Trial Outcomes & Findings for Efficacy and Safety of Palonosetron Intravenous in Prevention of Chemotherapy Induced Nausea and Vomiting in Pediatric Patients (NCT NCT01442376)

Last Updated: 2014-08-07

Results Overview

Complete Response (CR) was defined as no vomiting, no retching, and no use of antiemetic rescue medication from 0 to 24 hours (acute phase) after T0 (start of administration of the most emetogenic chemotherapy) during first cycle. Time 0 (T0) is defined as the time when the patient starts the first cycle of chemotherapy.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

502 participants

Primary outcome timeframe

0 to 24 hours after T0

Results posted on

2014-08-07

Participant Flow

A total of 502 patients were enrolled and randomly assigned to treatment. Study drug was not administered to 8 randomized patients, of these patients 2 had also an adverse event and were counted under this category in overall study statement. Therefore 494 patients did receive the study drug and are part of the analysis for the safety population.

Participant milestones

Participant milestones
Measure	Palonosetron 10 mcg/kg Palonosetron and placebo to Ondansetron Intervention: Drug: Palonosetron Palonosetron: Single dose Palonosetron IV 10 mcg/kg up to a maximum total dose of 0.75 mg Placebo to Ondansetron	Palonosetron 20 mcg/kg Palonosetron and placebo to Ondansetron Intervention: Drug: Palonosetron Palonosetron: Single dose Palonosetron IV 20 mcg/kg up to a maximum total dose of 1.5 mg Placebo to Ondansetron	Ondansetron Ondansetron and placebo to Palonosetron Drug: Comparator: Ondansetron Ondansetron: Single three (every 4 hours) Ondansetron IV doses 0.15 mg/kg up to a maximum total dose of 32 mg Placebo to Palonosetron
Overall Study STARTED	169	169	164
Overall Study COMPLETED	166	160	159
Overall Study NOT COMPLETED	3	9	5

Reasons for withdrawal

Reasons for withdrawal
Measure	Palonosetron 10 mcg/kg Palonosetron and placebo to Ondansetron Intervention: Drug: Palonosetron Palonosetron: Single dose Palonosetron IV 10 mcg/kg up to a maximum total dose of 0.75 mg Placebo to Ondansetron	Palonosetron 20 mcg/kg Palonosetron and placebo to Ondansetron Intervention: Drug: Palonosetron Palonosetron: Single dose Palonosetron IV 20 mcg/kg up to a maximum total dose of 1.5 mg Placebo to Ondansetron	Ondansetron Ondansetron and placebo to Palonosetron Drug: Comparator: Ondansetron Ondansetron: Single three (every 4 hours) Ondansetron IV doses 0.15 mg/kg up to a maximum total dose of 32 mg Placebo to Palonosetron
Overall Study Adverse Event	0	3	2
Overall Study Death	0	1	1
Overall Study Withdrawal of consent	0	0	1
Overall Study Patients not treated	2	3	1
Overall Study Not eligible for subsequent cycles	1	2	0

Baseline Characteristics

Efficacy and Safety of Palonosetron Intravenous in Prevention of Chemotherapy Induced Nausea and Vomiting in Pediatric Patients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Palonosetron 10 mcg/kg n=166 Participants Palonosetron and placebo to Ondansetron Intervention: Drug: Palonosetron Palonosetron: Single dose Palonosetron IV 10 mcg/kg up to a maximum total dose of 0.75 mg Placebo to Ondansetron	Palonosetron 20 mcg/kg n=165 Participants Palonosetron and placebo to Ondansetron Intervention: Drug: Palonosetron Palonosetron: Single dose Palonosetron IV 20 mcg/kg up to a maximum total dose of 1.5 mg Placebo to Ondansetron	Ondansetron n=162 Participants Ondansetron and placebo to Palonosetron Drug: Comparator: Ondansetron Ondansetron: Single three (every 4 hours) Ondansetron IV doses 0.15 mg/kg up to a maximum total dose of 32 mg Placebo to Palonosetron	Total n=493 Participants Total of all reporting groups
Age, Customized <2 years	15 participants n=5 Participants	15 participants n=7 Participants	15 participants n=5 Participants	45 participants n=4 Participants
Age, Customized 2 to <6 years	54 participants n=5 Participants	54 participants n=7 Participants	54 participants n=5 Participants	162 participants n=4 Participants
Age, Customized 6 to <12 years	46 participants n=5 Participants	46 participants n=7 Participants	44 participants n=5 Participants	136 participants n=4 Participants
Age, Customized 12 to <17 years	51 participants n=5 Participants	50 participants n=7 Participants	49 participants n=5 Participants	150 participants n=4 Participants
Sex: Female, Male Female	88 Participants n=5 Participants	76 Participants n=7 Participants	98 Participants n=5 Participants	262 Participants n=4 Participants
Sex: Female, Male Male	78 Participants n=5 Participants	89 Participants n=7 Participants	64 Participants n=5 Participants	231 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	26 Participants n=5 Participants	26 Participants n=7 Participants	12 Participants n=5 Participants	64 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	140 Participants n=5 Participants	139 Participants n=7 Participants	150 Participants n=5 Participants	429 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) White	156 Participants n=5 Participants	154 Participants n=7 Participants	159 Participants n=5 Participants	469 Participants n=4 Participants
Race (NIH/OMB) More than one race	5 Participants n=5 Participants	11 Participants n=7 Participants	3 Participants n=5 Participants	19 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Emetogenicity of chemotherapy in Cycle 1 MEC	112 participants n=5 Participants	116 participants n=7 Participants	111 participants n=5 Participants	339 participants n=4 Participants
Emetogenicity of chemotherapy in Cycle 1 HEC	54 participants n=5 Participants	49 participants n=7 Participants	51 participants n=5 Participants	154 participants n=4 Participants

