Trial Outcomes & Findings for Bioequivalence Study Bevacizumab Biosimilar (BEVZ92) Versus Bevacizumab (AVASTIN®) in First-line Treatment mCRC Patients (NCT NCT02069704)

NCT ID: NCT02069704

Last Updated: 2019-07-23

Results Overview

To compare the pharmacokinetic (PK) profile of BEVZ92 and Avastin®, both administered in combination with FOLFOX (any) or FOLFIRI, by means of comparing the truncated AUC calculated from start of the first infusion until start of the second infusion (i.e. at Cycle 1; AUC0-336h) For the PK similarity assessments, regulatory guidelines on bioequivalence were followed whereby two treatments are judged not to be different from one another if the 90% confidence interval (CI) of the ratio of a log-transformed exposure measure (AUC) falls completely within the range 80-125%.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

142 participants

Primary outcome timeframe

AUC0-336 hrs: 0 to 336 hours after start of the first infusion

Results posted on

2019-07-23

Participant Flow

Participant milestones

Participant milestones
Measure	Bevacizumab Biosimilar (BEVZ92) Bevacizumab biosimilar (BEVZ92): Bevacizumab biosimilar (BEVZ92), Active ingredient Bevacizumab 25 mg/mL (strength = 100mg/mL). 30-minute\* IV infusion (5 mg/kg) every 2 weeks, prior to chemotherapy (Folfox any or Folfiri).	Avastin® (Bevacizumab, Ref. Product) Avastin® (bevacizumab, reference product): Avastin® (bevacizumab, reference product). Active ingredient: Bevacizumab 25 mg/mL (strength: 100 mg/4 mL). 30-minute\* IV infusion (5 mg/kg) every 2 weeks, prior to administration of chemotherapy (Folfox any or Folfiri).
Overall Study STARTED	69	71
Overall Study COMPLETED	69	71
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Missing data for two patients in each treatment arm

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Bevacizumab Biosimilar (BEVZ92) n=69 Participants Bevacizumab biosimilar (BEVZ92): Bevacizumab biosimilar (BEVZ92), Active ingredient Bevacizumab 25 mg/mL (strength = 100mg/mL). 30-minute\* IV infusion (5 mg/kg) every 2 weeks, prior to chemotherapy (Folfox any or Folfiri).	Avastin® (Bevacizumab, Ref. Product) n=71 Participants Avastin® (bevacizumab, reference product): Avastin® (bevacizumab, reference product). Active ingredient: Bevacizumab 25 mg/mL (strength: 100 mg/4 mL). 30-minute\* IV infusion (5 mg/kg) every 2 weeks, prior to administration of chemotherapy (Folfox any or Folfiri).	Total n=140 Participants Total of all reporting groups
Age, Continuous	56.3 years STANDARD_DEVIATION 12.9 • n=69 Participants	56.7 years STANDARD_DEVIATION 11.6 • n=71 Participants	56.5 years STANDARD_DEVIATION 12.2 • n=140 Participants
Age, Customized Aged · < 65 years	49 Participants n=69 Participants	51 Participants n=71 Participants	100 Participants n=140 Participants
Age, Customized Aged · >= 65 years	20 Participants n=69 Participants	20 Participants n=71 Participants	40 Participants n=140 Participants
Sex: Female, Male Female	30 Participants n=69 Participants	32 Participants n=71 Participants	62 Participants n=140 Participants
Sex: Female, Male Male	39 Participants n=69 Participants	39 Participants n=71 Participants	78 Participants n=140 Participants
Race/Ethnicity, Customized Race · White	50 Participants n=69 Participants	55 Participants n=71 Participants	105 Participants n=140 Participants
Race/Ethnicity, Customized Race · Asian	14 Participants n=69 Participants	12 Participants n=71 Participants	26 Participants n=140 Participants
Race/Ethnicity, Customized Race · Black	2 Participants n=69 Participants	3 Participants n=71 Participants	5 Participants n=140 Participants
Race/Ethnicity, Customized Race · Other	3 Participants n=69 Participants	1 Participants n=71 Participants	4 Participants n=140 Participants
Eastern Cooperative Oncology Group (ECOG) performance status 0	7 Participants n=69 Participants	18 Participants n=71 Participants	25 Participants n=140 Participants
Eastern Cooperative Oncology Group (ECOG) performance status 1	57 Participants n=69 Participants	43 Participants n=71 Participants	100 Participants n=140 Participants
Eastern Cooperative Oncology Group (ECOG) performance status 2	5 Participants n=69 Participants	10 Participants n=71 Participants	15 Participants n=140 Participants
Tumor, lymph Nodes and Metastases (TNM) stage IVa	30 Participants n=69 Participants	32 Participants n=71 Participants	62 Participants n=140 Participants
Tumor, lymph Nodes and Metastases (TNM) stage IVb	38 Participants n=69 Participants	38 Participants n=71 Participants	76 Participants n=140 Participants
Tumor, lymph Nodes and Metastases (TNM) stage missing	1 Participants n=69 Participants	1 Participants n=71 Participants	2 Participants n=140 Participants
Months since diagnosis of metastatic colorectal cancer	13.0 months STANDARD_DEVIATION 14.7 • n=67 Participants • Missing data for two patients in each treatment arm	13.0 months STANDARD_DEVIATION 17.5 • n=69 Participants • Missing data for two patients in each treatment arm	13.0 months STANDARD_DEVIATION 16.1 • n=136 Participants • Missing data for two patients in each treatment arm
Number of target lesions 1	9 Participants n=69 Participants	11 Participants n=71 Participants	20 Participants n=140 Participants
Number of target lesions 2	29 Participants n=69 Participants	31 Participants n=71 Participants	60 Participants n=140 Participants
Number of target lesions >=3	31 Participants n=69 Participants	29 Participants n=71 Participants	60 Participants n=140 Participants
Extent of disease Liver disease only	7 Participants n=69 Participants	5 Participants n=71 Participants	12 Participants n=140 Participants
Extent of disease Other	62 Participants n=69 Participants	66 Participants n=71 Participants	128 Participants n=140 Participants
Previous treatment Surgery	55 participants n=69 Participants	53 participants n=71 Participants	108 participants n=140 Participants
Previous treatment Radiotherapy	14 participants n=69 Participants	15 participants n=71 Participants	29 participants n=140 Participants
Previous treatment Chemotherapy	24 participants n=69 Participants	23 participants n=71 Participants	47 participants n=140 Participants

