OCEANS: A Study of Carboplatin and Gemcitabine Plus Bevacizumab in Patients With Ovary, Peritoneal, or Fallopian Tube Carcinoma

• Sponsor: Genentech, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00434642
• Collaborator: (none)
• Enrollment: 484
• Arms: 2
• Duration (Months): 75

Study Details

Study Description

Brief Summary

This is a placebo-controlled, randomized, multicenter Phase III study that will evaluate the safety and efficacy of bevacizumab, administered in combination with carboplatin with gemcitabine, in women with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube carcinoma.

Condition or Disease	Intervention/Treatment	Phase
Ovarian Cancer	Drug: Carboplatin; Drug: Gemcitabine; Drug: Bevacizumab; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 484 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III, Multicenter, Randomized, Blinded, Placebo-controlled Trial of Carboplatin and Gemcitabine Plus Bevacizumab in Patients With Platinum-sensitive Recurrent Ovary, Primary Peritoneal, or Fallopian Tube Carcinoma
• Study Start Date: Apr 1, 2007
• Actual Primary Completion Date: Sep 1, 2010
• Actual Study Completion Date: Jul 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Carboplatin and gemcitabine + bevacizumab Carboplatin (AUC 4 mg/mL/minute) was administered intravenously (IV) on Day 1 of each of six 21-day treatment cycles. The carboplatin dose was calculated to reach a target area under the curve (AUC) of concentration x time according to the Calvert formula. Gemcitabine 1000 mg/m^2 was administered IV on Days 1 and Day 8 of each of the six 21-day treatment cycles. Bevacizumab 15 mg/kg was administered IV on Day 1 of each of the six 21-day treatment cycles. The bevacizumab dose was based on the patient's weight at baseline and remained the same throughout the study.	Drug: Carboplatin; Carboplatin was provided as commercially available drug.; Drug: Gemcitabine; Gemcitabine was provided as commercially available drug.; Drug: Bevacizumab; Bevacizumab was supplied as a clear to slightly opalescent, sterile liquid in glass vials (400 mg in 8 mL [25 mg/mL]) with a vehicle consisting of sodium phosphate, trehalose, polysorbate 20, and Sterile Water for Injection, USP.; Other Names: Avastin
Active Comparator: Carboplatin and gemcitabine + placebo Carboplatin (AUC 4 mg/mL/minute) was administered intravenously (IV) on Day 1 of each of six 21-day treatment cycles. The carboplatin dose was calculated to reach a target area under the curve (AUC) of concentration x time according to the Calvert formula. Gemcitabine 1000 mg/m^2 was administered IV on Days 1 and Day 8 of each of the six 21-day treatment cycles. Placebo was administered by IV on Day 1 of each of the six 21-day treatment cycles.	Drug: Carboplatin; Carboplatin was provided as commercially available drug.; Drug: Gemcitabine; Gemcitabine was provided as commercially available drug.; Drug: Placebo; Placebo consisted of the vehicle for bevacizumab without the antibody and contained sodium phosphate, trehalose, polysorbate 20, and Sterile Water for Injection, USP.

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) as Determined by the Investigator, Per Response Evaluation Criteria for Solid Tumors (RECIST) [From randomization through September 17, 2010 (up to 3 years, 5 months)]

   PFS was defined as the time from randomization to disease progression (PD), as determined by the investigator, or death due to any cause. PD: At least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started; the appearance of 1 or more new lesions; and/or the unequivocal progression of existing non-target lesions. Lesions were assessed by computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound every 9 weeks.

Secondary Outcome Measures

1. Percentage of Patients With an Objective Response as Determined by the Investigator, Per Response Evaluation Criteria for Solid Tumors (RECIST) [From randomization through September 17, 2010 (up to 3 years, 5 months)]

   An objective response was the occurrence of either a partial response (PR) or complete response (CR). PR: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. CR: The disappearance of all target and non-target lesions. Lesions were assessed by computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound every 9 weeks.

2. Duration of Objective Response (OR) as Determined by the Investigator, Per Response Evaluation Criteria for Solid Tumors (RECIST) [From randomization through September 17, 2010 (up to 3 years, 5 months)]

   Duration of OR was analyzed in the subset of patients who achieved an OR. The duration of OR was defined as the time from the initial CR or PR until documented PD or death. Lesions were assessed by computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound every 9 weeks.

3. Overall Survival [From randomization through July 19, 2013 (up to 6 years, 3 months)]

   Overall survival was defined as the time from randomization to death from any cause.

4. Percentage of Patients Who Had a Gastrointestinal Perforation (GIP) [From randomization through September 17, 2010 (up to 3 years, 5 months)]

   A gastrointestinal perforation is a hole that develops through the entire wall of the stomach, small intestine, large bowel, or gallbladder.

