Cmax in the Fasted State for Solid Tumor Subjects ^[65]

End point description

Cmax was the maximum observed serum concentration. Analysis population included solid tumor subjects who were enrolled in the food-effect sub-study, were treated and had evaluable PK data under both fed and fasted states.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr postdose) or Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)

Notes
[65] - 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: This endpoint apples to only solid tumor subjects who participated in food effects study

End point values	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects
Number of subjects analysed	9	4
Units: ng/mL
geometric mean (geometric coefficient of variation)	795.1 ± 104	2334 ± 93

No statistical analyses for this end point

Secondary: Cmax in the Fed State for Solid Tumor Subjects

Top of page

End point title

Cmax in the Fed State for Solid Tumor Subjects ^[66]

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr postdose) or Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)

Notes
[66] - 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: This endpoint apples to only solid tumor subjects who participated in food effects study

End point values	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects
Number of subjects analysed	9	4
Units: ng/mL
geometric mean (geometric coefficient of variation)	862.3 ± 74	924.4 ± 40

No statistical analyses for this end point

Secondary: AUCtau on Cycle 2 Day 1

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End point title

AUCtau on Cycle 2 Day 1 ^[67]

End point description

AUCtau was area under the serum concentration-time profile from time 0 to tau (dosing interval). Analysis population included all treated subjects who had at least 1 of the PK parameters of interest. N=number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)

Notes
[67] - 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: This endpoint applies to 150 mg BID and 220 mg BID in solid tumor subjects arms only

End point values	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects
Number of subjects analysed	8	4
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)	2784 ± 80	11870 ± 57

No statistical analyses for this end point

Secondary: Dose-normalized AUCtau [AUCtau (dn)] on Cycle 2 Day 1

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End point title

Dose-normalized AUCtau [AUCtau (dn)] on Cycle 2 Day 1 ^[68]

End point description

AUCtau(dn) was calculated by area under the serum concentration-time profile from time 0 to tau (dosing interval) (AUCtau) divided by administered dose. Analysis population included all treated subjects who had at least 1 of the PK parameters of interest. N=number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)

Notes
[68] - 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: This endpoint applies to 150 mg BID and 220 mg BID in solid tumor subjects arms only

End point values	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects
Number of subjects analysed	8	4
Units: ng*hr/mL/mg
geometric mean (geometric coefficient of variation)	18.6 ± 80	54.0 ± 57

No statistical analyses for this end point

Secondary: Cmax on Cycle 2 Day 1

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End point title

Cmax on Cycle 2 Day 1 ^[69]

End point description

Cmax was the maximum observed serum concentration. Analysis population included all treated subjects who had at least 1 of the PK parameters of interest. N=number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)

Notes
[69] - 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: This endpoint applies to 150 mg BID and 220 mg BID in solid tumor subjects arms only

End point values	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects
Number of subjects analysed	9	4
Units: ng/mL
geometric mean (geometric coefficient of variation)	834.6 ± 76	2640 ± 63

No statistical analyses for this end point

Secondary: Dose-normalized Cmax [Cmax (dn)] on Cycle 2 Day 1

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End point title

Dose-normalized Cmax [Cmax (dn)] on Cycle 2 Day 1 ^[70]

End point description

End point type

Secondary

End point timeframe

Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)

Notes
[70] - 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: This endpoint applies to 150 mg BID and 220 mg BID in solid tumor subjects arms only

End point values	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects
Number of subjects analysed	9	4
Units: ng/mL/mg
geometric mean (geometric coefficient of variation)	5.6 ± 76	12.0 ± 63

No statistical analyses for this end point

Secondary: Tmax on Cycle 2 Day 1

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End point title

Tmax on Cycle 2 Day 1 ^[71]

End point description

End point type

Secondary

End point timeframe

Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)

Notes
[71] - 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: This endpoint applies to 150 mg BID and 220 mg BID in solid tumor subjects arms only

End point values	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects
Number of subjects analysed	9	4
Units: hr
median (full range (min-max))	2.00 (1.00 to 4.03)	1.53 (0.98 to 4.00)

No statistical analyses for this end point

Post-hoc: Time to Response (TTR) for Solid Tumor Subjects

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End point title

Time to Response (TTR) for Solid Tumor Subjects ^[72]

End point description

TTR was only defined for subjects with an OR. TTR (months) was calculated as (date of first documentation of PR or CR minus date of first dose of study medication plus 1) divided by 30. 99999 signifies data not estimable.