PRIMARY outcome

Timeframe: AUC0-336 hrs: 0 to 336 hours after start of the first infusion

Population: Overall number of participants Analyzed equals to number of subjects who contributed to summary statistics.

Outcome measures

Outcome measures
Measure	Bevacizumab Biosimilar (BEVZ92) n=55 Participants Bevacizumab proposed biosimilar (BEVZ92)	Avastin® (Bevacizumab, Ref. Product). n=61 Participants Avastin® (bevacizumab, reference product).
Area Under the Concentration-versus-time Curve (AUC) at Cycle 1 (AUC0-336h) of BEVZ92 and Avastin®	16500000 ng.h/mL Geometric Coefficient of Variation 30.7	16600000 ng.h/mL Geometric Coefficient of Variation 31.8

PRIMARY outcome

Timeframe: AUCss: 0 to 336 hours after the administration of Cycle 7 infusion (Week 13).

Population: In the Avastin arm there were 3 missing samples at the timepoint required for the specific PK parameters within Cycle 7.

To compare the PK profile of BEVZ92 and Avastin®, both administered in combination with FOLFOX (any) or FOLFIRI, by means of comparing the truncated area under the concentration-versus-time curve calculated over a dosage interval at steady state (i.e. at Cycle 7; AUCss). For the PK similarity assessments, regulatory guidelines on bioequivalence were followed whereby two treatments are judged not to be different from one another if the 90% CI of the ratio of a log-transformed exposure measure (AUC) falls completely within the range 80-125%.

Outcome measures

Outcome measures
Measure	Bevacizumab Biosimilar (BEVZ92) n=55 Participants Bevacizumab proposed biosimilar (BEVZ92)	Avastin® (Bevacizumab, Ref. Product). n=58 Participants Avastin® (bevacizumab, reference product).
AUC at Steady State (AUCss) of BEVZ92 and Avastin®	35900000 ng.h/mL Geometric Coefficient of Variation 34.8	35700000 ng.h/mL Geometric Coefficient of Variation 36.6

SECONDARY outcome

Timeframe: From first study dose and up to 30 days after the end of study treatment for each patient, for an average of 11 months

Population: All patients receiving at least one dose of study medication.

Compare the safety profile by means of the frequency and severity of TEAEs and SAEs reported in each treatment arm.

