Trial Outcomes & Findings for A Comparative Study Of PF-06439535 Plus Paclitaxel-Carboplatin And Bevacizumab Plus Paclitaxel-Carboplatin Patients With Advanced Non-Squamous NSCLC (NCT NCT02364999)

Last Updated: 2019-02-07

Results Overview

ORR refers to percentage of participants who achieved complete response (CR) or partial response (PR) by Week 19 of the study in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 which was subsequently confirmed by Week 25. A participant achieved CR if both target and non-target lesions achieved CR, no new lesions; achieved PR if target lesions achieved CR or PR, non-target lesions were assessed as non-CR/non-PD (progressive disease), indeterminate or missing, and no new lesions. For target lesions, CR: complete disappearance of all target lesions except nodal disease (target nodes must decrease to normal size); PR: \>= 30% decrease under baseline of the sum of diameters of all target measurable lesions. For non-target lesions, CR: disappearance of all non-target lesions and normalization of tumor marker levels and all lymph nodes must be normal in size; non-CR/non-PD: persistence of any non-target lesions and/or tumor marker level above the normal limits.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

719 participants

Primary outcome timeframe

25 weeks

Results posted on

2019-02-07

Participant Flow

A total of 719 participants were enrolled in this study, and 5 of them did not receive any therapy. One (1) additional participant received only chemotherapy, and did not receive blinded bevacizumab.

Participant milestones

Participant milestones
Measure	PF-06439535 Participants received up to a maximum of 6 cycles of PF-06439535 (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by PF-06439535 monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.	Bevacizumab-EU Participants received up to a maximum of 6 cycles of Bevacizumab-EU (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by Bevacizumab-EU monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.
Overall Study STARTED	358	361
Overall Study Received Treatment	356	358
Overall Study COMPLETED	193	188
Overall Study NOT COMPLETED	165	173

Reasons for withdrawal

Reasons for withdrawal
Measure	PF-06439535 Participants received up to a maximum of 6 cycles of PF-06439535 (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by PF-06439535 monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.	Bevacizumab-EU Participants received up to a maximum of 6 cycles of Bevacizumab-EU (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by Bevacizumab-EU monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.
Overall Study Death	136	138
Overall Study Lost to Follow-up	10	15
Overall Study Protocol Violation	3	2
Overall Study Withdrawal by Subject	14	14
Overall Study Other	0	1
Overall Study Randomized but did not receive treatment	2	3

Baseline Characteristics

A Comparative Study Of PF-06439535 Plus Paclitaxel-Carboplatin And Bevacizumab Plus Paclitaxel-Carboplatin Patients With Advanced Non-Squamous NSCLC

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	PF-06439535 n=358 Participants Participants received up to a maximum of 6 cycles of PF-06439535 (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by PF-06439535 monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.	Bevacizumab-EU n=361 Participants Participants received up to a maximum of 6 cycles of Bevacizumab-EU (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by Bevacizumab-EU monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.	Total n=719 Participants Total of all reporting groups
Age, Continuous	61.7 years STANDARD_DEVIATION 9.5 • n=5 Participants	60.9 years STANDARD_DEVIATION 8.9 • n=7 Participants	61.3 years STANDARD_DEVIATION 9.2 • n=5 Participants
Age, Customized 18-44 years	19 Participants n=5 Participants	17 Participants n=7 Participants	36 Participants n=5 Participants
Age, Customized 45-64 years	198 Participants n=5 Participants	222 Participants n=7 Participants	420 Participants n=5 Participants
Age, Customized >= 65 years	141 Participants n=5 Participants	122 Participants n=7 Participants	263 Participants n=5 Participants
Sex/Gender, Customized Female	121 Participants n=5 Participants	131 Participants n=7 Participants	252 Participants n=5 Participants
Sex/Gender, Customized Male	237 Participants n=5 Participants	230 Participants n=7 Participants	467 Participants n=5 Participants
Race/Ethnicity, Customized WHITE	319 Participants n=5 Participants	319 Participants n=7 Participants	638 Participants n=5 Participants
Race/Ethnicity, Customized BLACK	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Race/Ethnicity, Customized ASIAN	36 Participants n=5 Participants	40 Participants n=7 Participants	76 Participants n=5 Participants
Race/Ethnicity, Customized OTHER	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: 25 weeks

Population: The Intent-to-Treat (ITT) population was used for analysis of ORR, and it included all participants who were randomized to study treatment.