End point type

Post-hoc

End point timeframe

Baseline, Cycle 2 Day 1, Cycle 3 Day 1 and then Day 1 (+ or -5 days) of every odd cycle or as clinically indicated, up to Cycle 9. Afterwards, assessed on Day 1 (+ or -5 days) every 4 cycles.

Notes
[72] - 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: This endpoint applies to solid tumor subjects only

End point values	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 330 mg BID in Solid Tumor Subjects
Number of subjects analysed	1 ^[73]	2	1 ^[74]	1 ^[75]	1 ^[76]
Units: months
median (confidence interval 95%)	11.2 (00000 to 99999)	19.4 (8.5 to 30.4)	2.9 (00000 to 99999)	10.1 (00000 to 99999)	5.9 (00000 to 99999)

Notes
[73] - Data for upper and lower limit of 95% CI were not estimable since only 1 subject was analyzed.
[74] - Data for upper and lower limit of 95% CI were not estimable since only 1 subject was analyzed.
[75] - Data for upper and lower limit of 95% CI were not estimable since only 1 subject was analyzed.
[76] - Data for upper and lower limit of 95% CI were not estimable since only 1 subject was analyzed.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Two (2) years

Adverse event reporting additional description

Same event may appear as AE and SAE, what is presented are distinct events. Event may be categorized as serious in 1 subject and non-serious in another subject or 1 subject may have experienced both serious and non-serious event. The safety analysis set includes all enrolled subjects who receive at least 1 dose of study medication.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

PF-03084014 40 mg BID in Solid Tumor Subjects

Reporting group description

PF-03084014 was administered orally BID, beginning on Day 1 of each cycle, for 21 days. In Cycle 1 only, patients were to receive PF-03084014 BID for 21 days (on Cycle 1 Day 21 only the morning dose was to be administered) followed by 7 days' off-treatment for the purpose of PK assessments. In Cycle 2 and beyond, PF-03084014 was to be administered BID continuously.

Reporting group title

PF-03084014 20 mg BID in Solid Tumor Subjects

Reporting group description

PF-03084014 was administered orally twice daily (BID), beginning on Day 1 of each cycle, for 21 days. In Cycle 1 only, patients were to receive PF-03084014 BID for 21 days (on Cycle 1 Day 21 only the morning dose was to be administered) followed by 7 days' off-treatment for the purpose of pharmacokinetic (PK) assessments. In Cycle 2 and beyond, PF-03084014 was to be administered BID continuously.

Reporting group title

PF-03084014 100 mg BID in Solid Tumor Subjects

Reporting group description

Reporting group title

PF-03084014 80 mg BID in Solid Tumor Subjects

Reporting group description

Reporting group title

PF-03084014 130 mg BID in Solid Tumor Subjects

Reporting group description

Reporting group title

PF-03084014 150 mg BID in Solid Tumor Subjects

Reporting group description

Reporting group title

PF-03084014 220 mg BID in Solid Tumor Subjects

Reporting group description

Reporting group title

PF-03084014 330 mg BID in Solid Tumor Subjects

Reporting group description

Reporting group title

PF-03084014 in T-ALL/LBL Subjects

Reporting group description

Serious adverse events	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 330 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	4 / 8 (50.00%)	2 / 4 (50.00%)	2 / 4 (50.00%)	8 / 23 (34.78%)	7 / 16 (43.75%)	2 / 3 (66.67%)	4 / 8 (50.00%)
number of deaths (all causes)	1	0	1	0	0	1	2	0	1
number of deaths resulting from adverse events
Investigations
GRAM POSITIVE COCCI
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (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
Alanine aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
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
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
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
Blood bilirubin increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
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
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
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
Hepatic enzyme abnormal
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
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
Neutrophil count increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (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
White blood cell count increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (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
Injury, poisoning and procedural complications
Arterial injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (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
Hip fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (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
Injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (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
Joint dislocation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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
General disorders and administration site conditions
Disease progression
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	2 / 16 (12.50%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0	0 / 1
General physical health deterioration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
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
Malaise
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	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
Immune system disorders
Anaphylactic shock
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 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
Drug hypersensitivity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (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
Gastrointestinal disorders
Constipation
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (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
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	1 / 1	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
Dysphagia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
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
Nausea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	2 / 4 (50.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	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
Small intestinal obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	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 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	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
Respiratory, thoracic and mediastinal disorders
Haemoptysis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (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
Lung infiltration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (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
Pleural effusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (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
Pulmonary embolism
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	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
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (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
Mental status changes
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (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
Infections and infestations
Abdominal abscess
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (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
Fungal infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
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
Pneumonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (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
Sepsis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (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
Product issues
Device dislocation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (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
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 23 (8.70%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (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
Hypoglycaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (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
Hypophosphataemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (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

