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Clinical Trial Results:
A Phase Ib/II, open label, multi-center study evaluating the safety and efficacy of BKM120 in combination with trastuzumab in patients with relapsing HER2 overexpressing breast cancer who have previously failed trastuzumab

Summary
EudraCT number	2009-015417-46
Trial protocol	GB BE
Global end of trial date	07 Aug 2014

Results information
Results version number	v1(current)
This version publication date	28 Jul 2016
First version publication date	28 Jul 2016
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

CBKM120X2107

ISRCTN number

US NCT number

NCT01132664

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,

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

07 Aug 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

07 Aug 2014

Was the trial ended prematurely?

Main objective of the trial

The Phase Ib was to determine the maximum-tolerated dose (MTD) of buparlisib when administered orally in combination with weekly trastuzumab to adult patients with HER2-overexpressing breast cancer that is resistant to trastuzumab therapy. The phase II was to determine the activity of buparlisib in combination with weekly trastuzumab as measured by objective response rate (ORR) in patients with HER2-overexpressing breast cancer that is resistant to trastuzumab therapy. This study was extended to include HER2 positive breast cancer patients with brain metastasis (to determine the MTD/RP2D, safety, tolerability and preliminary anti-tumor activity) of oral buparlisib and capecitabine in combination with fixed dose trastuzumab. However, the brain metastasis part was terminated after completion of the first three dose escalation cohorts due to recruitment challenges.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

17 May 2010

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 8

Country: Number of subjects enrolled

France: 3

Country: Number of subjects enrolled

Italy: 11

Country: Number of subjects enrolled

Spain: 12

Country: Number of subjects enrolled

United Kingdom: 19

Country: Number of subjects enrolled

United States: 15

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

72 patients (pts) were enrolled: 18 in ph lb, 53 in ph ll, including 8 from ph lb, with 45 new pts in ph ll & 9 in the brain metastasis (BM) cohort. Of the 72 pts, 1 in ph lb & 3 in phase ll, did not receive Burparlisib, only Trastuzumab. Therefore, 68 patients (17 in ph l, 42 in ph ll, 9 in BM cohort) were treated with buparlisib + trastuzumab.

Screening details

Primary outcome measure for BM cohort was MTD/RP2D which was not reached/established due to termination of the study. Objective Response Rate (ORR), Disease Control Rate (DCR), Clinical Benefit Rate (CBR) & Progression Free Survival (PFS)were not calculated for the BM cohort either.

Period 1 title

Overall (Phase I, Phase II, BM Cohort) (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Phase Ib - 50 mg

Arm description

Patients in the phase Ib dose escalation cohort who received 50 mg of buparlisib - investigational drug + trastuzumab 4 mg/kg loading dose iv infusion (if required) on Day -7, 2 mg/kg weekly iv infusion subsequently

Arm type

Experimental

Investigational medicinal product name

Buparlisib

Investigational medicinal product code

BKM120

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Burparlisib was supplied as 10 mg and 50 mg hard gelatin capsules

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

4 mg/kg loading dose iv infusion (if required) on Day -7, 2 mg/kg weekly iv infusion subsequently

Phase Ib - 100mg

Arm description

Patients in the phase Ib dose escalation cohort who received 100 mg of buparlisib - investigational drug + trastuzumab 4 mg/kg loading dose iv infusion (if required) on Day -7, 2 mg/kg weekly iv infusion subsequently

Arm type

Experimental

Investigational medicinal product name

Buparlisib

Investigational medicinal product code

BKM120

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Burparlisib was supplied as 10 mg and 50 mg hard gelatin capsules

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

4 mg/kg loading dose iv infusion (if required) on Day -7, 2 mg/kg weekly iv infusion subsequently

Phase II - 100mg

Arm description

Patients in the phase II expansion + patients from phase Ib dose escalation were included in phase II and received 100 mg of investigational drug - buparsilib + trastuzumab 4 mg/kg loading dose iv infusion (if required) on Day -7, 2 mg/kg weekly iv infusion subsequently

Arm type

Experimental

Investigational medicinal product name

Buparlisib

Investigational medicinal product code

BKM120

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Burparlisib was supplied as 10 mg and 50 mg hard gelatin capsules

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

4 mg/kg loading dose iv infusion (if required) on Day -7, 2 mg/kg weekly iv infusion subsequently

BM Cohort - 80mg

Arm description

Patients in the BM cohort who received 80 mg of buparlisib - investigational drug + trastuzumab 4 mg/kg loading dose iv infusion (if required) on Day -7, 2 mg/kg weekly iv infusion subsequently + capecitabine 1000 mg/m2 twice a day from Day 1 to Day 14 of a 21- day cycle.

Arm type

Experimental

Investigational medicinal product name

Buparlisib

Investigational medicinal product code

BKM120

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Burparlisib was supplied as 10 mg and 50 mg hard gelatin capsules

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

4 mg/kg loading dose iv infusion (if required) on Day -7, 2 mg/kg weekly iv infusion subsequently

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

1000 mg/m2 twice a day from Day 1 to Day 14 of a 21- day cycle

BM Cohort - 100mg

Arm description

Patients in the BM cohort who received 100 mg of buparlisib - investigational drug + trastuzumab 4 mg/kg loading dose iv infusion (if required) on Day -7, 2 mg/kg weekly iv infusion subsequently + capecitabine 1000 mg/m2 twice a day from Day 1 to Day 14 of a 21- day cycle.

