Veliparib, Doxorubicin Hydrochloride, Carboplatin, and Bevacizumab in Treating Patients With Recurrent Ovarian Cancer, Primary Peritoneal Cancer, or Fallopian Tube Cancer

• MTD as determined by dose-limiting toxicity (DLT), assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4 [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
• MTD of veliparib when given with bevacizumab, determined by DLT assessed by NCI CTCAE version 4 [ Time Frame: 16 weeks (4 courses) ] [ Designated as safety issue: Yes ]

• MTD and dose-limiting toxicity [ Designated as safety issue: Yes ]
• Toxicities of veliparib as assessed by CTEP NCI CTCAE v. 4.0 [ Designated as safety issue: Yes ]

• Toxicities, as classified using NCI CTCAE version 4.0 [ Time Frame: Up to 1 year ] [ Designated as safety issue: Yes ]
  Tabulated by regimen.
• Objective tumor response (complete and partial response) [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
  Objective tumor response will be tabulated by regimen.

This randomized phase I trial studies the side effects and the best dose of veliparib given together with doxorubicin hydrochloride and carboplatin in treating patients with recurrent ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as doxorubicin hydrochloride and carboplatin, may stop the growth of tumor cells by, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving veliparib together with doxorubicin hydrochloride, carboplatin,and bevacizumab may kill more tumor cells.

PRIMARY OBJECTIVES:

I. To determine the maximum-tolerated doses (MTD) and dose-limiting toxicities of two different regimens of ABT-888(veliparib) when administered with carboplatin and PLD (Doxil, Lipodox) (doxorubicin hydrochloride) in recurrent, platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer.

II. To assess the toxicity of these regimens using the Cancer Therapy Evaluation Program (CTEP) National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.

III. To examine the tolerability of these treatment regimens in combination with bevacizumab at the MTD.

SECONDARY OBJECTIVES:

I. To estimate the objective response rate (complete and partial) in patients with measurable disease.

TERTIARY OBJECTIVES:

I. To examine the relationships between platinum-free interval, activity of ABT-888 (objective response rate) and measures of breast cancer susceptibility gene 1/2 (BRCA1/2) status including mutations, alterations, rearrangements, promoter methylation, and immunohistochemical expression).

OUTLINE: This is a dose-escalation study of veliparib. Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive veliparib orally (PO) twice daily (BID) on days 1-7, and doxorubicin hydrochloride intravenously (IV) over 30 minutes and carboplatin IV over 30 minutes on day 1. Some patients also receive bevacizumab IV over 30-90 minutes on days 1 and 15.

ARM II: Patients receive veliparib PO BID on days 1-28, and doxorubicin hydrochloride and carboplatin as in arm I. Some patients also receive bevacizumab IV over 30-90 minutes on days 1 and 15.

In both arms, treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 year.

• Ovarian Clear Cell Cystadenocarcinoma
• Ovarian Endometrioid Adenocarcinoma
• Ovarian Mixed Epithelial Carcinoma
• Ovarian Serous Cystadenocarcinoma
• Ovarian Undifferentiated Adenocarcinoma
• Recurrent Fallopian Tube Cancer
• Recurrent Ovarian Epithelial Cancer
• Recurrent Primary Peritoneal Cavity Cancer

• Drug: doxorubicin hydrochloride
  Given IV
  Other Names:

  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
• Drug: veliparib
  Given PO
  Other Name: ABT-888
• Drug: carboplatin
  Given IV
  Other Names:

  • Carboplat
  • CBDCA
  • JM-8
  • Paraplat
  • Paraplatin
• Biological: bevacizumab
  Given IV
  Other Names:

  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
• Other: laboratory biomarker analysis
  Correlative studies

• Experimental: Arm I (intermittent veliparib)
  Patients receive veliparib PO BID on days 1-7, and doxorubicin hydrochloride IV over 30 minutes and carboplatin IV 30 minutes on day 1. Some patients also receive bevacizumab IV over 30-90 minutes on days 1 and 15.
  Interventions:

  • Drug: doxorubicin hydrochloride
  • Drug: veliparib
  • Drug: carboplatin
  • Biological: bevacizumab
  • Other: laboratory biomarker analysis
• Experimental: Arm II (continuous veliparib)
  Patients receive veliparib PO BID on days 1-28, and doxorubicin hydrochloride and carboplatin as patients in arm I. Some patients also receive bevacizumab IV over 30-90 minutes on days 1 and 15.
  Interventions:

  • Drug: doxorubicin hydrochloride
  • Drug: veliparib
  • Drug: carboplatin
  • Biological: bevacizumab
  • Other: laboratory biomarker analysis

Inclusion Criteria:

• Patients must have histologic diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal carcinoma which is now recurrent

  • Histologic documentation of the original primary tumor is required via the pathology report
• Patients with the following histologic epithelial cell types are eligible: high-grade serous adenocarcinoma, endometrioid adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, or adenocarcinoma not otherwise specified (N.O.S.)