Outcome measures

Outcome measures
Measure	PF-06439535 n=358 Participants Participants received up to a maximum of 6 cycles of PF-06439535 (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by PF-06439535 monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.	Bevacizumab-EU n=361 Participants Participants received up to a maximum of 6 cycles of Bevacizumab-EU (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by Bevacizumab-EU monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.
Objective Response Rate (ORR) by Week 19	45.3 percentage of participants Interval 40.01 to 50.57	44.6 percentage of participants Interval 39.4 to 49.89

SECONDARY outcome

Timeframe: 55 weeks

Population: The analysis population included all participants who were randomized and received at least 1 dose of study treatment.

AE was defined as any untoward medical occurrence in a clinical investigation participant administered a product or medical device, regardless of the causal relationship to study treatment. Treatment-emergent AEs (TEAEs) were defined as AEs which occurred for the first time during the effective duration of treatment or AEs that increased in severity during treatment. Serious AEs (SAEs) were defined as any untoward medical occurrence at any dose that resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or caused prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduction normal life functions). AEs included SAEs and non-serious AEs. Causality to study treatment was determined by the investigator. Severity was graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Outcome measures

Outcome measures
Measure	PF-06439535 n=356 Participants Participants received up to a maximum of 6 cycles of PF-06439535 (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by PF-06439535 monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.	Bevacizumab-EU n=358 Participants Participants received up to a maximum of 6 cycles of Bevacizumab-EU (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by Bevacizumab-EU monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.
Number of Participants With Treatment-Emergent Adverse Events All-causality SAE	81 Participants	80 Participants
Number of Participants With Treatment-Emergent Adverse Events Bevacizumab-related AE	190 Participants	199 Participants
Number of Participants With Treatment-Emergent Adverse Events Bevacizumab-related SAE	23 Participants	17 Participants
Number of Participants With Treatment-Emergent Adverse Events Grade 1 all-causality AE	32 Participants	41 Participants
Number of Participants With Treatment-Emergent Adverse Events All-causality AE	344 Participants	347 Participants
Number of Participants With Treatment-Emergent Adverse Events Grade 2 all-causality AE	141 Participants	134 Participants
Number of Participants With Treatment-Emergent Adverse Events Grade 3 all-causality AE	125 Participants	104 Participants
Number of Participants With Treatment-Emergent Adverse Events Grade 4 all-causality AE	25 Participants	44 Participants
Number of Participants With Treatment-Emergent Adverse Events Grade 5 all-causality AE	21 Participants	24 Participants

SECONDARY outcome

Timeframe: 55 weeks

Population: The analysis population included all participants who were randomized and received at least 1 dose of study treatment, and had laboratory evaluation done.

Laboratory evaluation included hematology (hemoglobin, white blood cells, platelets and absolute neutrophil count), blood chemistry (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, serum or plasma creatinine, sodium, potassium, total calcium, magnesium, blood urea nitrogen or urea, and albumin ), coagulation (international normalized ratio for prothrombin time and activated partial thromboplastin time) and urinalysis (dipstick followed by a quantitative urine protein analysis for results of 2+ or greater).

Outcome measures

Outcome measures
Measure	PF-06439535 n=342 Participants Participants received up to a maximum of 6 cycles of PF-06439535 (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by PF-06439535 monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.	Bevacizumab-EU n=348 Participants Participants received up to a maximum of 6 cycles of Bevacizumab-EU (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by Bevacizumab-EU monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.
Number of Participants With Laboratory Abnormalities (Without Regard to Baseline Abnormality)	303 Participants	304 Participants

SECONDARY outcome

Timeframe: 55 weeks

Population: The analysis population included participants in ITT population (all participants who were randomized to study treatment) who had a confirmed objective response achieved by Week 19.

DOR was defined as the time from date of the first documentation of objective tumor response (CR or PR) to the first documentation of PD or to death due to any cause in the absence of documented PD. DOR was based on the Brookmeyer and Crowley method.

