Aghajanian, et al DOI: /JCO

Transcription

1 The following protocol information is provided solely to describe how the authors conducted the research underlying the published report associated with the following article: OCEANS: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Chemotherapy With or Without Bevacizumab in Patients With Platinum-Sensitive Recurrent Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer Aghajanian, et al DOI: /JCO The information provided may not reflect the complete protocol or any previous amendments or modifications. As described in the Information for Contributors ( only specific elements of the most recent version of the protocol are requested by JCO. The protocol information is not intended to replace good clinical judgment in selecting appropriate therapy and in determining drug doses, schedules, and dose modifications. The treating physician or other health care provider is responsible for determining the best treatment for the patient. ASCO and JCO assume no responsibility for any injury or damage to persons or property arising out of the use of these protocol materials or due to any errors or omissions. Individuals seeking additional information about the protocol are encouraged to consult with the corresponding author directly. 1

2 REDACTED PROTOCOL 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 PROTOCOL NUMBER: STUDY DRUG: AVF4095g Bevacizumab IND: BB-IND 7023 SPONSOR: Genentech, Inc. 1 DNA Way South San Francisco, CA U.S.A. 2

3 TABLE OF CONTENTS I. SELECTION OF PATIENTS, INCLUDING BOTH ELIGIBILITY AND INELIGIBILITY CRITERIA Page 3 II. SCHEMA AND TREATMENT PLAN, INCLUDING ADMINISTRATION SCHEDULE 8 III. RULES FOR DOSE MODIFICATION 14 IV. MEASUREMENT OF TREATMENT EFFECT INCLUDING RESPONSE CRITERIA, DEFINITION OF RESPONSE AND SURVIVAL, AND METHODS OF MEASUREMENT 23 V. REASONS FOR EARLY CESSATION OF TRIAL THERAPY 25 VI. OBJECTIVES AND ENTIRE STATISTICAL SECTION (INCLUDING ENDPOINTS) 27 3

4 I. SELECTION OF PATIENTS, INCLUDING BOTH ELIGIBILITY AND INELIGIBILITY CRITERIA 1. MATERIALS AND METHODS 1.1 PATIENTS PATIENT SELECTION Patients with epithelial carcinoma of the ovary, PPC, or fallopian tube carcinoma that has recurred 6 months since platinum-based chemotherapy (first recurrence) will be eligible for this study. Additional specific inclusion and exclusion criteria are listed below INCLUSION CRITERIA Patients must meet the following criteria to be eligible for study entry: Signed Informed Consent Form Age 18 years Histologically documented ovarian, primary peritoneal, or fallopian tube carcinoma that has recurred 6 months after platinum-based chemotherapy The patient must have recurrent epithelial ovarian, primary peritoneal, or fallopian tube carcinoma. This must be the first recurrence of epithelial ovarian, primary peritoneal, or fallopian tube carcinoma. Examples of eligible histological cell types include: serous adenocarcinoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, transitional cell carcinoma, malignant Brenner s Tumor, or adenocarcinoma not otherwise specified No prior chemotherapy in the recurrent setting 4

5 Measurable disease according to modified RECIST with at least one lesion that can be accurately measured in at least one dimension (longest dimension recorded) Each measurable lesion must be 20 mm when measured by conventional techniques, CT and magnetic resonance imaging (MRI), or 10 mm when measured by spiral CT Greater than 28 days from and recovered from prior radiation therapy or surgery ECOG performance status 0 or 1 Use of an effective means of contraception (for women of childbearing potential) Ability to comply with study and follow-up procedures EXCLUSION CRITERIA Patients who meet any of the following criteria will be excluded from study entry. a. Disease Treatment History Prior chemotherapy treatment for recurrent ovarian, primary peritoneal, or fallopian tube carcinoma Hormonal therapy (i.e., progesterones, estrogens, anti-estrogens, aromatase inhibitors) will not be considered a prior chemotherapy regimen. Concomitant anti-neoplastic anti-hormonal therapy (including tamoxifen, aromatase inhibitors, etc.) is not allowed for patients participating in study treatment. Low-dose (physiologic) estrogen hormone-replacement therapy (HRT) may be given. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess Patients with clinical symptoms or signs of 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 5

