Download PDF

Clinical Trial Results:
A Study of HSP90 Inhibitor AT13387 Alone and in Combination with Crizotinib in the Treatment of Non-small Cell Lung Cancer (NSCLC).

Summary
EudraCT number	2012-001575-37
Trial protocol	ES
Global end of trial date	21 Feb 2017

Results information
Results version number	v1
This version publication date	06 Jul 2018
First version publication date	06 Jul 2018
Other versions	v2

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

AT13387-05

ISRCTN number

US NCT number

NCT01712217

WHO universal trial number (UTN)

Sponsor organisation name

Astex Pharmaceuticals, Inc.

Sponsor organisation address

4420 Rosewood Drive, Suite 200, Pleasanton, CA, United States, 94588

Public contact

Dr Harold Keer, Astex Pharmaceuticals Inc., 001 9257190741, Harold.Keer@astx.com

Scientific contact

Dr Harold Keer, Astex Pharmaceuticals Inc., 001 9257190741, Harold.Keer@astx.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

21 Feb 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

21 Feb 2017

Was the trial ended prematurely?

Main objective of the trial

Part A: To establish the safety and maximum tolerated dose (MTD) of AT13387 when administered in combination with crizotinib. Part B: To compare the progression-free survival (PFS) between the administration of single-agent crizotinib and the combination of crizotinib + AT13387 in subjects with NSCLC who will be treated with crizotinib or who were treated with crizotinib and have not yet progressed. Part C: To assess the efficacy (Objective Response Rate [ORR] = complete response [CR] + partial response [PR]) of single-agent AT13387 and to assess the efficacy of the addition of AT13387 to crizotinib in subjects who progressed on treatment with crizotinib.

Protection of trial subjects

Ethical Conduct of the Study: The study was conducted in accordance with the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, applicable local regulatory requirements, and the principles enunciated in the Declaration of Helsinki. Subject Information and Consent: The informed consent forms (ICFs) used for each study centre complied with ICH, the principles enunciated in the Declaration of Helsinki, local regulatory requirements, and ICH GCP guidelines and was approved by the sponsor and the investigator's IRB/IEC. The investigator, or a person delegated by the investigator, explained the medical aspects of the study, including the nature and purpose of the study and the treatment, the procedures involved, and the potential benefits and risks. Other tasks in the informed consent process may have been delegated by the investigator. After having been informed that participation was voluntary and that subjects may withdraw from the study at any time, without prejudice, each subject signed the IRB/IEC-approved ICF prior to undergoing any study specific procedures and enrolment in the study.

Background therapy

Prior and Concomitant Therapy: All medications (prescription and over-the-counter), vitamin and mineral supplements, and/or herbs taken by the subject were documented on the concomitant medication eCRF and included start and stop dates and indication. Medications taken for a procedure (e.g., biopsy) were also included. Supportive treatment was provided, according to the institution standards and at the investigator’s discretion. Dexamethasone and/or antihistamines could be given to treat or prevent systemic infusion reactions. Anti-emetics, anti-diarrhoeal agents, etc., were given as needed to treat or prevent gastrointestinal toxicities. Crizotinib is a moderate inhibitor of cytochrome P3A (CYP3A); however, the potential of significant clinical drug-drug interaction with CYP3A substrates is unlikely. The aqueous solubility of crizotinib is pH-dependent, with higher pH resulting in lower solubility. Drugs that elevate gastric pH such as proton pump inhibitors, H2 blockers, or antacids may decrease the solubility and reduce the bioavailability of crizotinib, although no formal studies have been conducted. Crizotinib is an inhibitor of P-glycoprotein (P-gp) in vitro. Therefore, it may have the potential to increase the plasma concentrations of co-administered substrates of P-gp. Electrocardiogram assessments of crizotinib has revealed 1.3% of subjects with QT corrected by the Fridericia’s method (QTcF_ >500 msec, and 3.8% of subjects with QTcF increase from baseline greater than 60 msec. A pharmacokinetic (PK)/pharmacodynamic (PD) analysis suggested a dose-dependent increase in QTcF (Xalkori [crizotinib] prescribing information). Drugs that are known to increase QTc were to be avoided or at least used with caution in subjects treated in this study.

Evidence for comparator

Rationale for Study of Crizotinib and Onalespib Combination Therapy in ALK+ NSCLC: With the discovery of ALK gene translocations (and resulting EML4-ALK fusion proteins) in ALK+ NSCLC, research on crizotinib, a multi-targeted inhibitor of tyrosine kinases (including ALK), intensified (Ou, 2011). Crizotinib demonstrated concentration-dependent inhibition of ALK phosphorylation in cell-based assays using tumour cell lines and demonstrated anti-tumour activity in mice bearing tumour xenografts that expressed EML4-ALK fusion proteins (Xalkori [crizotinib] Package Insert 2011). Crizotinib efficacy was subsequently demonstrated in randomised active-controlled clinical trials in patients with metastatic ALK+NSCLC who had not received prior cancer therapy (n=340; first-line treatment; Study 1) and in patients who had previously received treatment with 1 platinum-based chemotherapy regimen (n=343; second-line treatment; Study 2). In both studies, there was a statistically significant improvement in PFS in the patients treated with crizotinib compared with the control arms (Xalkori [crizotinib] Package Insert 2011). Notably, in the second-line treatment study, the median PFS for the crizotinib cohort was 7.7 months (95% CI, 6.0-8.8), compared with PFS in the chemotherapy (pemetrexed or docetaxel) cohort (3.0 months [95% CI, 2.6-4.3], based on Kaplan-Meier estimation; P=<.001 from stratified log-rank test.

Actual start date of recruitment

04 Feb 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 8

Country: Number of subjects enrolled

Korea, Republic of: 87

Country: Number of subjects enrolled

United States: 85

Country: Number of subjects enrolled

Spain: 9

Country: Number of subjects enrolled

France: 31

Worldwide total number of subjects

220

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)

173

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

A total of 52 principal investigators at 52 study centres (28 in the US, 12 in Europe, 4 in Canada, and 8 in South Korea) enrolled subjects in this study. Dates of first treatment was on 04 February 2013, and last observation was on 21 February 2017.

Screening details

278 subjects were assessed (220 subjects enrolled), 57 subjects excluded & 1 subject was enrolled but withdrawn before treatment. Part A, 32 subjects were enrolled & treated. Part B, 136 subjects were enrolled (133 subjects treated). Part C, 52 subjects were enrolled & treated. Baseline characteristics are provided for the subjects in Part A.

Period 1 title

Part A (Dose Escalation)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Part A: Arm 1 - Crizotinib 250 mg PO & onalespib IV 150 mg/m2

Arm description

Arm type

Experimental

Investigational medicinal product name

Crizotinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

250 mg crizotinib by mouth twice daily

Investigational medicinal product name

Onalespib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for infusion

Routes of administration

Intravenous use

Dosage and administration details

150 mg/m2 onalespib by IV infusion once weekly for 3 weeks in every 4-week cycle (on Days 1, 8 and 15 of a 28-day cycle)

Part A: Arm 2 - Crizotinib 250 mg PO & onalespib IV 180 mg/m2

Arm description

Arm type

Experimental

Investigational medicinal product name

Crizotinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

250 mg crizotinib by mouth twice daily

Investigational medicinal product name

Onalespib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for infusion

Routes of administration

Intravenous use

Dosage and administration details

180 mg/m2 onalespib by IV infusion once weekly for 3 weeks in every 4-week cycle (on Days 1, 8 and 15 of a 28-day cycle)

Part A: Arm 3- Crizotinib 250mg PO and onalespib IV 220 mg/m2

Arm description

Arm type

Experimental

Investigational medicinal product name

Crizotinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

250 mg crizotinib by mouth twice daily

Investigational medicinal product name

Onalespib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for infusion

Routes of administration

Intravenous use

Dosage and administration details

220 mg/m2 onalespib by IV infusion once weekly for 3 weeks in every 4-week cycle (on Days 1, 8 and 15 of a 28-day cycle)

Number of subjects in period 1 ^[1]	Part A: Arm 1 - Crizotinib 250 mg PO & onalespib IV 150 mg/m2	Part A: Arm 2 - Crizotinib 250 mg PO & onalespib IV 180 mg/m2	Part A: Arm 3- Crizotinib 250mg PO and onalespib IV 220 mg/m2
Started	8	9	15
Completed	8	9	15

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The study was conducted in 3 parts. Only 1 part can be identified as the baseline period.