Outcome measures

Outcome measures
Measure	Bevacizumab Biosimilar (BEVZ92) n=69 Participants Bevacizumab proposed biosimilar (BEVZ92)	Avastin® (Bevacizumab, Ref. Product). n=71 Participants Avastin® (bevacizumab, reference product).
Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® Any TEAE (any causality)	66 participants	71 participants
Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® Any grade>=3 TEAE	44 participants	49 participants
Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® Any TEAE leading to discontinuation	13 participants	6 participants
Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® Any treatment-related TEAE	63 participants	70 participants
Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® Any grade >=3 treatment-related TEAE	63 participants	70 participants
Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® Any serious TEAE	19 participants	21 participants
Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® Any bleeding event	14 participants	19 participants

SECONDARY outcome

Timeframe: At baseline, and on Day 1 (pre-dose) of Cycles: 1, 5 and 8, and 12 months after first drug administration

Population: All patients receiving at least one dose of study medication.

Immunogenicity profile by means of measurement of ADA developed de novo (seroconversion) after cycle 5, cycle 8, and 12 months after first drug administration (pre-dose).

Outcome measures

Outcome measures
Measure	Bevacizumab Biosimilar (BEVZ92) n=69 Participants Bevacizumab proposed biosimilar (BEVZ92)	Avastin® (Bevacizumab, Ref. Product). n=71 Participants Avastin® (bevacizumab, reference product).
Anti-Drug Antibody (ADA) of BEVZ92 and Avastin® Seroconversion	2 participants	0 participants
Anti-Drug Antibody (ADA) of BEVZ92 and Avastin® No seroconversion	67 participants	71 participants

SECONDARY outcome

Timeframe: Every four weeks. Up to 48 weeks

Population: Intent-to-treat population

To compare efficacy in terms of ORR between arms. Clinical and radiological tumor assessments were performed according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 using computed tomography (CT) or magnetic resonance imaging (MRI) scans. Objective response (OR) is defined as a best overall response of partial response (PR) or complete response (CR) as defined by RECIST v1.1. All participants who did not meet the criteria for CR or PR by the end of the study were considered non-responders.

Outcome measures

Outcome measures
Measure	Bevacizumab Biosimilar (BEVZ92) n=71 Participants Bevacizumab proposed biosimilar (BEVZ92)	Avastin® (Bevacizumab, Ref. Product). n=71 Participants Avastin® (bevacizumab, reference product).
Objective Response Rate (ORR) of BEVZ92 and Avastin® ORR (CR+PR)	35 Participants	40 Participants
Objective Response Rate (ORR) of BEVZ92 and Avastin® Stable disease	27 Participants	25 Participants
Objective Response Rate (ORR) of BEVZ92 and Avastin® Progressive disease	4 Participants	2 Participants
Objective Response Rate (ORR) of BEVZ92 and Avastin® unevaluable	5 Participants	4 Participants

SECONDARY outcome

Timeframe: Cmax, sd: 0 to 336 hours after start of the first infusion.

Population: Overall number of participants Analyzed equals to number of subjects who contributed to summary statistics.

Secondary PK endpoints included the Cmax calculated at Cycle 1 (Cmax,sd )

Outcome measures

Outcome measures
Measure	Bevacizumab Biosimilar (BEVZ92) n=55 Participants Bevacizumab proposed biosimilar (BEVZ92)	Avastin® (Bevacizumab, Ref. Product). n=61 Participants Avastin® (bevacizumab, reference product).
Cmax,sd of BEVZ92 and Avastin®	120000 ng/mL Geometric Coefficient of Variation 30	123000 ng/mL Geometric Coefficient of Variation 27.2

SECONDARY outcome

Timeframe: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 weeks.

Population: Intent-to-treat population

Compare PFS between the randomized treatment arms. Progression-free survival (PFS) was defined as the time from the randomization date to the date of disease progression using RECIST v1.1, or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions plus 5 mm absolute increase, and/or unequivocal progression of known non-target lesion, and/or the appearance of new lesions".

Outcome measures

Outcome measures
Measure	Bevacizumab Biosimilar (BEVZ92) n=71 Participants Bevacizumab proposed biosimilar (BEVZ92)	Avastin® (Bevacizumab, Ref. Product). n=71 Participants Avastin® (bevacizumab, reference product).
Progression-free Survival (PFS) of BEVZ92 and Avastin®	10.8 months Interval 7.4 to 11.5	11.1 months Interval 8.6 to 12.8

SECONDARY outcome

Timeframe: Cmax, ss: 0 to 336 hours post-dose after the administration of Cycle 7 infusion (Week 13)

Population: In the Avastin arm there were 3 missing samples at the timepoint required for the specific PK parameter within Cycle 7.