5. Percentage of Patients Who Had at Least 1 Adverse Event [From randomization through July 19, 2013 (up to 6 years, 3 months)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Signed Informed Consent Form

• Age ≥ 18 years

• Documented ovarian, primary peritoneal, or fallopian tube carcinoma that has recurred

• No prior chemotherapy in the recurrent setting

• Measurable disease

• Recovered from prior radiation therapy or surgery

Exclusion Criteria:

• Prior chemotherapy treatment for recurrent ovarian, primary peritoneal, or fallopian tube carcinoma

• History of abdominal fistula, gastrointestinal perforation (GIP), or intra-abdominal abscess

• Patients with clinical symptoms or signs of gastrointestinal (GI) obstruction or who require parenteral hydration, parenteral nutrition, or tube feeding

• Patients with evidence of abdominal free air not explained by paracentesis or recent surgical procedure

• Current, recent, or planned participation in an experimental drug study

• History of systemic bevacizumab (Avastin) or other vascular endothelial growth factor (VEGF) or VEGF receptor-targeted agent use

• Inadequately controlled hypertension

• Prior history of hypertensive crisis or hypertensive encephalopathy

• New York Heart Association Class II or greater congestive heart failure (CHF)

• History of myocardial infarction or unstable angina

• History of stroke or transient ischemic attack (TIA)

• Known central nervous system (CNS) disease except for treated brain metastasis

• Significant vascular disease or recent peripheral arterial thrombosis

• History of hemoptysis

• Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Genentech, Inc.

Investigators

• Study Director: Amreen Husain, MD, Genentech, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT00434642
• Other Study ID Numbers: AVF4095g
• First Posted: Feb 13, 2007
• Last Update Posted: Aug 9, 2017
• Last Verified: Jul 1, 2017

• Keywords provided by Genentech, Inc.: Avastin; Ovarian carcinoma; Peritoneal carcinoma; Peritoneal cancer; Fallopian tube cancer; Fallopian tube carcinoma; OCEANS
• Additional relevant MeSH terms: Carcinoma; Gemcitabine; Bevacizumab; Carboplatin

Study Results

Participant Flow

Arm/Group Title	Carboplatin and Gemcitabine + Placebo	Carboplatin and Gemcitabine + Bevacizumab
Arm/Group Description	Carboplatin (AUC 4 mg/mL/minute) was administered intravenously (IV) on Day 1 of each of six 21-day treatment cycles. The carboplatin dose was calculated to reach a target area under the curve (AUC) of concentration x time according to the Calvert formula. Gemcitabine 1000 mg/m^2 was administered IV on Days 1 and Day 8 of each of the six 21-day treatment cycles. Placebo was administered by IV on Day 1 of each of the six 21-day treatment cycles.	Carboplatin (AUC 4 mg/mL/minute) was administered intravenously (IV) on Day 1 of each of six 21-day treatment cycles. The carboplatin dose was calculated to reach a target area under the curve (AUC) of concentration x time according to the Calvert formula. Gemcitabine 1000 mg/m^2 was administered IV on Days 1 and Day 8 of each of the six 21-day treatment cycles. Bevacizumab 15 mg/kg was administered IV on Day 1 of each of the six 21-day treatment cycles. The bevacizumab dose was based on the patient's weight at baseline and remained the same throughout the study.
Period Title: Blinded Treatment Phase
STARTED	242	242
COMPLETED	0	13
NOT COMPLETED	242	229
Period Title: Blinded Treatment Phase
STARTED	0	12
COMPLETED	0	1
NOT COMPLETED	0	11

Baseline Characteristics

Arm/Group Title	Carboplatin and Gemcitabine + Placebo	Carboplatin and Gemcitabine + Bevacizumab	Total
Arm/Group Description	Carboplatin (AUC 4 mg/mL/minute) was administered intravenously (IV) on Day 1 of each of six 21-day treatment cycles. The carboplatin dose was calculated to reach a target area under the curve (AUC) of concentration x time according to the Calvert formula. Gemcitabine 1000 mg/m^2 was administered IV on Days 1 and Day 8 of each of the six 21-day treatment cycles. Placebo was administered by IV on Day 1 of each of the six 21-day treatment cycles.	Carboplatin (AUC 4 mg/mL/minute) was administered intravenously (IV) on Day 1 of each of six 21-day treatment cycles. The carboplatin dose was calculated to reach a target area under the curve (AUC) of concentration x time according to the Calvert formula. Gemcitabine 1000 mg/m^2 was administered IV on Days 1 and Day 8 of each of the six 21-day treatment cycles. Bevacizumab 15 mg/kg was administered IV on Day 1 of each of the six 21-day treatment cycles. The bevacizumab dose was based on the patient's weight at baseline and remained the same throughout the study.	Total of all reporting groups
Overall Participants	242	242	484
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.6 (10.2)	60.5 (9.8)	61.0 (10.0)
Sex: Female, Male (Count of Participants)
Female	242 100%	242 100%	484 100%
Male	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS) as Determined by the Investigator, Per Response Evaluation Criteria for Solid Tumors (RECIST)
Description	PFS was defined as the time from randomization to disease progression (PD), as determined by the investigator, or death due to any cause. PD: At least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started; the appearance of 1 or more new lesions; and/or the unequivocal progression of existing non-target lesions. Lesions were assessed by computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound every 9 weeks.
Time Frame	From randomization through September 17, 2010 (up to 3 years, 5 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All patients randomized to treatment (242 patients in each treatment group).

