Study Title

A Phase III Trial of Carboplatin and Paclitaxel Plus Placebo Versus Carboplatin and Paclitaxel Plus Concurrent Bevacizumab (NSC #704865, IND #7921) Followed by Placebo, Versus Carboplatin and Paclitaxel Plus Concurrent and Extended Bevacizumab, in Women with Newly Diagnosed, Previously Untreated, Suboptimal Advanced Stage Epithelial Ovarian and Primary Peritoneal Cancer

Study Objectives

• To determine if the addition of 5 concurrent cycles of Bevacizumab to 6 cycles of standard therapy (carboplatin and paclitaxel) [Arm II] reduces the death rate when compared to 6 cycles of standard therapy alone [Arm I] in women with newly diagnosed suboptimal advanced epithelial ovarian and peritoneal primary cancer.
• To determine if the addition of 5 concurrent cycles plus extended Bevacizumab for 15 months total treatment time to 6 cycles of standard therapy (carboplatin and paclitaxel) [Arm III] reduces the death rate when compared to 6 cycles of standard therapy [Arm I] in women with newly diagnosed suboptimal advanced epithelial ovarian and peritoneal primary cancer.
• To determine whether the Arm III regimen reduces the death rate when compared to the Arm II regimen if both Arm II and Arm III regimens are superior to the Arm I regimen with respect to overall survival
• To determine whether the Arm II or Arm III regimen increases the duration of progression-free survival (PFS) when compared with the Arm I regimen.
• To compare each of the experimental regimens to the Arm I regimen with respect to the incidence of severe toxicities or serious adverse events.
• To determine the impact on Quality of Life (QOL, as measured by the FACT-O TOI) following treatment with the above regimens.
• To assess the relationship between angiogenic markers and clinical outcome including tumor response, progression-free survival and overall survival in patients randomized to standard cytotoxic chemotherapy (paclitaxel and carboplatin) without Bevacizumab, with concurrent Bevacizumab or with extended Bevacizumab.
• To assess the predictive value of a set of genes whose expression correlates with survival of patients with advanced stage suboptimal epithelial ovarian or peritoneal primary cancer.

Study Requirements

Patients will be randomized to receive one of three arms of therapy:

• Arm I (standard chemotherapy) is chemotherapy* every 21 days for 6 cycles followed by placebo (for Bevacizumab) every 21 days for 15 months (for a total of 22 cycles)
• Arm II (concurrent Bevacizumab) is chemotherapy* every 21 days for 6 cycles and Bevacizumab every 21 days for 5 cycles beginning with cycle 2 followed by placebo (for Bevacizumab) every 21 days for 15 months (for a total of 22 cycles)
• Arm III (extended Bevacizumab) is chemotherapy* every 21 days for 6 cycles and Bevacizumab every 21 days for 5 cycles beginning with cycle 2 followed by Bevacizumab every 21 days for 15 months (for a total of 22 cycles)

* The chemotherapy consists of Paclitaxel followed by Carboplatin.  Quality of Life assessments will be made Prior to cycles 1, 4, 7, 13, 21, and 6 months after completion of the study.

Inclusion Criteria

• Patients with a histologic diagnosis of epithelial ovarian cancer or peritoneal primary carcinoma, FIGO states III or IV with suboptimal residual disease following initial surgery.
• Patients with the following histologic epithelial cell types are eligible: serous adenocarcinoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, transitional cell carcinoma, malignant Brenner’s Tumor, or adenocarcinoma not otherwise specified.
• Patients must have adequate:
• bone marrow function with ANC ³ 1,500/microliter
• platelets, ³ 100,000/microliter
• renal function with creatinine £ 1.5 X institutional upper limit normal
• hepatic function with bilirubin £ 1.5 X ULN and SGOT and alkaline phosphatase £ 2.5 X ULN
• neurologic function with neuropathy £ CTCAE Grade 1
• blood coagulation parameters
• GOG Performance Status of 0, 1, or 2
• Patients must be entered between 1 and 12 weeks after initial surgery performed for diagnosis, staging and cytoreduction
• Patients with measurable and non-measurable disease are eligible.

Exclusion Criteria

• Patients with a current diagnosis of borderline epithelial ovarian tumor or recurrent invasive epithelial ovarian cancer treated with surgery only (Stage IA or IB low grade lesions)
• Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis
• Patients who have received prior chemotherapy for any abdominal or pelvic tumor
• Patients who have received any targeted therapy (including but not limited to vaccines, antibodies, tyrosine kinase inhibitors) or hormonal therapy for management of their ovarian, peritoneal primary or fallopian tube carcinoma
• Patients with synchronous primary endometrial cancer or a past history of primary endometrial cancer unless certain criteria are met
• Patients with invasive malignancies who have had any evidence of that cancer within the last five years
• Patients with acute hepatitis or active infection that requires parenteral antibiotics
• Patients with a non-healing wound, ulcer or bone fracture
• Patients with active bleeding or pathologic conditions that carry high risk of bleeding
• Patients with CNS disease including brain tumor, uncontrolled seizures, brain metastases or history of cerebrovascular accident, transient ischemic attack, or subarrachnoid hemorrhage within six months of first study treatment
• Patients with clinically significant cardiovascular disease including:
• Uncontrolled hypertension with systolic ³ 150/90 mm Hg
• Myocardial infarction or unstable angina < 6 months prior to registration
• Grade II or greater congestive heart failure
• Serious cardiac arrhythmia requiring medication
• CTCAE Grade 2 or greater peripheral vascular disease
• History of CVA within six months
• Patients known to be sensitive to Chinese hamster ovary cell products or other recombinant human or humanized antibodies
• Patients with clinically significant proteinuria
• Patients with anticipation of major surgical procedures within 28 days of beginning the study or during the course of the study
• Patients with GOG Performance Grade 3 or 4
• Patients who are pregnant or nursing
• Patients under the age of 18
• Patients who have received prior therapy with any anti-VEGF drug, including Bevacizumab