Secondary PK endpoints included the Cmax calculated at Cycle 7 (Cmax, ss )

Outcome measures

Outcome measures
Measure	Bevacizumab Biosimilar (BEVZ92) n=55 Participants Bevacizumab proposed biosimilar (BEVZ92)	Avastin® (Bevacizumab, Ref. Product). n=58 Participants Avastin® (bevacizumab, reference product).
Cmax,ss of BEVZ92 and Avastin®	195000 ng/mL Geometric Coefficient of Variation 29.5	200000 ng/mL Geometric Coefficient of Variation 30.7

SECONDARY outcome

Timeframe: Ctrough, sd: 0 to 336 hours after start of the first infusion.

Population: In the Avastin arm there was 1 missing samples at the timepoint required for the specific PK parameter within Cycle 1.

Secondary PK endpoints included the Ctrough calculated at Cycle 1 (Ctrough,sd )

Outcome measures

Outcome measures
Measure	Bevacizumab Biosimilar (BEVZ92) n=55 Participants Bevacizumab proposed biosimilar (BEVZ92)	Avastin® (Bevacizumab, Ref. Product). n=60 Participants Avastin® (bevacizumab, reference product).
Ctrough,sd of BEVZ92 and Avastin®	344 ng/mL Geometric Coefficient of Variation 12.5	349 ng/mL Geometric Coefficient of Variation 13.7

SECONDARY outcome

Timeframe: Ctrough, ss: 0 to 336 hours after the administration of the Cycle 7 infusion.

Population: There were 4 missing samples (1 in the BEVZ92 and 3 in the Avastin arm) at the timepoint required for the specific PK parameter within Cycle 7.

Secondary PK endpoints included the Ctrough calculated at Cycle 7 (Ctrough,ss)

Outcome measures

Outcome measures
Measure	Bevacizumab Biosimilar (BEVZ92) n=54 Participants Bevacizumab proposed biosimilar (BEVZ92)	Avastin® (Bevacizumab, Ref. Product). n=58 Participants Avastin® (bevacizumab, reference product).
Ctrough,ss of BEVZ92 and Avastin®	69600 ng/mL Geometric Coefficient of Variation 52.1	69300 ng/mL Geometric Coefficient of Variation 50.5

SECONDARY outcome

Timeframe: t1/2: 0 to 336 hours after the administration of the Cycle 7 infusion.

Population: In the Avastin arm there were several missing samples at the timepoint required for the specific PK parameter

Secondary PK endpoints included the t1/2 calculated at Cycle 7

Outcome measures

Outcome measures
Measure	Bevacizumab Biosimilar (BEVZ92) n=49 Participants Bevacizumab proposed biosimilar (BEVZ92)	Avastin® (Bevacizumab, Ref. Product). n=52 Participants Avastin® (bevacizumab, reference product).
Elimination Half-life (t1/2) of BEVZ92 and Avastin®	294 h Geometric Coefficient of Variation 33.3	289 h Geometric Coefficient of Variation 32.8

SECONDARY outcome

Timeframe: Kel: 0 to 336 hours after the administration of the Cycle 7 infusion.

Population: Overall number of participants Analyzed equals to number of subjects who contributed to summary statistics.

Secondary PK endpoints included the Kel calculated at Cycle 7 (Ctrough,ss)

Outcome measures

Outcome measures
Measure	Bevacizumab Biosimilar (BEVZ92) n=55 Participants Bevacizumab proposed biosimilar (BEVZ92)	Avastin® (Bevacizumab, Ref. Product). n=61 Participants Avastin® (bevacizumab, reference product).
Elimination Rate Constant (Kel) of BEVZ92 and Avastin®	0.00236 l/h Geometric Coefficient of Variation 33.3	0.00240 l/h Geometric Coefficient of Variation 32.8

SECONDARY outcome

Timeframe: Vd: 0 to 336 hours after the administration of the Cycle 7 infusion.