Outcome measures

Outcome measures
Measure	PF-06439535 n=162 Participants Participants received up to a maximum of 6 cycles of PF-06439535 (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by PF-06439535 monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.	Bevacizumab-EU n=161 Participants Participants received up to a maximum of 6 cycles of Bevacizumab-EU (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by Bevacizumab-EU monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.
Duration of Response (DOR)	36.3 weeks Interval 31.6 to 43.6	28.7 weeks Interval 27.0 to 36.3

SECONDARY outcome

Timeframe: 55 weeks

Population: The ITT population was used for analysis, and it included all participants who were randomized to study treatment.

This outcome measure refers to the possibility of being progression free at 55 weeks since start of study treatment, estimated from the Kaplan-Meier curve using the product-limit method.

Outcome measures

Outcome measures
Measure	PF-06439535 n=358 Participants Participants received up to a maximum of 6 cycles of PF-06439535 (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by PF-06439535 monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.	Bevacizumab-EU n=361 Participants Participants received up to a maximum of 6 cycles of Bevacizumab-EU (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by Bevacizumab-EU monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.
Progression Free Survival Rate at 55 Weeks	32.3 percentage of participants Interval 26.9 to 37.8	30.5 percentage of participants Interval 25.3 to 35.8

SECONDARY outcome

Timeframe: 55 weeks

Population: The ITT population was used for analysis, and it included all participants who were randomized to study treatment.

This outcome measure refers to the possibility of being alive at 55 weeks since start of study treatment, estimated from the Kaplan-Meier curve using the product-limit method.

Outcome measures

Outcome measures
Measure	PF-06439535 n=358 Participants Participants received up to a maximum of 6 cycles of PF-06439535 (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by PF-06439535 monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.	Bevacizumab-EU n=361 Participants Participants received up to a maximum of 6 cycles of Bevacizumab-EU (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by Bevacizumab-EU monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.
Survival Rate at 55 Weeks	65.8 percentage of participants Interval 60.5 to 70.6	64.1 percentage of participants Interval 58.6 to 69.0

SECONDARY outcome

Timeframe: Pre-dose from Cycle 1 to Cycle 17, 2.5 hours post-dose in Cycle 1, and 1.5 hours post-dose in Cycle 5

Population: The analysis population included all participants in the per-protocol population (all participants who were randomized and received study treatment as planned and had no major protocol deviations) who had at least 1 drug concentration measurement after administration of study treatment.