Arm type

Experimental

Investigational medicinal product name

Buparlisib

Investigational medicinal product code

BKM120

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Burparlisib was supplied as 10 mg and 50 mg hard gelatin capsules

Investigational medicinal product name

Trastuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

4 mg/kg loading dose iv infusion (if required) on Day -7, 2 mg/kg weekly iv infusion subsequently

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

1000 mg/m2 twice a day from Day 1 to Day 14 of a 21- day cycle

Number of subjects in period 1	Phase Ib - 50 mg	Phase Ib - 100mg	Phase II - 100mg	BM Cohort - 80mg	BM Cohort - 100mg
Started	5	12	42	3	6
Completed	0	0	0	0	0
Not completed	5	12	42	3	6
Adverse event, serious fatal	-	-	2	-	-
Consent withdrawn by subject	1	2	2	-	1
Adverse event, non-fatal	-	1	9	-	1
Disease Progression	4	9	29	3	4

Baseline characteristics

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Reporting group title

Phase Ib - 50 mg

Reporting group description

Reporting group title

Phase Ib - 100mg

Reporting group description

Reporting group title

Phase II - 100mg

Reporting group description

Reporting group title

BM Cohort - 80mg

Reporting group description

Reporting group title

BM Cohort - 100mg

Reporting group description

Reporting group values	Phase Ib - 50 mg	Phase Ib - 100mg	Phase II - 100mg	BM Cohort - 80mg	BM Cohort - 100mg	Total
Number of subjects	5	12	42	3	6	68
Age categorical
Units: Subjects
Adults (18-64 years)	5	11	35	3	6	60
From 65-84 years	0	1	7	0	0	8
Gender, Male/Female
Units: Participants
Female	5	12	42	3	6	68
Male	0	0	0	0	0	0
Study Specific Characteristic
Units: Subjects
Able to bear children	2	3	8	1	1	15
Premenarche	0	0	0	0	0	0
Post-menopausal	3	8	31	2	4	48
Sterile - of child bearing age	0	1	3	0	1	5

End points

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Reporting group title

Phase Ib - 50 mg

Reporting group description

Reporting group title

Phase Ib - 100mg

Reporting group description

Reporting group title

Phase II - 100mg

Reporting group description

Reporting group title

BM Cohort - 80mg

Reporting group description

Reporting group title

BM Cohort - 100mg

Reporting group description

Subject analysis set title

Phase ll 100 mg 50 patients

Subject analysis set type

Full analysis

Subject analysis set description

phase II plus 8 patients from phase Ib

Primary: Dose Limiting Toxicity (DLT) - Phase l only

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End point title

Dose Limiting Toxicity (DLT) - Phase l only ^[1] ^[2]

End point description

Determination of the maximum tolerated dose (MTD) in the dose escalation part of the study was based upon the estimation of the probability of DLT in Cycle 1 in patients of the dose-determining set. The Dose–determining set (DDS) for the determination of the MTD consisted of all patients from the safety set in the dose escalation phase who had met the minimum safety evaluation requirements and the minimum exposure criterion or had experienced DLT during Cycle 1 and were discontinued. MTD analysis was done only on the phase lb group.

End point type

Primary

End point timeframe

cycle 1 - 28 days

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: There was no planned analysis.
[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: Only summary analysis are provided for this measure and EudraCT can only accept analysis that compares one arm versus another.

End point values	Phase Ib - 50 mg	Phase Ib - 100mg	BM Cohort - 80mg	BM Cohort - 100mg
Number of subjects analysed	4	11	3	5
Units: Participants
Primary system orgran class (SOC) PT - grade 1	0	0	0	0
Primary SOC PT - grade 2	0	0	0	0
Primary SOC PT (asthenia) - grade 3	0	1	0	0
Primary SOC PT - grade 4	0	0	0	0
Primary SOC PT - missing	0	0	0	0
Primary SOC PT (somatits/diarrhea) - grade 3	0	0	0	1

No statistical analyses for this end point

Primary: Overall Response Rate (ORR) - Phase ll

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End point title

Overall Response Rate (ORR) - Phase ll ^[3]

End point description

Objective response rate (ORR) was defined as the rate of patients with best overall response (BOR) equal to complete response (CR) or partial response (PR) according to RECIST 1.0 from the Investigators review. Per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 assessed of the disease status by imaging (i.e. CT/MRI): Complete Response (CR) = Disappearance of all tumor lesions; Partial Response (PR)= >=30% shrinkage of lesions; Overall Response (OR) = patients with CR and PR. The full analysis set (FAS) consisted of all patients who received at least one dose of study drug (buparlisib)

End point type

Primary

End point timeframe

18 months

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: There was no planned analysis.

End point values	Phase ll 100 mg 50 patients
Number of subjects analysed	50
Units: Participants	5

No statistical analyses for this end point

Secondary: Disease control rate (DCR) based on Investigator assessment- Phase l & ll

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End point title

Disease control rate (DCR) based on Investigator assessment- Phase l & ll ^[4]

End point description

Disease control rate (DCR) = patients with complete response (CR), partial response (PR) or stable disease (SD) as per RECIST criteria. Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 assessed the disease status by imaging (i.e. CT/MRI): CR = disappearance of all tumor lesions; PR = >=30% shrinkage of lesions; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease (PD); PD = At least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline. The full analysis set (FAS) consisted of all patients who received at least one dose of study drug (buparlisib).