Period 2 title

Part B Criz. vs Criz.+ Onalespib

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Part B: Arm 1 - Crizotinib monotherapy (250 mg PO BID)

Arm description

Arm type

Experimental

Investigational medicinal product name

Crizotinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

250 mg crizotinib by mouth twice daily

Part B: Arm 2-Crizotinib (250mg PO) + onalespib (220 mg/m2 IV)

Arm description

Arm type

Experimental

Investigational medicinal product name

Onalespib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for infusion

Routes of administration

Intravenous use

Dosage and administration details

220 mg/m2 onalespib by IV infusion once weekly for 3 weeks in every 4-week cycle (on Days 1, 8 and 15 of a 28-day cycle)

Investigational medicinal product name

Crizotinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

250 mg crizotinib by mouth twice daily

Number of subjects in period 2	Part B: Arm 1 - Crizotinib monotherapy (250 mg PO BID)	Part B: Arm 2-Crizotinib (250mg PO) + onalespib (220 mg/m2 IV)
Started	68	68
Completed	55	50
Not completed	13	18
Consent withdrawn by subject	8	13
Did not complete for other reasons	2	4
Lost to follow-up	3	1

Period 3 title

Part C Onalespib vs Criz. + Onalespib

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Part C: Arm 1- Onalespib monotherapy (260 mg/m2 IV)

Arm description

Onalespib monotherapy (260 mg/m2 IV)

Arm type

Experimental

Investigational medicinal product name

Onalespib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for infusion

Routes of administration

Intravenous use

Dosage and administration details

260 mg/m2 onalespib by IV infusion once weekly for 3 weeks in every 4-week cycle (on Days 1, 8 and 15 of a 28-day cycle)

Part C: Arm 2- Crizotinib 250mg + onalespib 220mg/m2

Arm description

Crizotinib 250mg + onalespib 220mg/m2

Arm type

Experimental

Investigational medicinal product name

Crizotinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

250 mg crizotinib by mouth twice daily

Investigational medicinal product name

Onalespib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for infusion

Routes of administration

Intravenous use

Dosage and administration details

220 mg/m2 onalespib by IV infusion once weekly for 3 weeks in every 4-week cycle (on Days 1, 8 and 15 of a 28-day cycle)

Number of subjects in period 3	Part C: Arm 1- Onalespib monotherapy (260 mg/m2 IV)	Part C: Arm 2- Crizotinib 250mg + onalespib 220mg/m2
Started	24	28
Completed	23	25
Not completed	1	3
Consent withdrawn by subject	1	2
Did not complete for other reasons	-	1

Baseline characteristics

Top of page

Reporting group title

Part A: Arm 1 - Crizotinib 250 mg PO & onalespib IV 150 mg/m2

Reporting group description

Reporting group title

Part A: Arm 2 - Crizotinib 250 mg PO & onalespib IV 180 mg/m2

Reporting group description

Reporting group title

Part A: Arm 3- Crizotinib 250mg PO and onalespib IV 220 mg/m2

Reporting group description

Reporting group values	Part A: Arm 1 - Crizotinib 250 mg PO & onalespib IV 150 mg/m2	Part A: Arm 2 - Crizotinib 250 mg PO & onalespib IV 180 mg/m2	Part A: Arm 3- Crizotinib 250mg PO and onalespib IV 220 mg/m2	Total
Number of subjects	8	9	15	32
Age categorical
Units: Subjects
Part A	8	9	15	32
Age continuous
Units: years
arithmetic mean (standard deviation)	51.9 ± 10.4	56.7 ± 13.2	58.5 ± 11.2	-
Gender categorical
Units: Subjects
Female	4	6	8	18
Male	4	3	7	14

End points

Top of page

Reporting group title

Part A: Arm 1 - Crizotinib 250 mg PO & onalespib IV 150 mg/m2

Reporting group description

Reporting group title

Part A: Arm 2 - Crizotinib 250 mg PO & onalespib IV 180 mg/m2

Reporting group description

Reporting group title

Part A: Arm 3- Crizotinib 250mg PO and onalespib IV 220 mg/m2

Reporting group description

Reporting group title

Part B: Arm 1 - Crizotinib monotherapy (250 mg PO BID)

Reporting group description

Reporting group title

Part B: Arm 2-Crizotinib (250mg PO) + onalespib (220 mg/m2 IV)

Reporting group description

Reporting group title

Part C: Arm 1- Onalespib monotherapy (260 mg/m2 IV)

Reporting group description

Onalespib monotherapy (260 mg/m2 IV)

Reporting group title

Part C: Arm 2- Crizotinib 250mg + onalespib 220mg/m2

Reporting group description

Crizotinib 250mg + onalespib 220mg/m2

Primary: Part A - The incidence of DLTs when onalespib was administered in combination with crizotinib.

Top of page

End point title

Part A - The incidence of DLTs when onalespib was administered in combination with crizotinib. ^[1]

End point description

Dose-limiting toxicities were defined in the protocol as AEs occurring in Cycle 1 of Part A or any cycle of Parts B and C judged to be related to the study treatment (onalespib or crizotinib) that represent any 1 of the following: • Grade 4 neutropenia or thrombocytopenia that lasts for more than 1 week or associated with neutropenic fever or bleeding. • Grade 3 or 4 non-hematologic toxicity, including: o ≥Grade 3 nausea and vomiting despite maximal anti-emetic treatment and lasting >48 hours, o ≥Grade 3 diarrhea despite maximal anti-diarrheal treatment and lasting >48 hours, or o ≥Grade 3 fatigue lasting >3 days. • Toxicity that results in discontinuation of treatment or ≥4 weeks delay of treatment. The Data and Safety Review Committee (DSRC) could consider other clinically significant adverse events as dose limiting based on their collective clinical judgment.

End point type

Primary

End point timeframe

Subjects treated once weekly for 3 weeks in a 4-week cycle. Subjects could continue to receive treatment until disease progression, unacceptable toxicity, early termination of the study, or at the discretion of the investigator.

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: Only the descriptive statistics are reported here.