Outcome measures

Outcome measures
Measure	PF-06439535 n=351 Participants Participants received up to a maximum of 6 cycles of PF-06439535 (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by PF-06439535 monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.	Bevacizumab-EU n=354 Participants Participants received up to a maximum of 6 cycles of Bevacizumab-EU (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by Bevacizumab-EU monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.
Serum Concentration of Bevacizumab up to 1 Year Pre-dose in Cycle 1	68.08 ng/mL Standard Deviation 705.53	116.4 ng/mL Standard Deviation 1032.1
Serum Concentration of Bevacizumab up to 1 Year 1.5 hours post-dose in Cycle 5	360700 ng/mL Standard Deviation 131170	377200 ng/mL Standard Deviation 142250
Serum Concentration of Bevacizumab up to 1 Year Pre-dose in Cycle 6	112000 ng/mL Standard Deviation 40825	116700 ng/mL Standard Deviation 53844
Serum Concentration of Bevacizumab up to 1 Year Pre-dose in Cycle 9	127200 ng/mL Standard Deviation 46200	140900 ng/mL Standard Deviation 62548
Serum Concentration of Bevacizumab up to 1 Year Pre-dose in Cycle 10	125700 ng/mL Standard Deviation 50769	135900 ng/mL Standard Deviation 53975
Serum Concentration of Bevacizumab up to 1 Year Pre-dose in Cycle 11	129500 ng/mL Standard Deviation 61329	135600 ng/mL Standard Deviation 54531
Serum Concentration of Bevacizumab up to 1 Year Pre-dose in Cycle 12	135200 ng/mL Standard Deviation 64560	136300 ng/mL Standard Deviation 51312
Serum Concentration of Bevacizumab up to 1 Year Pre-dose in Cycle 13	130900 ng/mL Standard Deviation 58093	139700 ng/mL Standard Deviation 53750
Serum Concentration of Bevacizumab up to 1 Year Pre-dose in Cycle 14	128000 ng/mL Standard Deviation 50840	136200 ng/mL Standard Deviation 53439
Serum Concentration of Bevacizumab up to 1 Year Pre-dose in Cycle 15	134000 ng/mL Standard Deviation 55933	134000 ng/mL Standard Deviation 49663
Serum Concentration of Bevacizumab up to 1 Year Pre-dose in Cycle 16	137000 ng/mL Standard Deviation 54813	128600 ng/mL Standard Deviation 49742
Serum Concentration of Bevacizumab up to 1 Year Pre-dose in Cycle 17	134800 ng/mL Standard Deviation 86847	127500 ng/mL Standard Deviation 52784
Serum Concentration of Bevacizumab up to 1 Year 2.5 hours post-dose in Cycle 1	280000 ng/mL Standard Deviation 103260	302200 ng/mL Standard Deviation 100360
Serum Concentration of Bevacizumab up to 1 Year Pre-dose in Cycle 2	54350 ng/mL Standard Deviation 44479	58930 ng/mL Standard Deviation 49452
Serum Concentration of Bevacizumab up to 1 Year Pre-dose in Cycle 3	81090 ng/mL Standard Deviation 48671	83350 ng/mL Standard Deviation 32384
Serum Concentration of Bevacizumab up to 1 Year Pre-dose in Cycle 4	100900 ng/mL Standard Deviation 54979	99750 ng/mL Standard Deviation 50531
Serum Concentration of Bevacizumab up to 1 Year Pre-dose in Cycle 5	105300 ng/mL Standard Deviation 48469	110000 ng/mL Standard Deviation 65416
Serum Concentration of Bevacizumab up to 1 Year Pre-dose in Cycle 7	117300 ng/mL Standard Deviation 53844	122100 ng/mL Standard Deviation 47793
Serum Concentration of Bevacizumab up to 1 Year Pre-dose in Cycle 8	123600 ng/mL Standard Deviation 48893	126400 ng/mL Standard Deviation 52985

SECONDARY outcome

Timeframe: 55 weeks

Population: The analysis population included all participants who were randomized and received at least 1 dose of study treatment.

ADA assay was performed using a sensitive, specific, and semi-quantitative electrochemiluminescent (ECL) method, which used biotinylated- and ruthenium-labeled PF-06439535 as reagents. Samples with ADA titer greater than or equal to (\>=) 2.29 were considered positive.

Outcome measures

Outcome measures
Measure	PF-06439535 n=356 Participants Participants received up to a maximum of 6 cycles of PF-06439535 (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by PF-06439535 monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.	Bevacizumab-EU n=358 Participants Participants received up to a maximum of 6 cycles of Bevacizumab-EU (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by Bevacizumab-EU monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.
Number of Participants With Anti-Drug Antibody (ADA) Cycle 1 pre-dose	1 Participants	3 Participants
Number of Participants With Anti-Drug Antibody (ADA) Overall (post-treatment)	5 Participants	5 Participants

SECONDARY outcome

Timeframe: 55 weeks

Population: The analysis population included all participants who had positive ADA results at any time point.

Only samples that were confirmed positive for ADA were further tested for NAb. The NAb analysis was conducted using a single validated quasi-quantitative enzyme-linked immunosorbent assay (ELISA) that utilized PF-06439535 as a reagent. Samples with NAb titer \>=1.70 were considered positive.

Outcome measures

Outcome measures
Measure	PF-06439535 n=6 Participants Participants received up to a maximum of 6 cycles of PF-06439535 (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by PF-06439535 monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.	Bevacizumab-EU n=7 Participants Participants received up to a maximum of 6 cycles of Bevacizumab-EU (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by Bevacizumab-EU monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.
Number of Participants With Neutralizing Antibody (NAb) Cycle 1 pre-dose	1 Participants	0 Participants
Number of Participants With Neutralizing Antibody (NAb) Overall (post-treatment)	0 Participants	3 Participants

Adverse Events

PF-06439535

Serious events: 81 serious events

Other events: 328 other events

Deaths: 144 deaths

Bevacizumab-EU

Serious events: 80 serious events

Other events: 333 other events

Deaths: 149 deaths

Total

Serious events: 161 serious events

Other events: 661 other events

Deaths: 293 deaths

Serious adverse events

Other adverse events

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer, Inc.