End point type

Secondary

End point timeframe

18 months

Notes
[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 was for only Phase I and II arms.

End point values	Phase Ib - 50 mg	Phase Ib - 100mg	Phase ll 100 mg 50 patients
Number of subjects analysed	5	12	50
Units: Participants
Phase l	1	7	0
Phase ll	0	0	25

No statistical analyses for this end point

Secondary: Clinical benefit rate (CBR) - Phase l & ll

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End point title

Clinical benefit rate (CBR) - Phase l & ll ^[5]

End point description

CBR = patients with CR, PR or SD ≥ 24 weeks according to RECIST by the investigator. Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 assessed the disease status by imaging (i.e. CT/MRI): CR = Disappearance of all tumor lesions; PR= >=30% shrinkage of lesions;SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease (PD); PD = At least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline. The full analysis set (FAS) consisted of all patients who received at least one dose of study drug (buparlisib).

End point type

Secondary

End point timeframe

18 months

Notes
[5] - 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: There was no planned analysis.

End point values	Phase Ib - 50 mg	Phase Ib - 100mg	Phase ll 100 mg 50 patients
Number of subjects analysed	5	12	50
Units: Participants
Phase l	0	3	0
Phase ll	0	0	7

No statistical analyses for this end point

Secondary: Progression free survival (PFS) - based on investigator review using Kaplan Meier - Phase l

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End point title

Progression free survival (PFS) - based on investigator review using Kaplan Meier - Phase l ^[6]

End point description

End point type

Secondary

End point timeframe

18 months

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: This endpoint was only for Phase I arm.

End point values	Phase Ib - 50 mg	Phase Ib - 100mg
Number of subjects analysed	5	12
Units: Months
median (confidence interval 90%)	1.7 (1.3 to 3.6)	3.3 (1.6 to 5.4)

No statistical analyses for this end point

Secondary: Progression free survival (PFS) - based on investigator review using Kaplan Meier - Phase II

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End point title

Progression free survival (PFS) - based on investigator review using Kaplan Meier - Phase II

End point description

PFS Was Analyzed Only in Patients With Known PIK3 Status, Thus Only 26/50 Patients Were Analyzed. The full analysis set (FAS) consisted of all patients who received at least one dose of study drug (buparlisib).

End point type

Secondary

End point timeframe

18 months

End point values	Phase ll 100 mg 50 patients
Number of subjects analysed	26
Units: Months
median (confidence interval 90%)
Phase ll: PIK3CA wildtype (n =18)	1.7 (1.5 to 5.4)
Phase ll: PIK3CA mutated (n =8)	1.8 (1.3 to 3.4)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.

Adverse event reporting additional description

Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Phase Ib Dose escalation 50 mg/day