End point values	Part A: Arm 1 - Crizotinib 250 mg PO & onalespib IV 150 mg/m2	Part A: Arm 2 - Crizotinib 250 mg PO & onalespib IV 180 mg/m2	Part A: Arm 3- Crizotinib 250mg PO and onalespib IV 220 mg/m2
Number of subjects analysed	8	9	15
Units: Subject	0	0	0

No statistical analyses for this end point

Primary: Progression Free Survival (PFS)

Top of page

End point title

Progression Free Survival (PFS)

End point description

PFS was defined as the number of days from randomization date to the earliest of any PFS events, which were defined as follows: • Disease progression determined by earliest date of progressive disease in the derived evaluation of target lesion, unequivocal progression in the evaluation of nontarget lesion, or appearance of any new lesions. • Clinical progression reported in the treatment discontinuation CRF page. • Death from any cause. Subjects were censored for PFS analysis based as follow, Subjects: • without a PFS event were censored on the last tumor assessment date. • who had not baseline or postbaseline disease diagnosis were censored at the date of randomization. • who received subsequent anticancer therapy or crossed over to the crizotinib monotherapy arm before experiencing an event were right-censored at the date of the last adequate tumor or clinical progression assessment prior to the date of initiation of subsequent therapy or crossover

End point type

Primary

End point timeframe

End point values	Part B: Arm 1 - Crizotinib monotherapy (250 mg PO BID)	Part B: Arm 2-Crizotinib (250mg PO) + onalespib (220 mg/m2 IV)
Number of subjects analysed	65	65
Units: days
arithmetic mean (confidence interval 95%)	320.0 (239.0 to 392.0)	280.0 (223.0 to 941.0)

Progression-Free Survival - Part B

Statistical analysis description

PFS was analyzed by Kaplan-Meier procedure for Part B. Median PFS and its 95% CI were provided. Stratified log-rank tests were conducted to compare PFS for treatment groups with stratification factor, duration of prior crizotinib therapy (≤4 months vs >4 months), and 2-sided significance level alpha at 0.05. Hazard ratio and 95% CI were provided using Cox proportional hazard model with treatment group and duration of prior crizotinib therapy as covariates.

Comparison groups

Part B: Arm 1 - Crizotinib monotherapy (250 mg PO BID) v Part B: Arm 2-Crizotinib (250mg PO) + onalespib (220 mg/m2 IV)

Number of subjects included in analysis

130

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3905

Method

Logrank

Confidence interval

Primary: Objective Response Rate (ORR)

Top of page

End point title

Objective Response Rate (ORR) ^[2]

End point description

Objective Response Rate (ORR) was defined as the proportion of subjects who achieved a best overall objective response of CR (complete response) or PR (partial response). Best overall response in this study was defined as the best response across all time points and was determined once all the data for the subject was known. Best response confirmation of CR or PR was not required. A response of stable disease had to meet the protocol specified minimum time interval of 6 weeks from baseline in order to be considered the best response; a subject lost to follow-up after a first assessment of stable disease would be considered inevaluable. Subjects who did not have disease assessments were considered nonresponders.

End point type

Primary

End point timeframe

Notes
[2] - 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: Only the descriptive statistics are reported here.

End point values	Part C: Arm 1- Onalespib monotherapy (260 mg/m2 IV)	Part C: Arm 2- Crizotinib 250mg + onalespib 220mg/m2
Number of subjects analysed	23	27
Units: percent
number (confidence interval 95%)	4.3 (0.1 to 21.9)	18.5 (6.3 to 38.1)

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Adverse events were recorded on scheduled study days and at study follow-up.

Adverse event reporting additional description

Note: Non-serious Adverse Events (≥5% of Subjects in any group) are reported

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Part A- Arm 1-Crizotinib 250 mg PO and onalespib IV 150 mg/m2

Reporting group description

Reporting group title

Part A- Arm 2-Crizotinib 250 mg PO and onalespib IV 180 mg/m2

Reporting group description

Reporting group title

Part A- Arm 3-Crizotinib 250 mg PO and onalespib IV 220 mg/m2

Reporting group description

Reporting group title

Part B- Arm 1- Crizotinib monotherapy (250 mg PO BID)

Reporting group description

Reporting group title

Part B- Arm 2- Crizotinib (250 mg) + onalespib (220 mg/m2 IV

Reporting group description

Reporting group title

Part C- Arm 1- Onalespib monotherapy (260 mg/m2 IV once weekly

Reporting group description

Reporting group title

Part C- Arm 2- Combin of crizotinib + onalespib

Reporting group description

Combination of crizotinib (250 mg PO) + onalespib (220 mg/m2)