• Patients must have recurrence documented by elevated cancer antigen (CA)-125 (biochemical recurrence) or clinically evident measurable or non-measurable recurrent disease

  • Patients with measurable disease must have had at least one "target lesion" to be used to assess response on this protocol as defined by Response Evaluation Criteria in Solid Tumors (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

• Absolute neutrophil count (ANC) >= 1,500/mcL

  • This ANC cannot have been induced or supported by granulocyte colony-stimulating factors
• Platelets >= to 100,000/mcL
• Creatinine =< 1.5 times institutional upper limit of normal (ULN)
• Bilirubin < 1.2 times ULN
• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamic pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) ≤ 3.0 times ULN
• Alkaline phosphatase =< 2.5 times ULN
• LVEF greater than or equal to institutional lower limit of normal (LLN) as determined by gated cardiac radionucleotide scan (MUGA) or echocardiogram
• Neuropathy (sensory and motor) ≤ to grade 1

• Patients must have a platinum-free interval following initial platinum-based chemotherapy of at least 6 months at first recurrence

  • Front-line therapy may have included a biologic/targeted agent (e.g., bevacizumab)
  • Front-line treatment may have included maintenance therapy; patients receiving maintenance therapy (biological therapy, hormonal, or taxane therapy) are ELIGIBLE provided their platinum-free interval is at least 6 months from initial chemotherapy AND a minimum of 4 weeks has elapsed since their last dose of biologic/targeted or taxane therapy or a minimum of 1 week has elapsed since their last dose of hormonal therapy
• Patients must have a Gynecologic Oncology Group (GOG) performance status of 0 or 1
• Patients of childbearing potential must have a negative pregnancy test prior to the study entry and be practicing an effective form of contraception; if applicable, patients must discontinue breastfeeding prior to study entry
• Patients who have met the pre-entry requirements
• Patients must have signed an Institutional Review Board (IRB)-approved informed consent and authorization permitting release of personal health information
• ADDITIONAL CRITERIA FOR PATIENTS BEING TREATED ON BEVACIZUMAB COHORT
• Prothrombin time (PT) such that international normalized ratio (INR) is ≤ 1.5 X ULN (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin) and a partial thromboplastin time (PTT) < 1.5 X ULN
• Urine protein should be screened by urine analysis; if protein is 2+ or higher, 24-hour urine protein should be obtained and the level should be < 1000 mg for patient enrollment
• Patients treating with enoxaparin are eligible for inclusion in the study
• Bevacizumab is detrimental to fetal growth; for this reason and because anti-vascular endothelial growth factor (VEGF) inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, fertile women must agree to use adequate contraceptive measures during study therapy and for at least 6 months after the completion of bevacizumab therapy; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, the patient should inform the treating physician immediately

Exclusion Criteria:

• Patients who have received more than one previous regimen of chemotherapy (maintenance is not considered a second regimen)
• No patients who have received prior veliparib (ABT-888) or any other poly-ADP-ribose polymerase (PARP) inhibitor
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to veliparib (ABT-888) or other agents used in this study
• Patients with other invasive malignancies, with the exception of non-melanoma skin cancer and other specific malignancies are excluded if there is any evidence of other malignancy being present within the last three years; patients are also excluded if their previous cancer treatment contraindicates this protocol therapy
• Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis are excluded. Prior radiation for localized cancer of the breast, head and neck, or skin is permitted, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease
• Patients who have received prior chemotherapy for any abdominal or pelvic tumor (other than ovarian, fallopian tube and primary peritoneal) are excluded; patients may have received prior adjuvant chemotherapy for localized breast cancer, provided that it was completed more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease

• No patients with synchronous primary endometrial cancer or a history of endometrial cancer, unless all of the following conditions are met:

  • Stage not greater than IB
  • No more than superficial myometrial invasion
  • No vascular or lymphatic invasion
  • No poorly differentiated subtypes, including papillary serous, clear cell, or other FIGO Grade 3 lesions
• Patients with known chronic or active hepatitis or ongoing or active infection that requires parenteral antibiotics
• Patients with concurrent severe medical problems unrelated to the malignancy that would significantly limit full compliance with the study or expose the patient to extreme risk or decreased life expectancy
• Patients of childbearing potential, not practicing adequate contraception, patients who are pregnant or patients who are breastfeeding are not eligible for this trial
• Patients with seizures or a history of seizures are ineligible
• Patients with history or evidence upon physical examination of central nervous system (CNS) disease, including primary brain tumor, any CNS metastases, or history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within six months of the first date of treatment on this study; patients with CNS metastases must be stable for > 3 months after treatment and off steroid treatment prior to study enrollment

• Patients with clinically significant cardiovascular disease; this includes:

  • Uncontrolled hypertension, defined as systolic > 150 mm Hg or diastolic > 90 mm Hg
  • Congestive heart failure, myocardial infarction or unstable angina within 6 months prior to registration
  • History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation) or cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation that is well controlled with anti-arrhythmic medication)
  • New York Heart Association (NYHA) Class II or higher congestive heart failure
  • Grade 2 or higher peripheral ischemia brief (<24 hrs) episode of ischemia managed non-surgically and without permanent deficit
• Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1
• Known CNS disease except for treated brain metastases; treated brain metastases are defined as having no ongoing requirement for steroids and no evidence of progression or hemorrhage after treatment for at least 3 months, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT]); (stable dose of anticonvulsants are allowed); treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; 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
• Evidence of bleeding diathesis or coagulopathy
• Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
• Patients who cannot swallow pills
• History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months to day 1

• Invasive procedures defined as follows:

  • Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1 therapy
  • Anticipation of need for major surgical procedures during the course of the study
  • Core biopsy within 7 days prior to D1 therapy