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

Non-serious adverse events	PF-03084014 40 mg BID in Solid Tumor Subjects	PF-03084014 20 mg BID in Solid Tumor Subjects	PF-03084014 100 mg BID in Solid Tumor Subjects	PF-03084014 80 mg BID in Solid Tumor Subjects	PF-03084014 130 mg BID in Solid Tumor Subjects	PF-03084014 150 mg BID in Solid Tumor Subjects	PF-03084014 220 mg BID in Solid Tumor Subjects	PF-03084014 330 mg BID in Solid Tumor Subjects	PF-03084014 in T-ALL/LBL Subjects
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	3 / 3 (100.00%)	7 / 8 (87.50%)	4 / 4 (100.00%)	3 / 4 (75.00%)	23 / 23 (100.00%)	16 / 16 (100.00%)	3 / 3 (100.00%)	8 / 8 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Central nervous system leukaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Lipoma
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Meningioma
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Tumour haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Tumour pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	3	0	0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Flushing
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	2	1	0	0
Hot flush
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	1 / 23 (4.35%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	1	1	0	0
Lymphoedema
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Peripheral vascular disorder
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Vena cava thrombosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	0 / 16 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)
occurrences all number	0	1	0	0	0	2	0	1	1
Chest discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	1	0	0	0	0	1
Chills
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0	0	1	0
Early satiety
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0	0
Facial pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Fatigue
subjects affected / exposed	2 / 3 (66.67%)	2 / 3 (66.67%)	1 / 8 (12.50%)	2 / 4 (50.00%)	1 / 4 (25.00%)	12 / 23 (52.17%)	7 / 16 (43.75%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	3	2	2	4	1	14	11	2	0
General physical health deterioration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Induration
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Influenza like illness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0
Mucosal dryness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Mucosal inflammation
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	2 / 23 (8.70%)	0 / 16 (0.00%)	2 / 3 (66.67%)	0 / 8 (0.00%)
occurrences all number	0	1	0	1	0	2	0	3	0
Oedema peripheral
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	1	0	1	0	1	1	0	0
Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0	0	1	0
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	3 / 23 (13.04%)	2 / 16 (12.50%)	1 / 3 (33.33%)	2 / 8 (25.00%)
occurrences all number	0	1	0	0	1	3	2	1	3
Immune system disorders
Contrast media allergy
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Seasonal allergy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Reproductive system and breast disorders
Amenorrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Breast disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Scrotal mass
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Sexual dysfunction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Cough
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	2 / 4 (50.00%)	5 / 23 (21.74%)	5 / 16 (31.25%)	1 / 3 (33.33%)	1 / 8 (12.50%)
occurrences all number	0	0	0	1	3	5	5	2	2
Dysphonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Dyspnoea
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	4 / 23 (17.39%)	2 / 16 (12.50%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	1	1	0	0	4	2	1	0
Dyspnoea exertional
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	1	0	0	0	0	0	0
Epistaxis
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	2 / 16 (12.50%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1	0	0	0	1	2	0	1
Hypoxia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	8
Nasal congestion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	1	0	1	0
Oropharyngeal pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	4 / 23 (17.39%)	1 / 16 (6.25%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	5	1	2	0
Pleural effusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	1	0	0	0	0	0	1
Productive cough
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)
occurrences all number	0	0	1	0	0	0	0	1	1
Pulmonary embolism
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Respiratory tract congestion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Rhinitis allergic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Rhinorrhoea
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	1	0	0
Rhonchi
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Sinus congestion
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	1 / 16 (6.25%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	1	1	1	0
Throat irritation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Upper-airway cough syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0
Psychiatric disorders
Affective disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Anxiety
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)
occurrences all number	0	1	0	0	0	0	0	2	1
Confusional state
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	1	1
Depressed mood
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	3
Depression
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	1	0	0	0	0
Enuresis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Hallucination
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Insomnia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	3 / 23 (13.04%)	3 / 16 (18.75%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	1	0	1	0	0	3	3	0	1
Obsessive-compulsive disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)	2 / 4 (50.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	0 / 16 (0.00%)	0 / 3 (0.00%)	2 / 8 (25.00%)
occurrences all number	0	1	4	2	0	1	0	0	5
Alpha 1 foetoprotein increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)	2 / 4 (50.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	2 / 16 (12.50%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1	2	2	0	1	2	0	1
Bacterial test positive
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1	1	1	0	0	1	0	3
Blood bilirubin increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	2 / 8 (25.00%)
occurrences all number	0	0	0	0	0	0	0	0	4
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Blood creatinine increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	1 / 16 (6.25%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	1	1	0