Serious adverse events	Part A- Arm 1-Crizotinib 250 mg PO and onalespib IV 150 mg/m2	Part A- Arm 2-Crizotinib 250 mg PO and onalespib IV 180 mg/m2	Part A- Arm 3-Crizotinib 250 mg PO and onalespib IV 220 mg/m2	Part B- Arm 1- Crizotinib monotherapy (250 mg PO BID)	Part B- Arm 2- Crizotinib (250 mg) + onalespib (220 mg/m2 IV	Part C- Arm 1- Onalespib monotherapy (260 mg/m2 IV once weekly	Part C- Arm 2- Combin of crizotinib + onalespib
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 8 (50.00%)	4 / 9 (44.44%)	6 / 15 (40.00%)	12 / 66 (18.18%)	22 / 67 (32.84%)	11 / 24 (45.83%)	16 / 28 (57.14%)
number of deaths (all causes)	7	5	8	10	11	17	18
number of deaths resulting from adverse events	0	0	1	0	1	0	1
Vascular disorders
Embolism
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Syncope
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Phlebitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Superior vena cava syndrome
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Subdural haematoma
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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
Haemorrhage intracranial
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (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
Vascular stent restenosis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (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
General disorders and administration site conditions
General physical health deterioration
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	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
Hemiparesis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	1 / 24 (4.17%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	3 / 66 (4.55%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Fatigue
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	2 / 67 (2.99%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Diplegia
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (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
Fall
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Malignant pleural effusion
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Accidental overdose
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	1 / 24 (4.17%)	0 / 28 (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
Influenza
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	1 / 24 (4.17%)	0 / 28 (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
Scrotal abscess
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	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
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	1 / 24 (4.17%)	0 / 28 (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
Reproductive system and breast disorders
Breast cancer
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (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, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	1 / 8 (12.50%)	1 / 9 (11.11%)	1 / 15 (6.67%)	1 / 66 (1.52%)	2 / 67 (2.99%)	2 / 24 (8.33%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	1 / 15 (6.67%)	1 / 66 (1.52%)	1 / 67 (1.49%)	0 / 24 (0.00%)	2 / 28 (7.14%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Pleural effusion
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Tracheal stenosis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (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
Atelectasis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	1 / 24 (4.17%)	0 / 28 (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
Hypoxia
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	1 / 24 (4.17%)	0 / 28 (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
Lung disorder
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	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
Psychiatric disorders
Seizure
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	1 / 67 (1.49%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypophagia
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Mental status changes
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (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
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Aspartate aminotransferase increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Cellulitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	1 / 28 (3.57%)
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
Injury, poisoning and procedural complications
Hepatocellular injury
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Chemical peritonitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (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
Congenital, familial and genetic disorders
Orchitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	1 / 24 (4.17%)	0 / 28 (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
Cardiac disorders
Pericardial effusion
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	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 / 1
ECG QT prolonged
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	1 / 24 (4.17%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Aphasia
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to meninges
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	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
Perineal abscess
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	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
Blood and lymphatic system disorders
Jugular vein thrombosis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Anaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	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
Deep vein thrombosis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	2 / 66 (3.03%)	2 / 67 (2.99%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	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
Eye disorders
Vision blurred
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Palpitations
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	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
Gastrointestinal disorders
Vomiting
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	1 / 24 (4.17%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	2 / 67 (2.99%)	1 / 24 (4.17%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	2 / 67 (2.99%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Nausea
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Sepsis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (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
Abdominal pain upper
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	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
Confusional state
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	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
Constipation
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	1 / 24 (4.17%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic pain
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Endocrine disorders
Inappropriate antidiuretic hormone secretion
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	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
Musculoskeletal and connective tissue disorders
Thoracic vertebral fracture
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Muscular weakness
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	2 / 28 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	2 / 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
Back pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	1 / 24 (4.17%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gait disturbance
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	1 / 24 (4.17%)	0 / 28 (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
Infections and infestations
Pneumonia
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	2 / 67 (2.99%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 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
Spinal cord infection
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Respiratory tract infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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
Cholecystitis infective
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (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
Infectious pleural effusion
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (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
Nosocomial infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Pneumonia aspiration
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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 / 1	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Post procedural infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (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
Urinary tract infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	1 / 24 (4.17%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Cellulitis of male external genital organ
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	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
Cholestasis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	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
Salmonella bacteraemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences causally related to treatment / all	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
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	2 / 28 (7.14%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Hyperkalaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences causally related to treatment / all	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
Hyponatraemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	2 / 28 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
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	Part A- Arm 1-Crizotinib 250 mg PO and onalespib IV 150 mg/m2	Part A- Arm 2-Crizotinib 250 mg PO and onalespib IV 180 mg/m2	Part A- Arm 3-Crizotinib 250 mg PO and onalespib IV 220 mg/m2	Part B- Arm 1- Crizotinib monotherapy (250 mg PO BID)	Part B- Arm 2- Crizotinib (250 mg) + onalespib (220 mg/m2 IV	Part C- Arm 1- Onalespib monotherapy (260 mg/m2 IV once weekly	Part C- Arm 2- Combin of crizotinib + onalespib
