Efficacy and Safety Study of ABP 215 Compared With Bevacizumab in Patients With Advanced Non-Small Cell Lung Cancer

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01966003
• Collaborator: Actavis Inc. (Industry)
• Enrollment: 642
• Locations: 4
• Arms: 2
• Actual Duration (Months): 20.3
• Patients Per Site: 160.5
• Patients Per Site Per Month: 7.9

Study Details

Study Description

Brief Summary

The purpose of this research study is to compare the effectiveness and safety of ABP 215 against bevacizumab in men and women with advanced non-small cell lung cancer.

Condition or Disease	Intervention/Treatment	Phase
Non-small Cell Lung Cancer Metastatic	Drug: Carboplatin; Drug: Paclitaxel; Drug: ABP 215; Drug: Bevacizumab	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 642 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Phase 3 Study Evaluating the Efficacy and Safety of ABP 215 Compared With Bevacizumab in Subjects With Advanced Non-Small Cell Lung Cancer
• Actual Study Start Date: Nov 11, 2013
• Actual Primary Completion Date: Jul 23, 2015
• Actual Study Completion Date: Jul 23, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ABP 215 Participants received 15 mg/kg ABP 215 administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.	Drug: Carboplatin; Administered at an area under the concentration-time curve (AUC) 6 by IV infusion Q3W; Other Names: Paraplatin ; Drug: Paclitaxel; Administered 200 mg/m² IV Q3W; Other Names: Taxol ; Drug: ABP 215; Administered 15 mg/kg Q3W by IV infusion
Active Comparator: Bevacizumab Participants received bevacizumab 15 mg/kg administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.	Drug: Carboplatin; Administered at an area under the concentration-time curve (AUC) 6 by IV infusion Q3W; Other Names: Paraplatin ; Drug: Paclitaxel; Administered 200 mg/m² IV Q3W; Other Names: Taxol ; Drug: Bevacizumab; Administered 15 mg/kg Q3W by IV infusion; Other Names: Avastin

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With an Objective Response [Disease assessments were performed at weeks 1, 7, 13, 19, and approximately every 9 weeks thereafter. The mean actual follow-up time from randomization was 4.7 and 5.0 months for ABP 215 and bevacizumab, respectively.]

   Tumor assessments were performed by central, independent, blinded radiologists according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 using computed tomography (CT) or magnetic resonance imaging (MRI) scans of the chest and abdomen. Objective response is defined as a best overall response of partial response (PR) or complete response (CR) as defined by RECIST v1.1. All participants who did not meet the criteria for CR or PR by the end of the study were considered non-responders. CR: Disappearance of all target and non-target lesions and no new lesions. Any pathological lymph nodes must be reduced in short axis to < 10 mm. PR: Disappearance of all target lesions with persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits, and no new lesions, or, at least a 30% decrease in the sum of diameters of target lesions, with no progression of existing non-target lesions and no new lesions.

Secondary Outcome Measures

1. Duration of Response [Disease assessments were performed at weeks 1, 7, 13, 19, and approximately every 9 weeks thereafter. The mean actual follow-up time from randomization was 4.7 and 5.0 months for ABP 215 and bevacizumab, respectively.]

   Duration of response (DOR) was calculated as the time from the first objective response (PR or CR) to disease progression per RECIST v1.1 based on the central, independent, blinded radiologists' review. DOR was only calculated for participants with an objective response. For responders not meeting the criterion for progression by the end of the study, DOR was censored at the date of the last evaluable tumor assessment. Progressive Disease was defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm, or, unequivocal progression of existing non-target lesions, or any new lesions.

2. Progression-free Survival [From randomization until the end of study; The mean actual follow-up time from randomization was 4.7 and 5.0 months for ABP 215 and bevacizumab, respectively.]