Reporting group description

Phase Ib Dose escalation 50 mg/day

Reporting group title

Phase II Dose expansion 0 mg/day

Reporting group description

Phase II Dose expansion 0 mg/day

Reporting group title

Phase Ib Dose escalation 100 mg/day

Reporting group description

Phase Ib Dose escalation 100 mg/day

Reporting group title

BM cohort 80 mg/day

Reporting group description

BM cohort 80 mg/day

Reporting group title

All Phase Ib + II

Reporting group description

All Phase Ib + II

Reporting group title

BM cohort 100 mg/day

Reporting group description

BM cohort 100 mg/day

Reporting group title

Phase II Dose expansion 100 mg/day

Reporting group description

Phase II Dose expansion 100 mg/day

Serious adverse events	Phase Ib Dose escalation 50 mg/day	Phase II Dose expansion 0 mg/day	Phase Ib Dose escalation 100 mg/day	BM cohort 80 mg/day	All Phase Ib + II	BM cohort 100 mg/day	Phase II Dose expansion 100 mg/day
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 5 (40.00%)	1 / 3 (33.33%)	2 / 12 (16.67%)	2 / 3 (66.67%)	20 / 63 (31.75%)	4 / 6 (66.67%)	17 / 50 (34.00%)
number of deaths (all causes)	1	0	1	0	5	0	4
number of deaths resulting from adverse events	0	0	0	0	0	0	0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 3 (0.00%)	3 / 63 (4.76%)	0 / 6 (0.00%)	3 / 50 (6.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	3 / 3	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General Physical Health Deterioration
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperpyrexia
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	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
Oedema Peripheral
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Systemic Inflammatory Response Syndrome
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 63 (0.00%)	1 / 6 (16.67%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	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
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 63 (0.00%)	1 / 6 (16.67%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	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
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	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
Dyspnoea
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	2 / 50 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural Effusion
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	2 / 50 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Pneumonitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	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
Respiratory Failure
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Affective Disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Confusional State
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Delirium
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 63 (0.00%)	1 / 6 (16.67%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	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
Depressed Mood
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mood Altered
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine Aminotransferase Increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	2 / 50 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Aspartate Aminotransferase Increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Bilirubin Conjugated Increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Blood Bilirubin Increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Nervous system disorders
Cerebral Haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular Accident
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Convulsion
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	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
Epilepsy
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Status Epilepticus
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal Pain Upper
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Constipation
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	3 / 63 (4.76%)	0 / 6 (0.00%)	3 / 50 (6.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	2 / 3	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	2 / 50 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic Failure
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Photosensitivity Reaction
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	2 / 50 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash Maculo-Papular
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Bone Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 63 (0.00%)	1 / 6 (16.67%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	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
Muscular Weakness
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal Stiffness
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Device Related Infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	2 / 50 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lobar Pneumonia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	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
Lower Respiratory Tract Infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 63 (0.00%)	1 / 6 (16.67%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	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
Lung Infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	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
Metabolism and nutrition disorders
Diabetic Ketoacidosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypercreatininaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Phase Ib Dose escalation 50 mg/day	Phase II Dose expansion 0 mg/day	Phase Ib Dose escalation 100 mg/day	BM cohort 80 mg/day	All Phase Ib + II	BM cohort 100 mg/day	Phase II Dose expansion 100 mg/day
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 5 (100.00%)	2 / 3 (66.67%)	12 / 12 (100.00%)	3 / 3 (100.00%)	61 / 63 (96.83%)	6 / 6 (100.00%)	50 / 50 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	1	0	1
Vascular disorders
Hot Flush
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	1	0	1	0	0
Hypertension
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)	0 / 3 (0.00%)	6 / 63 (9.52%)	0 / 6 (0.00%)	6 / 50 (12.00%)
occurrences all number	0	0	4	0	7	0	7
Orthostatic Hypotension
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	6 / 12 (50.00%)	0 / 3 (0.00%)	16 / 63 (25.40%)	1 / 6 (16.67%)	13 / 50 (26.00%)
occurrences all number	2	0	8	0	20	1	16
Chest Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	2	0	1
Chills
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	3 / 63 (4.76%)	0 / 6 (0.00%)	2 / 50 (4.00%)
occurrences all number	1	0	0	0	5	0	4
Face Oedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	1	1	0	1
Fatigue
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	3 / 3 (100.00%)	16 / 63 (25.40%)	4 / 6 (66.67%)	16 / 50 (32.00%)
occurrences all number	0	0	0	4	20	5	20
Gait Disturbance
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	3	0	0	0
Injection Site Reaction
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Mucosal Dryness