6 b. General Medical Exclusions Life expectancy of 12 weeks Current, recent (within 4 weeks of Day 1, Cycle 1), or planned participation in an experimental drug study Screening clinical laboratory values o Granulocyte count 1500/µL o Platelet count 100,000/µL o Hemoglobin 8.5 g/dl (hemoglobin may be supported by transfusion or erythropoietin or other approved hematopoietic growth factors) o Serum bilirubin 2.0 upper limit of normal (ULN) o Alkaline phosphatase, aspartate transaminase (AST), and/or alanine transaminase (ALT) 2.5 ULN (AST, ALT 5 ULN for patients with liver metastasis) o Serum creatinine 1.6 mg/dl o International normalized ratio (INR) 1.5 and/or activated partial thromboplastin time (aptt) 1.5 ULN (except for patients receiving anticoagulation therapy) o For patients on full-dose warfarin, in-range INR (usually between 2 and 3) and a PTT <1.2 times the ULN History of other malignancies within 5 years of Day 1, Cycle 1, except for tumors with a negligible risk for metastasis or death, such as adequately controlled basal-cell carcinoma or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk for treatment complications 6

7 c. Bevacizumab-Specific Exclusions History of systemic bevacizumab (Avastin ) or other VEGF or VEGF receptor-targeted agent use Inadequately controlled hypertension (defined as systolic blood pressure 150 mmhg and/or diastolic blood pressure 100 mmhg on antihypertensive medications) Prior history of hypertensive crisis or hypertensive encephalopathy New York Heart Association Class II or greater CHF History of myocardial infarction or unstable angina within 6 months prior to Day 1, Cycle 1 (day of the first bevacizumab/placebo infusion) History of stroke or TIA within 6 months prior to study enrollment Known CNS disease except for treated brain metastasis o Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. These metastases must not be located in the brainstem, midbrain, pons, medulla, or leptomeninges. Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will be excluded. History of significant vascular disease (e.g., aortic aneurysm, aortic dissection) Recent peripheral arterial thrombosis within 6 months prior to Day 1, Cycle 1 History of hemoptysis ( 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1, Cycle 1 Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation) 7

8 Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1, Cycle 1 or anticipation of need for major surgical procedure during the course of the study Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1, Cycle 1 Serious, non-healing wound; active ulcer; or untreated bone fracture Proteinuria at screening, as demonstrated by a UPCR of 1.0 at screening Known hypersensitivity to any component of bevacizumab Pregnancy (positive pregnancy test) or lactation Patients of childbearing potential must use an effective means of contraception. 8

9 II. SCHEMA AND TREATMENT PLAN, INCLUDING ADMINISTRATION SCHEDULE 2. STUDY DESIGN 2.1 Description Of The Study This is a placebo-controlled, randomized, multicenter Phase III study evaluating the efficacy and safety of bevacizumab (15 mg/kg, Day 1, every 21 days), administered in combination with carboplatin (area under the curve [AUC] 4, Day 1, every 21 days) with gemcitabine (1000 mg/m 2, Day 1 and Day 8, every 21 days) in women with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube carcinoma. Approximately 480 patients will be enrolled over a period of approximately 2.5 years. Patients who meet the eligibility criteria and consent to participate will be randomized 1:1 to carboplatin and gemcitabine placebo versus carboplatin and gemcitabine bevacizumab. At randomization, patients will be stratified by platinum-sensitive disease (recurrence 6 12 months from last platinum-based treatment vs. recurrence 12 months from last platinum-based treatment) and cytoreductive surgery for recurrent epithelial ovarian, primary peritoneal, or fallopian tube carcinomas (surgery was performed vs. was not performed). Patients receive carboplatin and gemcitabine for 6 cycles (up to 10 cycles if deemed necessary by the investigator and approved by the Sponsor) with study drug (bevacizumab or placebo). The patient then continues single-agent study drug (bevacizumab or placebo) until unacceptable toxicity or progression of disease. Upon unblinding, patients receiving bevacizumab who are still on treatment may continue to receive bevacizumab on open-label treatment. 9

10 Patients who require discontinuation of either carboplatin or gemcitabine due to toxicity should continue receiving study drug with the non-discontinued chemotherapy to complete 6 cycles (7 10 cycles if deemed necessary by the investigator and approved by the Sponsor). Patients requiring discontinuation of both carboplatin and gemcitabine prior to disease progression should continue single-agent study drug until disease progression or unacceptable toxicity, as determined by the investigator. In the event that a patient requires discontinuation of study drug (bevacizumab or placebo) due to toxicity prior to completion of the chemotherapy phase, the patient may continue with the chemotherapy (gemcitabine, carboplatin) to complete 6 cycles (up to 10 cycles if deemed necessary by the investigator and approved by the Sponsor) in the treatment phase of the study. All study assessments required during the treatment phase should be followed. Such patients will enter the follow-up phase and continue tumor assessments once the chemotherapy is completed. Patients who discontinue treatment (carboplatin and gemcitabine study drug) for reasons other than disease progression should continue to have tumor assessments every 9 weeks until progression. Scan collection is on a 9-week schedule from C1 D1, regardless of whether Patient prematurely discontinues bevacizumab/placebo for reasons other than progression There is a delay in treatment due to toxicity; One scheduled scan is delayed; the subsequent scan should be performed on the original 9-week schedule. If an unscheduled scan is performed off the 9-week schedule, the subsequent scan should be performed on the original 9-week schedule. 10