Total subjects affected by non serious adverse events
subjects affected / exposed	8 / 8 (100.00%)	9 / 9 (100.00%)	11 / 15 (73.33%)	65 / 66 (98.48%)	66 / 67 (98.51%)	24 / 24 (100.00%)	28 / 28 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	1 / 66 (1.52%)	2 / 67 (2.99%)	2 / 24 (8.33%)	0 / 28 (0.00%)
occurrences all number	0	0	1	1	2	2	0
Seborrhoeic keratosis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Vascular disorders
Embolism
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	1	0	0
Flushing
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	1 / 66 (1.52%)	2 / 67 (2.99%)	2 / 24 (8.33%)	2 / 28 (7.14%)
occurrences all number	0	0	1	1	2	7	3
Hot flush
subjects affected / exposed	0 / 8 (0.00%)	3 / 9 (33.33%)	1 / 15 (6.67%)	2 / 66 (3.03%)	4 / 67 (5.97%)	0 / 24 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	3	1	2	6	0	2
Hypertension
subjects affected / exposed	0 / 8 (0.00%)	2 / 9 (22.22%)	0 / 15 (0.00%)	3 / 66 (4.55%)	2 / 67 (2.99%)	1 / 24 (4.17%)	0 / 28 (0.00%)
occurrences all number	0	5	0	3	4	1	0
Hypotension
subjects affected / exposed	0 / 8 (0.00%)	2 / 9 (22.22%)	2 / 15 (13.33%)	1 / 66 (1.52%)	5 / 67 (7.46%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	2	2	1	6	0	0
Vascular pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	2 / 67 (2.99%)	1 / 24 (4.17%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	2	1	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	8 / 8 (100.00%)	9 / 9 (100.00%)	10 / 15 (66.67%)	16 / 66 (24.24%)	32 / 67 (47.76%)	11 / 24 (45.83%)	12 / 28 (42.86%)
occurrences all number	20	20	14	23	90	17	24
Asthenia
subjects affected / exposed	0 / 8 (0.00%)	2 / 9 (22.22%)	3 / 15 (20.00%)	6 / 66 (9.09%)	11 / 67 (16.42%)	6 / 24 (25.00%)	5 / 28 (17.86%)
occurrences all number	0	4	5	7	29	7	5
General physical health deterioration
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	2 / 24 (8.33%)	0 / 28 (0.00%)
occurrences all number	0	0	3	0	0	2	0
Anal fissure
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Chest discomfort
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	3 / 66 (4.55%)	4 / 67 (5.97%)	1 / 24 (4.17%)	1 / 28 (3.57%)
occurrences all number	0	0	0	3	5	1	1
Chest pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	1 / 24 (4.17%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	1	0
Chills
subjects affected / exposed	0 / 8 (0.00%)	4 / 9 (44.44%)	0 / 15 (0.00%)	7 / 66 (10.61%)	8 / 67 (11.94%)	1 / 24 (4.17%)	1 / 28 (3.57%)
occurrences all number	0	10	0	9	17	1	1
Early satiety
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	1	0	0	0	0
Face oedema
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	2 / 66 (3.03%)	9 / 67 (13.43%)	0 / 24 (0.00%)	3 / 28 (10.71%)
occurrences all number	0	0	2	3	10	0	3
Gait disturbance
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	1 / 66 (1.52%)	2 / 67 (2.99%)	1 / 24 (4.17%)	1 / 28 (3.57%)
occurrences all number	0	0	1	1	3	1	4
Generalised oedema
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	4 / 66 (6.06%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	5	1	0	0
Influenza like illness
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	2 / 66 (3.03%)	1 / 67 (1.49%)	3 / 24 (12.50%)	1 / 28 (3.57%)
occurrences all number	0	1	0	2	1	3	1
Infusion site bruising
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Infusion site pain
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 15 (6.67%)	0 / 66 (0.00%)	6 / 67 (8.96%)	3 / 24 (12.50%)	2 / 28 (7.14%)
occurrences all number	0	2	1	0	9	3	2
Injection site pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	4 / 67 (5.97%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	0	0	27	0	1
Injection site reaction
subjects affected / exposed	0 / 8 (0.00%)	2 / 9 (22.22%)	1 / 15 (6.67%)	0 / 66 (0.00%)	4 / 67 (5.97%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	4	3	0	4	0	0
Localised oedema
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Malaise
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	1 / 67 (1.49%)	2 / 24 (8.33%)	1 / 28 (3.57%)
occurrences all number	0	0	0	1	1	2	1
Non-cardiac chest pain
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	1 / 15 (6.67%)	5 / 66 (7.58%)	3 / 67 (4.48%)	3 / 24 (12.50%)	1 / 28 (3.57%)
occurrences all number	1	0	1	7	3	3	2
Oedema peripheral
subjects affected / exposed	3 / 8 (37.50%)	3 / 9 (33.33%)	5 / 15 (33.33%)	16 / 66 (24.24%)	23 / 67 (34.33%)	3 / 24 (12.50%)	8 / 28 (28.57%)
occurrences all number	6	5	6	20	55	5	15
Pain
subjects affected / exposed	1 / 8 (12.50%)	1 / 9 (11.11%)	0 / 15 (0.00%)	3 / 66 (4.55%)	2 / 67 (2.99%)	1 / 24 (4.17%)	1 / 28 (3.57%)
occurrences all number	1	1	0	3	6	1	2
Peripheral swelling
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	4 / 66 (6.06%)	4 / 67 (5.97%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	7	6	0	0
Pyrexia
subjects affected / exposed	1 / 8 (12.50%)	2 / 9 (22.22%)	2 / 15 (13.33%)	8 / 66 (12.12%)	10 / 67 (14.93%)	2 / 24 (8.33%)	3 / 28 (10.71%)
occurrences all number	1	2	2	11	13	2	3
Temperature intolerance
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	1	0	0	0
Thirst
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	1	0	0	0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	1	0	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	4 / 8 (50.00%)	4 / 9 (44.44%)	6 / 15 (40.00%)	8 / 66 (12.12%)	11 / 67 (16.42%)	1 / 24 (4.17%)	4 / 28 (14.29%)
occurrences all number	6	4	10	16	17	1	7
Pulmonary embolism
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	2 / 67 (2.99%)	0 / 24 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	1	0	2	0	2
Pneumonitis
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Cough
subjects affected / exposed	3 / 8 (37.50%)	2 / 9 (22.22%)	6 / 15 (40.00%)	13 / 66 (19.70%)	18 / 67 (26.87%)	3 / 24 (12.50%)	6 / 28 (21.43%)
occurrences all number	5	2	7	17	26	4	8
Dysphonia
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	1 / 67 (1.49%)	1 / 24 (4.17%)	1 / 28 (3.57%)
occurrences all number	0	0	2	0	1	1	1
Dyspnoea exertional
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	1 / 66 (1.52%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Epistaxis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	0	0	0	0	2
Haemoptysis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	3 / 67 (4.48%)	2 / 24 (8.33%)	3 / 28 (10.71%)
occurrences all number	0	0	0	0	3	2	5
Hiccups
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	1 / 66 (1.52%)	2 / 67 (2.99%)	2 / 24 (8.33%)	2 / 28 (7.14%)
occurrences all number	0	0	1	1	7	2	2
Laryngeal inflammation
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Lung disorder
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	1 / 24 (4.17%)	0 / 28 (0.00%)
occurrences all number	0	1	0	0	0	1	0
Nasal congestion
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 15 (6.67%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	1	4	0	1	0	1
Oropharyngeal pain
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	2 / 15 (13.33%)	5 / 66 (7.58%)	9 / 67 (13.43%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	5	6	18	0	0
Productive cough
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	10 / 66 (15.15%)	11 / 67 (16.42%)	1 / 24 (4.17%)	1 / 28 (3.57%)
occurrences all number	0	0	0	17	15	1	1
Rales
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Respiratory tract congestion
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	0	0	0	0	0	0
Rhinitis allergic
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	3 / 66 (4.55%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	3	1	0	0
Rhinorrhoea
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	1 / 66 (1.52%)	7 / 67 (10.45%)	0 / 24 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	1	1	8	0	2
Sinus congestion
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	1	0	0
Upper-airway cough syndrome
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Wheezing
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	2 / 24 (8.33%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	2	0
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Alcohol withdrawal syndrome
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Anxiety
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	2 / 67 (2.99%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	2	0	0	0	2	0	1
Confusional state
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 15 (13.33%)	3 / 66 (4.55%)	1 / 67 (1.49%)	2 / 24 (8.33%)	1 / 28 (3.57%)
occurrences all number	0	0	2	5	2	2	1
Depression
subjects affected / exposed	1 / 8 (12.50%)	1 / 9 (11.11%)	0 / 15 (0.00%)	3 / 66 (4.55%)	1 / 67 (1.49%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	1	2	0	4	1	0	2
Hallucination
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	1	0	0
Insomnia
subjects affected / exposed	2 / 8 (25.00%)	3 / 9 (33.33%)	1 / 15 (6.67%)	8 / 66 (12.12%)	21 / 67 (31.34%)	6 / 24 (25.00%)	1 / 28 (3.57%)
occurrences all number	0	2	1	11	32	6	1
Investigations
Neutrophil count decreased
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	3 / 15 (20.00%)	5 / 66 (7.58%)	2 / 67 (2.99%)	0 / 24 (0.00%)	3 / 28 (10.71%)
occurrences all number	0	10	10	4	0	3	37
Lymphocyte count decreased
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	2 / 15 (13.33%)	1 / 66 (1.52%)	2 / 67 (2.99%)	0 / 24 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	11	12	6	4	0	3
Alanine aminotransferase increased
subjects affected / exposed	0 / 8 (0.00%)	2 / 9 (22.22%)	3 / 15 (20.00%)	12 / 66 (18.18%)	13 / 67 (19.40%)	2 / 24 (8.33%)	3 / 28 (10.71%)
occurrences all number	0	4	13	23	25	2	3
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 15 (6.67%)	0 / 66 (0.00%)	2 / 67 (2.99%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	4	0	3	0	0
Weight decreased
subjects affected / exposed	3 / 8 (37.50%)	2 / 9 (22.22%)	6 / 15 (40.00%)	5 / 66 (7.58%)	8 / 67 (11.94%)	2 / 24 (8.33%)	6 / 28 (21.43%)
occurrences all number	3	3	8	5	17	2	7
Aspartate transaminase increased