Phone: 1-800-718-1021

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	PF-06439535 n=356 participants at risk Participants received up to a maximum of 6 cycles of PF-06439535 (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by PF-06439535 monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.	Bevacizumab-EU n=358 participants at risk Participants received up to a maximum of 6 cycles of Bevacizumab-EU (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by Bevacizumab-EU monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.	Total n=714 participants at risk This reporting group include all participants who received at least 1 dose of study treatment from PF-06439535 and Bevacizumab-EU groups.
Cardiac disorders Cardiovascular insufficiency	0.28% 1/356 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 1/358 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 2/714 • Number of events 2 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Infections and infestations Lung abscess	0.00% 0/356 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 1/358 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.14% 1/714 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Infections and infestations Lung infection	0.28% 1/356 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 1/358 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 2/714 • Number of events 2 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Blood and lymphatic system disorders Anaemia	0.56% 2/356 • Number of events 4 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	1.4% 5/358 • Number of events 6 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.98% 7/714 • Number of events 10 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Blood and lymphatic system disorders Febrile neutropenia	1.4% 5/356 • Number of events 7 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	2.0% 7/358 • Number of events 7 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	1.7% 12/714 • Number of events 14 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Blood and lymphatic system disorders Leukopenia	0.56% 2/356 • Number of events 3 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.00% 0/358 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 2/714 • Number of events 3 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Blood and lymphatic system disorders Neutropenia	1.1% 4/356 • Number of events 5 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	1.7% 6/358 • Number of events 8 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	1.4% 10/714 • Number of events 13 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Blood and lymphatic system disorders Pancytopenia	0.28% 1/356 • Number of events 2 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 1/358 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 2/714 • Number of events 3 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Blood and lymphatic system disorders Thrombocytopenia	0.84% 3/356 • Number of events 5 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.84% 3/358 • Number of events 3 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.84% 6/714 • Number of events 8 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Cardiac disorders Acute coronary syndrome	0.28% 1/356 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 1/358 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 2/714 • Number of events 2 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Cardiac disorders Acute myocardial infarction	0.28% 1/356 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 1/358 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 2/714 • Number of events 2 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Cardiac disorders Angina unstable	0.28% 1/356 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.00% 0/358 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.14% 1/714 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Cardiac disorders Cardiac arrest	0.28% 1/356 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 1/358 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 2/714 • Number of events 2 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Cardiac disorders Cardiac failure	0.28% 1/356 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.00% 0/358 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.14% 1/714 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Cardiac disorders Cardio-respiratory arrest	0.00% 0/356 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.56% 2/358 • Number of events 2 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 2/714 • Number of events 2 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Cardiac disorders Myocardial infarction	0.28% 1/356 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 1/358 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 2/714 • Number of events 2 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Cardiac disorders Right ventricular failure	0.00% 0/356 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 1/358 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.14% 1/714 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Abdominal pain	0.00% 0/356 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 1/358 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.14% 1/714 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Colitis	0.00% 0/356 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 1/358 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.14% 1/714 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Colitis ischaemic	0.28% 1/356 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.00% 0/358 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.14% 1/714 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Constipation	0.00% 0/356 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.56% 2/358 • Number of events 2 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 2/714 • Number of events 2 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Diarrhoea	0.56% 2/356 • Number of events 3 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.56% 2/358 • Number of events 3 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.56% 4/714 • Number of events 6 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Enterocolitis	0.28% 1/356 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.00% 0/358 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.14% 1/714 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Faecaloma	0.00% 0/356 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 1/358 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.14% 1/714 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Gastritis	0.28% 1/356 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.00% 0/358 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.14% 1/714 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Haemorrhoidal haemorrhage	0.28% 1/356 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.00% 0/358 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.14% 1/714 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Ileus	0.00% 0/356 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 1/358 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.14% 1/714 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Intestinal obstruction	0.00% 0/356 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 1/358 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.14% 1/714 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Nausea	0.00% 0/356 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.56% 2/358 • Number of events 2 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 2/714 • Number of events 2 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Neutropenic colitis	0.00% 0/356 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 1/358 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.14% 1/714 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Peptic ulcer	0.28% 1/356 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.00% 0/358 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.14% 1/714 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Rectal haemorrhage	0.00% 0/356 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 1/358 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.14% 1/714 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Small intestinal perforation	0.00% 0/356 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 1/358 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.14% 1/714 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Subileus	0.00% 0/356 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 1/358 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.14% 1/714 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Vomiting	0.28% 1/356 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 1/358 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 2/714 • Number of events 2 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
General disorders Asthenia	1.1% 4/356 • Number of events 5 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 1/358 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.70% 5/714 • Number of events 6 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
General disorders Chest pain	0.28% 1/356 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 1/358 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.28% 2/714 • Number of events 2 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
General disorders Death	0.56% 2/356 • Number of events 2 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.84% 3/358 • Number of events 3 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.70% 5/714 • Number of events 5 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
General disorders Disease progression	1.1% 4/356 • Number of events 4 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	1.4% 5/358 • Number of events 5 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	1.3% 9/714 • Number of events 9 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
General disorders General physical health deterioration	0.28% 1/356 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.00% 0/358 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	0.14% 1/714 • Number of events 1 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.