11 While on the treatment phase of the study, patients receiving placebo are not allowed to cross over to receive bevacizumab. Furthermore, patients who discontinue placebo treatment prior to progression of disease should not cross-over to receive bevacizumab prior to progression. Patients may be unblinded to treatment assignment at the time of disease progression (investigator determined), at the request of the investigator, or after the final analysis of PFS has occurred. In cases where progression is determined clinically (i.e., not radiographic), a rise in CA 125 alone will not be sufficient as the basis for progression. Additional signs and symptoms of clinical progression will be required. Patients will be followed for adverse events for 30 days after study treatment discontinuation. Patients will be followed for survival every 3 months, until death, withdrawal of consent, loss to follow-up, or study termination. Measurable disease will be investigator assessed using modified RECIST (Therasse et al. 2000). Response will be assessed according to modified RECIST every 9 weeks throughout the course of the study. Responses will be confirmed at least 4 weeks after the initial documentation of response. If the primary endpoint of the study is met (i.e., an improvement in PFS when bevacizumab is added to chemotherapy accompanied by a positive benefit-risk profile), an open-label bevacizumab phase will be available but limited to patients randomized to the chemotherapy plus bevacizumab arm who are still receiving treatment at the time of study unblinding. Patients who choose to participate in the open-label treatment phase will continue to receive bevacizumab per their previous treatment schedule in the prior blinded phase of the study and will also continue with specified study assessments. From the time of study unblinding, all eligible patients will have 120 days to transition from blinded to open-label treatment. 11

12 Patients randomized to the chemotherapy plus placebo arm will be discontinued from study treatment at the time of unblinding. No additional protocol therapy will be offered to these patients. All study patients, regardless of what arm of the study they were on at the time of unblinding, will continue to be followed for survival every 3 months until death, withdrawal of consent, loss to follow-up or completion of the study by Genentech, Inc, Figure 1 Study Schema R A N D O M I Z E n 480 Carboplatin: AUC 4, d1, q 21d Gemcitabine: 1000 mg/m 2, d1, d8, q 21d Carboplatin: AUC 4, d1, q 21d Gemcitabine: 1000 mg/m 2, d1, d8, q 21d Bevacizumab 15 mg/kg q 21d to PD or unacceptable Placebo q 21d to PD or unacceptable AUC area under the concentration time curve; d day; IV intravenous; PD progressive disease DOSAGE AND ADMINISTRATION Premedications (anti-emetics, hydration, antihistamines, corticosteroids, etc.), dosage, and administration for chemotherapy should be according to institutional standards and the respective product package insert(s), when applicable. a. Study Drug (Bevacizumab/Placebo) The dose of bevacizumab in this study is 15 mg/kg administered by intravenous (IV) 12

13 infusion on the first day of Week 1, every-3-week (21-day) cycle; the interval between infusions must not be 15 days from Day 1 of the previous cycle. The bevacizumab dose will be based on the patient s weight at baseline, within 28 days of Day 1, and will remain the same throughout the study. It is not necessary to correct dosing on the basis of ideal weight. If a cycle of chemotherapy is delayed, bevacizumab may also be delayed to allow same-day administration of chemotherapy and bevacizumab. The initial dose will be delivered over minutes. If the first infusion is tolerated without infusion-associated adverse events (fever and/or chills), the second infusion may be delivered over minutes. If the 60-minute infusion is well tolerated, all subsequent infusions may be delivered over minutes. If a patient experiences an infusion-associated adverse event, he or she may be premedicated for the next bevacizumab infusion; however, the infusion time may not be decreased for the subsequent infusion. If the next infusion is well tolerated with premedication, the subsequent infusion time may then be decreased by minutes as long as the patient continues to be premedicated. If a patient experiences an infusion-associated adverse event with the 60-minute infusion, all subsequent doses should be given over minutes. Similarly, if a patient experiences an infusion-associated adverse event with the 30-minute infusion, all subsequent doses should be given over minutes. Study drug (bevacizumab or placebo) continues as a single agent in the maintenance phase until disease progression or unacceptable toxicity occurs, as determined by the investigator. Patient may be unblinded to treatment assignment at the time of investigator-determined disease progression. b. Open-Label Bevacizumab Phase For patients who transition to receiving bevacizumab in the open-label phase of the study, the dose and schedule of bevacizumab will be maintained per the prior 13