subjects affected / exposed	0 / 8 (0.00%)	2 / 9 (22.22%)	3 / 15 (20.00%)	10 / 66 (15.15%)	9 / 67 (13.43%)	1 / 24 (4.17%)	2 / 28 (7.14%)
occurrences all number	0	7	10	19	17	1	2
Blood creatine phosphokinase increased
subjects affected / exposed	3 / 8 (37.50%)	1 / 9 (11.11%)	1 / 15 (6.67%)	9 / 66 (13.64%)	3 / 67 (4.48%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	3	1	1	20	6	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	2 / 15 (13.33%)	4 / 66 (6.06%)	3 / 67 (4.48%)	0 / 24 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	1	5	6	3	0	2
Blood bilirubin increased
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	2 / 66 (3.03%)	0 / 67 (0.00%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	1	0	4	0	0	1
Blood creatinine increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 15 (13.33%)	4 / 66 (6.06%)	5 / 67 (7.46%)	0 / 24 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	4	4	13	0	2
Blood phosphorus decreased
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Breath sounds abnormal
subjects affected / exposed	1 / 8 (12.50%)	2 / 9 (22.22%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	2	3	0	0	0	0	1
Electrocardiogram QT prolonged
subjects affected / exposed	2 / 8 (25.00%)	1 / 9 (11.11%)	1 / 15 (6.67%)	5 / 66 (7.58%)	11 / 67 (16.42%)	1 / 24 (4.17%)	1 / 28 (3.57%)
occurrences all number	2	1	3	6	16	2	1
International normalised ratio increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	1	0	0
Lipase increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Platelet count decreased
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	1 / 66 (1.52%)	0 / 67 (0.00%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	1	0	1	0	0	2
Protein urine present
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	0	0	0	0
White blood cell count decreased
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	2 / 15 (13.33%)	0 / 66 (0.00%)	3 / 67 (4.48%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	10	6	0	4	0	2
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Burn oesophageal
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Contusion
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 15 (6.67%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	1	0	1	0	0
Eye contusion
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Fall
subjects affected / exposed	0 / 8 (0.00%)	2 / 9 (22.22%)	2 / 15 (13.33%)	0 / 66 (0.00%)	3 / 67 (4.48%)	0 / 24 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	6	4	0	3	0	3
Infusion related reaction
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	3 / 15 (20.00%)	0 / 66 (0.00%)	2 / 67 (2.99%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	1	6	0	3	0	2
Procedural pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	1 / 66 (1.52%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Traumatic haematoma
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	2 / 24 (8.33%)	1 / 28 (3.57%)
occurrences all number	0	0	0	0	1	2	1
Sinus bradycardia
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	2 / 66 (3.03%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	2	0	0	0
Tachycardia
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	1	1	0	0	0	1
Ventricular extrasystoles
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Nervous system disorders
Syncope
subjects affected / exposed	0 / 8 (0.00%)	2 / 9 (22.22%)	1 / 15 (6.67%)	1 / 66 (1.52%)	2 / 67 (2.99%)	1 / 24 (4.17%)	0 / 28 (0.00%)
occurrences all number	0	4	1	1	3	1	0
Aphasia
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	1	0	0
Balance disorder
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1	0	1	0	1
Cauda equina syndrome
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Cognitive disorder
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	2 / 67 (2.99%)	1 / 24 (4.17%)	0 / 28 (0.00%)
occurrences all number	1	0	0	1	2	1	0
Dizziness
subjects affected / exposed	2 / 8 (25.00%)	4 / 9 (44.44%)	8 / 15 (53.33%)	14 / 66 (21.21%)	17 / 67 (25.37%)	4 / 24 (16.67%)	5 / 28 (17.86%)
occurrences all number	2	4	11	17	30	4	5
Dysgeusia
subjects affected / exposed	2 / 8 (25.00%)	2 / 9 (22.22%)	4 / 15 (26.67%)	10 / 66 (15.15%)	20 / 67 (29.85%)	2 / 24 (8.33%)	1 / 28 (3.57%)
occurrences all number	2	2	5	10	30	2	1
Headache
subjects affected / exposed	3 / 8 (37.50%)	2 / 9 (22.22%)	2 / 15 (13.33%)	17 / 66 (25.76%)	18 / 67 (26.87%)	9 / 24 (37.50%)	5 / 28 (17.86%)
occurrences all number	3	2	3	21	28	11	7
Hypoaesthesia
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	6 / 67 (8.96%)	0 / 24 (0.00%)	3 / 28 (10.71%)
occurrences all number	1	0	0	0	9	0	4
Neuralgia
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	1 / 67 (1.49%)	0 / 24 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	0	1	2	0	2
Neuropathy peripheral
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 15 (13.33%)	3 / 66 (4.55%)	2 / 67 (2.99%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	2	3	2	0	0
Paraesthesia
subjects affected / exposed	1 / 8 (12.50%)	1 / 9 (11.11%)	1 / 15 (6.67%)	0 / 66 (0.00%)	8 / 67 (11.94%)	1 / 24 (4.17%)	2 / 28 (7.14%)
occurrences all number	1	3	1	0	11	1	2
Peripheral sensory neuropathy
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 15 (13.33%)	5 / 66 (7.58%)	6 / 67 (8.96%)	1 / 24 (4.17%)	0 / 28 (0.00%)
occurrences all number	0	0	3	6	7	1	0
Presyncope
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	4	0	0	1	0	0
Restless legs syndrome
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	0 / 67 (0.00%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	1	0	0	1	0	0	2
Somnolence
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 15 (13.33%)	2 / 66 (3.03%)	2 / 67 (2.99%)	0 / 24 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	0	2	2	2	0	2
Tremor
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	2 / 67 (2.99%)	2 / 24 (8.33%)	3 / 28 (10.71%)
occurrences all number	0	0	0	0	2	2	3
Vasogenic cerebral oedema
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 8 (0.00%)	4 / 9 (44.44%)	6 / 15 (40.00%)	7 / 66 (10.61%)	10 / 67 (14.93%)	2 / 24 (8.33%)	5 / 28 (17.86%)
occurrences all number	0	13	16	8	14	2	8
Iron deficiency anaemia
subjects affected / exposed	2 / 8 (25.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	2	0	0	0	0	0	1
Lymph node pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	2 / 24 (8.33%)	1 / 28 (3.57%)
occurrences all number	0	0	0	0	0	2	1
Lymphopenia
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	2 / 67 (2.99%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	0	2	0	0
Neutropenia
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 15 (6.67%)	2 / 66 (3.03%)	3 / 67 (4.48%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	1	1	4	12	0	5
Thrombocytopenia
subjects affected / exposed	1 / 8 (12.50%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	1	0	0	0	0	0
Ear and labyrinth disorders
Deafness bilateral
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Ear congestion
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	2	0	0	0	0
Hypoacusis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Tinnitus
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	4 / 66 (6.06%)	2 / 67 (2.99%)	1 / 24 (4.17%)	0 / 28 (0.00%)
occurrences all number	0	0	1	4	5	1	0
Vertigo
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	1 / 24 (4.17%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	1	0
Eye disorders
Conjunctival haemorrhage
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Diplopia
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	2 / 66 (3.03%)	1 / 67 (1.49%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	1	0	2	1	0	1
Eye pain
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	1 / 66 (1.52%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	1	0	0	0
Eye swelling
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	1 / 24 (4.17%)	0 / 28 (0.00%)
occurrences all number	0	1	1	0	0	1	0
Eyelid oedema
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Lacrimation increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 15 (13.33%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	2	0	1	0	0
Periorbital oedema
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	1	0	0	0	1
Photophobia
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Photopsia
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	1 / 15 (6.67%)	12 / 66 (18.18%)	12 / 67 (17.91%)	3 / 24 (12.50%)	0 / 28 (0.00%)
occurrences all number	1	0	1	15	18	3	0
Vision blurred
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	2 / 15 (13.33%)	3 / 66 (4.55%)	2 / 67 (2.99%)	3 / 24 (12.50%)	2 / 28 (7.14%)
occurrences all number	1	0	2	4	3	4	4
Visual impairment
subjects affected / exposed	2 / 8 (25.00%)	1 / 9 (11.11%)	1 / 15 (6.67%)	11 / 66 (16.67%)	12 / 67 (17.91%)	2 / 24 (8.33%)	5 / 28 (17.86%)
occurrences all number	2	1	1	15	18	2	6
Vitreous floaters
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	3 / 66 (4.55%)	4 / 67 (5.97%)	1 / 24 (4.17%)	0 / 28 (0.00%)
occurrences all number	0	0	0	3	5	1	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	7 / 8 (87.50%)	8 / 9 (88.89%)	11 / 15 (73.33%)	34 / 66 (51.52%)	55 / 67 (82.09%)	18 / 24 (75.00%)	20 / 28 (71.43%)
occurrences all number	21	31	43	75	393	44	41
Vomiting
subjects affected / exposed	5 / 8 (62.50%)	5 / 9 (55.56%)	7 / 15 (46.67%)	26 / 66 (39.39%)	44 / 67 (65.67%)	9 / 24 (37.50%)	15 / 28 (53.57%)
occurrences all number	7	21	12	53	191	13	32
Nausea
subjects affected / exposed	7 / 8 (87.50%)	6 / 9 (66.67%)	9 / 15 (60.00%)	35 / 66 (53.03%)	51 / 67 (76.12%)	11 / 24 (45.83%)	20 / 28 (71.43%)
occurrences all number	11	17	15	56	145	35	28
Abdominal discomfort
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	1 / 66 (1.52%)	4 / 67 (5.97%)	1 / 24 (4.17%)	1 / 28 (3.57%)
occurrences all number	0	1	0	1	4	1	1
Abdominal distension
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	1 / 66 (1.52%)	4 / 67 (5.97%)	1 / 24 (4.17%)	0 / 28 (0.00%)
occurrences all number	0	0	2	1	4	1	0
Abdominal pain
subjects affected / exposed	0 / 8 (0.00%)	2 / 9 (22.22%)	2 / 15 (13.33%)	4 / 66 (6.06%)	14 / 67 (20.90%)	5 / 24 (20.83%)	4 / 28 (14.29%)
occurrences all number	0	4	2	5	18	6	6
Abdominal pain upper