Other adverse events
Measure	PF-06439535 n=356 participants at risk Participants received up to a maximum of 6 cycles of PF-06439535 (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by PF-06439535 monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.	Bevacizumab-EU n=358 participants at risk Participants received up to a maximum of 6 cycles of Bevacizumab-EU (initial dose was 15 mg/kg) plus paclitaxel (initial dose was 200 mg/m\*2) and carboplatin (initial dose was AUC 6, based on participant's pre-existing renal function and desired platelet nadir), followed by Bevacizumab-EU monotherapy until disease progression, unacceptable toxicity, discretion of the investigator, regulatory request, death, withdrawal of consent occurred. All 3 drugs were given by intravenous (IV) infusion on Day 1 in each 21-day cycle and dose reduction was allowed for paclitaxel and carboplatin in response to toxicity. Paclitaxel was administered before carboplatin.	Total n=714 participants at risk This reporting group include all participants who received at least 1 dose of study treatment from PF-06439535 and Bevacizumab-EU groups.
Blood and lymphatic system disorders Leukopenia	7.3% 26/356 • Number of events 44 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	8.4% 30/358 • Number of events 56 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	7.8% 56/714 • Number of events 100 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Blood and lymphatic system disorders Neutropenia	16.6% 59/356 • Number of events 130 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	18.4% 66/358 • Number of events 144 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	17.5% 125/714 • Number of events 274 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Blood and lymphatic system disorders Thrombocytopenia	15.4% 55/356 • Number of events 122 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	18.4% 66/358 • Number of events 125 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	16.9% 121/714 • Number of events 247 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Constipation	11.0% 39/356 • Number of events 45 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	7.5% 27/358 • Number of events 36 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	9.2% 66/714 • Number of events 81 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Diarrhoea	12.9% 46/356 • Number of events 59 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	13.4% 48/358 • Number of events 66 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	13.2% 94/714 • Number of events 125 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Nausea	19.9% 71/356 • Number of events 111 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	19.3% 69/358 • Number of events 112 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	19.6% 140/714 • Number of events 223 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Nervous system disorders Paraesthesia	11.2% 40/356 • Number of events 64 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	8.7% 31/358 • Number of events 36 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	9.9% 71/714 • Number of events 100 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Vomiting	11.5% 41/356 • Number of events 52 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	9.2% 33/358 • Number of events 42 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	10.4% 74/714 • Number of events 94 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
General disorders Asthenia	12.9% 46/356 • Number of events 78 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	12.0% 43/358 • Number of events 65 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	12.5% 89/714 • Number of events 143 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
General disorders Fatigue	20.5% 73/356 • Number of events 110 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	19.8% 71/358 • Number of events 87 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	20.2% 144/714 • Number of events 197 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
General disorders Pyrexia	6.7% 24/356 • Number of events 31 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	6.4% 23/358 • Number of events 41 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	6.6% 47/714 • Number of events 72 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Injury, poisoning and procedural complications Infusion related reaction	5.3% 19/356 • Number of events 26 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	6.1% 22/358 • Number of events 26 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	5.7% 41/714 • Number of events 52 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Investigations Alanine aminotransferase increased	13.8% 49/356 • Number of events 95 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	10.9% 39/358 • Number of events 53 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	12.3% 88/714 • Number of events 148 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Investigations Aspartate aminotransferase increased	12.4% 44/356 • Number of events 94 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	10.3% 37/358 • Number of events 59 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	11.3% 81/714 • Number of events 153 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Nervous system disorders Peripheral sensory neuropathy	9.6% 34/356 • Number of events 45 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	12.8% 46/358 • Number of events 70 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	11.2% 80/714 • Number of events 115 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Investigations Blood alkaline phosphatase increased	8.1% 29/356 • Number of events 46 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	8.9% 32/358 • Number of events 48 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	8.5% 61/714 • Number of events 94 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Investigations