Arm/Group Title	Carboplatin and Gemcitabine + Bevacizumab	Carboplatin and Gemcitabine + Placebo
Arm/Group Description	Carboplatin (AUC 4 mg/mL/minute) was administered intravenously (IV) on Day 1 of each of six 21-day treatment cycles. The carboplatin dose was calculated to reach a target area under the curve (AUC) of concentration x time according to the Calvert formula. Gemcitabine 1000 mg/m^2 was administered IV on Days 1 and Day 8 of each of the six 21-day treatment cycles. Bevacizumab 15 mg/kg was administered IV on Day 1 of each of the six 21-day treatment cycles. The bevacizumab dose was based on the patient's weight at baseline and remained the same throughout the study.	Carboplatin (AUC 4 mg/mL/minute) was administered intravenously (IV) on Day 1 of each of six 21-day treatment cycles. The carboplatin dose was calculated to reach a target area under the curve (AUC) of concentration x time according to the Calvert formula. Gemcitabine 1000 mg/m^2 was administered IV on Days 1 and Day 8 of each of the six 21-day treatment cycles. Placebo was administered by IV on Day 1 of each of the six 21-day treatment cycles.
Measure Participants	242	242
Median (95% Confidence Interval) [Months]	12.4	8.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Carboplatin and Gemcitabine + Bevacizumab, Carboplatin and Gemcitabine + Placebo
	Comments	The null hypothesis was that there was no difference between the 2 treatment groups, ie, that the hazard ratio is equal to 1. The alternative hypothesis was that progression free survival was longer in the carboplatin and gemcitabine + bevacizumab group, ie, that the hazard ratio is not equal to 1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	A P-value < 0.05 was required for significance.
	Method	Log Rank
	Comments	The analysis was stratified for time since the last platinum therapy (6-12, > 12 months) and cytoreductive surgery for recurrent disease (yes, no).
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.484
	Confidence Interval	(2-Sided) 95%; 0.388 to 0.605
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was estimated using Cox regression. The hazard ratio is relative to the carboplatin and gemcitabine + placebo group.

2. Secondary Outcome

Title	Percentage of Patients With an Objective Response as Determined by the Investigator, Per Response Evaluation Criteria for Solid Tumors (RECIST)
Description	An objective response was the occurrence of either a partial response (PR) or complete response (CR). PR: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. CR: The disappearance of all target and non-target lesions. Lesions were assessed by computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound every 9 weeks.
Time Frame	From randomization through September 17, 2010 (up to 3 years, 5 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All patients randomized to treatment (242 patients in each treatment group).

Arm/Group Title	Carboplatin and Gemcitabine + Bevacizumab	Carboplatin and Gemcitabine + Placebo
Arm/Group Description	Carboplatin (AUC 4 mg/mL/minute) was administered intravenously (IV) on Day 1 of each of six 21-day treatment cycles. The carboplatin dose was calculated to reach a target area under the curve (AUC) of concentration x time according to the Calvert formula. Gemcitabine 1000 mg/m^2 was administered IV on Days 1 and Day 8 of each of the six 21-day treatment cycles. Bevacizumab 15 mg/kg was administered IV on Day 1 of each of the six 21-day treatment cycles. The bevacizumab dose was based on the patient's weight at baseline and remained the same throughout the study.	Carboplatin (AUC 4 mg/mL/minute) was administered intravenously (IV) on Day 1 of each of six 21-day treatment cycles. The carboplatin dose was calculated to reach a target area under the curve (AUC) of concentration x time according to the Calvert formula. Gemcitabine 1000 mg/m^2 was administered IV on Days 1 and Day 8 of each of the six 21-day treatment cycles. Placebo was administered by IV on Day 1 of each of the six 21-day treatment cycles.
Measure Participants	242	242
Number [Percentage of participants]	78.5 32.4%	57.4 23.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Carboplatin and Gemcitabine + Bevacizumab, Carboplatin and Gemcitabine + Placebo
	Comments	The null hypothesis was that there was no difference in the percentage of patients with an objective response between the 2 treatment groups. The alternative hypothesis was that a larger percentage of patients had an objective response in the carboplatin and gemcitabine + bevacizumab group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	A P-value < 0.05 was required for significance.
	Method	Cochran-Mantel-Haenszel
	Comments	The analysis was stratified for time since the last platinum therapy (6-12, > 12 months) and cytoreductive surgery for recurrent disease (yes, no).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	21.1
	Confidence Interval	(2-Sided) 95%; 13.0 to 29.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference in response rates and the 95% confidence intervals for response rates were computed using the normal approximation to the binomial distribution.

3. Secondary Outcome

Title	Duration of Objective Response (OR) as Determined by the Investigator, Per Response Evaluation Criteria for Solid Tumors (RECIST)
Description	Duration of OR was analyzed in the subset of patients who achieved an OR. The duration of OR was defined as the time from the initial CR or PR until documented PD or death. Lesions were assessed by computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound every 9 weeks.
Time Frame	From randomization through September 17, 2010 (up to 3 years, 5 months)

Outcome Measure Data

Analysis Population Description

Subset of the intent-to-treat population: All patients randomized to treatment who achieved an objective response.