14 blinded treatment phase. Open-label bevacizumab may be continued until disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, or death, or to a maximum of 24 months post-unblinding, whichever occurs first. c. Carboplatin and Gemcitabine Premedications (anti-emetics, hydration, antihistamines, corticosteroids, etc.), dosage, and administration for chemotherapy should be according to institutional standards and the respective product package insert(s), when applicable. The carboplatin dose will be calculated to reach a target AUC of concentration time according to the Calvert formula with use of an estimated glomerular filtration rate (GFR); for the purposes of this protocol, the GFR is considered to be equivalent to the creatinine clearance. Calvert Formula for Carboplatin (AUC) Dosing total dose (mg) target AUC (in mg/ml/minute) [GFR (in ml/minute) + 25] Creatinine clearance can be calculated according to institutional guidelines. In the example below, the Jelliffe formula is used to calculate estimated Ccr. Ccr 0.9 x Where: Ccr creatinine clearance in ml/min Age patient's age in years (from 20 80) Scr serum creatinine in mg/dl {98 - [0.8 (age - 20)]} Scr 14

15 III. On the day that study drug and carboplatin and gemcitabine are given together, study drug should be dosed prior to carboplatin and gemcitabine. RULES FOR DOSE MODIFICATION 3. DOSAGE MODIFICATION a. Study Drug (Bevacizumab/Placebo) No reductions in study drug dose are allowed in this study. Criteria for treatment modification and guidelines for the management of toxicities are summarized in Table 1. If adverse events occur that necessitate holding study drug, the dose will remain unchanged once treatment resumes. Any toxicities associated or possibly associated with study-drug treatment should be managed according to standard medical practice. Discontinuation of bevacizumab will have no immediate therapeutic effect. Bevacizumab has a terminal half-life of approximately 21 days; therefore, its discontinuation results in slow elimination over several months. There is no available antidote for bevacizumab. Patients should be assessed clinically for toxicity prior to, during, and after each infusion. If unmanageable toxicity due to study drug occurs at any time during the study, treatment with study drug should be discontinued. In the event that a patient requires discontinuation of study drug (bevacizumab or placebo) due to toxicity prior to completion of the chemotherapy phase, the patient may continue with chemotherapy (gemcitabine/carboplatin) to complete 6 cycles (up to 10 cycles if deemed necessary by the investigator and approved by the Sponsor) in the treatment phase of the study. If study drug is held for more than 6 weeks, during the maintenance phase, the patient should be discontinued. (6 weeks is counted from the date of last dose of study drug administration). Infusion Reaction 15

16 Infusion of study drug should be interrupted in patients who develop dyspnea or clinically significant hypotension. Patients who experience an NCI CTCAE Grade 3 or 4 allergic reaction/hypersensitivity, adult respiratory distress syndrome, or drug-related bronchospasm (regardless of grade) will be discontinued from study drug treatment. The infusion should be slowed to 50% or interrupted for patients who experience any infusion-associated symptoms not specified above. When the patient s symptoms have completely resolved, the infusion may be continued at 50% of the rate prior to the reaction and increased in 50% increments every 30 minutes if well tolerated. Infusions may be restarted at the full rate during the next cycle. 16

17 Table 1 Study Drug Dose Management Due to Adverse Events (NCI CTC Version 3.0) Event Action to be Taken Hypertension Grade 1 or 2 No study drug dose modifications. Grade 3 If not controlled to 150/100 mmhg with medication, discontinue study drug. Grade 4 Discontinue study drug. (including hypertensive encephalopathy) Hemorrhage Grade 1 or 2 non-pulmonary and No study drug dose modifications. non-cns events Grade 3 non-pulmonary and non- Patients who are also receiving full-dose CNS hemorrhage anticoagulation will be discontinued from receiving study drug. All other patients will have study drug held until all of the following criteria are met: The bleeding has been resolved and hemoglobin is stable. There is no bleeding diathesis that would increase the risk of therapy. There is no anatomic or pathologic condition that significantly increases the risk of hemorrhage recurrence. Patients who experience a repeat Grade 3 hemorrhagic event will be discontinued from receiving study drug. Grade 4 non-pulmonary and non- Discontinue study drug. CNS hemorrhage 17