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	3	0	3	0	2
Mucosal Inflammation
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 63 (0.00%)	1 / 6 (16.67%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Non-Cardiac Chest Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	7 / 63 (11.11%)	0 / 6 (0.00%)	7 / 50 (14.00%)
occurrences all number	0	0	0	1	8	0	8
Oedema Peripheral
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	4 / 63 (6.35%)	0 / 6 (0.00%)	4 / 50 (8.00%)
occurrences all number	0	0	0	0	6	0	6
Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)	1 / 63 (1.59%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	1	1	1	0	0
Pyrexia
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	6 / 63 (9.52%)	1 / 6 (16.67%)	5 / 50 (10.00%)
occurrences all number	1	0	0	1	7	1	6
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	1	0	1
Reproductive system and breast disorders
Breast Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	1 / 6 (16.67%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	2	0
Vulvovaginal Discomfort
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 63 (0.00%)	1 / 6 (16.67%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	4 / 12 (33.33%)	2 / 3 (66.67%)	16 / 63 (25.40%)	1 / 6 (16.67%)	15 / 50 (30.00%)
occurrences all number	0	0	8	2	21	1	19
Dyspnoea
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)	6 / 63 (9.52%)	0 / 6 (0.00%)	6 / 50 (12.00%)
occurrences all number	0	0	1	1	6	0	6
Epistaxis
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	1	0	0	0	3	0	2
Hiccups
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	1	1	0	1
Interstitial Lung Disease
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	1	0	1
Oropharyngeal Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)	4 / 63 (6.35%)	2 / 6 (33.33%)	4 / 50 (8.00%)
occurrences all number	0	0	1	1	4	2	4
Pleural Effusion
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	1	2	0	2
Pleuritic Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	1	0	1
Productive Cough
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	3	0	0	0
Respiratory Disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Psychiatric disorders
Affective Disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)	0 / 3 (0.00%)	5 / 63 (7.94%)	0 / 6 (0.00%)	5 / 50 (10.00%)
occurrences all number	0	0	6	0	8	0	8
Anxiety
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)	11 / 63 (17.46%)	2 / 6 (33.33%)	11 / 50 (22.00%)
occurrences all number	0	0	1	4	11	2	11
Binge Eating
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Delirium
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 63 (0.00%)	1 / 6 (16.67%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Depressed Mood
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	3 / 63 (4.76%)	0 / 6 (0.00%)	3 / 50 (6.00%)
occurrences all number	0	0	0	0	3	0	3
Depression
subjects affected / exposed	2 / 5 (40.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	10 / 63 (15.87%)	1 / 6 (16.67%)	8 / 50 (16.00%)
occurrences all number	2	0	1	0	11	1	9
Initial Insomnia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Insomnia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	1 / 3 (33.33%)	9 / 63 (14.29%)	0 / 6 (0.00%)	7 / 50 (14.00%)
occurrences all number	0	0	2	1	9	0	7
Irritability
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	1 / 6 (16.67%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	1	0
Mood Altered
subjects affected / exposed	3 / 5 (60.00%)	0 / 3 (0.00%)	4 / 12 (33.33%)	0 / 3 (0.00%)	11 / 63 (17.46%)	1 / 6 (16.67%)	7 / 50 (14.00%)
occurrences all number	3	0	4	0	11	1	7
Nervousness
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	2	1	2	0	2
Restlessness
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	3	0	0	0
Suicidal Ideation
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 63 (0.00%)	1 / 6 (16.67%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Investigations
Alanine Aminotransferase Decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 63 (0.00%)	1 / 6 (16.67%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Alanine Aminotransferase Increased
subjects affected / exposed	1 / 5 (20.00%)	1 / 3 (33.33%)	4 / 12 (33.33%)	0 / 3 (0.00%)	20 / 63 (31.75%)	1 / 6 (16.67%)	18 / 50 (36.00%)
occurrences all number	1	1	7	0	25	1	23
Amylase Increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	1	0	1
Aspartate Aminotransferase Increased
subjects affected / exposed	1 / 5 (20.00%)	1 / 3 (33.33%)	4 / 12 (33.33%)	0 / 3 (0.00%)	19 / 63 (30.16%)	1 / 6 (16.67%)	17 / 50 (34.00%)
occurrences all number	1	1	9	0	26	1	24
Blood Alkaline Phosphatase Increased
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	2 / 12 (16.67%)	0 / 3 (0.00%)	9 / 63 (14.29%)	0 / 6 (0.00%)	8 / 50 (16.00%)
occurrences all number	0	1	3	0	10	0	9
Blood Bilirubin Increased
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 3 (0.00%)	4 / 63 (6.35%)	0 / 6 (0.00%)	3 / 50 (6.00%)
occurrences all number	0	1	0	0	5	0	4
Blood Calcium Decreased
subjects affected / exposed	2 / 5 (40.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	3	0	0	0	3	0	0
Blood Cholesterol Increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	1	0	1
Blood Creatine Phosphokinase Increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	3	3	0	3
Blood Creatine Phosphokinase Mb Increased
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	1	0	0	2	0	1
Blood Creatinine Increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	2 / 50 (4.00%)
occurrences all number	0	0	1	0	2	0	2
Blood Glucose Decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	1	0	1
Blood Glucose Increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	2 / 50 (4.00%)
occurrences all number	0	0	1	0	2	0	2
Blood Thyroid Stimulating Hormone Increased
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	1	0	0	0	1	0	0
Blood Uric Acid Increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	2 / 50 (4.00%)
occurrences all number	0	0	1	0	2	0	2
C-Reactive Protein Increased
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	1 / 3 (33.33%)	2 / 63 (3.17%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	1	0	1	2	0	1
Eastern Cooperative Oncology Group Performance Status Worsened
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	3 / 63 (4.76%)	0 / 6 (0.00%)	3 / 50 (6.00%)
occurrences all number	0	0	1	0	3	0	3
Ejection Fraction Decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	2 / 50 (4.00%)
occurrences all number	0	0	1	0	2	0	2
Glycosylated Haemoglobin Increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Gamma-Glutamyltransferase Increased
subjects affected / exposed	1 / 5 (20.00%)	1 / 3 (33.33%)	3 / 12 (25.00%)	0 / 3 (0.00%)	10 / 63 (15.87%)	0 / 6 (0.00%)	8 / 50 (16.00%)
occurrences all number	1	1	5	0	12	0	10
Haemoglobin Decreased
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	1	0	0	0	2	0	1
Insulin C-Peptide Increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	3	1	0	1
Lipase Increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	1 / 6 (16.67%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	1	1	1
Liver Function Test Abnormal
