Ovarian Cancer
Conditions
Keywords
Avastin, Ovarian carcinoma, Peritoneal carcinoma, Peritoneal cancer, Fallopian tube cancer, Fallopian tube carcinoma, OCEANS
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.
Interventions
DRUGCarboplatin
Carboplatin was provided as commercially available drug.
DRUGGemcitabine
Gemcitabine was provided as commercially available drug.
DRUGBevacizumab
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.
DRUGPlacebo
Placebo consisted of the vehicle for bevacizumab without the antibody and contained sodium phosphate, trehalose, polysorbate 20, and Sterile Water for Injection, USP.
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| Percentage of Patients Who Had at Least 1 Adverse Event | From randomization through July 19, 2013 (up to 6 years, 3 months) | — |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 242 |
| 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. | 242 |
| Total | 484 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Blinded Treatment Phase | Adverse Event | 12 | 58 |
| Blinded Treatment Phase | Clinical Disease Progression | 4 | 5 |
| Blinded Treatment Phase | Did not Receive Treatment | 4 | 1 |
| Blinded Treatment Phase | Disease Progression Per RECIST | 168 | 109 |
| Blinded Treatment Phase | Physician Decision | 19 | 27 |
| Blinded Treatment Phase | Sponsor's Decision To Terminate Study | 3 | 0 |
| Blinded Treatment Phase | Subject's Decision-Discontinue Treatment | 32 | 29 |
| Open-label Treatment Phase | Adverse Event | 0 | 5 |
| Open-label Treatment Phase | Disease Progression Per RECIST | 0 | 6 |
Baseline characteristics
| Characteristic | Carboplatin and Gemcitabine + Placebo | Carboplatin and Gemcitabine + Bevacizumab | Total |
|---|---|---|---|
| Age, Continuous | 61.6 years STANDARD_DEVIATION 10.2 | 60.5 years STANDARD_DEVIATION 9.8 | 61.0 years STANDARD_DEVIATION 10 |
| Sex: Female, Male Female | 242 Participants | 242 Participants | 484 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 246 / 247 | 233 / 233 |
| serious Total, serious adverse events | 90 / 247 | 59 / 233 |
Outcome results
Primary
Progression Free Survival (PFS) as Determined by the Investigator, Per Response Evaluation Criteria for Solid Tumors (RECIST)
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)
Population: Intent-to-treat population: All patients randomized to treatment (242 patients in each treatment group).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carboplatin and Gemcitabine + Bevacizumab | Progression Free Survival (PFS) as Determined by the Investigator, Per Response Evaluation Criteria for Solid Tumors (RECIST) | 12.4 Months |
| Carboplatin and Gemcitabine + Placebo | Progression Free Survival (PFS) as Determined by the Investigator, Per Response Evaluation Criteria for Solid Tumors (RECIST) | 8.4 Months |
Comparison: 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.p-value: <0.000195% CI: [0.388, 0.605]Log Rank
Secondary
Duration of Objective Response (OR) as Determined by the Investigator, Per Response Evaluation Criteria for Solid Tumors (RECIST)
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)
Population: Subset of the intent-to-treat population: All patients randomized to treatment who achieved an objective response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carboplatin and Gemcitabine + Bevacizumab | Duration of Objective Response (OR) as Determined by the Investigator, Per Response Evaluation Criteria for Solid Tumors (RECIST) | 10.4 Months |
| Carboplatin and Gemcitabine + Placebo | Duration of Objective Response (OR) as Determined by the Investigator, Per Response Evaluation Criteria for Solid Tumors (RECIST) | 7.4 Months |
Secondary
Overall Survival
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)
Population: Intent-to-treat population: All patients randomized to treatment (242 patients in each treatment group).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carboplatin and Gemcitabine + Bevacizumab | Overall Survival | 33.6 Months |
| Carboplatin and Gemcitabine + Placebo | Overall Survival | 32.9 Months |
p-value: 0.647995% CI: [0.771, 1.176]Log Rank
Secondary
Percentage of Patients Who Had a Gastrointestinal Perforation (GIP)
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)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Carboplatin and Gemcitabine + Bevacizumab | Percentage of Patients Who Had a Gastrointestinal Perforation (GIP) | 0 Percentage of participants |
| Carboplatin and Gemcitabine + Placebo | Percentage of Patients Who Had a Gastrointestinal Perforation (GIP) | 0 Percentage of participants |
Secondary
Percentage of Patients Who Had at Least 1 Adverse Event
Time frame: From randomization through July 19, 2013 (up to 6 years, 3 months)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Carboplatin and Gemcitabine + Bevacizumab | Percentage of Patients Who Had at Least 1 Adverse Event | 100.0 Percentage of participants |
| Carboplatin and Gemcitabine + Placebo | Percentage of Patients Who Had at Least 1 Adverse Event | 100.0 Percentage of participants |
Secondary
Percentage of Patients With an Objective Response as Determined by the Investigator, Per Response Evaluation Criteria for Solid Tumors (RECIST)
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)
Population: Intent-to-treat population: All patients randomized to treatment (242 patients in each treatment group).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carboplatin and Gemcitabine + Bevacizumab | Percentage of Patients With an Objective Response as Determined by the Investigator, Per Response Evaluation Criteria for Solid Tumors (RECIST) | 78.5 Percentage of participants |
| Carboplatin and Gemcitabine + Placebo | Percentage of Patients With an Objective Response as Determined by the Investigator, Per Response Evaluation Criteria for Solid Tumors (RECIST) | 57.4 Percentage of participants |
Comparison: 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.p-value: <0.000195% CI: [13, 29.2]Cochran-Mantel-Haenszel