Population: In the Avastin arm there were several missing samples at the timepoint required for the specific PK parameter

Secondary PK endpoints included the Vd calculated at Cycle 7

Outcome measures

Outcome measures
Measure	Bevacizumab Biosimilar (BEVZ92) n=49 Participants Bevacizumab proposed biosimilar (BEVZ92)	Avastin® (Bevacizumab, Ref. Product). n=52 Participants Avastin® (bevacizumab, reference product).
Volume of Distribution (Vd) of BEVZ92 and Avastin®	4.06 L Geometric Coefficient of Variation 37.7	3.86 L Geometric Coefficient of Variation 39.4

Adverse Events

Bevacizumab Biosimilar (BEVZ92)

Serious events: 19 serious events

Other events: 66 other events

Deaths: 11 deaths

Avastin® (Bevacizumab, Ref. Product)

Serious events: 21 serious events

Other events: 71 other events

Deaths: 7 deaths

Serious adverse events

Other adverse events

Additional Information

Susana Millan

mAbxience

Phone: +34917711500

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	Bevacizumab Biosimilar (BEVZ92) n=69 participants at risk Bevacizumab biosimilar (BEVZ92): Bevacizumab biosimilar (BEVZ92), Active ingredient Bevacizumab 25 mg/mL (strength = 100mg/mL). 30-minute\* IV infusion (5 mg/kg) every 2 weeks, prior to chemotherapy (Folfox any or Folfiri).	Avastin® (Bevacizumab, Ref. Product) n=71 participants at risk Avastin® (bevacizumab, reference product): Avastin® (bevacizumab, reference product). Active ingredient: Bevacizumab 25 mg/mL (strength: 100 mg/4 mL). 30-minute\* IV infusion (5 mg/kg) every 2 weeks, prior to administration of chemotherapy (Folfox any or Folfiri).
Gastrointestinal disorders Diarrhea	1.4% 1/69 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	5.6% 4/71 • Number of events 5 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Gastrointestinal disorders Constipation	1.4% 1/69 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	0.00% 0/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Gastrointestinal disorders Enteritis	0.00% 0/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Gastrointestinal disorders Intestinal obstruction	7.2% 5/69 • Number of events 6 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	0.00% 0/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Gastrointestinal disorders Ileus paralytic	0.00% 0/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Gastrointestinal disorders Abdominal pain	0.00% 0/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Gastrointestinal disorders Lower Gastrointestinal hemorrhage	1.4% 1/69 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	0.00% 0/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Gastrointestinal disorders Large intestine perforation	0.00% 0/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Gastrointestinal disorders Subileus	0.00% 0/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Infections and infestations Bronchopneumonia	1.4% 1/69 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	0.00% 0/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Infections and infestations Sepsis	1.4% 1/69 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	4.2% 3/71 • Number of events 3 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Infections and infestations Urinary tract infection	1.4% 1/69 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	2.8% 2/71 • Number of events 2 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Infections and infestations Catheter site abscess	0.00% 0/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Infections and infestations Oral candidiasis	1.4% 1/69 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Infections and infestations Peritonitis	0.00% 0/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Infections and infestations Septic shock	1.4% 1/69 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Infections and infestations Diarrhea infectious	1.4% 1/69 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	0.00% 0/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Infections and infestations Pelvic Abscess	0.00% 0/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Infections and infestations Pneumonia	1.4% 1/69 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Blood and lymphatic system disorders Neutropenia	1.4% 1/69 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	5.6% 4/71 • Number of events 6 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Blood and lymphatic system disorders Anemia	1.4% 1/69 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	4.2% 3/71 • Number of events 4 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Blood and lymphatic system disorders Leukopenia	0.00% 0/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	2.8% 2/71 • Number of events 2 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Blood and lymphatic system disorders Disseminated intravascular coagulation	1.4% 1/69 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	0.00% 0/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Blood and lymphatic system disorders Febrile neutropenia	1.4% 1/69 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Number of events 2 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Metabolism and nutrition disorders Hypernatremia	1.4% 1/69 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Metabolism and nutrition disorders Hypoalbuminemia	0.00% 0/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Metabolism and nutrition disorders Hypokalemia	0.00% 0/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Number of events 3 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Nervous system disorders Monoparesis	0.00% 0/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Nervous system disorders Paresthesia	1.4% 1/69 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Nervous system disorders Dystonia	0.00% 0/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
General disorders Death	1.4% 1/69 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	0.00% 0/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
General disorders General physical health deterioration	1.4% 1/69 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	0.00% 0/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
General disorders Multi- organ failure	1.4% 1/69 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	0.00% 0/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
General disorders Sudden death	1.4% 1/69 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	0.00% 0/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Vascular disorders Embolism	1.4% 1/69 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	0.00% 0/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Vascular disorders Hypotension	0.00% 0/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	2.8% 2/71 • Number of events 2 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Vascular disorders Vena Cava Thrombosis	0.00% 0/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Injury, poisoning and procedural complications Ankle fracture	0.00% 0/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Injury, poisoning and procedural complications Infusion Related Reaction	0.00% 0/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Number of events 1 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).