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	1 / 6 (16.67%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	1	1	1
Low Density Lipoprotein Increased
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	1	0	0	0	1	0	0
Lymphocyte Count Decreased
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	1	0	0	0	1	0	0
Protein Urine Present
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	1	0	1
Weight Decreased
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)	8 / 63 (12.70%)	1 / 6 (16.67%)	7 / 50 (14.00%)
occurrences all number	1	0	1	1	8	1	7
White Blood Cell Count Decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Fall
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	3	1	0	1
Rib Fracture
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	2	0	1
Spinal Fracture
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	1	0	0	0	2	0	1
Tooth Fracture
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	2	0	0	0
Vaginal Laceration
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	4	0	4	0	0
Wound Complication
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	2	0	1
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	2	0	1
Nervous system disorders
Balance Disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)	5 / 63 (7.94%)	0 / 6 (0.00%)	5 / 50 (10.00%)
occurrences all number	0	0	1	1	6	0	6
Cluster Headache
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	2	0	0	0
Dizziness
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)	6 / 63 (9.52%)	1 / 6 (16.67%)	6 / 50 (12.00%)
occurrences all number	0	0	1	1	6	2	6
Dysgeusia
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)	8 / 63 (12.70%)	1 / 6 (16.67%)	7 / 50 (14.00%)
occurrences all number	1	0	1	1	8	1	7
Headache
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)	12 / 63 (19.05%)	2 / 6 (33.33%)	11 / 50 (22.00%)
occurrences all number	1	0	1	3	12	2	11
Memory Impairment
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	2 / 63 (3.17%)	0 / 6 (0.00%)	2 / 50 (4.00%)
occurrences all number	0	0	0	2	2	0	2
Neuropathy Peripheral
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	1 / 6 (16.67%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	1	1	1
Paraesthesia
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	5 / 63 (7.94%)	0 / 6 (0.00%)	3 / 50 (6.00%)
occurrences all number	1	0	1	0	5	0	3
Peripheral Sensory Neuropathy
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	1 / 6 (16.67%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	1	0
Somnolence
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	3 / 63 (4.76%)	0 / 6 (0.00%)	2 / 50 (4.00%)
occurrences all number	1	0	0	0	3	0	2
Syncope
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	1 / 6 (16.67%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	1	1	1
Tremor
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	4 / 63 (6.35%)	1 / 6 (16.67%)	3 / 50 (6.00%)
occurrences all number	1	0	0	1	4	1	3
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	6 / 63 (9.52%)	0 / 6 (0.00%)	5 / 50 (10.00%)
occurrences all number	0	0	1	0	6	0	5
Neutropenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	2 / 3 (66.67%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	2	0	0	0
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	3 / 63 (4.76%)	0 / 6 (0.00%)	3 / 50 (6.00%)
occurrences all number	0	0	0	2	3	0	3
Eye disorders
Dry Eye
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 3 (0.00%)	3 / 63 (4.76%)	0 / 6 (0.00%)	2 / 50 (4.00%)
occurrences all number	0	0	3	0	4	0	3
Extraocular Muscle Paresis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	1	0	1
Eye Irritation
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Eye Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Ocular Hyperaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Photophobia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	1	0	1
Vision Blurred
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	2 / 3 (66.67%)	1 / 63 (1.59%)	1 / 6 (16.67%)	1 / 50 (2.00%)
occurrences all number	0	0	1	4	1	1	1
Visual Impairment
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	2 / 63 (3.17%)	1 / 6 (16.67%)	1 / 50 (2.00%)
occurrences all number	1	0	0	1	2	1	1
Gastrointestinal disorders
Abdominal Distension
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	1	1	0	1
Abdominal Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)	0 / 3 (0.00%)	7 / 63 (11.11%)	1 / 6 (16.67%)	7 / 50 (14.00%)
occurrences all number	0	0	3	0	12	1	12
Abdominal Pain Lower
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Abdominal Pain Upper
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	1 / 3 (33.33%)	6 / 63 (9.52%)	1 / 6 (16.67%)	5 / 50 (10.00%)
occurrences all number	1	0	2	2	7	1	6
Anal Fissure
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	1	2	0	2
Aphthous Stomatitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	3 / 63 (4.76%)	0 / 6 (0.00%)	3 / 50 (6.00%)
occurrences all number	0	0	0	0	5	0	5
Cheilitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	1	1	0	1
Constipation
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)	7 / 63 (11.11%)	2 / 6 (33.33%)	6 / 50 (12.00%)
occurrences all number	1	0	1	1	9	2	8
Diarrhoea
subjects affected / exposed	2 / 5 (40.00%)	0 / 3 (0.00%)	5 / 12 (41.67%)	3 / 3 (100.00%)	29 / 63 (46.03%)	5 / 6 (83.33%)	25 / 50 (50.00%)
occurrences all number	2	0	35	8	83	12	77
Dry Mouth
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)	3 / 63 (4.76%)	0 / 6 (0.00%)	2 / 50 (4.00%)
occurrences all number	0	0	1	1	3	0	2
Dyspepsia
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	3 / 3 (100.00%)	8 / 63 (12.70%)	0 / 6 (0.00%)	7 / 50 (14.00%)
occurrences all number	1	0	1	3	8	0	7
Dysphagia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	3 / 63 (4.76%)	0 / 6 (0.00%)	3 / 50 (6.00%)
occurrences all number	0	0	0	1	3	0	3
Flatulence
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	1	0	1	0	0
Gastrooesophageal Reflux Disease
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	3 / 63 (4.76%)	0 / 6 (0.00%)	3 / 50 (6.00%)
occurrences all number	0	0	0	0	3	0	3
Haematochezia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	1 / 6 (16.67%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	1	0
Haemorrhoids
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)	1 / 63 (1.59%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	4	1	4	0	0
Haemorrhoids Thrombosed
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Lip Ulceration
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Mouth Ulceration
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	3 / 63 (4.76%)	0 / 6 (0.00%)	3 / 50 (6.00%)
occurrences all number	0	0	1	0	3	0	3
Nausea
subjects affected / exposed	2 / 5 (40.00%)	1 / 3 (33.33%)	3 / 12 (25.00%)	2 / 3 (66.67%)	29 / 63 (46.03%)	4 / 6 (66.67%)	26 / 50 (52.00%)
occurrences all number	3	1	3	3	53	8	49
Pigmentation Lip
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Stomatitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	4 / 12 (33.33%)	1 / 3 (33.33%)	12 / 63 (19.05%)	2 / 6 (33.33%)	12 / 50 (24.00%)
occurrences all number	0	0	6	1	22	2	22
Tongue Discolouration
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Tooth Disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Toothache