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Blood urea increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
C-reactive protein increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	2 / 4 (50.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	2	0	0	0	0	0
Fungal test positive
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Gamma-glutamyltransferase
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	5
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	1	0	0	0	0	0	5
Haemoglobin decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0
International normalised ratio increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	3	0	0
Platelet count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Prothrombin time prolonged
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	3	0	0
Transaminases increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	1	0	0	0	0	1
Weight decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0	0	0	1	0
White blood cell count increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	1 / 16 (6.25%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	1	1	0
Fall
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0	1	0	1	0
Meniscus injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Muscle strain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Procedural pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Rib fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Road traffic accident
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Skin abrasion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Stoma site pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Wound complication
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Palpitations
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0	0	2	0
Sinus tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	1	0	0	0	0	0	1
Nervous system disorders
Balance disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Cerebrovascular disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Disturbance in attention
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Dizziness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 23 (8.70%)	0 / 16 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	3	0	1	1
Dysgeusia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0
Dyskinesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	1	0	1
Headache
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 23 (8.70%)	3 / 16 (18.75%)	1 / 3 (33.33%)	1 / 8 (12.50%)
occurrences all number	0	2	0	0	0	2	3	3	1
Hypoaesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	1	1	0	0	0	1	0
Intracranial aneurysm
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Memory impairment
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Neuralgia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Neuropathy peripheral
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	2 / 8 (25.00%)
occurrences all number	0	1	0	1	0	0	0	1	2
Paraparesis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	2
Presyncope
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Sinus headache
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Speech disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Syncope
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	2 / 23 (8.70%)	1 / 16 (6.25%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	2	0	3	1	0	3
Leukocytosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	1 / 16 (6.25%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	1	1	0	1
Leukopenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	1	0	1
Neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Splenomegaly
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Thrombocytopenia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1	0	0	0	0	1	0	1
Ear and labyrinth disorders
Hypoacusis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Vertigo
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0
Eye disorders
Dry eye
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0
Eye irritation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Eye movement disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Eye pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Eye pruritus
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Orbital oedema
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Photophobia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Visual impairment
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0	1	0	2	0
Vitreous floaters
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0	0
Abdominal distension
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Abdominal pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 23 (8.70%)	2 / 16 (12.50%)	1 / 3 (33.33%)	1 / 8 (12.50%)
occurrences all number	0	2	1	0	0	4	3	1	1
Abdominal pain lower
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Abdominal pain upper
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	3 / 23 (13.04%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	2	0	0	1	0	3	0	0	0
Ascites
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Constipation
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 23 (8.70%)	2 / 16 (12.50%)	1 / 3 (33.33%)	2 / 8 (25.00%)
occurrences all number	1	1	0	0	0	2	2	1	2
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	2 / 4 (50.00%)	3 / 4 (75.00%)	15 / 23 (65.22%)	12 / 16 (75.00%)	3 / 3 (100.00%)	2 / 8 (25.00%)
occurrences all number	0	2	0	5	5	28	18	4	7
Dry mouth
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	5 / 16 (31.25%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	1	5	1	0
Dyspepsia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 23 (8.70%)	1 / 16 (6.25%)	1 / 3 (33.33%)	2 / 8 (25.00%)
occurrences all number	0	0	1	0	0	3	1	2	2
Dysphagia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Faeces soft
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Flatulence
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	2	0	0	0	1	0	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0	1	0	0
Nausea
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	2 / 8 (25.00%)	1 / 4 (25.00%)	3 / 4 (75.00%)	14 / 23 (60.87%)	8 / 16 (50.00%)	2 / 3 (66.67%)	5 / 8 (62.50%)
occurrences all number	0	3	2	1	4	21	11	3	11
Oesophageal ulcer haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Oral pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 23 (8.70%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Stomatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	2	0	0	1
Toothache
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 8 (25.00%)	1 / 4 (25.00%)	2 / 4 (50.00%)	10 / 23 (43.48%)	5 / 16 (31.25%)	2 / 3 (66.67%)	5 / 8 (62.50%)