PRIMARY outcome

Timeframe: 0 to 24 hours after T0

Population: Full Analysis Set (FAS) population

Outcome measures

Outcome measures
Measure	Palonosetron 10 mcg/kg n=166 Participants Palonosetron and placebo to Ondansetron Intervention: Drug: Palonosetron Palonosetron: Single dose Palonosetron IV 10 mcg/kg up to a maximum total dose of 0.75 mg Placebo to Ondansetron	Palonosetron 20 mcg/kg n=165 Participants Palonosetron and placebo to Ondansetron Intervention: Drug: Palonosetron Palonosetron: Single dose Palonosetron IV 20 mcg/kg up to a maximum total dose of 1.5 mg Placebo to Ondansetron	Ondansetron n=162 Participants Ondansetron and placebo to Palonosetron Drug: Comparator: Ondansetron Ondansetron: Single three (every 4 hours) Ondansetron IV doses 0.15 mg/kg up to a maximum total dose of 32 mg Placebo to Palonosetron
Proportion of Patients With Complete Response 0 to 24 Hours (Acute Phase) in Cycle 1	54.2 percentage of patients Interval 46.3 to 61.9	59.4 percentage of patients Interval 51.5 to 66.9	58.6 percentage of patients Interval 50.6 to 66.2

SECONDARY outcome

Timeframe: from >24 to 120 hours (delayed phase) after T0

Population: Full Analysis Set (FAS) population.

Complete Response (CR) was defined as no vomiting, no retching, and no use of antiemetic rescue medication from \>24 to 120 hours (delayed phase) after T0 (start of administration of the most emetogenic chemotherapy) during first cycle.

Outcome measures

Outcome measures
Measure	Palonosetron 10 mcg/kg n=166 Participants Palonosetron and placebo to Ondansetron Intervention: Drug: Palonosetron Palonosetron: Single dose Palonosetron IV 10 mcg/kg up to a maximum total dose of 0.75 mg Placebo to Ondansetron	Palonosetron 20 mcg/kg n=165 Participants Palonosetron and placebo to Ondansetron Intervention: Drug: Palonosetron Palonosetron: Single dose Palonosetron IV 20 mcg/kg up to a maximum total dose of 1.5 mg Placebo to Ondansetron	Ondansetron n=162 Participants Ondansetron and placebo to Palonosetron Drug: Comparator: Ondansetron Ondansetron: Single three (every 4 hours) Ondansetron IV doses 0.15 mg/kg up to a maximum total dose of 32 mg Placebo to Palonosetron
Proportion of Patients With Complete Response >24 to 120 Hours (Delayed Phase) in Cycle 1	28.9 percentage of patients Interval 22.3 to 36.5	38.8 percentage of patients Interval 31.4 to 46.7	28.4 percentage of patients Interval 21.7 to 36.1

Adverse Events

Palonosetron 10 mcg/kg

Serious events: 68 serious events

Other events: 143 other events

Deaths: 0 deaths

Palonosetron 20 mcg/kg

Serious events: 62 serious events

Other events: 130 other events

Deaths: 0 deaths

Ondansetron

Serious events: 70 serious events

Other events: 145 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Spinelli Tulla