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	1	1	0	1
Vomiting
subjects affected / exposed	2 / 5 (40.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)	1 / 3 (33.33%)	16 / 63 (25.40%)	4 / 6 (66.67%)	14 / 50 (28.00%)
occurrences all number	3	0	3	2	26	11	23
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	1	1	0	1
Skin and subcutaneous tissue disorders
Blister
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	1	0	1
Dermatitis Acneiform
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	2	0	3	0	1
Dry Skin
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)	1 / 3 (33.33%)	7 / 63 (11.11%)	0 / 6 (0.00%)	6 / 50 (12.00%)
occurrences all number	0	0	4	1	8	0	6
Eczema
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	3 / 63 (4.76%)	0 / 6 (0.00%)	3 / 50 (6.00%)
occurrences all number	0	0	0	0	6	0	6
Erythema
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	3 / 63 (4.76%)	0 / 6 (0.00%)	3 / 50 (6.00%)
occurrences all number	0	0	1	0	4	0	4
Nail Disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	1	0	1	0	0
Night Sweats
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 63 (0.00%)	1 / 6 (16.67%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Palmar-Plantar Erythrodysaesthesia Syndrome
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	2 / 63 (3.17%)	3 / 6 (50.00%)	2 / 50 (4.00%)
occurrences all number	0	0	0	1	2	5	2
Photosensitivity Reaction
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	1 / 6 (16.67%)	1 / 50 (2.00%)
occurrences all number	0	0	5	0	5	1	5
Pruritus
subjects affected / exposed	2 / 5 (40.00%)	0 / 3 (0.00%)	5 / 12 (41.67%)	3 / 3 (100.00%)	12 / 63 (19.05%)	0 / 6 (0.00%)	9 / 50 (18.00%)
occurrences all number	3	0	7	3	23	0	19
Rash
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	6 / 12 (50.00%)	2 / 3 (66.67%)	19 / 63 (30.16%)	1 / 6 (16.67%)	16 / 50 (32.00%)
occurrences all number	1	0	8	2	38	2	35
Rash Generalised
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	1	0	0	0	1	0	0
Rash Maculo-Papular
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	3 / 63 (4.76%)	0 / 6 (0.00%)	3 / 50 (6.00%)
occurrences all number	0	0	0	0	3	0	3
Rash Pruritic
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	4 / 63 (6.35%)	0 / 6 (0.00%)	4 / 50 (8.00%)
occurrences all number	0	0	0	0	4	0	4
Skin Discolouration
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Skin Exfoliation
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	1	0	1
Skin Lesion
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 63 (0.00%)	1 / 6 (16.67%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Swelling Face
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	1	0	0	0	1	0	0
Renal and urinary disorders
Chromaturia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Dysuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	1 / 6 (16.67%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	1	1	1
Haematuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	1	0	1
Micturition Urgency
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	3 / 63 (4.76%)	0 / 6 (0.00%)	3 / 50 (6.00%)
occurrences all number	0	0	1	0	4	0	4
Back Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 3 (0.00%)	7 / 63 (11.11%)	2 / 6 (33.33%)	6 / 50 (12.00%)
occurrences all number	0	0	2	0	9	2	8
Bone Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	3 / 63 (4.76%)	1 / 6 (16.67%)	3 / 50 (6.00%)
occurrences all number	0	0	0	0	3	1	3
Muscle Spasms
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	2 / 3 (66.67%)	5 / 63 (7.94%)	2 / 6 (33.33%)	4 / 50 (8.00%)
occurrences all number	0	0	1	3	11	2	10
Muscular Weakness
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	2	0	0	0
Musculoskeletal Chest Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	2	0	1
Musculoskeletal Pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	1 / 3 (33.33%)	3 / 63 (4.76%)	0 / 6 (0.00%)	2 / 50 (4.00%)
occurrences all number	1	0	2	1	3	0	2
Myalgia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	1	0	1
Pain In Extremity
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	5 / 63 (7.94%)	1 / 6 (16.67%)	5 / 50 (10.00%)
occurrences all number	0	0	1	0	7	2	7
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Conjunctivitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	4	0	0	0
Cystitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	1 / 63 (1.59%)	1 / 6 (16.67%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	1	1	1
Device Related Sepsis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	1	0	1
Ear Infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	1	2	0	2
Eczema Infected
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	1	0	1
Furuncle
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	1	0	1	0	0
Herpes Zoster
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Influenza
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	3 / 63 (4.76%)	0 / 6 (0.00%)	2 / 50 (4.00%)
occurrences all number	1	0	0	0	3	0	2
Nasopharyngitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	2	0	3	0	1
Oral Herpes
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	3 / 63 (4.76%)	0 / 6 (0.00%)	3 / 50 (6.00%)
occurrences all number	0	0	0	0	3	0	3
Paronychia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	2 / 50 (4.00%)
occurrences all number	0	0	3	0	4	0	4
Pharyngitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	3	0	2
Sinusitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	0 / 63 (0.00%)	1 / 6 (16.67%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Urinary Tract Infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)	3 / 63 (4.76%)	0 / 6 (0.00%)	3 / 50 (6.00%)
occurrences all number	0	0	1	2	3	0	3
Metabolism and nutrition disorders
Decreased Appetite
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	2 / 3 (66.67%)	19 / 63 (30.16%)	4 / 6 (66.67%)	18 / 50 (36.00%)
occurrences all number	2	0	1	3	21	4	19
Hypercholesterolaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	3 / 63 (4.76%)	0 / 6 (0.00%)	2 / 50 (4.00%)
occurrences all number	0	0	1	0	3	0	2
Hyperglycaemia
subjects affected / exposed	2 / 5 (40.00%)	0 / 3 (0.00%)	5 / 12 (41.67%)	1 / 3 (33.33%)	19 / 63 (30.16%)	1 / 6 (16.67%)	15 / 50 (30.00%)
occurrences all number	2	0	8	1	24	1	18
Hyperphagia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Hypoalbuminaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	2	0	0	0
Hypocalcaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	2 / 63 (3.17%)	0 / 6 (0.00%)	2 / 50 (4.00%)
occurrences all number	0	0	1	0	3	0	3
Hypoglycaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	5	0	5	0	5
Hypokalaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)	3 / 63 (4.76%)	1 / 6 (16.67%)	3 / 50 (6.00%)
occurrences all number	0	0	1	2	5	3	5
Hyponatraemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)	1 / 63 (1.59%)	0 / 6 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	1	0	1
Hypophosphataemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)	3 / 63 (4.76%)	0 / 6 (0.00%)	3 / 50 (6.00%)
occurrences all number	0	0	0	0	4	0	4
Increased Appetite
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)	0 / 63 (0.00%)	0 / 6 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