occurrences all number	0	0	2	1	2	13	8	4	5
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	3	1	0	0	0	3	0	0	0
Ocular icterus
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Skin and subcutaneous tissue disorders
PRURITIS
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0	1	0	0
Alopecia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Blister
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Cold sweat
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Dermal cyst
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0	0	2	0	0
Dermatitis acneiform
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 23 (8.70%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	3	1	0	0
Dry skin
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	1 / 16 (6.25%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	1	1	0
Exfoliative rash
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Nail bed disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Pain of skin
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Photosensitivity reaction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 23 (8.70%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Pruritus
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 23 (8.70%)	0 / 16 (0.00%)	0 / 3 (0.00%)	2 / 8 (25.00%)
occurrences all number	0	0	1	0	0	2	0	0	3
Rash
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	4 / 23 (17.39%)	3 / 16 (18.75%)	2 / 3 (66.67%)	0 / 8 (0.00%)
occurrences all number	1	3	2	0	0	5	3	2	0
Rash erythematous
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 23 (8.70%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Rash macular
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0
Rash maculo-papular
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Rash pruritic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Skin lesion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0	1	0	1	0
Skin ulcer
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0
Renal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	2 / 4 (50.00%)	0 / 4 (0.00%)	2 / 23 (8.70%)	2 / 16 (12.50%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	3	0	2	2	4	0
Back pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	0 / 16 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	1	0	1	1
Bone cyst
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Bone pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	1	0	1
Bone swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Bursitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Flank pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0
Joint hyperextension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Joint stiffness
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Joint swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Musculoskeletal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Osteopenia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Pain in extremity
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 23 (8.70%)	0 / 16 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)
occurrences all number	1	0	0	0	0	2	0	1	1
Infections and infestations
Candida infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Conjunctivitis
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0	0
Ear infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0	3	0	0	0
Eye infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Folliculitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 23 (8.70%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Gastroenteritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0
Gastroenteritis viral
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	1 / 23 (4.35%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0
Influenza
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Laryngitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	1	0	0	0	1
Lung infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Oral herpes
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Oropharyngeal candidiasis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Pneumonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	1	0	0	0	0	1
Rhinitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Sinusitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	2 / 4 (50.00%)	2 / 23 (8.70%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	2	2	0	1	0
Tooth infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	1 / 4 (25.00%)	3 / 23 (13.04%)	1 / 16 (6.25%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	1	3	1	3	0
Urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 23 (8.70%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	5	0	0	0
Urinary tract infection viral
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Viral infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Metabolism and nutrition disorders
Cachexia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Decreased appetite
subjects affected / exposed	2 / 3 (66.67%)	2 / 3 (66.67%)	1 / 8 (12.50%)	0 / 4 (0.00%)	1 / 4 (25.00%)	7 / 23 (30.43%)	3 / 16 (18.75%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	3	2	1	0	1	9	4	2	0
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	3 / 23 (13.04%)	1 / 16 (6.25%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	3	1	1	0
Diabetes mellitus
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Fluid overload
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Fluid retention
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Hyperglycaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Hyperuricaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Hypoalbuminaemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	1 / 16 (6.25%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	1	0	0	0	0	2	1	0	3
Hypocalcaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0
Hypokalaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	1 / 4 (25.00%)	1 / 4 (25.00%)	5 / 23 (21.74%)	2 / 16 (12.50%)	1 / 3 (33.33%)	1 / 8 (12.50%)
occurrences all number	0	2	0	1	1	5	2	2	1
Hypomagnesaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	1 / 16 (6.25%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	1	1	0	1
Hyponatraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 23 (4.35%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	1	1	0	0
Hypophosphataemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 8 (25.00%)	2 / 4 (50.00%)	2 / 4 (50.00%)	6 / 23 (26.09%)	9 / 16 (56.25%)	1 / 3 (33.33%)	0 / 8 (0.00%)
occurrences all number	0	0	2	3	2	18	17	4	0
Malnutrition
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 23 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1