18 Grade 1 pulmonary or CNS Patients who are also receiving full-dose hemorrhage anticoagulation will be discontinued from receiving study drug. All other patients will have study drug held until all of the following criteria are met: The bleeding has resolved and hemoglobin is stable. There is no bleeding diathesis that would increase the risk of therapy. There is no anatomic or pathologic condition that significantly increases the risk of hemorrhage recurrence. Grades 2, 3, or 4 pulmonary or CNS Discontinue study drug. hemorrhage CNS central nervous system; CTC Common Toxicity Criteria; GI gastrointestinal; INR international normalized ratio; MRI magnetic resonance imaging; NCI National Cancer Institute; UPCR urine:protein creatinine ratio. 18

19 Table 1 (cont d) Study Drug Dose Management Due to Adverse Events (NCI CTC Version 3.0) Event Action to be Taken Venous Thrombosis Grade 1 or 2 No study drug dose modifications. Grade 3 or Hold study drug treatment. If the planned duration of asymptomatic Grade 4 full-dose anticoagulation is 2 weeks, study drug should be held until the full-dose anticoagulation period is over. If the planned duration of full-dose anticoagulation is 2 weeks, study drug may be resumed during the period of full-dose anticoagulation if all of the following criteria are met: The patient must have an in-range INR (usually between 2 and 3) if on warfarin; LMWH, coumadin, or other anticoagulant dosing must be stable prior to restarting study drug treatment. The patient must not have had a Grade 3 or 4 hemorrhagic event while on anticoagulation. Symptomatic Grade 4 Discontinue study drug. Arterial Thromboembolic Event (new onset, worsening, or unstable angina; myocardial infarction; transient ischemic attack; cerebrovascular accident; and any other arterial thromboembolic event) Any grade Discontinue study drug. Congestive Heart Failure (left ventricular systolic dysfunction) Grade 1 or 2 No study drug dose modifications. Grade 3 Hold study drug until resolution to Grade 1. Grade 4 Discontinue study drug. Proteinuria Grade 1 or 2 No study drug dose modifications. Grade 3 Hold study drug treatment until Grade 2, (UPCR 3.5, urine collection 3.5 g/24 as determined by either UPCR 3.5 or 24-hr hr) collection 3.5 g. Grade 4 Discontinue study drug. (nephrotic syndrome) 19

20 GI Perforation Unexplainable Grade 1 (excluding Discontinue study drug. evidence of abdominal free air attributable to other causes such as paracentesis or recent surgical procedure) or Grade 2 and above (including intra-abdominal abscess or GI fistula) CNS central nervous system; CTC Common Toxicity Criteria; GI gastrointestinal; INR international normalized ratio; MRI magnetic resonance imaging; NCI National Cancer Institute; UPCR urine:protein creatinine ratio. 20

21 Table 1 (cont d) Study Drug Dose Management Due to Adverse Events (NCI CTC Version 3.0) Event Action to be Taken Bowel Obstruction Grade 1 Continue patient on study for partial obstruction not requiring medical intervention. Grade 2 Hold study drug for partial obstruction requiring medical intervention. Patient may restart upon complete resolution. Grade 3 or 4 Hold study drug for complete obstruction. If surgery is necessary, patient may restart study drug after full recovery from surgery, and at investigator s discretion. Wound Dehiscence Any grade Discontinue study drug. (requiring medical or surgical therapy) Reversible Posterior Leukoencephalopathy Any grade Discontinue study drug. (confirmed by MRI) Other Unspecified Study Drug-Related Adverse Events Grade 3 Hold study drug until recovery to Grade 1 Grade 4 Discontinue study drug. CNS central nervous system; CTC Common Toxicity Criteria; GI gastrointestinal; INR international normalized ratio; MRI magnetic resonance imaging; NCI National Cancer Institute; UPCR urine:protein creatinine ratio. b. Carboplatin and Gemcitabine (Day 1) Carboplatin and gemcitabine dosing on Day 1 of each cycle should be held if ANC is <1500/µL, Hgb is <8.5 g/dl, or platelets are <100,000/µL within 24 hours of the scheduled treatment. The chemotherapy can be delayed for a maximum of 3 weeks until these values are achieved. Patients who fail to recover adequate 21