   Progression-free survival (PFS) was defined as the time from the randomization date to the date of disease progression using RECIST v1.1 based on the central, independent, blinded radiologists' review, or death. Participants who were alive and did not meet the criteria for progression by the end of the study were censored at their last evaluable disease assessment date. Participants with no evaluable tumor assessments after randomization who did not die by the end of the study were censored on the randomization date. Progressive Disease was defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm, or, unequivocal progression of existing non-target lesions, or any new lesions.

3. Number of Participants With Adverse Events [up to 19 weeks]

   Adverse events (AEs) were graded for severity according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4, and according to the following scale: Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death due to AE. A serious adverse event (SAE) is defined as an AE that meets at least 1 of the following serious criteria: fatal life-threatening required inpatient hospitalization or prolongation of existing hospitalization resulted in persistent or significant disability/incapacity congenital anomaly/birth defect other medically important serious event

4. Number of Participants Who Developed Anti-drug Antibodies [44 weeks (6 months after end of treatment)]

   Two validated assays were used to detect the presence of anti-ABP 215 antibodies. Samples were first tested in an electrochemiluminescence (ECL)- based bridging immunoassay to detect antibodies capable of binding to ABP 215 (Binding Antibody Assay). Samples confirmed to be positive for binding antibodies were subsequently tested in a non-cell based target binding assay to determine neutralizing activity against ABP 215 (Neutralizing Antibody Assay). If a post-dose sample was positive for binding antibodies and demonstrated neutralizing activity at the same time point, the sample was defined as positive for neutralizing antibodies.

5. Overall Survival [From randomization until the end of study; The mean actual follow-up time from randomization was 4.7 and 5.0 months for ABP 215 and bevacizumab, respectively.]

   Overall survival (OS) was defined as the time from the randomization date to date of death. Participants alive at the end of study were censored at the last date known to be alive, derived from dates collected within the study that implied a participant was alive. Participants were followed for survival status during the treatment phase and thereafter every 9 weeks until the end of the clinical study, consent was withdrawn, they were lost to follow-up, died, or had proscribed therapy (eg, commercial bevacizumab, non-study anti-cancer treatment).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically or cytologically confirmed non-squamous non-small cell lung cancer (NSCLC)

• Subjects must be initiating first-line carboplatin/paclitaxel chemotherapy within 8 days after randomization and expected to receive at least 4 cycles of chemotherapy

• Eastern Cooperative Oncology Group (ECOG) performance status score 0 or 1

Exclusion Criteria:

• Small cell lung cancer (SCLC) or mixed SCLC and NSCLC

• Central nervous system (CNS) metastases

• Malignancy other than NSCLC

• Palliative radiotherapy for bone lesions inside the thorax

• Prior radiotherapy of bone marrow

• Known to be positive for hepatitis B surface antigen (HbsAg), hepatitis C virus (HCV), or human immunodeficiency virus (HIV)

• Life expectancy < 6 months

• Woman of child-bearing potential who is pregnant or is breast feeding or who is not consenting to use highly effective methods of birth control during treatment and for an additional 6 months after the last administration of the protocol specified treatment

• Man with a partner of childbearing potential who does not consent to use highly effective methods of birth control during treatment and for an additional 6 months after the last administration of the protocol specified treatment

• Subject has known sensitivity to any of the products to be administered during the study, including mammalian cell derived drug products

• Other inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Bismarck	North Dakota	United States	58501
2	Research Site	Fremantle	Western Australia	Australia	6160
3	Research Site	Veliko Tarnovo	Veliko Turnovo	Bulgaria	5000
4	Research Site	Ruse		Bulgaria	7003

Sponsors and Collaborators

• Amgen
• Actavis Inc.

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

None provided.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT01966003
• Other Study ID Numbers: 20120265; 2013-000738-36
• First Posted: Oct 21, 2013
• Last Update Posted: Oct 19, 2017
• Last Verified: Sep 1, 2017

• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Paclitaxel; Bevacizumab; Carboplatin

Study Results

Participant Flow

Recruitment Details	This study was conducted at 101 sites (14 sites in the US, 11 in Russia, 10 in Australia, 9 in Germany, 8 in Poland, 7 in Hungary, 7 in Romania, 6 in Italy, 6 in Spain, 5 in Bulgaria, 5 in Greece, 3 in the Czech Republic, 3 in Mexico, 3 in Taiwan, 2 in the Netherlands, 1 in Canada, and 1 in Hong Kong).
Pre-assignment Detail	Eligible participants were randomized in a 1:1 ratio to receive ABP 215 or bevacizumab. Participants were stratified by geographic region (Eastern Europe vs Western Europe vs Asia Pacific/Other vs North America), Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1), and sex.

Arm/Group Title	ABP 215	Bevacizumab
Arm/Group Description	Participants received 15 mg/kg ABP 215 administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.	Participants received bevacizumab 15 mg/kg administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.
Period Title: Overall Study
STARTED	328	314
Received Study Drug	324	309
COMPLETED	58	44
NOT COMPLETED	270	270

Baseline Characteristics

Arm/Group Title	ABP 215	Bevacizumab	Total
Arm/Group Description	Participants received 15 mg/kg ABP 215 administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.	Participants received bevacizumab 15 mg/kg administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.	Total of all reporting groups
Overall Participants	328	314	642
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.6 (9.09)	61.6 (8.88)	61.6 (8.98)
Age, Customized (participants) [Number]
< 65 years	199 60.7%	191 60.8%	390 60.7%
≥ 65 years	129 39.3%	123 39.2%	252 39.3%
Sex: Female, Male (Count of Participants)
Female	132 40.2%	126 40.1%	258 40.2%
Male	196 59.8%	188 59.9%	384 59.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	14 4.3%	16 5.1%	30 4.7%
Not Hispanic or Latino	314 95.7%	298 94.9%	612 95.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
White	315 96%	300 95.5%	615 95.8%
Black or African American	2 0.6%	5 1.6%	7 1.1%
Asian	6 1.8%	7 2.2%	13 2%
American Indian or Alaska Native	2 0.6%	0 0%	2 0.3%
Native Hawaiian or other Pacific Islander	1 0.3%	0 0%	1 0.2%
Other	4 1.2%	2 0.6%	6 0.9%
Geographic Region (participants) [Number]
Eastern Europe	189 57.6%	186 59.2%	375 58.4%
Western Europe	78 23.8%	76 24.2%	154 24%
North America	31 9.5%	26 8.3%	57 8.9%
Asia Pacific/Other	30 9.1%	26 8.3%	56 8.7%
Eastern Cooperative Oncology Group (ECOG) Performance Status (participants) [Number]
Grade 0	127 38.7%	117 37.3%	244 38%
Grade 1	201 61.3%	197 62.7%	398 62%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With an Objective Response
Description	Tumor assessments were performed by central, independent, blinded radiologists according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 using computed tomography (CT) or magnetic resonance imaging (MRI) scans of the chest and abdomen. Objective response is defined as a best overall response of partial response (PR) or complete response (CR) as defined by RECIST v1.1. All participants who did not meet the criteria for CR or PR by the end of the study were considered non-responders. CR: Disappearance of all target and non-target lesions and no new lesions. Any pathological lymph nodes must be reduced in short axis to < 10 mm. PR: Disappearance of all target lesions with persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits, and no new lesions, or, at least a 30% decrease in the sum of diameters of target lesions, with no progression of existing non-target lesions and no new lesions.
Time Frame	Disease assessments were performed at weeks 1, 7, 13, 19, and approximately every 9 weeks thereafter. The mean actual follow-up time from randomization was 4.7 and 5.0 months for ABP 215 and bevacizumab, respectively.

Outcome Measure Data

Analysis Population Description

Intent-to-treat population which consisted of all randomized participants.

Arm/Group Title	ABP 215	Bevacizumab
Arm/Group Description	Participants received 15 mg/kg ABP 215 administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.	Participants received bevacizumab 15 mg/kg administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.
Measure Participants	328	314
Number [percentage of participants]	39.0 11.9%	41.7 13.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ABP 215, Bevacizumab
	Comments	The risk ratio (ABP 215/Bevacizumab) and 90% confidence interval (CI) were estimated using a generalized linear model adjusted for the stratification factors (region, sex, and ECOG performance status).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Clinical equivalence of the primary endpoint was demonstrated by comparing the 2-sided 90% CI of the risk ratio in objective response rate between ABP 215 and bevacizumab with an equivalence margin of (0.67, 1.5).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 90%; 0.80 to 1.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ABP 215, Bevacizumab
	Comments	Risk difference (ABP 215 - Bevacizumab) and 90% CI were estimated using a generalized linear model adjusted for the randomization stratification factors geographic region, ECOG performance status, and sex.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-2.90
	Confidence Interval	(2-Sided) 90%; -9.26 to 3.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Duration of Response
Description	Duration of response (DOR) was calculated as the time from the first objective response (PR or CR) to disease progression per RECIST v1.1 based on the central, independent, blinded radiologists' review. DOR was only calculated for participants with an objective response. For responders not meeting the criterion for progression by the end of the study, DOR was censored at the date of the last evaluable tumor assessment. Progressive Disease was defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm, or, unequivocal progression of existing non-target lesions, or any new lesions.
Time Frame	Disease assessments were performed at weeks 1, 7, 13, 19, and approximately every 9 weeks thereafter. The mean actual follow-up time from randomization was 4.7 and 5.0 months for ABP 215 and bevacizumab, respectively.

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with an objective response

Arm/Group Title	ABP 215	Bevacizumab
Arm/Group Description	Participants received 15 mg/kg ABP 215 administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.	Participants received bevacizumab 15 mg/kg administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.
Measure Participants	128	131
Median (95% Confidence Interval) [months]	5.8	5.6

3. Secondary Outcome

Title	Progression-free Survival
Description	Progression-free survival (PFS) was defined as the time from the randomization date to the date of disease progression using RECIST v1.1 based on the central, independent, blinded radiologists' review, or death. Participants who were alive and did not meet the criteria for progression by the end of the study were censored at their last evaluable disease assessment date. Participants with no evaluable tumor assessments after randomization who did not die by the end of the study were censored on the randomization date. Progressive Disease was defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm, or, unequivocal progression of existing non-target lesions, or any new lesions.
Time Frame	From randomization until the end of study; The mean actual follow-up time from randomization was 4.7 and 5.0 months for ABP 215 and bevacizumab, respectively.

Outcome Measure Data

Analysis Population Description

Intent-to-treat population

Arm/Group Title	ABP 215	Bevacizumab
Arm/Group Description	Participants received 15 mg/kg ABP 215 administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.	Participants received bevacizumab 15 mg/kg administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.
Measure Participants	328	314
Median (95% Confidence Interval) [months]	6.6	7.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ABP 215, Bevacizumab
	Comments	The hazard ratio for ABP 215 relative to bevacizumab was based on a stratified Cox proportional hazards model. Stratification factors are geographic region, ECOG performance status, and sex.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 90%; 0.83 to 1.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	Adverse events (AEs) were graded for severity according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4, and according to the following scale: Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death due to AE. A serious adverse event (SAE) is defined as an AE that meets at least 1 of the following serious criteria: fatal life-threatening required inpatient hospitalization or prolongation of existing hospitalization resulted in persistent or significant disability/incapacity congenital anomaly/birth defect other medically important serious event
Time Frame	up to 19 weeks

Outcome Measure Data

Analysis Population Description

Safety analysis population consisted of all participants who received any amount of study drug.

Arm/Group Title	ABP 215	Bevacizumab
Arm/Group Description	Participants received 15 mg/kg ABP 215 administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.	Participants received bevacizumab 15 mg/kg administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.
Measure Participants	324	309
Any adverse event	308 93.9%	289 92%
Any grade ≥ 3 adverse event	139 42.4%	137 43.6%
Any fatal adverse event	13 4%	11 3.5%
Any serious adverse event	85 25.9%	71 22.6%
Any AE leading to discontinuation of study drug	61 18.6%	53 16.9%
Any AE leading to discontinuation of chemotherapy	74 22.6%	59 18.8%
Any AE leading to dose delay of study drug	73 22.3%	69 22%
Any AE leading to dose delay of any chemotherapy	86 26.2%	83 26.4%
Any AE leading to dose reduction of chemotherapy	48 14.6%	49 15.6%

5. Secondary Outcome

Title	Number of Participants Who Developed Anti-drug Antibodies
Description	Two validated assays were used to detect the presence of anti-ABP 215 antibodies. Samples were first tested in an electrochemiluminescence (ECL)- based bridging immunoassay to detect antibodies capable of binding to ABP 215 (Binding Antibody Assay). Samples confirmed to be positive for binding antibodies were subsequently tested in a non-cell based target binding assay to determine neutralizing activity against ABP 215 (Neutralizing Antibody Assay). If a post-dose sample was positive for binding antibodies and demonstrated neutralizing activity at the same time point, the sample was defined as positive for neutralizing antibodies.
Time Frame	44 weeks (6 months after end of treatment)

Outcome Measure Data

Analysis Population Description

Safety analysis population with available data

Arm/Group Title	ABP 215	Bevacizumab
Arm/Group Description	Participants received 15 mg/kg ABP 215 administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.	Participants received bevacizumab 15 mg/kg administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.
Measure Participants	294	284
Binding antibody positive	4 1.2%	7 2.2%
Neutralizing antibody positive	0 0%	0 0%

6. Secondary Outcome

Title	Overall Survival
Description	Overall survival (OS) was defined as the time from the randomization date to date of death. Participants alive at the end of study were censored at the last date known to be alive, derived from dates collected within the study that implied a participant was alive. Participants were followed for survival status during the treatment phase and thereafter every 9 weeks until the end of the clinical study, consent was withdrawn, they were lost to follow-up, died, or had proscribed therapy (eg, commercial bevacizumab, non-study anti-cancer treatment).
Time Frame	From randomization until the end of study; The mean actual follow-up time from randomization was 4.7 and 5.0 months for ABP 215 and bevacizumab, respectively.

Outcome Measure Data

Analysis Population Description

Safety analysis population

Arm/Group Title	ABP 215	Bevacizumab
Arm/Group Description	Participants received 15 mg/kg ABP 215 administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.	Participants received bevacizumab 15 mg/kg administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.
Measure Participants	324	309
Median (95% Confidence Interval) [months]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ABP 215, Bevacizumab
	Comments	Hazard ratio for ABP 215 relative to bevacizumab, based on a stratified Cox proportional hazards model. Stratification factors are geographic region, ECOG performance status, and sex.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 90%; 0.75 to 1.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	19 weeks
Adverse Event Reporting Description	Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	ABP 215		Bevacizumab
Arm/Group Description	Participants received 15 mg/kg ABP 215 administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.		Participants received bevacizumab 15 mg/kg administered as an intravenous (IV) infusion every 3 weeks (Q3W) for 6 cycles and carboplatin and paclitaxel chemotherapy Q3W for at least 4 and not more than 6 cycles.
All Cause Mortality
	ABP 215		Bevacizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	ABP 215		Bevacizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	85/324 (26.2%)		71/309 (23%)
Blood and lymphatic system disorders
Anaemia	3/324 (0.9%)		6/309 (1.9%)
Febrile neutropenia	11/324 (3.4%)		8/309 (2.6%)
Hypercoagulation	0/324 (0%)		1/309 (0.3%)
Neutropenia	6/324 (1.9%)		3/309 (1%)
Pancytopenia	0/324 (0%)		1/309 (0.3%)
Thrombocytopenia	2/324 (0.6%)		2/309 (0.6%)
Cardiac disorders
Acute left ventricular failure	0/324 (0%)		1/309 (0.3%)
Acute myocardial infarction	1/324 (0.3%)		0/309 (0%)
Atrial fibrillation	1/324 (0.3%)		1/309 (0.3%)
Cardiac arrest	1/324 (0.3%)		0/309 (0%)
Cardiopulmonary failure	1/324 (0.3%)		0/309 (0%)
Coronary artery disease	1/324 (0.3%)		0/309 (0%)
Paroxysmal arrhythmia	0/324 (0%)		1/309 (0.3%)
Pericardial effusion	1/324 (0.3%)		0/309 (0%)
Ventricular extrasystoles	1/324 (0.3%)		0/309 (0%)
Ear and labyrinth disorders
Vertigo	0/324 (0%)		1/309 (0.3%)
Gastrointestinal disorders
Abdominal pain	1/324 (0.3%)		0/309 (0%)
Anal haemorrhage	1/324 (0.3%)		0/309 (0%)
Constipation	1/324 (0.3%)		0/309 (0%)
Diarrhoea	3/324 (0.9%)		2/309 (0.6%)
Diarrhoea haemorrhagic	1/324 (0.3%)		0/309 (0%)
Diverticular perforation	0/324 (0%)		1/309 (0.3%)
Faecaloma	0/324 (0%)		1/309 (0.3%)
Gastrointestinal haemorrhage	1/324 (0.3%)		0/309 (0%)
Intestinal perforation	1/324 (0.3%)		1/309 (0.3%)
Large intestinal haemorrhage	1/324 (0.3%)		0/309 (0%)
Large intestine perforation	1/324 (0.3%)		1/309 (0.3%)
Melaena	1/324 (0.3%)		0/309 (0%)
Mesenteric artery embolism	1/324 (0.3%)		0/309 (0%)
Nausea	2/324 (0.6%)		1/309 (0.3%)
Rectal haemorrhage	2/324 (0.6%)		0/309 (0%)
Small intestinal obstruction	1/324 (0.3%)		0/309 (0%)
Upper gastrointestinal haemorrhage	1/324 (0.3%)		0/309 (0%)
Vomiting	2/324 (0.6%)		1/309 (0.3%)
General disorders
Death	2/324 (0.6%)		1/309 (0.3%)
Fatigue	2/324 (0.6%)		0/309 (0%)
General physical health deterioration	2/324 (0.6%)		2/309 (0.6%)
Non-cardiac chest pain	1/324 (0.3%)		0/309 (0%)
Pyrexia	1/324 (0.3%)		2/309 (0.6%)
Sudden death	0/324 (0%)		1/309 (0.3%)
Hepatobiliary disorders
Hepatitis	1/324 (0.3%)		0/309 (0%)
Immune system disorders
Hypersensitivity	1/324 (0.3%)		0/309 (0%)
Infections and infestations
Abscess soft tissue	0/324 (0%)		1/309 (0.3%)
Anal abscess	0/324 (0%)		1/309 (0.3%)
Appendicitis	1/324 (0.3%)		0/309 (0%)
Bronchopneumonia	0/324 (0%)		1/309 (0.3%)
Bronchopulmonary aspergillosis	1/324 (0.3%)		0/309 (0%)
Cellulitis	1/324 (0.3%)		0/309 (0%)
Cytomegalovirus hepatitis	0/324 (0%)		1/309 (0.3%)
Empyema	0/324 (0%)		2/309 (0.6%)
Escherichia bacteraemia	1/324 (0.3%)		0/309 (0%)
Influenza	1/324 (0.3%)		0/309 (0%)
Lower respiratory tract infection	1/324 (0.3%)		0/309 (0%)
Lung infection	1/324 (0.3%)		1/309 (0.3%)
Neutropenic infection	0/324 (0%)		1/309 (0.3%)
Neutropenic sepsis	1/324 (0.3%)		0/309 (0%)
Peritonitis	0/324 (0%)		2/309 (0.6%)
Pilonidal cyst	0/324 (0%)		1/309 (0.3%)
Pneumonia	6/324 (1.9%)		5/309 (1.6%)
Pseudomonas infection	1/324 (0.3%)		0/309 (0%)
Pulmonary sepsis	1/324 (0.3%)		0/309 (0%)
Respiratory tract infection	2/324 (0.6%)		2/309 (0.6%)
Sepsis	1/324 (0.3%)		1/309 (0.3%)
Septic shock	1/324 (0.3%)		0/309 (0%)
Urinary tract infection	0/324 (0%)		1/309 (0.3%)
Injury, poisoning and procedural complications
Brain contusion	1/324 (0.3%)		0/309 (0%)
Femoral neck fracture	1/324 (0.3%)		0/309 (0%)
Humerus fracture	1/324 (0.3%)		0/309 (0%)
Infusion related reaction	0/324 (0%)		1/309 (0.3%)
Lumbar vertebral fracture	1/324 (0.3%)		0/309 (0%)
Road traffic accident	1/324 (0.3%)		0/309 (0%)
Toxicity to various agents	1/324 (0.3%)		0/309 (0%)
Investigations
Blood bilirubin increased	1/324 (0.3%)		0/309 (0%)
Metabolism and nutrition disorders
Cachexia	1/324 (0.3%)		0/309 (0%)
Decreased appetite	0/324 (0%)		1/309 (0.3%)
Dehydration	0/324 (0%)		2/309 (0.6%)
Hyperglycaemia	1/324 (0.3%)		0/309 (0%)
Hyponatraemia	1/324 (0.3%)		0/309 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/324 (0%)		1/309 (0.3%)
Back pain	0/324 (0%)		1/309 (0.3%)
Musculoskeletal chest pain	1/324 (0.3%)		1/309 (0.3%)
Pathological fracture	1/324 (0.3%)		0/309 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to bone	1/324 (0.3%)		0/309 (0%)
Tumour pain	0/324 (0%)		1/309 (0.3%)
Nervous system disorders
Brain oedema	0/324 (0%)		1/309 (0.3%)
Cerebral ischaemia	2/324 (0.6%)		1/309 (0.3%)
Depressed level of consciousness	1/324 (0.3%)		0/309 (0%)
Dysarthria	1/324 (0.3%)		0/309 (0%)
Encephalopathy	2/324 (0.6%)		0/309 (0%)
Ischaemic cerebral infarction	1/324 (0.3%)		0/309 (0%)
Ischaemic stroke	0/324 (0%)		1/309 (0.3%)
Migraine	2/324 (0.6%)		0/309 (0%)
Paraesthesia	1/324 (0.3%)		0/309 (0%)
Seizure	0/324 (0%)		1/309 (0.3%)
Spinal cord compression	0/324 (0%)		1/309 (0.3%)
Syncope	0/324 (0%)		1/309 (0.3%)
Transient ischaemic attack	2/324 (0.6%)		1/309 (0.3%)
Psychiatric disorders
Hallucinations, mixed	1/324 (0.3%)		0/309 (0%)
Renal and urinary disorders
Acute kidney injury	0/324 (0%)		1/309 (0.3%)
Renal failure	1/324 (0.3%)		0/309 (0%)
Respiratory, thoracic and mediastinal disorders
Bronchial fistula	1/324 (0.3%)		1/309 (0.3%)
Chronic obstructive pulmonary disease	1/324 (0.3%)		1/309 (0.3%)
Dyspnoea	3/324 (0.9%)		4/309 (1.3%)
Epistaxis	2/324 (0.6%)		0/309 (0%)
Haemoptysis	3/324 (0.9%)		5/309 (1.6%)
Pleural effusion	1/324 (0.3%)		0/309 (0%)
Pneumothorax	2/324 (0.6%)		1/309 (0.3%)
Pulmonary artery thrombosis	0/324 (0%)		1/309 (0.3%)
Pulmonary embolism	5/324 (1.5%)		6/309 (1.9%)
Pulmonary haemorrhage	0/324 (0%)		1/309 (0.3%)
Respiratory distress	1/324 (0.3%)		0/309 (0%)
Respiratory failure	2/324 (0.6%)		1/309 (0.3%)
Skin and subcutaneous tissue disorders
Rash generalised	1/324 (0.3%)		0/309 (0%)
Subcutaneous emphysema	0/324 (0%)		1/309 (0.3%)
Surgical and medical procedures
Prophylaxis	1/324 (0.3%)		0/309 (0%)
Vascular disorders
Deep vein thrombosis	1/324 (0.3%)		1/309 (0.3%)
Embolism arterial	1/324 (0.3%)		1/309 (0.3%)
Haematoma	0/324 (0%)		1/309 (0.3%)
Hypotension	0/324 (0%)		1/309 (0.3%)
Thrombosis	1/324 (0.3%)		0/309 (0%)
Venous thrombosis	1/324 (0.3%)		1/309 (0.3%)
Other (Not Including Serious) Adverse Events
	ABP 215		Bevacizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	286/324 (88.3%)		276/309 (89.3%)
Blood and lymphatic system disorders
Anaemia	65/324 (20.1%)		60/309 (19.4%)
Leukopenia	23/324 (7.1%)		23/309 (7.4%)
Neutropenia	55/324 (17%)		60/309 (19.4%)
Thrombocytopenia	47/324 (14.5%)		43/309 (13.9%)
Gastrointestinal disorders
Constipation	36/324 (11.1%)		36/309 (11.7%)
Diarrhoea	39/324 (12%)		55/309 (17.8%)
Gingival bleeding	9/324 (2.8%)		19/309 (6.1%)
Nausea	82/324 (25.3%)		95/309 (30.7%)
Stomatitis	15/324 (4.6%)		18/309 (5.8%)
Vomiting	37/324 (11.4%)		41/309 (13.3%)
General disorders
Asthenia	49/324 (15.1%)		42/309 (13.6%)
Fatigue	57/324 (17.6%)		59/309 (19.1%)
Pyrexia	19/324 (5.9%)		20/309 (6.5%)
Investigations
Weight decreased	18/324 (5.6%)		16/309 (5.2%)
Metabolism and nutrition disorders
Decreased appetite	54/324 (16.7%)		42/309 (13.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	23/324 (7.1%)		29/309 (9.4%)
Back pain	14/324 (4.3%)		19/309 (6.1%)
Bone pain	20/324 (6.2%)		25/309 (8.1%)
Myalgia	39/324 (12%)		44/309 (14.2%)
Pain in extremity	24/324 (7.4%)		20/309 (6.5%)
Nervous system disorders
Dizziness	13/324 (4%)		25/309 (8.1%)
Headache	28/324 (8.6%)		24/309 (7.8%)
Neuropathy peripheral	56/324 (17.3%)		38/309 (12.3%)
Paraesthesia	28/324 (8.6%)		40/309 (12.9%)
Peripheral sensory neuropathy	18/324 (5.6%)		16/309 (5.2%)
Polyneuropathy	20/324 (6.2%)		22/309 (7.1%)
Renal and urinary disorders
Proteinuria	26/324 (8%)		19/309 (6.1%)
Respiratory, thoracic and mediastinal disorders
Cough	26/324 (8%)		21/309 (6.8%)
Dyspnoea	24/324 (7.4%)		24/309 (7.8%)
Epistaxis	44/324 (13.6%)		39/309 (12.6%)
Skin and subcutaneous tissue disorders
Alopecia	140/324 (43.2%)		127/309 (41.1%)
Vascular disorders
Hypertension	51/324 (15.7%)		41/309 (13.3%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.