subjects affected / exposed	1 / 8 (12.50%)	3 / 9 (33.33%)	0 / 15 (0.00%)	7 / 66 (10.61%)	11 / 67 (16.42%)	1 / 24 (4.17%)	0 / 28 (0.00%)
occurrences all number	1	3	0	14	16	1	0
Acquired oesophageal web
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Constipation
subjects affected / exposed	2 / 8 (25.00%)	3 / 9 (33.33%)	4 / 15 (26.67%)	23 / 66 (34.85%)	27 / 67 (40.30%)	3 / 24 (12.50%)	10 / 28 (35.71%)
occurrences all number	2	5	6	38	44	5	10
Dry mouth
subjects affected / exposed	2 / 8 (25.00%)	2 / 9 (22.22%)	5 / 15 (33.33%)	3 / 66 (4.55%)	14 / 67 (20.90%)	7 / 24 (29.17%)	4 / 28 (14.29%)
occurrences all number	3	2	5	4	23	9	4
Dyspepsia
subjects affected / exposed	1 / 8 (12.50%)	1 / 9 (11.11%)	3 / 15 (20.00%)	7 / 66 (10.61%)	15 / 67 (22.39%)	2 / 24 (8.33%)	1 / 28 (3.57%)
occurrences all number	1	1	3	13	29	2	4
Dysphagia
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 15 (13.33%)	3 / 66 (4.55%)	2 / 67 (2.99%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	2	3	2	0	1
Epigastric discomfort
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	2 / 66 (3.03%)	3 / 67 (4.48%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	2	3	3	0	0
Eructation
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	1	0	0	0	0
Faeces discoloured
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Flatulence
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	1 / 66 (1.52%)	1 / 67 (1.49%)	1 / 24 (4.17%)	0 / 28 (0.00%)
occurrences all number	0	0	1	1	2	1	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 15 (6.67%)	2 / 66 (3.03%)	1 / 67 (1.49%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	1	1	2	2	0	1
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	9	0	0	0	0
Oesophageal ulcer
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Oral pain
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Stomatitis
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	1 / 15 (6.67%)	2 / 66 (3.03%)	1 / 67 (1.49%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	2	0	1	2	1	0	1
Hepatobiliary disorders
Hepatocellular injury
subjects affected / exposed	2 / 8 (25.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	1 / 67 (1.49%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	2	0	0	3	1	0	1
Cholestasis
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	1	0	0	0	0
Hepatic pain
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Skin and subcutaneous tissue disorders
Dermatitis acneiform
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 15 (13.33%)	1 / 66 (1.52%)	0 / 67 (0.00%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	4	1	0	0	1
Dry skin
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	1 / 15 (6.67%)	1 / 66 (1.52%)	2 / 67 (2.99%)	1 / 24 (4.17%)	2 / 28 (7.14%)
occurrences all number	1	0	1	1	5	1	2
Hyperhidrosis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	1 / 66 (1.52%)	6 / 67 (8.96%)	1 / 24 (4.17%)	3 / 28 (10.71%)
occurrences all number	0	0	0	1	12	1	4
Night sweats
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	4 / 67 (5.97%)	1 / 24 (4.17%)	1 / 28 (3.57%)
occurrences all number	0	1	0	0	7	1	1
Pruritus
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	2 / 15 (13.33%)	6 / 66 (9.09%)	7 / 67 (10.45%)	2 / 24 (8.33%)	0 / 28 (0.00%)
occurrences all number	1	0	5	6	17	2	0
Rash
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 15 (0.00%)	9 / 66 (13.64%)	13 / 67 (19.40%)	3 / 24 (12.50%)	3 / 28 (10.71%)
occurrences all number	1	0	0	12	29	3	5
Rash maculo-papular
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 15 (6.67%)	2 / 66 (3.03%)	4 / 67 (5.97%)	2 / 24 (8.33%)	0 / 28 (0.00%)
occurrences all number	0	4	1	2	6	2	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	3 / 66 (4.55%)	5 / 67 (7.46%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	0	0	4	8	0	1
Nocturia
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	1 / 66 (1.52%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	1	1	0	0
Pollakiuria
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	3 / 67 (4.48%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	3	0	0
Urinary retention
subjects affected / exposed	1 / 8 (12.50%)	1 / 9 (11.11%)	1 / 15 (6.67%)	1 / 66 (1.52%)	0 / 67 (0.00%)	0 / 24 (0.00%)	2 / 28 (7.14%)
occurrences all number	1	1	1	1	0	0	2
Endocrine disorders
Hypogonadism
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Hypothyroidism
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	1	0	0	0	0
Musculoskeletal and connective tissue disorders
Muscular weakness
subjects affected / exposed	0 / 8 (0.00%)	2 / 9 (22.22%)	2 / 15 (13.33%)	4 / 66 (6.06%)	3 / 67 (4.48%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	5	4	4	7	0	2
Back pain
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	4 / 15 (26.67%)	4 / 66 (6.06%)	7 / 67 (10.45%)	3 / 24 (12.50%)	4 / 28 (14.29%)
occurrences all number	1	0	5	5	10	4	4
Arthralgia
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	3 / 15 (20.00%)	3 / 66 (4.55%)	4 / 67 (5.97%)	2 / 24 (8.33%)	1 / 28 (3.57%)
occurrences all number	0	1	3	3	4	2	1
Bone pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	3 / 67 (4.48%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	3	0	0
Flank pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	4 / 66 (6.06%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	0	5	0	0	0
Groin pain
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Muscle spasms
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	2 / 15 (13.33%)	2 / 66 (3.03%)	7 / 67 (10.45%)	3 / 24 (12.50%)	3 / 28 (10.71%)
occurrences all number	1	0	2	4	10	4	3
Musculoskeletal chest pain
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 15 (0.00%)	3 / 66 (4.55%)	4 / 67 (5.97%)	3 / 24 (12.50%)	1 / 28 (3.57%)
occurrences all number	1	0	0	3	4	4	1
Musculoskeletal pain
subjects affected / exposed	1 / 8 (12.50%)	2 / 9 (22.22%)	1 / 15 (6.67%)	6 / 66 (9.09%)	3 / 67 (4.48%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	2	3	1	6	4	0	0
Myalgia
subjects affected / exposed	0 / 8 (0.00%)	3 / 9 (33.33%)	0 / 15 (0.00%)	3 / 66 (4.55%)	12 / 67 (17.91%)	1 / 24 (4.17%)	4 / 28 (14.29%)
occurrences all number	0	3	0	4	24	1	6
Neck pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	3 / 66 (4.55%)	1 / 67 (1.49%)	0 / 24 (0.00%)	3 / 28 (10.71%)
occurrences all number	0	0	0	3	1	0	3
Pain in extremity
subjects affected / exposed	1 / 8 (12.50%)	1 / 9 (11.11%)	0 / 15 (0.00%)	4 / 66 (6.06%)	5 / 67 (7.46%)	3 / 24 (12.50%)	2 / 28 (7.14%)
occurrences all number	9	1	0	4	9	3	2
Tendonitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	1 / 24 (4.17%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	1	1	0
Cellulitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 15 (13.33%)	0 / 66 (0.00%)	3 / 67 (4.48%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	2	0	6	0	0
Herpes zoster
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	0	0	1	0	0
Influenza
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Lung infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	1	0	0
Nasopharyngitis
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	1 / 15 (6.67%)	5 / 66 (7.58%)	7 / 67 (10.45%)	1 / 24 (4.17%)	2 / 28 (7.14%)
occurrences all number	1	0	1	5	7	1	3
Oesophageal candidiasis
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Oral candidiasis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 15 (0.00%)	0 / 66 (0.00%)	1 / 67 (1.49%)	0 / 24 (0.00%)	3 / 28 (10.71%)
occurrences all number	0	0	0	0	1	0	3
Rhinitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	1 / 66 (1.52%)	2 / 67 (2.99%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	2	1	2	0	0
Sinusitis
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 15 (0.00%)	0 / 66 (0.00%)	2 / 67 (2.99%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	1	0	0	2	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 15 (6.67%)	2 / 66 (3.03%)	4 / 67 (5.97%)	0 / 24 (0.00%)	1 / 28 (3.57%)
occurrences all number	0	2	1	3	4	0	1
Urinary tract infection
subjects affected / exposed	0 / 8 (0.00%)	2 / 9 (22.22%)	1 / 15 (6.67%)	5 / 66 (7.58%)	8 / 67 (11.94%)	1 / 24 (4.17%)	1 / 28 (3.57%)
occurrences all number	0	2	1	6	13	1	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	5 / 8 (62.50%)	5 / 9 (55.56%)	8 / 15 (53.33%)	16 / 66 (24.24%)	24 / 67 (35.82%)	10 / 24 (41.67%)	6 / 28 (21.43%)
occurrences all number	6	9	16	17	56	10	10
Dehydration
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	3 / 15 (20.00%)	2 / 66 (3.03%)	4 / 67 (5.97%)	0 / 24 (0.00%)	3 / 28 (10.71%)
occurrences all number	0	1	3	2	6	0	3
Hyperglycemia
subjects affected / exposed	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 15 (6.67%)	3 / 66 (4.55%)	1 / 67 (1.49%)	1 / 24 (4.17%)	1 / 28 (3.57%)
occurrences all number	0	3	1	5	1	1	1
Hyperkalemia
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	1 / 15 (6.67%)	3 / 66 (4.55%)	2 / 67 (2.99%)	0 / 24 (0.00%)	2 / 28 (7.14%)
occurrences all number	2	0	1	3	4	0	2
Hypocalcemia
subjects affected / exposed	1 / 8 (12.50%)	1 / 9 (11.11%)	4 / 15 (26.67%)	5 / 66 (7.58%)	2 / 67 (2.99%)	0 / 24 (0.00%)	2 / 28 (7.14%)
occurrences all number	1	1	8	10	3	0	4
Hyponatremia
subjects affected / exposed	0 / 8 (0.00%)	2 / 9 (22.22%)	0 / 15 (0.00%)	3 / 66 (4.55%)	1 / 67 (1.49%)	1 / 24 (4.17%)	3 / 28 (10.71%)
occurrences all number	0	5	0	4	1	4	7
Malnutrition
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 66 (0.00%)	0 / 67 (0.00%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Hypoalbuminaemia
subjects affected / exposed	0 / 8 (0.00%)	3 / 9 (33.33%)	3 / 15 (20.00%)	6 / 66 (9.09%)	4 / 67 (5.97%)	0 / 24 (0.00%)	2 / 28 (7.14%)
occurrences all number	0	11	15	8	7	0	2
Hypoglycaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 15 (6.67%)	1 / 66 (1.52%)	0 / 67 (0.00%)	1 / 24 (4.17%)	0 / 28 (0.00%)
occurrences all number	0	0	1	1	0	1	0
Hypokalaemia
subjects affected / exposed	1 / 8 (12.50%)	1 / 9 (11.11%)	5 / 15 (33.33%)	7 / 66 (10.61%)	5 / 67 (7.46%)	1 / 24 (4.17%)	0 / 28 (0.00%)
occurrences all number	1	1	6	11	11	1	0
Hypophosphataemia
subjects affected / exposed	1 / 8 (12.50%)	0 / 9 (0.00%)	1 / 15 (6.67%)	1 / 66 (1.52%)	2 / 67 (2.99%)	0 / 24 (0.00%)	0 / 28 (0.00%)
occurrences all number	1	0	1	1	2	0	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

