A Phase II Randomized, Double-Blinded Evaluation of Oral Everolimus (RAD001) Plus Bevacizumab vs. Oral Placebo Plus Bevacizumab in the Treatment of Recurrent or Persistent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Inclusion Criteria

DISEASE CHARACTERISTICS:

- Histologically confirmed ovarian epithelial, fallopian tube, or primary peritoneal
cancer

- Recurrent or persistent disease

- Meets 1 of the following criteria:

- Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1
dimension (longest dimension to be recorded) as ≥ 20 mm by chest x-ray OR as ≥
10 mm by spiral CT scan, MRI, or caliper measurement by clinical exam

- Must have ≥ 1 "target lesion" that can be used to assess response to study
treatment as defined by RECIST criteria

- Tumors within a previously irradiated field will be designated as
"non-target" lesions unless progression is documented or a biopsy is
obtained to confirm persistence ≥ 90 days following completion of
radiotherapy

- Lymph nodes must be ≥ 15 mm in short axis by CT scan or MRI

- Detectable disease, defined as non-measurable disease meeting ≥ 1 of the
following criteria:

- CA-125 ≥ 2 times upper limit of normal (ULN) at baseline

- Ascites and/or pleural effusion attributed to tumor

- Solid and/or cystic abnormalities on radiographic imaging that do not meet
RECIST criteria definitions for target lesions

- Must have received 1 prior platinum-based chemotherapeutic regimen that contained
carboplatin, cisplatin, or another organoplatinum compound for management of the
primary disease

- Initial treatment may have included intraperitoneal therapy, consolidation
therapy, non-cytotoxic therapy, or extended therapy administered after surgical
or non-surgical assessment

- Prior biologic (non-cytotoxic) therapy as part of the primary treatment regimen
allowed

- No prior non-cytotoxic therapy for management of recurrent or persistent
disease

- Two additional prior cytotoxic regimens for management of recurrent or
persistent disease allowed (≤ 1 non-platinum, non-taxane regimen allowed)

- Patients who have received only one prior cytotoxic regimen (i.e.,
platinum-based regimen for management of primary disease) must have a
platinum-free interval of < 12 months OR have progressed during platinum-based
therapy OR have persistent disease after platinum-based therapy

- Not eligible for a higher priority GOG clinical trial (i.e., any active phase III GOG
protocol or Rare Tumor protocol for the same patient population)

- No history or evidence of CNS disease by physical exam, including primary brain tumor
or brain metastases

PATIENT CHARACTERISTICS:

- GOG performance status (PS) 0-2 (for patients who have had 1 prior treatment)

- GOG PS 0-1 (for patients who have had 2 or 3 prior treatments)

- ANC ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Creatinine ≤ 1.5 times ULN

- Bilirubin ≤ 1.5 times ULN

- SGOT ≤ 3.0 times ULN

- Alkaline phosphatase ≤ 2.5 times ULN

- PT/INR ≤ 1.5 (or an in-range INR, usually between 2 and 3, if the patient is on a
stable dose of therapeutic warfarin for management of deep vein thrombosis, including
pulmonary embolism)

- PTT ≤ 1.5 times ULN

- Fasting serum cholesterol ≤ 300 mg/dL (or ≤ 7.75 mmol/L) AND fasting triglycerides ≤
300 mg/dL (or ≤ 3.42 mmol/L)

- Urine protein:creatinine ratio < 1.0

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No other invasive malignancies within the past 3 years except nonmelanoma skin cancer

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

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

- 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 allowed)

- Ejection fraction < 50% in patients who received prior treatment with an
anthracycline (including doxorubicin hydrochloride and/or liposomal doxorubicin
hydrochloride)

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

- Cerebrovascular accident or transient ischemic attack within the past 6 months

- No acute hepatitis or active infection requiring parenteral antibiotics (except for
uncomplicated urinary tract infection)

- No history or evidence of seizures not controlled with standard medical therapy

- No subarachnoid hemorrhage within the past 6 months

- 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 abdominal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess
within the past 28 days

- No clinical symptoms or signs of GI obstruction or requirement for parenteral
hydration and/or nutrition

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

- No known hypersensitivity to murine or chimeric antibodies

- No other medical history or condition that, in the opinion of the investigator, would
preclude study participation

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Recovered from prior surgery, radiotherapy, or chemotherapy

- No prior everolimus or any other mTOR inhibitor

- No prior cancer treatment that would contraindicate study therapy

- No prior radiotherapy to any portion of the abdominal cavity or pelvis other than for
the treatment of ovarian, fallopian tube, or primary peritoneal cancer within the
past 5 years

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

- No prior chemotherapy for any abdominal or pelvic tumor other than for the treatment
of ovarian, fallopian tube, or primary peritoneal cancer within the past 5 years

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

- For the purposes of this study, poly (ADP-ribose) polymerase (PARP) inhibitors will
be considered "cytotoxic," and prior treatment with PARP inhibitors for primary or
recurrent disease WILL be allowed (either alone or in combination with chemotherapy)

- At least 12 weeks since prior chimeric, human, or humanized monoclonal antibodies
(including bevacizumab) or VEGF receptor fusion protein (including aflibercept)

- More than 30 days since prior and no other concurrent investigational therapy

- More than 28 days since prior major surgery

- At least 3 weeks since any other prior therapy directed at the malignant tumor,
including biological or immunologic agents (small molecules or murine monoclonal
antibodies)

- At least 1 week since prior hormonal therapy directed at the malignant tumor

- No other concurrent anticancer agents

- No concurrent chronic treatment with systemic steroids or other immunosuppressive
agents

- Concurrent warfarin allowed for prophylaxis or treatment of thrombosis

- Concurrent low molecular weight heparin allowed provided PT/INR is ≤ 1.5

- Concurrent low-dose aspirin (≤ 325 mg/day) allowed for patients at a higher risk for
arterial thromboembolic disease