Arm/Group Title	Carboplatin and Gemcitabine + Bevacizumab	Carboplatin and Gemcitabine + Placebo
Arm/Group Description	Carboplatin (AUC 4 mg/mL/minute) was administered intravenously (IV) on Day 1 of each of six 21-day treatment cycles. The carboplatin dose was calculated to reach a target area under the curve (AUC) of concentration x time according to the Calvert formula. Gemcitabine 1000 mg/m^2 was administered IV on Days 1 and Day 8 of each of the six 21-day treatment cycles. Bevacizumab 15 mg/kg was administered IV on Day 1 of each of the six 21-day treatment cycles. The bevacizumab dose was based on the patient's weight at baseline and remained the same throughout the study.	Carboplatin (AUC 4 mg/mL/minute) was administered intravenously (IV) on Day 1 of each of six 21-day treatment cycles. The carboplatin dose was calculated to reach a target area under the curve (AUC) of concentration x time according to the Calvert formula. Gemcitabine 1000 mg/m^2 was administered IV on Days 1 and Day 8 of each of the six 21-day treatment cycles. Placebo was administered by IV on Day 1 of each of the six 21-day treatment cycles.
Measure Participants	190	139
Median (95% Confidence Interval) [Months]	10.4	7.4

4. Secondary Outcome

Title	Overall Survival
Description	Overall survival was defined as the time from randomization to death from any cause.
Time Frame	From randomization through July 19, 2013 (up to 6 years, 3 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All patients randomized to treatment (242 patients in each treatment group).

Arm/Group Title	Carboplatin and Gemcitabine + Bevacizumab	Carboplatin and Gemcitabine + Placebo
Arm/Group Description	Carboplatin (AUC 4 mg/mL/minute) was administered intravenously (IV) on Day 1 of each of six 21-day treatment cycles. The carboplatin dose was calculated to reach a target area under the curve (AUC) of concentration x time according to the Calvert formula. Gemcitabine 1000 mg/m^2 was administered IV on Days 1 and Day 8 of each of the six 21-day treatment cycles. Bevacizumab 15 mg/kg was administered IV on Day 1 of each of the six 21-day treatment cycles. The bevacizumab dose was based on the patient's weight at baseline and remained the same throughout the study.	Carboplatin (AUC 4 mg/mL/minute) was administered intravenously (IV) on Day 1 of each of six 21-day treatment cycles. The carboplatin dose was calculated to reach a target area under the curve (AUC) of concentration x time according to the Calvert formula. Gemcitabine 1000 mg/m^2 was administered IV on Days 1 and Day 8 of each of the six 21-day treatment cycles. Placebo was administered by IV on Day 1 of each of the six 21-day treatment cycles.
Measure Participants	242	242
Median (95% Confidence Interval) [Months]	33.6	32.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Carboplatin and Gemcitabine + Bevacizumab, Carboplatin and Gemcitabine + Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6479
	Comments	Summaries of duration of overall survival (median, percentiles) were estimated from Kaplan-Meier curves. The 95% confidence interval for the median was computed using the method of Brookmeyer and Crowley.
	Method	Log Rank
	Comments	The analysis was stratified for time since the last platinum therapy (≤12, >12 months) and cytoreductive surgery for recurrent disease (Yes, No).
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.952
	Confidence Interval	(2-Sided) 95%; 0.771 to 1.176
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was estimated using Cox regression. The hazard ratio is relative to the carboplatin and gemcitabine + placebo group.

5. Secondary Outcome

Title	Percentage of Patients Who Had a Gastrointestinal Perforation (GIP)
Description	A gastrointestinal perforation is a hole that develops through the entire wall of the stomach, small intestine, large bowel, or gallbladder.
Time Frame	From randomization through September 17, 2010 (up to 3 years, 5 months)

Outcome Measure Data

Analysis Population Description

Safety population: All patients who received at least 1 dose of protocol treatment. Due to errors in drug administration, the safety population included 247 patients in the carboplatin and gemcitabine + bevacizumab group and 233 patients in the carboplatin and gemcitabine + placebo group.