04 Mar 2010

• Removed references to consenting and collecting follow-up data on partners of male patients who become pregnant while the male patient was receiving treatment with buparlisib and Trastuzumab. • Clarified the dose modification requirements around mood disorders particularly as it related to total score on the PHQ-9 assessment and response to question number 9 regarding suicidality.

15 Jan 2011

• Greater specificity was provided concerning patient inclusion criteria with respect to prior chemotherapy and prior biological therapy received. • The pre-screening and analysis in the Phase II part of the study according to PIK3CA status (mutants vs. wild-type) was no longer required • Some of the secondary objectives and endpoints associated with biomarker assessments were changed to exploratory objectives and endpoints • The response rate thresholds for futility (15%) and activity (25%) were modified based on the population change in the Phase II setting (PIK3CA mutants and wild type patients were evaluated together in the same expansion cohort), and to be clinically relevant • The changes to inclusion/exclusion criteria, dose reduction guidelines, toxicity management guidelines were made to enhance the safety of enrolled patients • New preclinical data revealed the genotoxic potential of buparlisib, and the language regarding the contraception requirements and pregnancy follow up was revised • The minimum required number of 12 paired (6 per arm) pre- and post-buparlisib treatment fresh biopsies, although still strongly recommended, was changed to only occur if feasible

13 Aug 2012

• Objectives and study design for BM cohorts were updated • Additional inclusion and exclusion criteria, and treatment specified for patients in the BM cohorts were added • Data analysis plan for BM cohorts and statistical model for dose escalation in the BM cohorts was added • CBR was added as a secondary efficacy endpoint for the Phase Ib and Phase II parts • Pregnancy testing was required at Baseline and EOT for all women, regardless of childbearing potential • Dose modification guidelines were updated for hyperglycemia, LVEF change, skin toxicity and diarrhea based on additional clinical experience gained from studies of buparlisib • The FAS definition was clarified and now comprised patients who received at least one dose of buparlisib treatment • The cut-off score of PHQ-9 at the Screening visit was increased from 10 to 12 to be consistent with the evolving clinical experience of buparlisib in patients with cancer, and overruling of the cut-off score of PHQ-9 or GAD-7 by a psychiatric assessment at the Screening visit was removed

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 BM cohort was to include a Phase Ib dose escalation part and safety expansion part, however, the study was terminated during the dose escalation part due to the rare patient population and challenges to enroll patients.

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Clinical trials

Clinical Trial Results:
A Phase Ib/II, open label, multi-center study evaluating the safety and efficacy of BKM120 in combination with trastuzumab in patients with relapsing HER2 overexpressing breast cancer who have previously failed trastuzumab

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Dose Limiting Toxicity (DLT) - Phase l only

Primary: Dose Limiting Toxicity (DLT) - Phase l only

Primary: Overall Response Rate (ORR) - Phase ll

Primary: Overall Response Rate (ORR) - Phase ll

Secondary: Disease control rate (DCR) based on Investigator assessment- Phase l & ll

Secondary: Disease control rate (DCR) based on Investigator assessment- Phase l & ll

Secondary: Clinical benefit rate (CBR) - Phase l & ll

Secondary: Clinical benefit rate (CBR) - Phase l & ll

Secondary: Progression free survival (PFS) - based on investigator review using Kaplan Meier - Phase l

Secondary: Progression free survival (PFS) - based on investigator review using Kaplan Meier - Phase l

Secondary: Progression free survival (PFS) - based on investigator review using Kaplan Meier - Phase II

Secondary: Progression free survival (PFS) - based on investigator review using Kaplan Meier - Phase II

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A Phase Ib/II, open label, multi-center study evaluating the safety and efficacy of BKM120 in combination with trastuzumab in patients with relapsing HER2 overexpressing breast cancer who have previously failed trastuzumab

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Dose Limiting Toxicity (DLT) - Phase l only

Primary: Dose Limiting Toxicity (DLT) - Phase l only

Primary: Overall Response Rate (ORR) - Phase ll

Primary: Overall Response Rate (ORR) - Phase ll

Secondary: Disease control rate (DCR) based on Investigator assessment- Phase l & ll

Secondary: Disease control rate (DCR) based on Investigator assessment- Phase l & ll

Secondary: Clinical benefit rate (CBR) - Phase l & ll

Secondary: Clinical benefit rate (CBR) - Phase l & ll

Secondary: Progression free survival (PFS) - based on investigator review using Kaplan Meier - Phase l

Secondary: Progression free survival (PFS) - based on investigator review using Kaplan Meier - Phase l

Secondary: Progression free survival (PFS) - based on investigator review using Kaplan Meier - Phase II

Secondary: Progression free survival (PFS) - based on investigator review using Kaplan Meier - Phase II

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase Ib/II, open label, multi-center study evaluating the safety and efficacy of BKM120 in combination with trastuzumab in patients with relapsing HER2 overexpressing breast cancer who have previously failed trastuzumab