Bevacizumab With or Without Fosbretabulin Tromethamine in Patients With Recurrent or Persistent Ovarian Epithelial, Fallopian Tube, or Peritoneal Cavity Cancer

Inclusion Criteria:

• Patients must have recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma

  • Histologic documentation of the original primary tumor is required via the pathology report

• Patients must have measurable disease or detectable (non-measurable) disease:

  • Measurable disease defined as at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded)

    • Each lesion must be ≥ 10 mm when measured by CT scan, MRI or caliper measurement by clinical exam, OR ≥ 20 mm when measured by chest x-ray
    • Lymph nodes must be ≥ 15 mm in short axis when measured by CT scan or MRI

  • Detectable disease defined as no measurable disease but has at least one of the following conditions:

    • Baseline values of CA-125 at least 2 times upper limit of normal
    • Ascites and/or pleural effusion attributed to tumor
    • Solid and/or cystic abnormalities on radiographic imaging that do not meet RECIST 1.1 definition for target lesions

• Patients in the measurable disease cohort must have at least one "target lesion" to be used to assess response on this protocol as defined by RECIST 1.1

  • 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 at least 90 days following completion of radiation therapy

• Prior therapy:

  • Patients must have had one prior platinum-based chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin, or another organoplatinum compound; this initial treatment may have included intraperitoneal therapy, consolidation, non-cytotoxic (biologic/targeted agents, such as bevacizumab) or extended therapy administered after surgical or non-surgical assessment
  • Patients are allowed to receive, but are not required to receive, two additional cytotoxic regimens for management of recurrent or persistent disease, with no more than 1 non-platinum, non-taxane regimen
  • Patients are allowed to receive, but are not required to receive, non-cytotoxic (biologic/targeted agents, such as bevacizumab) therapy as part of their primary treatment regimen; patients must have NOT received any non-cytotoxic therapy (biologic/targeted agents) for management of recurrent or persistent disease (e.g., GOG protocol 170 series drugs or bevacizumab)
  • 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) (12/19/2011)
  • Patients with both platinum-sensitive and platinum-resistant disease are eligible; patients with platinum-refractory disease are NOT eligible; platinum-refractory disease is defined as patients who have progression of disease during the preceding platinum treatment
  • PFI for the most recent platinum therapy will need to be calculated before enrollment onto this study for stratification purposes (i.e. balanced randomization)
  • Patients who have a PFI =< 182 days (26 weeks) are defined as "platinum resistant"; patients who have 182 < PFI =< 365 days are defined as "GOG platinum sensitive"; finally, patients with PFI > 365 days are defined as "platinum sensitive"

• Not eligible for a higher-priority GOG protocol, if one exists

  • Any active GOG Phase III protocol or Rare Tumor protocol for the same patient population
• No history or evidence upon physical examination of CNS disease, including primary brain tumor or any brain metastases
• Performance status (PS) 0-2 (for patients who had 1 prior treatment) OR PS 0-1 (for patients who had 2-3 prior treatments)
• ANC ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 9 g/dL
• Creatinine ≤ 1.5 times upper limit of normal (ULN)
• Potassium ≥ 4.0 mmol/L*
• Magnesium ≥ 1.8 mmol/L*
• Calcium ≥ 8.4 mg/dL*
• NOTE: *Correction with supplements allowed.
• Bilirubin ≤ 1.5 times ULN
• AST ≤ 3 times ULN
• Alkaline phosphatase ≤ 2.5 times ULN
• INR ≤ 1.5 times ULN (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin)
• PTT ≤ 1.5 times ULN
• Urine protein: if protein is 2+ or higher, a 24-hour urine protein should be obtained and the level must be < 1,000 mg (< 1.0 g/24 hrs)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Free of acute hepatitis and active infection requiring parenteral antibiotics (with the exception of uncomplicated urinary tract infection [UTI])
• No other invasive malignancy except non-melanoma skin cancer, localized cancer of the breast, head and neck, or skin provided disease was curatively treated and patient remains free of recurrent or metastatic disease for more than 3 years

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

  • No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 90 days
• No active bleeding or pathologic conditions that carry high-risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels
• No seizures that are not controlled with standard medical therapy, history of cerebrovascular accident (CVA, stroke), TIA, or subarachnoid hemorrhage within 6 months prior to the first date of treatment on this study

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

  • Uncontrolled hypertension, defined as systolic blood pressure (BP) > 150 mm Hg or diastolic BP > 90 mm Hg, despite antihypertensive medications
  • History of Torsade de Pointes, ventricular tachycardia or fibrillation, pathologic sinus bradycardia (< 60 bpm), heart block (excluding 1st degree block PR interval prolongation only), congenital long QT syndrome, new ST segment elevation or depression, or new Q waves on ECG

  • Patients with QTc >= 470 msec

    • Stable regimen of antidepressants of the selective serotonin reuptake inhibitor (SSRI) class is allowed
  • Myocardial infarction or unstable angina within 6 months prior to registration
  • NYHA Class II or greater congestive heart failure

  • Serious cardiac arrhythmia requiring medication

    • Asymptomatic, atrial fibrillation with controlled ventricular rate not included
  • CTCAE grade ≥ 2 peripheral vascular disease (at least brief < 24 hrs) episodes of ischemia managed non-surgically and without permanent deficit
• Patients who have received prior therapy with an anthracycline (including doxorubicin or liposomal doxorubicin) must have an echocardiogram assessment and are excluded if the ejection fraction < 50%
• No known hypersensitivity to any of the components of fosbretabulin tromethamine or bevacizumab
• No clinical symptoms or signs of gastrointestinal obstruction or requirement parenteral hydration and/or nutrition; patients with bowel involvement on CT scan
• No patients with medical history or conditions not otherwise previously specified that, in the opinion of the investigator, should exclude participation in this study
• No concurrent drugs known to prolong the QTc interval, including anti-arrhythmic medications
• Recovered from the effects of recent surgery, radiotherapy, or chemotherapy
• At least 1 week since any hormonal therapy directed at the malignant tumor
• At least 3 weeks since any other prior therapy directed to the malignant tumor, including chemotherapy or biological/targeted and immunologic agents (including small molecules and murine monoclonal antibodies)
• At least 12 weeks since prior chimeric or human or humanized monoclonal antibodies (including bevacizumab) or VEGF-receptor fusion protein (including VEGF Trap/aflibercept)
• At least 4 weeks since prior radiotherapy
• More than 30 days since prior investigational therapy
• Patients are allowed to receive, but are not required to receive, 2 additional cytotoxic regimens for management of recurrent or persistent disease, with no more than 1 non-platinum, non-taxane regimen allowed
• No prior fosbretabulin tromethamine or any other vascular-disrupting agent (VDA)

• 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 3 years

  • Prior radiotherapy for localized cancer of the breast, head and neck, or skin is permitted, provided that it was completed more than 3 years prior to registration

• 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 3 years

  • Prior adjuvant chemotherapy for localized breast cancer allowed provided it was completed more than 3 years prior to registration
• No prior cancer treatment that contraindicates this protocol therapy
• No major surgery within the past 28 days and no anticipation of need for major surgery procedures during the course of the study
• No core biopsy within the past 7 days