22 counts (with or without growth factors) within the 3 weeks will no longer receive protocol-defined chemotherapy but will enter into the maintenance phase to receive the study drug (bevacizumab or placebo) alone. Study drug can be held for up to 3 weeks if carboplatin and gemcitabine are held in order to allow for same-day administration of carboplatin and gemcitabine and study drug. Dose adjustment for gemcitabine in combination with carboplatin for subsequent cycles is based on toxicity observed during the preceding cycle. The dose of gemcitabine should be permanently reduced to the 800 mg/m 2 on Days 1 and 8, in case of any of the following hematologic toxicities: Absolute granulocyte count <500 x 10 6 /L for more than 5 days Absolute granulocyte count <100 x 10 6 /L for more than 3 days Febrile neutropenia Platelets <25,000 x 10 6 /L Cycle delay of more than one week due to toxicity If any of the above toxicities recur after the initial dose reduction for the subsequent cycles, gemcitabine should be given only on day 1 at 800 mg/m 2 (omit gemcitabine on Day 8). c. Gemcitabine Dose Modification within a Treatment Cycle (Day 8) Gemcitabine dosage adjustments for hematologic toxicity within a cycle of treatment is based on the granulocyte and platelet counts taken on Day 8 of therapy, as shown in Table 2. Table 2 Day 8, Gemcitabine Dose Modification for Hematological Toxicity Absolute granulocyte count (/mm 3 ) Platelet count (/mm 3 ) Gemcitabine Dose 1500 and 100, % D1 dose and/or 75,000 99,999 50% D1 dose 1000 and/or <75,000 Omit D8 dose 22

23 If a patient experiences an HSR, platinum desensitization may be allowed after discussion with the Medical Monitor. For any other dose modifications for non-hematologic toxicity, please follow institutional practice and prescribing information. In general, for severe (Grade 3 or 4) non-hematological toxicities, except nausea/vomiting, therapy with gemcitabine should be held or decreased by 50% depending on the judgment of the treating physician. Patients who require discontinuation of either carboplatin or gemcitabine due to toxicity should continue receiving study drug with the non-discontinued chemotherapy to complete 6 cycles (7 10 cycles if deemed necessary by the investigator and approved by the Sponsor). Patients requiring discontinuation of both carboplatin and gemcitabine prior to disease progression should continue single-agent study drug until disease progression or unacceptable toxicity, as determined by the investigator. 23

24 IV. MEASUREMENT OF TREATMENT EFFECT INCLUDING RESPONSE CRITERIA, DEFINITION OF RESPONSE AND SURVIVAL, AND METHODS OF MEASUREMENT 4. OUTCOME MEASURES 4.1 Primary Efficacy Outcome Measure The primary efficacy outcome measure for this study is investigator-determined PFS, using modified RECIST. 4.2 Secondary Efficacy Outcome Measures Objective response (partial response [PR] or complete response [CR] as determined by the investigator, using modified RECIST) Overall survival Duration of objective response (as determined by the investigator, using modified RECIST) Incidence of all adverse events, graded according to the NCI-CTC, Version 3 Incidence of all serious adverse events Incidence of the following select adverse events (determined using NCI CTCAE, Version 3.0 grading): o Hypertension (Grade 3) o Proteinuria (Grade 3) o Arterial thromboembolic (TE) events (any grade) o Gastrointestinal perforation (any grade) o Wound dehiscence (Grade 3) o Pulmonary or central nervous system (CNS) bleeding (any grade) o Bleeding other than pulmonary or CNS bleeding (Grade 3) o Left ventricular systolic dysfunction (Grade 3) o Reversible posterior leukoencephalopathy syndrome (RPLS) (any grade) o Febrile neutropenia 24

25 4.3 Exploratory Outcome Measures The exploratory outcome measures are as follows: PFS, overall response, and duration of response, as determined by the IRC CA-125 tumor marker levels and their relation to treatment and tumor response as measured by the investigator using modified RECIST 25

26 V. REASONS FOR EARLY CESSATION OF TRIAL THERAPY 5. STUDY DRUG DISCONTINUATION Patients may withdraw or be removed from the treatment or open-label phase of the study at any time. Reasons for withdrawal may include, but are not limited to, the following (all references to severity grade pertain to the NCI CTCAE): Patients who meet any of the following criteria should be discontinued from study drug treatment (see Table 1): o Grade 4 hypertension or Grade 3 hypertension not controlled with medication o Pulmonary or CNS hemorrhage (Grade 2) or any other Grade 4 hemorrhage o Symptomatic Grade 4 venous thrombosis o Arterial TE event (any grade) o Grade 4 left ventricular systolic dysfunction o Nephrotic syndrome o Grade 1 unexplainable gastrointestinal perforation, including intra-abdominal abscess and fistula (excluding evidence of abdominal free air attributable to other causes such as paracentesis or recent surgical procedure) or Grade 2 and above gastrointestinal perforation (including intra-abdominal abscess or fistula) o Grade 2 bowel obstruction that has not fully recovered despite medical or surgical intervention o Wound dehiscence requiring medical or surgical intervention o RPLS (any grade) o Any Grade 4 event thought to be related to study drug by the investigator Study drug has been held for 6 weeks or more during the maintenance phase. (Six weeks is counted from the date of last dose of study drug administration). Determination by the investigator that it is no longer safe for the patient to continue therapy 26

