Carboplatin, Paclitaxel, Bevacizumab, and Veliparib in Treating Patients With Newly Diagnosed Stage II-IV Ovarian Epithelial, Fallopian Tube, or Primary Peritoneal Cancer

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and dose-limiting toxicities of ABT-888
(veliparib) when administered using continuous versus intermittent dosing schedules with
intravenous carboplatin, paclitaxel and bevacizumab using two different treatment regimens;
or with intraperitoneal cisplatin and intravenous and intraperitoneal paclitaxel and
bevacizumab in women with newly diagnosed, previously untreated, epithelial ovarian,
fallopian tube, or primary peritoneal cancer.

II. To determine the feasibility of these treatment regimens over four cycles in a 2-stage
group sequential design once the MTD is established.

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

SECONDARY OBJECTIVES:

I. To estimate the response rate (in measurable disease patients) and progression-free
survival in patients treated with these treatment regimens.

TERTIARY OBJECTIVES:

I. To assess the extent of poly-ADP-ribose polymerase (PARP) inhibition in peripheral blood
mononuclear cells (PBMCs) on day 1 of cycles 1 and 2.

II. To assess genomic breast cancer, early onset (BRCA) mutation status in all patients in
regimens I and II with continuous ABT-888 dosing and descriptively correlate with toxicity
and efficacy.

OUTLINE: This is a dose-escalation study of veliparib followed by a feasibility study.
Patients are sequentially assigned to 1 of 3 treatment regimens.

REGIMEN I: Patients receive paclitaxel intravenously (IV) over 3 hours, carboplatin IV over
30 minutes, and bevacizumab IV over 30-90 minutes (beginning in course 2) on day 1. Patients
also receive veliparib orally (PO) twice daily (BID) on days 1-21. Treatment repeats every 21
days for 6 courses. Patients then receive bevacizumab alone on day 1. Treatment with
bevacizumab repeats every 21 days for 16 courses in the absence of disease progression or
unacceptable toxicity.

REGIMEN II: Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15. Patients also
receive carboplatin, bevacizumab, and veliparib as in Regimen I. Treatment repeats every 21
days for 6 courses. Patients then receive bevacizumab alone on day 1. Treatment with
bevacizumab repeats every 21 days for 16 courses in the absence of disease progression or
unacceptable toxicity.

REGIMEN III: Patients receive paclitaxel IV over 3 hours on day 1 and intraperitoneally (IP)
on day 8, and cisplatin IP on day 1 or 2. Patients also receive bevacizumab and veliparib as
in Regimen I. Treatment repeats every 21 days for 6 courses. Patients then receive
bevacizumab alone on day 1. Treatment repeats every 21 days for 16 courses in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

- Patients with a histologic diagnosis of epithelial ovarian, fallopian tube, or primary
peritoneal carcinoma, or carcinosarcoma stage II, III, or IV with either optimal (=< 1
cm residual disease) or suboptimal residual disease

- All patients must have a procedure for determining diagnosis of epithelial ovarian,
fallopian tube, primary peritoneal, or carcinosarcoma with appropriate tissue for
histologic evaluation

- Patients with the following histologic cell types are eligible:

- Serous adenocarcinoma, endometrioid adenocarcinoma, mucinous adenocarcinoma,
undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial
adenocarcinoma, transitional cell carcinoma, malignant Brenner's tumor,
adenocarcinoma not otherwise specified (N.O.S.) or carcinosarcoma

- Absolute neutrophil count (ANC) greater than or equal to 1,500/mm^3, equivalent to
CTEP Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, grade 1; this
ANC cannot have been induced or supported by granulocyte colony stimulating factors

- Platelets greater than or equal to 100,000/mm^3

- Regimens I and II: Creatinine =< 1.5 x institutional upper limit normal (ULN), CTCAE
grade 1

- Regimen III: Creatinine no greater than the institutional upper limits of normal

- Bilirubin less than or equal to 1.5 x ULN (CTEP CTCAE version 4.0, grade 1)

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) less
than or equal to 3 x ULN (CTEP CTCAE version 4.0, grade 1)

- Alkaline phosphatase less than or equal to 2.5 x ULN (CTEP CTCAE version 4.0, grade 1)

- Albumin greater than or equal to 3.0 g/dL

- Neuropathy (sensory and motor) less than or equal to CTEP CTCAE version 4.0, grade 1

- 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

- Patients must have a Gynecologic Oncology Group (GOG) performance status of 0, 1, or 2

- Patients must be entered between 1 and 12 weeks after initial surgery performed for
the combined purpose of diagnosis, staging and cytoreduction

- Patients who have met the pre-entry requirements specified

- Patients must have signed an approved informed consent and authorization permitting
release of personal health information

Exclusion Criteria:

- Patients with a current diagnosis of borderline epithelial ovarian tumor (formerly
"tumors of low malignant potential") or recurrent invasive epithelial ovarian, primary
peritoneal or fallopian tube cancer treated with surgery only (such as patients with
stage IA or IB low-grade epithelial ovarian or fallopian tube cancers) are not
eligible

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

- Patients with synchronous primary endometrial cancer or a past 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 International Federation of Gynecology and Obstetrics (FIGO) grade 3
lesions

- Patients with a history of other invasive malignancies, with the exception of
non-melanoma skin cancer and other specific malignancies as noted, are excluded if
there is any evidence of other malignancy being present within the last five 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 within
the last five years 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

- Patients with acute hepatitis or active infection that requires parenteral antibiotics

- Patients with serious non-healing wound, ulcer, or bone fracture; this includes
history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
within 28 days; patients with granulating incisions healing by secondary intention
with no evidence of fascial dehiscence or infection are eligible but require weekly
wound examinations

- Patients with active bleeding or pathologic conditions that carry high risk of
bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major
vessels

- Patients with history or evidence upon physical examination of central nervous system
(CNS) disease, including primary brain tumor, seizures or history of seizures, and/or
any CNS metastases are ineligible

- Patients with 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 are ineligible

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

- Myocardial infarction or unstable angina < 6 months prior to registration

- New York Heart Association (NYHA) class II or higher congestive heart failure

- Serious cardiac arrhythmia requiring medication

- CTEP CTCAE version 4.0, grade 2 or higher peripheral ischemia (brief [< 24 hours
(hrs)] episode of ischemia managed non-surgically and without permanent deficit)

- Patients with known hypersensitivity to Chinese hamster ovary cell products or other
recombinant human or humanized antibodies

- Patients with clinically significant proteinuria (urine protein creatinine ratio
greater or equal to 1.0)

- Patients with invasive procedures or anticipation of invasive procedures within the
following timeframes as defined below:

- Major surgical procedure, open biopsy or significant traumatic injury within 28
days prior to the first date of bevacizumab therapy (cycle 2)

- Major surgical procedure anticipated during the course of the study

- Core biopsy within 7 days prior to the first date of bevacizumab therapy (cycle
2)

- Patients who are pregnant or nursing

- Patients with clinical symptoms or signs of gastrointestinal obstruction and who
require parenteral hydration or nutrition

- Patients with GOG performance status of 3 or 4