Helsinn Healthcare SA

Phone: +4191985 21 21

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If Sponsor does not submit a publication regarding the study to a journal within 12 months from study data analysis completion, the Investigator may publish an analysis of the study data collected as a result of the conduct of the study by the Investigator. The Investigator shall ensure that at least 60 days prior to submitting/presenting a manuscript/material relating to study to publishers a copy of all manuscripts/materials is provided to the Sponsor to allow the Sponsor sixty days to review.
Publication restrictions are in place

Restriction type: OTHER

Measure	Palonosetron 10 mcg/kg n=167 participants at risk Palonosetron and placebo to Ondansetron Intervention: Drug: Palonosetron Palonosetron: Single dose Palonosetron IV 10 mcg/kg up to a maximum total dose of 0.75 mg Placebo to Ondansetron	Palonosetron 20 mcg/kg n=163 participants at risk Palonosetron and placebo to Ondansetron Intervention: Drug: Palonosetron Palonosetron: Single dose Palonosetron IV 20 mcg/kg up to a maximum total dose of 1.5 mg Placebo to Ondansetron	Ondansetron n=164 participants at risk Ondansetron and placebo to Palonosetron Drug: Comparator: Ondansetron Ondansetron: Single three (every 4 hours) Ondansetron IV doses 0.15 mg/kg up to a maximum total dose of 32 mg Placebo to Palonosetron
Blood and lymphatic system disorders Anaemia	38.9% 65/167 • Number of events 107 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	36.8% 60/163 • Number of events 89 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	37.2% 61/164 • Number of events 105 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).
Blood and lymphatic system disorders Thrombocytopenia	21.0% 35/167 • Number of events 69 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	20.2% 33/163 • Number of events 61 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	22.6% 37/164 • Number of events 90 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).
Blood and lymphatic system disorders Leukopenia	22.2% 37/167 • Number of events 74 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	16.6% 27/163 • Number of events 59 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	26.2% 43/164 • Number of events 104 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).
Blood and lymphatic system disorders Neutropenia	21.0% 35/167 • Number of events 60 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	19.0% 31/163 • Number of events 51 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	13.4% 22/164 • Number of events 40 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).
Blood and lymphatic system disorders Febrile neutropenia	6.6% 11/167 • Number of events 13 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	2.5% 4/163 • Number of events 4 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	2.4% 4/164 • Number of events 7 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).
Gastrointestinal disorders Vomiting	7.8% 13/167 • Number of events 21 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	10.4% 17/163 • Number of events 39 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	13.4% 22/164 • Number of events 31 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).
Gastrointestinal disorders Abdominal pain	9.0% 15/167 • Number of events 20 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	8.0% 13/163 • Number of events 16 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	11.0% 18/164 • Number of events 24 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).
Gastrointestinal disorders Stomatitis	6.6% 11/167 • Number of events 15 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	7.4% 12/163 • Number of events 14 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	7.3% 12/164 • Number of events 16 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).
Gastrointestinal disorders Diarrhoea	7.8% 13/167 • Number of events 14 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	3.7% 6/163 • Number of events 7 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	8.5% 14/164 • Number of events 15 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).
Gastrointestinal disorders Constipation	4.8% 8/167 • Number of events 9 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	6.1% 10/163 • Number of events 12 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	4.9% 8/164 • Number of events 9 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).
Gastrointestinal disorders Nausea	4.8% 8/167 • Number of events 10 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	3.7% 6/163 • Number of events 8 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	7.9% 13/164 • Number of events 19 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).
General disorders Pyrexia	19.2% 32/167 • Number of events 40 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	11.7% 19/163 • Number of events 35 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	12.8% 21/164 • Number of events 38 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).
Investigations White blood cell count decreased	7.2% 12/167 • Number of events 14 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	9.2% 15/163 • Number of events 18 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	9.1% 15/164 • Number of events 24 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).
Investigations Platelet count decreased	6.0% 10/167 • Number of events 13 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	5.5% 9/163 • Number of events 12 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	6.1% 10/164 • Number of events 19 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).
Nervous system disorders Headache	10.2% 17/167 • Number of events 24 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	5.5% 9/163 • Number of events 10 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	9.8% 16/164 • Number of events 28 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).
Respiratory, thoracic and mediastinal disorders Cough	4.8% 8/167 • Number of events 8 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	2.5% 4/163 • Number of events 4 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	5.5% 9/164 • Number of events 10 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).
Musculoskeletal and connective tissue disorders Pain in extremity	3.6% 6/167 • Number of events 8 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	1.8% 3/163 • Number of events 3 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).	5.5% 9/164 • Number of events 9 Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).