27 Patient s request to withdraw from study treatment o All patients will be followed at 3-month intervals for survival information and any new cancer treatment, unless the patient s request to be withdrawn from study survival follow-up is documented in the source documents and signed by the investigator. Unwillingness or inability of the patient to comply with study requirements Clinical need for concomitant or ancillary therapy that is not permitted in the study Unrelated intercurrent illness that, in the judgment of the investigator, will affect assessments of clinical status to a significant degree Unacceptable toxicity Disease progression, based on modified RECIST, or clinical progression, based on a rising CA-125 AND clinical signs and symptoms It is the right and duty of the investigator to interrupt the treatment of any patient whose health or well-being may be threatened by continuation in this study. Such patients should be withdrawn from the treatment phase of the study rather than continue in the study under a modified regimen. 27

28 VI. OBJECTIVES AND ENTIRE STATISTICAL SECTION (INCLUDING ENDPOINTS) 6.1 OBJECTIVES Primary Objective The primary objective of this trial is to evaluate the efficacy of combining bevacizumab with carboplatin and gemcitabine compared with carboplatin and gemcitabine with placebo in patients with platinum-sensitive recurrent ovarian, primary peritoneal, or fallopian tube cancer. o The primary efficacy outcome measure is PFS, where the date of progression is based on investigator assessment using the modified Response Evaluation Criteria for Solid Tumors (RECIST) Secondary Objectives To evaluate the efficacy of bevacizumab as measured by: o Objective response as determined by the investigator using modified RECIST o Overall survival o Duration of objective response as determined by the investigator using modified RECIST To characterize the safety profile of bevacizumab in combination with carboplatin and gemcitabine in the study patients Exploratory Objectives PFS and objective response as determined by the Independent Review Committee (IRC), according to modified RECIST To characterize CA-125 tumor marker levels and their relation to tumor response and treatment as measured by modified RECIST To assess the effect of bevacizumab on ascites 28

29 6.2 STATISTICAL METHODS This study is a randomized, placebo-controlled trial designed to evaluate the efficacy and safety of bevacizumab in combination with carboplatin and gemcitabine in patients with platinum-sensitive EOC, PPC, or fallopian tube carcinoma. Descriptive summaries for continuous data will include the mean, standard deviation, median, minimum, and maximum. Descriptive summaries of discrete data will include the frequency and percentage of each category, as well as overall frequency and percentage totals. The intent-to-treat (ITT) population includes all randomized patients. The primary safety population will consist of all randomized patients who received at least one full or partial dose of any component of the study treatment Analysis of Study Conduct Study treatment administration, reasons for treatment discontinuation, and non-protocol therapies will be summarized by treatment arms for all randomized patients Analysis of Treatment Group Comparability Demographic variables (including age, ethnicity, and race) and baseline characteristics (including baseline Eastern Cooperative Oncology Group [ECOG] performance status, platinum-sensitive disease, cytoreductive surgery for recurrent disease, histopathological type and histologic subtype, baseline sum of the longest diameters [SLD] of all target lesions category, prior non-platinum chemotherapy, prior biologic therapy, prior myeloablative therapy, prior hormonal therapy) will be summarized by treatment arms for all randomized patients Efficacy Analyses 29

30 a. Primary Efficacy Endpoint PFS is defined as the time from randomization to disease progression as determined by the investigator, or death due to any cause, whichever occurs first. Data for patients without documented disease progression or death will be censored at the time of the last tumor assessment. For those patients who do not receive a post-randomization tumor assessment, the date of randomization plus one will be used as the censor date. PFS data for patients receiving non-protocol cancer therapy prior to documented disease progression will also be censored at the last tumor assessment prior to therapy initiation. The primary analysis of PFS will be a two-sided stratified log-rank test comparing the two treatment arms. The stratification factors will be time of recurrence since platinum-based chemotherapy (6 12 months, 12 months) and cytoreductive surgery for recurrent epithelial cell ovarian, primary peritoneal, or fallopian tube carcinomas (yes, no). Results from an unstratified log-rank test will also be evaluated. Kaplan Meier methodology will be used to estimate the PFS curves and median times in the treatment groups. A stratified Cox regression model will be used to estimate the stratified hazard ratio. The ITT population is used for the analysis of PFS. b. Secondary Efficacy Endpoints Secondary endpoints include: objective response based on the investigator assessment, duration of objective response based on the investigator assessment, and OS. Final analyses of objective response and duration of objective response as well as an interim analysis of OS will occur at the time of full PFS information. The final analysis of OS is planned when 353 deaths are observed. Objective response is defined as the occurrence of a complete or partial response (per modified RECIST), confirmed by a repeat assessment performed 4 weeks after the criteria for response are first met. Randomized patients not meeting these criteria, including patients without a post-baseline tumor assessment, will be considered non-responders in the analysis of objective response. 30