Blood creatinine increased	4.5% 16/356 • Number of events 28 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	5.9% 21/358 • Number of events 33 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	5.2% 37/714 • Number of events 61 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Investigations Platelet count decreased	6.5% 23/356 • Number of events 31 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	5.3% 19/358 • Number of events 38 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	5.9% 42/714 • Number of events 69 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Investigations Weight decreased	10.1% 36/356 • Number of events 43 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	8.1% 29/358 • Number of events 40 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	9.1% 65/714 • Number of events 83 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Metabolism and nutrition disorders Decreased appetite	13.5% 48/356 • Number of events 76 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	12.8% 46/358 • Number of events 65 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	13.2% 94/714 • Number of events 141 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Musculoskeletal and connective tissue disorders Arthralgia	11.2% 40/356 • Number of events 82 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	12.0% 43/358 • Number of events 71 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	11.6% 83/714 • Number of events 153 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Musculoskeletal and connective tissue disorders Bone pain	7.0% 25/356 • Number of events 58 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	6.4% 23/358 • Number of events 47 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	6.7% 48/714 • Number of events 105 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Musculoskeletal and connective tissue disorders Myalgia	15.2% 54/356 • Number of events 131 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	13.7% 49/358 • Number of events 109 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	14.4% 103/714 • Number of events 240 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Musculoskeletal and connective tissue disorders Pain in extremity	4.5% 16/356 • Number of events 23 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	6.4% 23/358 • Number of events 29 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	5.5% 39/714 • Number of events 52 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Nervous system disorders Headache	8.4% 30/356 • Number of events 35 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	10.3% 37/358 • Number of events 45 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	9.4% 67/714 • Number of events 80 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Nervous system disorders Neuropathy peripheral	14.9% 53/356 • Number of events 67 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	18.2% 65/358 • Number of events 86 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	16.5% 118/714 • Number of events 153 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Nervous system disorders Polyneuropathy	6.5% 23/356 • Number of events 34 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	5.3% 19/358 • Number of events 22 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	5.9% 42/714 • Number of events 56 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Renal and urinary disorders Proteinuria	7.9% 28/356 • Number of events 50 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	9.5% 34/358 • Number of events 76 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	8.7% 62/714 • Number of events 126 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Respiratory, thoracic and mediastinal disorders Cough	11.5% 41/356 • Number of events 53 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	13.1% 47/358 • Number of events 58 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	12.3% 88/714 • Number of events 111 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Respiratory, thoracic and mediastinal disorders Dyspnoea	9.0% 32/356 • Number of events 38 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	9.8% 35/358 • Number of events 41 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	9.4% 67/714 • Number of events 79 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Respiratory, thoracic and mediastinal disorders Epistaxis	11.2% 40/356 • Number of events 51 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	8.9% 32/358 • Number of events 48 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	10.1% 72/714 • Number of events 99 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Skin and subcutaneous tissue disorders Alopecia	46.6% 166/356 • Number of events 216 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	46.1% 165/358 • Number of events 232 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	46.4% 331/714 • Number of events 448 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Skin and subcutaneous tissue disorders Rash	2.5% 9/356 • Number of events 10 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	5.9% 21/358 • Number of events 29 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	4.2% 30/714 • Number of events 39 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Vascular disorders Hypertension	16.9% 60/356 • Number of events 83 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	17.3% 62/358 • Number of events 110 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	17.1% 122/714 • Number of events 193 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Blood and lymphatic system disorders Anaemia	28.7% 102/356 • Number of events 196 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	29.6% 106/358 • Number of events 200 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.	29.1% 208/714 • Number of events 396 • 55 weeks The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.