Other adverse events
Measure	Bevacizumab Biosimilar (BEVZ92) n=69 participants at risk Bevacizumab biosimilar (BEVZ92): Bevacizumab biosimilar (BEVZ92), Active ingredient Bevacizumab 25 mg/mL (strength = 100mg/mL). 30-minute\* IV infusion (5 mg/kg) every 2 weeks, prior to chemotherapy (Folfox any or Folfiri).	Avastin® (Bevacizumab, Ref. Product) n=71 participants at risk Avastin® (bevacizumab, reference product): Avastin® (bevacizumab, reference product). Active ingredient: Bevacizumab 25 mg/mL (strength: 100 mg/4 mL). 30-minute\* IV infusion (5 mg/kg) every 2 weeks, prior to administration of chemotherapy (Folfox any or Folfiri).
Gastrointestinal disorders Proctalgia	7.2% 5/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Gastrointestinal disorders Dyspepsia	5.8% 4/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	5.6% 4/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Gastrointestinal disorders Diarrhea	49.3% 34/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	57.7% 41/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Gastrointestinal disorders Nausea	44.9% 31/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	45.1% 32/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Gastrointestinal disorders Vomiting	36.2% 25/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	33.8% 24/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Gastrointestinal disorders Constipation	13.0% 9/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	26.8% 19/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Gastrointestinal disorders Abdominal pain	8.7% 6/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	25.4% 18/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Gastrointestinal disorders Stomatitis	13.0% 9/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	11.3% 8/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Gastrointestinal disorders Abdominal pain upper	7.2% 5/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	7.0% 5/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Gastrointestinal disorders Intestinal obstruction	7.2% 5/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Gastrointestinal disorders Rectal hemorrhage	5.8% 4/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
General disorders Asthenia	31.9% 22/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	29.6% 21/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
General disorders Fatigue	23.2% 16/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	25.4% 18/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
General disorders Pyrexia	8.7% 6/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	19.7% 14/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
General disorders Mucosal inflammation	10.1% 7/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	8.5% 6/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
General disorders Edema peripheral	4.3% 3/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	8.5% 6/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Nervous system disorders Neuropathy peripheral	18.8% 13/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	18.3% 13/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Nervous system disorders Peripheral sensory neuropathy	15.9% 11/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	22.5% 16/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Nervous system disorders Paresthesia	14.5% 10/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	14.1% 10/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Nervous system disorders Headache	10.1% 7/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	14.1% 10/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Nervous system disorders Dysgeusia	5.8% 4/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	16.9% 12/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Nervous system disorders Dizziness	5.8% 4/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	5.6% 4/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Nervous system disorders Dysesthesia	4.3% 3/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	5.6% 4/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Blood and lymphatic system disorders Neutropenia	33.3% 23/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	36.6% 26/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Blood and lymphatic system disorders Anemia	27.5% 19/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	39.4% 28/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Blood and lymphatic system disorders Leukopenia	20.3% 14/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	22.5% 16/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Blood and lymphatic system disorders Thrombocytopenia	14.5% 10/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	18.3% 13/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Metabolism and nutrition disorders Decreased appetite	27.5% 19/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	28.2% 20/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Metabolism and nutrition disorders Hypertriglyceridemia	15.9% 11/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	23.9% 17/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Metabolism and nutrition disorders Hyperkalemia	5.8% 4/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	11.3% 8/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Metabolism and nutrition disorders Hyperglycemia	4.3% 3/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	14.1% 10/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Metabolism and nutrition disorders Hypercholesterolaemia	7.2% 5/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	7.0% 5/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Metabolism and nutrition disorders Hypernatraemia	5.8% 4/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Metabolism and nutrition disorders Hypocalcaemia	4.3% 3/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	5.6% 4/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Metabolism and nutrition disorders Hypokalemia	1.4% 1/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	5.6% 4/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Infections and infestations Urinary tract infection	10.1% 7/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	8.5% 6/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Infections and infestations Upper respiratory tract infection	8.7% 6/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	8.5% 6/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Infections and infestations Influenza	8.7% 6/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	7.0% 5/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Infections and infestations Respiratory tract infection viral	5.8% 4/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	4.2% 3/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).
Infections and infestations Viral upper respiratory tract infection	5.8% 4/69 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).	1.4% 1/71 • Throughout the study (on day 1 of every cycle and 30 days after the end of study treatment). Adverse event data were collected from the beginning of the study at 29 Oct 2014 till last patient last visit in 10 Dec 2017 (Database lock point). Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).