Arm/Group Title	Carboplatin and Gemcitabine + Bevacizumab	Carboplatin and Gemcitabine + Placebo
Arm/Group Description	Carboplatin (AUC 4 mg/mL/minute) was administered intravenously (IV) on Day 1 of each of six 21-day treatment cycles. The carboplatin dose was calculated to reach a target area under the curve (AUC) of concentration x time according to the Calvert formula. Gemcitabine 1000 mg/m^2 was administered IV on Days 1 and Day 8 of each of the six 21-day treatment cycles. Bevacizumab 15 mg/kg was administered IV on Day 1 of each of the six 21-day treatment cycles. The bevacizumab dose was based on the patient's weight at baseline and remained the same throughout the study.	Carboplatin (AUC 4 mg/mL/minute) was administered intravenously (IV) on Day 1 of each of six 21-day treatment cycles. The carboplatin dose was calculated to reach a target area under the curve (AUC) of concentration x time according to the Calvert formula. Gemcitabine 1000 mg/m^2 was administered IV on Days 1 and Day 8 of each of the six 21-day treatment cycles. Placebo was administered by IV on Day 1 of each of the six 21-day treatment cycles.
Measure Participants	247	233
Number [Percentage of participants]	0 0%	0 0%

6. Secondary Outcome

Title	Percentage of Patients Who Had at Least 1 Adverse Event
Time Frame	From randomization through July 19, 2013 (up to 6 years, 3 months)

Outcome Measure Data

Analysis Population Description

Safety population: All patients who received at least 1 dose of protocol treatment. Due to errors in drug administration, the safety population included 247 patients in the carboplatin and gemcitabine + bevacizumab group and 233 patients in the carboplatin and gemcitabine + placebo group.

Arm/Group Title	Carboplatin and Gemcitabine + Bevacizumab	Carboplatin and Gemcitabine + Placebo
Arm/Group Description	Carboplatin (AUC 4 mg/mL/minute) was administered intravenously (IV) on Day 1 of each of six 21-day treatment cycles. The carboplatin dose was calculated to reach a target area under the curve (AUC) of concentration x time according to the Calvert formula. Gemcitabine 1000 mg/m^2 was administered IV on Days 1 and Day 8 of each of the six 21-day treatment cycles. Bevacizumab 15 mg/kg was administered IV on Day 1 of each of the six 21-day treatment cycles. The bevacizumab dose was based on the patient's weight at baseline and remained the same throughout the study.	Carboplatin (AUC 4 mg/mL/minute) was administered intravenously (IV) on Day 1 of each of six 21-day treatment cycles. The carboplatin dose was calculated to reach a target area under the curve (AUC) of concentration x time according to the Calvert formula. Gemcitabine 1000 mg/m^2 was administered IV on Days 1 and Day 8 of each of the six 21-day treatment cycles. Placebo was administered by IV on Day 1 of each of the six 21-day treatment cycles.
Measure Participants	247	233
Number [Percentage of participants]	100.0 41.3%	100.0 41.3%