More information

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Were there any global substantial amendments to the protocol? No

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.

The study components related to combination therapy with dexamethasone were removed due to operational and scientific reasons.

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Clinical trials

Clinical Trial Results: A Phase 1 Trial of PF-03084014 in Patients With Advanced Solid Tumor Malignancy and T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Solid Tumor Subjects With First-Cycle Dose-Limiting Toxicity (DLT)

Primary: Number of Solid Tumor Subjects With First-Cycle Dose-Limiting Toxicity (DLT)

Primary: Number of T-ALL/LBL Subjects With First-Cycle DLT

Primary: Number of T-ALL/LBL Subjects With First-Cycle DLT

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) (All Causality)

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) (All Causality)

Secondary: Number of Subjects With TEAEs (Treatment-Related)

Secondary: Number of Subjects With TEAEs (Treatment-Related)

Secondary: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) (All Causality) by maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade

Secondary: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) (All Causality) by maximum Common Terminology Criteria for Adverse Events (CTCAE) Grade

Secondary: Number of Subjects with TEAEs (Treatment-Related) by Maximum CTCAE Grade

Secondary: Number of Subjects with TEAEs (Treatment-Related) by Maximum CTCAE Grade

Secondary: Number of Subjects With Potentially Clinical Significant Categorical Changes From Baseline in Electrocardiogram (ECG) Findings in QTc Interval

Secondary: Number of Subjects With Potentially Clinical Significant Categorical Changes From Baseline in Electrocardiogram (ECG) Findings in QTc Interval

Secondary: Number of Subjects With Laboratory Tests Abnormalities Meeting the Criteria of Potential Clinical Concern (Hematology and Chemistries, All Cycles)

Secondary: Number of Subjects With Laboratory Tests Abnormalities Meeting the Criteria of Potential Clinical Concern (Hematology and Chemistries, All Cycles)

Secondary: Maximum Observed Serum Concentration (Cmax) After a Single Dose on Cycle 1 Day 1

Secondary: Maximum Observed Serum Concentration (Cmax) After a Single Dose on Cycle 1 Day 1

Secondary: Time to Reach Cmax (Tmax) After a Single Dose on Cycle 1 Day 1

Secondary: Time to Reach Cmax (Tmax) After a Single Dose on Cycle 1 Day 1

Secondary: Area Under the Time-Concentration Curve From Time 0 to the Dosing Interval (AUCtau) After a Single Dose on Cycle 1 Day 1

Secondary: Area Under the Time-Concentration Curve From Time 0 to the Dosing Interval (AUCtau) After a Single Dose on Cycle 1 Day 1

Secondary: Cmax After Multiple Dose on Cycle 1 Day 21

Secondary: Cmax After Multiple Dose on Cycle 1 Day 21

Secondary: Time to Reach Cmax (Tmax) after multiple dose on Cycle 1 Day 21

Secondary: Time to Reach Cmax (Tmax) after multiple dose on Cycle 1 Day 21

Secondary: AUCtau After Multiple Dose on Cycle 1 Day 21

Secondary: AUCtau After Multiple Dose on Cycle 1 Day 21

Secondary: Apparent Volume of Distribution (Vz/F) on Cycle 1 Day 21

Secondary: Apparent Volume of Distribution (Vz/F) on Cycle 1 Day 21

Secondary: Serum Decay Half-Life (t1/2) After Multiple Dose on Cycle 1 Day 21

Secondary: Serum Decay Half-Life (t1/2) After Multiple Dose on Cycle 1 Day 21

Secondary: Apparent Oral Clearance (CL/F) on Cycle 1 Day 21

Secondary: Apparent Oral Clearance (CL/F) on Cycle 1 Day 21

Secondary: Minimum Observed Serum Concentration (Cmin) After Multiple Dose on Cycle 1 Day 21