12 Dec 2012

-Added Inclusion Criterion #3, so that subjects enrolled in Part A could have evaluable disease, rather than just measurable disease per RECIST. -Clarified Inclusion Criteria #2 and #4, such that subjects who had other prior anticancer therapies, including other ALK inhibitors, could be enrolled in the study, while still requiring at least 8 weeks of prior crizotinib exposure. -Added a requirement that, if neither archival nor pre-existing tumor tissue were available, a sample must be obtained, if safe and appropriate, during screening in Part A.

17 Apr 2014

-Modified Inclusion Criterion #3, to remove requirement for measurable disease to allow subjects who no longer had measurable disease during crizotinib treatment to be enrolled in Part B. -Modified Inclusion Criterion #4b (enrollment in Part B), to remove requirement for at least 8 weeks of prior treatment with crizotinib. -Modified Inclusion Criterion #4b to permit enrollment of subjects who were currently receiving and tolerating crizotinib and had not progressed by RECIST 1.1 or who had not yet started but were eligible to receive crizotinib. -Changed the primary endpoint in Part B to PFS (rather than objective response), since assessment of objective response would not be possible in subjects who did not have measurable disease at baseline. -Clarified Inclusion Criterion #4c (enrollment in Part C), to permit enrollment of subjects who had previously received other therapy including other ALK inhibitors before enrollment). -Modified Inclusion Criterion #9 to change the maximum allowed QTc interval from 450 to 480 msec. -Modified Exclusion Criterion #5 to clarify that exclusionary QTc prolongation (>480 msec) must be related to crizotinib on multiple measurements. -Modified Exclusion Criterion #6 to clarify that Grade 2 bilirubin or transaminases on multiple measurements must be related to crizotinib while receiving crizotinib. -Modified Exclusion Criterion #7 to clarify that Grade 2 visual disturbances must be related to crizotinib while receiving crizotinib. -Updated study objectives, endpoints, analyses, and discussion of study design to reflect changes due to the elimination of the requirement for measurable disease in Part B. -Updated power calculation for Part B. Sample size will provide 82% power to detect a difference between a median PFS of 5 months (control group of crizotinib alone) and 9 months (experimental group of crizotinib + onalespib) with 2-sided log-rank test at an α level of 0.05.

28 Mar 2016

- The study design was modified to add Part D so that subjects in South Korea could continue to receive crizotinib alone, if deemed appropriated by their physician. - In Part D, study assessments were reduced to collection (and reporting) of reported SAEs only.

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.

For this summary, we have used Part A as an overall baseline.

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Clinical trials

Clinical Trial Results:
A Study of HSP90 Inhibitor AT13387 Alone and in Combination with Crizotinib in the Treatment of Non-small Cell Lung Cancer (NSCLC).

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part A - The incidence of DLTs when onalespib was administered in combination with crizotinib.

Primary: Part A - The incidence of DLTs when onalespib was administered in combination with crizotinib.

Primary: Progression Free Survival (PFS)

Primary: Progression Free Survival (PFS)

Primary: Objective Response Rate (ORR)

Primary: Objective Response Rate (ORR)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A Study of HSP90 Inhibitor AT13387 Alone and in Combination with Crizotinib in the Treatment of Non-small Cell Lung Cancer (NSCLC).

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part A - The incidence of DLTs when onalespib was administered in combination with crizotinib.

Primary: Part A - The incidence of DLTs when onalespib was administered in combination with crizotinib.

Primary: Progression Free Survival (PFS)

Primary: Progression Free Survival (PFS)

Primary: Objective Response Rate (ORR)

Primary: Objective Response Rate (ORR)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Study of HSP90 Inhibitor AT13387 Alone and in Combination with Crizotinib in the Treatment of Non-small Cell Lung Cancer (NSCLC).