Adverse Events

Time Frame	From randomization through July 19, 2013
Adverse Event Reporting Description	Safety population: All patients who received at least 1 dose of protocol treatment. Due to errors in drug administration, the safety population included 247 patients in the carboplatin and gemcitabine + bevacizumab group and 233 patients in the carboplatin and gemcitabine + placebo group.
Arm/Group Title	Carboplatin and Gemcitabine + Bevacizumab		Carboplatin and Gemcitabine + Placebo
Arm/Group Description	Carboplatin (AUC 4 mg/mL/minute) was administered intravenously (IV) on Day 1 of each of six 21-day treatment cycles. The carboplatin dose was calculated to reach a target area under the curve (AUC) of concentration x time according to the Calvert formula. Gemcitabine 1000 mg/m^2 was administered IV on Days 1 and Day 8 of each of the six 21-day treatment cycles. Bevacizumab 15 mg/kg was administered IV on Day 1 of each of the six 21-day treatment cycles. The bevacizumab dose was based on the patient's weight at baseline and remained the same throughout the study.		Carboplatin (AUC 4 mg/mL/minute) was administered intravenously (IV) on Day 1 of each of six 21-day treatment cycles. The carboplatin dose was calculated to reach a target area under the curve (AUC) of concentration x time according to the Calvert formula. Gemcitabine 1000 mg/m^2 was administered IV on Days 1 and Day 8 of each of the six 21-day treatment cycles. Placebo was administered by IV on Day 1 of each of the six 21-day treatment cycles.
All Cause Mortality
	Carboplatin and Gemcitabine + Bevacizumab		Carboplatin and Gemcitabine + Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Carboplatin and Gemcitabine + Bevacizumab		Carboplatin and Gemcitabine + Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	90/247 (36.4%)		59/233 (25.3%)
Blood and lymphatic system disorders
Anaemia	6/247 (2.4%)		1/233 (0.4%)
Febrile Neutropenia	2/247 (0.8%)		4/233 (1.7%)
Haemolytic Uraemic Syndrome	0/247 (0%)		1/233 (0.4%)
Leukocytosis	0/247 (0%)		1/233 (0.4%)
Leukopenia	1/247 (0.4%)		0/233 (0%)
Neutropenia	1/247 (0.4%)		3/233 (1.3%)
Pancytopenia	1/247 (0.4%)		0/233 (0%)
Thrombocytopenia	8/247 (3.2%)		8/233 (3.4%)
Cardiac disorders
Acute Myocardial Infarction	0/247 (0%)		1/233 (0.4%)
Cardiac Failure	1/247 (0.4%)		0/233 (0%)
Cardiac Failure Congestive	1/247 (0.4%)		2/233 (0.9%)
Cardiomyopathy	1/247 (0.4%)		0/233 (0%)
Myocardial Infarction	1/247 (0.4%)		0/233 (0%)
Supraventricular Tachycardia	1/247 (0.4%)		0/233 (0%)
Gastrointestinal disorders
Abdominal Pain	3/247 (1.2%)		2/233 (0.9%)
Abdominal Pain Lower	0/247 (0%)		1/233 (0.4%)
Abdominal Pain Upper	0/247 (0%)		1/233 (0.4%)
Ascites	0/247 (0%)		1/233 (0.4%)
Constipation	0/247 (0%)		2/233 (0.9%)
Diarrhoea	1/247 (0.4%)		1/233 (0.4%)
Duodenal Ulcer	1/247 (0.4%)		0/233 (0%)
Gastric Ulcer	1/247 (0.4%)		0/233 (0%)
Gastritis	2/247 (0.8%)		0/233 (0%)
Haemorrhoids	1/247 (0.4%)		0/233 (0%)
Ileus	1/247 (0.4%)		2/233 (0.9%)
Ileus Spastic	1/247 (0.4%)		0/233 (0%)
Intestinal Obstruction	3/247 (1.2%)		1/233 (0.4%)
Nausea	3/247 (1.2%)		0/233 (0%)
Small Intestinal Obstruction	4/247 (1.6%)		6/233 (2.6%)
Upper Gastrointestinal Haemorrhage	0/247 (0%)		1/233 (0.4%)
Vomiting	2/247 (0.8%)		3/233 (1.3%)
General disorders
Adverse Drug Reaction	1/247 (0.4%)		1/233 (0.4%)
Infusion Related Reaction	1/247 (0.4%)		0/233 (0%)
Pyrexia	2/247 (0.8%)		6/233 (2.6%)
Thrombosis In Device	0/247 (0%)		1/233 (0.4%)
Influenza Like Illness	1/247 (0.4%)		0/233 (0%)
Hepatobiliary disorders
Bile Duct Obstruction	0/247 (0%)		1/233 (0.4%)
Biliary Colic	1/247 (0.4%)		0/233 (0%)
Cholecystitis	1/247 (0.4%)		3/233 (1.3%)
Cholecystitis Acute	1/247 (0.4%)		0/233 (0%)
Cholelithiasis	1/247 (0.4%)		0/233 (0%)
Immune system disorders
Drug Hypersensitivity	4/247 (1.6%)		3/233 (1.3%)
Hypersensitivity	1/247 (0.4%)		1/233 (0.4%)
Infections and infestations
Bacteraemia	1/247 (0.4%)		0/233 (0%)
Catheter Site Infection	1/247 (0.4%)		0/233 (0%)