Secondary: Minimum Observed Serum Concentration (Cmin) After Multiple Dose on Cycle 1 Day 21

Secondary: Average Serum Concentration (Cavg) at Steady State on Cycle 1 Day 21

Secondary: Average Serum Concentration (Cavg) at Steady State on Cycle 1 Day 21

Secondary: Accumulation ratio (Rac) on Cycle 1 Day 21

Secondary: Accumulation ratio (Rac) on Cycle 1 Day 21

Secondary: Dose-normalized AUCtau [AUCtau(dn)] in the Fasted State for Solid Tumor Subjects

Secondary: Dose-normalized AUCtau [AUCtau(dn)] in the Fasted State for Solid Tumor Subjects

Secondary: Dose-normalized AUCtau [AUCtau(dn)] in the Fed State for Solid Tumor Subjects

Secondary: Dose-normalized AUCtau [AUCtau(dn)] in the Fed State for Solid Tumor Subjects

Secondary: Dose-normalized Cmax [Cmax(dn)] in the Fasted State for Solid Tumor Subjects

Secondary: Dose-normalized Cmax [Cmax(dn)] in the Fasted State for Solid Tumor Subjects

Secondary: Dose-normalized Cmax(dn) in the Fed State for Solid Tumor Subjects

Secondary: Dose-normalized Cmax(dn) in the Fed State for Solid Tumor Subjects

Secondary: Percentage of Solid Tumor Subjects With Objective Response (OR)

Secondary: Percentage of Solid Tumor Subjects With Objective Response (OR)

Secondary: Time to Progression (TTP) for Solid Tumor Subjects

Secondary: Time to Progression (TTP) for Solid Tumor Subjects

Secondary: Duration of Response (DR) for Solid Tumor Subjects

Secondary: Duration of Response (DR) for Solid Tumor Subjects

Secondary: Progression-Free Survival (PFS) for Solid Tumor Subjects

Secondary: Progression-Free Survival (PFS) for Solid Tumor Subjects

Secondary: Percentage of T-ALL/LBL subjects with OR

Secondary: Percentage of T-ALL/LBL subjects with OR

Secondary: Relapse Free Survival (RFS) for T-ALL/LBL subjects

Secondary: Relapse Free Survival (RFS) for T-ALL/LBL subjects

Secondary: Peripheral Blast Count Reduction (PBR) for T-ALL/LBL Subjects

Secondary: Peripheral Blast Count Reduction (PBR) for T-ALL/LBL Subjects

Secondary: Changes in Expression Levels of Notch 1 Target Genes in Tumor Biopsies for Solid Tumor Subjects: Hes4 Gene Expression Levels on Cycle 1 Day 21 Relative to That at Baseline

Secondary: Changes in Expression Levels of Notch 1 Target Genes in Tumor Biopsies for Solid Tumor Subjects: Hes4 Gene Expression Levels on Cycle 1 Day 21 Relative to That at Baseline

Secondary: Changes From Baseline in Expression Levels of Notch 1 Target Genes in Peripheral Blood for T-ALL/LBL Subjects: Hes4 Gene Expression Levels on Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 21 Relative to That at Baseline

Secondary: Changes From Baseline in Expression Levels of Notch 1 Target Genes in Peripheral Blood for T-ALL/LBL Subjects: Hes4 Gene Expression Levels on Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 21 Relative to That at Baseline

Secondary: Changes in Expression Levels of Notch 1 Target Genes in Peripheral Blood for Solid Tumor Subjects: Hairy and Enhancer of Split-4 (Hes4) Gene Expression Level on Cycle 1 Day 8 and Cycle 1 Day 21 Relative to That at Baseline

Secondary: Changes in Expression Levels of Notch 1 Target Genes in Peripheral Blood for Solid Tumor Subjects: Hairy and Enhancer of Split-4 (Hes4) Gene Expression Level on Cycle 1 Day 8 and Cycle 1 Day 21 Relative to That at Baseline

Secondary: Changes From Baseline in Notch Intracellular Domain (NICD) Levels in Peripheral Blood for T-ALL/LBL Subjects

Secondary: Changes From Baseline in Notch Intracellular Domain (NICD) Levels in Peripheral Blood for T-ALL/LBL Subjects

Clinical Trial Results:
A Phase 1 Trial of PF-03084014 in Patients With Advanced Solid Tumor Malignancy and T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma