A Phase III Clinical Trial of Bevacizumab With IV Versus IP Chemotherapy in Ovarian, Fallopian Tube, and Primary Peritoneal Carcinoma NCI-Supplied Agent(s): Bevacizumab (NSC #704865, IND #7921)

Inclusion Criteria:

- Histologically confirmed ovarian epithelial, fallopian tube, or primary peritoneal
carcinoma, including any of the following epithelial cell types*:

- Serous adenocarcinoma

- Endometrioid adenocarcinoma

- Mucinous**adenocarcinoma

- Undifferentiated carcinoma

- Clear** cell adenocarcinoma

- Mixed epithelial carcinoma

- Transitional cell carcinoma

- Malignant Brenner tumor

- Adenocarcinoma not otherwise specified

- Stage II, III, or IV disease with either optimal (≤ 1 cm residual disease) or
suboptimal residual disease

- Must have undergone surgery for diagnosis, staging, and/or cytoreduction within the
past 12 weeks

- Prior or concurrent primary endometrial cancer allowed provided the primary origin of
the invasive tumor is ovarian or peritoneal and all of the following criteria are
met:

- Stage of endometrial cancer is ≤ IB

- No more than superficial myometrial invasion, without vascular or lymphatic
invasion

- No poorly differentiated subtypes, including papillary serous, clear cell, or
other FIGO grade 3 lesions

- No borderline ovarian epithelial tumor ("tumors of low malignant potential") (e.g.,
stage IA or IB disease with low-grade lesions)

- Patients with a prior diagnosis of a borderline tumor that was surgically
resected and who subsequently develop an unrelated, new invasive ovarian
epithelial or primary peritoneal cancer are eligible provided they have not
received prior chemotherapy for any ovarian tumor

- No recurrent invasive ovarian epithelial cancer treated with surgery only

- No history or evidence of major CNS disease by physical examination (e.g., primary
brain tumor, metastatic cancer in the brain, seizures not controlled with standard
medical therapy, or any brain metastases within the past 6 months

- No metastatic tumor in the parenchyma of the liver or lungs with proximity to large
vessels

- GOG performance status 0-2

- ANC ≥ 1,500/mm³ (without granulocyte colony-stimulating factor support)

- Platelet count ≥ 100,000/mm³

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST and ALT ≤ 2.5 times ULN

- Alkaline phosphatase ≤ 2.5 times ULN

- Creatinine normal

- Urine protein:creatinine ratio < 1.0

- PTT <1.5 times ULN

- Concurrent heparin, lovenox or alternative anticoagulants allowed

- PT/INR ≤ 1.5 times ULN (or an in-range INR, usually between 2 and 3, if patient is on
a stable dose of therapeutic warfarin)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for ≥ 6 months after
completion of study treatment

- No sensory or motor neuropathy > CTCAE grade 1

- No seizures not controlled with standard medical therapy

- No other invasive malignancies within the past 5 years, except nonmelanoma skin
cancer

- No acute hepatitis or active infection requiring parenteral antibiotics

- No serious non-healing wound, ulcer, or bone fracture

- Granulating incisions healing by secondary intention allowed provided there is
no evidence of fascial dehiscence or infection AND the wound is examined weekly
during study

- No clinical symptoms or signs of gastrointestinal obstruction and/or those who
require parenteral hydration and/or nutrition

- Patients with a history or current diagnosis of inflammatory bowel disease are
not eligible

- No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within
the past 28 days

- No active bleeding or pathologic condition that carries a high risk of bleeding
(e.g., known bleeding disorder, coagulopathy, or tumor involving major vessels)

- No cerebrovascular accident (stroke), transient ischemic attack, or subarachnoid
hemorrhage within the past 6 months

- No clinically significant cardiovascular disease, including any of the following:

- Uncontrolled hypertension, defined as systolic BP > 150 mmHg or diastolic BP >
90 mmHg

- Myocardial infarction or unstable angina within the past 6 months

- NYHA class II-IV congestive heart failure

- Serious cardiac arrhythmia requiring medication

- Asymptomatic atrial fibrillation with controlled ventricular rate or
history of supraventricular tachycardia controlled with medications and
asymptomatic allowed

- Peripheral vascular disease ≥ CTCAE grade 2 (at least brief [< 24 hrs] episodes
of ischemia managed non-surgically and without permanent deficit)

- No history or evidence of cerebrovascular accident (CVA, stroke), transient ischemic
attack, or subarachnoid hemorrhage within the past 6 months

- No known hypersensitivity to Chinese hamster ovary cell products or other recombinant
human or humanized antibodies

- No known allergy to Cremophor or polysorbate 80

- No significant traumatic injury within the past 28 days

- No other medical history or condition (e.g., persistent gastrointestinal symptoms
resulting from clostridia difficile enterocolitis or bowl surgery; or hearing loss or
neuropathy) that, in the opinion of the investigator, would preclude study
participation

- Concurrent ovarian estrogen (with or without progestin) replacement therapy for
control of menopausal symptoms allowed provided the lowest effective dose(s) is (are)
given

- No concurrent high-dose of progestins as an appetite stimulant

- No prior radiotherapy to any portion of the abdominal cavity or pelvis

- Prior radiotherapy for localized cancer of the breast, head and neck, or skin
allowed provided it was completed > 3 years ago AND patient remains free of
recurrent or metastatic disease

- No prior chemotherapy for any abdominal or pelvic tumor, including neoadjuvant
chemotherapy for ovarian or primary peritoneal cancer

- Prior adjuvant chemotherapy for localized breast cancer allowed provided it was
completed > 3 years ago AND patient remains free of recurrent or metastatic
disease

- No prior targeted therapy (including vaccines, antibodies, or tyrosine kinase
inhibitors) or hormonal therapy for management of ovarian epithelial or primary
peritoneal cancer

- No prior anti-VEGF therapy, including bevacizumab

- No prior cancer treatment that would contraindicate study treatment

- More than 7 days since prior core biopsy

- More than 28 days since prior major surgical procedure or open biopsy

- No concurrent major surgical procedure, including, but not limited to, abdominal
surgery (laparotomy or laparoscopy) before disease progression (e.g., colostomy or
enterostomy reversal, secondary cytoreductive surgery, or second-look surgery)

- No other concurrent anti-neoplastic therapy, including cytotoxic therapy, biologic
therapy, hormonal therapy, or radiotherapy

- No concurrent amifostine or other protective reagents