Cellulitis	2/247 (0.8%)		2/233 (0.9%)
Device Related Infection	1/247 (0.4%)		0/233 (0%)
Diverticulitis	1/247 (0.4%)		1/233 (0.4%)
Infection	1/247 (0.4%)		0/233 (0%)
Kidney Infection	1/247 (0.4%)		0/233 (0%)
Pneumonia	3/247 (1.2%)		2/233 (0.9%)
Thrombophlebitis Septic	1/247 (0.4%)		0/233 (0%)
Urinary Tract Infection	0/247 (0%)		1/233 (0.4%)
Urosepsis	0/247 (0%)		1/233 (0.4%)
Viral Infection	1/247 (0.4%)		0/233 (0%)
Appendicitis	1/247 (0.4%)		0/233 (0%)
Injury, poisoning and procedural complications
Overdose	1/247 (0.4%)		0/233 (0%)
Patella Fracture	1/247 (0.4%)		0/233 (0%)
Wound Complication	1/247 (0.4%)		0/233 (0%)
Femur Fracture	1/247 (0.4%)		0/233 (0%)
Incisional Hernia	0/247 (0%)		1/233 (0.4%)
Metabolism and nutrition disorders
Dehydration	2/247 (0.8%)		3/233 (1.3%)
Musculoskeletal and connective tissue disorders
Arthritis	1/247 (0.4%)		0/233 (0%)
Back Pain	1/247 (0.4%)		0/233 (0%)
Musculoskeletal Chest Pain	2/247 (0.8%)		0/233 (0%)
Pain In Extremity	0/247 (0%)		1/233 (0.4%)
Soft Tissue Haemorrhage	1/247 (0.4%)		0/233 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Glioblastoma	1/247 (0.4%)		0/233 (0%)
Squamous Cell Carcinoma	1/247 (0.4%)		0/233 (0%)
Papillary Thyroid Cancer	0/247 (0%)		1/233 (0.4%)
Tumour Compression	0/247 (0%)		1/233 (0.4%)
Basal Cell Carcinoma	1/247 (0.4%)		0/233 (0%)
Breast Cancer	1/247 (0.4%)		0/233 (0%)
Colorectal Cancer Metastatic	1/247 (0.4%)		0/233 (0%)
Nervous system disorders
Cerebral Ischaemia	0/247 (0%)		1/233 (0.4%)
Cerebrovascular Accident	0/247 (0%)		1/233 (0.4%)
Convulsion	0/247 (0%)		1/233 (0.4%)
Dizziness	0/247 (0%)		1/233 (0.4%)
Encephalopathy	1/247 (0.4%)		0/233 (0%)
Haemorrhage Intracranial	1/247 (0.4%)		0/233 (0%)
Haemorrhagic Stroke	1/247 (0.4%)		0/233 (0%)
Headache	1/247 (0.4%)		0/233 (0%)
Migraine	1/247 (0.4%)		0/233 (0%)
Peripheral Motor Neuropathy	0/247 (0%)		1/233 (0.4%)
Reversible Posterior Leukoencephalopathy Syndrome	2/247 (0.8%)		0/233 (0%)
Speech Disorder	1/247 (0.4%)		0/233 (0%)
Syncope	2/247 (0.8%)		1/233 (0.4%)
Transient Ischaemic Attack	1/247 (0.4%)		0/233 (0%)
Tremor	0/247 (0%)		1/233 (0.4%)
Psychiatric disorders
Mental Status Changes	2/247 (0.8%)		0/233 (0%)
Renal and urinary disorders
Haematuria	1/247 (0.4%)		0/233 (0%)
Hydronephrosis	1/247 (0.4%)		1/233 (0.4%)
Nephrotic Syndrome	1/247 (0.4%)		1/233 (0.4%)
Renal Failure Acute	1/247 (0.4%)		0/233 (0%)
Ureteric Obstruction	0/247 (0%)		1/233 (0.4%)
Reproductive system and breast disorders
Female Genital Tract Fistula	1/247 (0.4%)		0/233 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/247 (0.8%)		3/233 (1.3%)
Epistaxis	5/247 (2%)		1/233 (0.4%)
Hypoxia	1/247 (0.4%)		0/233 (0%)
Pneumothorax	0/247 (0%)		1/233 (0.4%)
Pulmonary Embolism	2/247 (0.8%)		3/233 (1.3%)
Surgical and medical procedures
Ureteral Stent Insertion	1/247 (0.4%)		0/233 (0%)
Vascular disorders
Arterial Thrombosis	1/247 (0.4%)		0/233 (0%)
Deep Vein Thrombosis	2/247 (0.8%)		1/233 (0.4%)
Embolism	1/247 (0.4%)		0/233 (0%)
Hypertension	4/247 (1.6%)		0/233 (0%)
Malignant Hypertension	2/247 (0.8%)		0/233 (0%)
Thrombophlebitis	0/247 (0%)		1/233 (0.4%)
Thrombophlebitis Superficial	1/247 (0.4%)		0/233 (0%)
Thrombosis	2/247 (0.8%)		0/233 (0%)
Vena Cava Thrombosis	1/247 (0.4%)		0/233 (0%)
Embolism Venous	1/247 (0.4%)		0/233 (0%)
Other (Not Including Serious) Adverse Events
	Carboplatin and Gemcitabine + Bevacizumab		Carboplatin and Gemcitabine + Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	246/247 (99.6%)		233/233 (100%)
Blood and lymphatic system disorders
Anaemia	126/247 (51%)		137/233 (58.8%)
Leukopenia	36/247 (14.6%)		32/233 (13.7%)
Neutropenia	172/247 (69.6%)		158/233 (67.8%)
Thrombocytopenia	135/247 (54.7%)		111/233 (47.6%)
Ear and labyrinth disorders
Tinnitus	14/247 (5.7%)		11/233 (4.7%)
Eye disorders
Vision Blurred	14/247 (5.7%)		17/233 (7.3%)
Gastrointestinal disorders
Abdominal Discomfort	15/247 (6.1%)		15/233 (6.4%)
Abdominal Distension	24/247 (9.7%)		21/233 (9%)
Abdominal Pain	60/247 (24.3%)		58/233 (24.9%)