31 The study enrolls only patients with measurable disease at baseline; as a result, the ITT population is used for the analysis of objective response. Duration of overall survival is defined as the time from randomization until death by any cause. The ITT population is used for the analysis of overall survival. Duration of objective response will be analyzed for the subset of patients who achieved an objective response. The duration of objective response is defined as the time from the initial CR or PR until documented disease progression or death, which ever occurs first. c. Sensitivity and Exploratory Analyses Sensitivity Analyses To demonstrate robustness of the primary endpoint of investigator-determined PFS, a sensitivity analysis is planned using the IRC-determined PFS. For this analysis, PFS is defined as the time from randomization until disease progression as determined by the IRC or on-study death, whichever occurs first. On-study death is defined as death occurring within 9 weeks of the last dose of protocol approved chemotherapy or study drug. Details of other sensitivity analyses are included in the SAP. Exploratory Analyses Exploratory endpoints include objective response and duration of objective response, based on the IRC assessment. Methodology analogous to those used for the analyses of secondary endpoints will be used for the respective exploratory endpoints. Analyses exploring the impacts of demographic and baseline characteristics will also be provided Safety Analyses 31

32 All safety analyses will be based on the primary safety patient population, which is defined as all patients who received any amount of carboplatin, gemcitabine, or study drug. Safety will be assessed by summarizing the frequency of all adverse events. The following subsets of adverse events will also be summarized: serious adverse events, adverse events leading to study treatment discontinuation, and selected adverse events. Adverse events, graded by the NCI CTCAE, Version 3.0, will be coded using the most recent version of the Medical Dictionary for Regulatory Activities (MedDRA). The following selected adverse events will be summarized: Hypertension (Grade 3) Proteinuria (Grade 3) Neutropenia (Grade 4) Febrile neutropenia Thrombocytopenia (Grade 4) Arterial thromboembolic events (any grade) Gastrointestinal perforation (any grade) Wound dehiscence (Grade 3) Pulmonary or CNS bleeding (any grade) Bleeding other than pulmonary or CNS bleeding (Grade 3) Left ventricular systolic dysfunction (Grade 3) RPLS (any grade) Determination of Sample Size The sample size was calculated on the basis of the following assumptions: 80% power to reject the null hypothesis Two-sided test at 0.05 A hazard ratio of 0.73 Median PFS in the control group of 8.6 months 32

33 The sample size calculation was performed using the S-PLUS, seqtrial module versions 7.0 and On the basis of these assumptions, a total of 317 events will need to be observed at the time of the final analysis. On the basis of an enrollment rate of 20 patients per month, a ramp-up period of approximately 3 months, and an exponential drop-out rate of , Genentech estimated that a total of 480 patients are required to achieve this goal in an acceptable time frame. Complete enrollment is expected to occur after approximately 2.5 years, and full information of the primary endpoint is expected approximately 3.5 years after study initiation. The final analysis of OS is planned when 353 deaths are observed. If the experimental arm truly decreases the death rate by 21% (i.e., a hazard ratio of 0.79), with the assumption of a median OS of 18 months for the control arm and a target enrollment of 480 patients, the final OS analysis is expected to occur approximately 1.5 years after the final analysis of PFS Interim Analyses Safety data will be reviewed at regular intervals by an external DMC. An interim futility analysis is planned for the primary endpoint of investigator-determined PFS at approximately 50% of total information. Details of the futility analysis including the futility boundary are included in the SAP. There is no intention to stop the study for efficacy at this interim futility analysis. No alpha will be spent for conducting the futility analysis. An external DCC prepares unblinded data summaries for the DMC reviews. Details of the DMC and DCC operation are included in the DMC charter. 33

34 Note that an interim analysis of OS, a secondary endpoint, will occur at the time of final PFS analysis and an additional interim OS analysis will be undertaken at the time of approximately 214 events. 34