Abdominal Pain Lower	20/247 (8.1%)		16/233 (6.9%)
Abdominal Pain Upper	19/247 (7.7%)		17/233 (7.3%)
Constipation	132/247 (53.4%)		122/233 (52.4%)
Diarrhoea	95/247 (38.5%)		67/233 (28.8%)
Dyspepsia	27/247 (10.9%)		29/233 (12.4%)
Gastrooesophageal Reflux Disease	20/247 (8.1%)		17/233 (7.3%)
Gingival Bleeding	17/247 (6.9%)		1/233 (0.4%)
Haemorrhoids	18/247 (7.3%)		6/233 (2.6%)
Nausea	177/247 (71.7%)		153/233 (65.7%)
Rectal Haemorrhage	21/247 (8.5%)		10/233 (4.3%)
Stomatitis	39/247 (15.8%)		16/233 (6.9%)
Vomiting	81/247 (32.8%)		66/233 (28.3%)
Oral Pain	13/247 (5.3%)		3/233 (1.3%)
General disorders
Asthenia	25/247 (10.1%)		27/233 (11.6%)
Catheter Site Pain	14/247 (5.7%)		6/233 (2.6%)
Chest Pain	19/247 (7.7%)		9/233 (3.9%)
Chills	28/247 (11.3%)		22/233 (9.4%)
Fatigue	201/247 (81.4%)		175/233 (75.1%)
Mucosal Inflammation	38/247 (15.4%)		25/233 (10.7%)
Oedema Peripheral	41/247 (16.6%)		46/233 (19.7%)
Pain	26/247 (10.5%)		28/233 (12%)
Pyrexia	41/247 (16.6%)		37/233 (15.9%)
Immune system disorders
Drug Hypersensitivity	26/247 (10.5%)		15/233 (6.4%)
Hypersensitivity	16/247 (6.5%)		12/233 (5.2%)
Infections and infestations
Nasopharyngitis	21/247 (8.5%)		17/233 (7.3%)
Sinusitis	38/247 (15.4%)		21/233 (9%)
Upper Respiratory Tract Infection	42/247 (17%)		28/233 (12%)
Urinary Tract Infection	37/247 (15%)		39/233 (16.7%)
Injury, poisoning and procedural complications
Contusion	43/247 (17.4%)		21/233 (9%)
Investigations
Alanine Aminotransferase Increased	14/247 (5.7%)		19/233 (8.2%)
Aspartate Aminotransferase Increased	12/247 (4.9%)		17/233 (7.3%)
Haemoglobin Decreased	30/247 (12.1%)		21/233 (9%)
Neutrophil Count Decreased	29/247 (11.7%)		23/233 (9.9%)
Platelet Count Decreased	22/247 (8.9%)		24/233 (10.3%)
White Blood Cell Count Decreased	13/247 (5.3%)		19/233 (8.2%)
Blood Creatinine Increased	13/247 (5.3%)		9/233 (3.9%)
Metabolism and nutrition disorders
Decreased Appetite	48/247 (19.4%)		61/233 (26.2%)
Dehydration	18/247 (7.3%)		13/233 (5.6%)
Hyperglycaemia	23/247 (9.3%)		17/233 (7.3%)
Hypokalaemia	24/247 (9.7%)		26/233 (11.2%)
Hypomagnesaemia	39/247 (15.8%)		35/233 (15%)
Hypocalcaemia	13/247 (5.3%)		8/233 (3.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	69/247 (27.9%)		44/233 (18.9%)
Back Pain	51/247 (20.6%)		32/233 (13.7%)
Bone Pain	29/247 (11.7%)		25/233 (10.7%)
Muscle Spasms	21/247 (8.5%)		14/233 (6%)
Muscular Weakness	9/247 (3.6%)		12/233 (5.2%)
Musculoskeletal Pain	22/247 (8.9%)		15/233 (6.4%)
Myalgia	42/247 (17%)		33/233 (14.2%)
Neck Pain	15/247 (6.1%)		14/233 (6%)
Pain In Extremity	40/247 (16.2%)		35/233 (15%)
Nervous system disorders
Dizziness	58/247 (23.5%)		38/233 (16.3%)
Dysgeusia	31/247 (12.6%)		32/233 (13.7%)
Headache	119/247 (48.2%)		70/233 (30%)
Neuropathy Peripheral	45/247 (18.2%)		48/233 (20.6%)
Peripheral Sensory Neuropathy	13/247 (5.3%)		18/233 (7.7%)
Hypoaesthesia	9/247 (3.6%)		12/233 (5.2%)
Psychiatric disorders
Anxiety	33/247 (13.4%)		18/233 (7.7%)
Depression	37/247 (15%)		24/233 (10.3%)
Insomnia	51/247 (20.6%)		36/233 (15.5%)
Renal and urinary disorders
Dysuria	13/247 (5.3%)		15/233 (6.4%)
Proteinuria	52/247 (21.1%)		8/233 (3.4%)
Respiratory, thoracic and mediastinal disorders
Cough	66/247 (26.7%)		43/233 (18.5%)
Dysphonia	34/247 (13.8%)		8/233 (3.4%)
Dyspnoea	74/247 (30%)		53/233 (22.7%)
Dyspnoea Exertional	22/247 (8.9%)		21/233 (9%)
Epistaxis	130/247 (52.6%)		32/233 (13.7%)
Nasal Congestion	20/247 (8.1%)		18/233 (7.7%)
Oropharyngeal Pain	40/247 (16.2%)		23/233 (9.9%)
Rhinorrhoea	26/247 (10.5%)		9/233 (3.9%)
Sinus Congestion	19/247 (7.7%)		4/233 (1.7%)
Skin and subcutaneous tissue disorders
Alopecia	64/247 (25.9%)		64/233 (27.5%)
Erythema	14/247 (5.7%)		12/233 (5.2%)
Pruritus	35/247 (14.2%)		28/233 (12%)
Rash	53/247 (21.5%)		51/233 (21.9%)
Dry Skin	13/247 (5.3%)		6/233 (2.6%)
Petechiae	13/247 (5.3%)		4/233 (1.7%)
Vascular disorders
Flushing	15/247 (6.1%)		9/233 (3.9%)
Hot Flush	19/247 (7.7%)		13/233 (5.6%)
Hypertension	102/247 (41.3%)		20/233 (8.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.