Veliparib and Carboplatin in Treating Patients With HER2-Negative Metastatic Breast Cancer

PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose of veliparib along with carboplatin on a 14-day
and 21-day schedule in patients with Her2 negative metastatic breast cancer that are estrogen
receptor (ER)/progesterone receptor(PR) negative or ER and/or PR positive with defects in
Fanconi Anemia (FA) pathway repair genes.

II. To determine the safety and tolerability of combining veliparib on a 14-day and 21-day
schedule with carboplatin in this patient population.

III. To determine the preliminary efficacy of this combination in this patient population.

SECONDARY OBJECTIVES:

I. To determine the pharmacodynamic endpoints of poly(ADP-ribose) polymerase (PARP)
inhibition in the tumor by using, A) 3'-[F-18]fluoro-3'-deoxythymidine positron emission
tomography (FLT-PET) of the target lesions, B) circulating tumor cells to detect the
induction of the histone variant gamma H2AX, and C) peripheral blood mononuclear cells to
assess poly ADP-Ribose (PAR) levels.

II. To determine biomarkers in the primary tumor that may predict antitumor responses to PARP
inhibition such as breast cancer 1/2, early onset (BRCA)1/2 protein, Fanconi anemia,
complementation group D2 (FANCD2) nuclear foci formation and expression of micro-ribonucleic
acid (RNA) 155 (miR 155).

OUTLINE: This is a dose-escalation study of veliparib.

Patients receive carboplatin intravenously (IV) over 1 hour on day 1 and veliparib orally
(PO) twice daily (BID) on days 1-7 or 1-14. Courses repeat every 21 days in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 12 weeks.

Inclusion Criteria:

- Patients must have histologically or cytologically proven metastatic or locally
advanced inoperable breast cancer that fulfills one of the following two criteria:

- Triple-negative breast cancer

- ER and/or PR positive, HER2 negative if their tumors have been shown to be
deficient for the FA pathway, based on FA triple stain immunofluorescence (FATSI)
screening

- HER negative with a known germline BRCA1/2 mutation

- Patients with ER- and/or PR-positive breast cancer will be consented to have
their existing, or to be obtained, paraffin-embedded tumor tissue screened
for FA deficiency

- No more than 3 prior chemotherapy regimens for metastatic disease will be allowed; any
number of prior hormone therapies will be allowed; however, at least 4 weeks should
have elapsed since prior chemotherapy (6 weeks for mitomycin C and nitrosoureas and 2
weeks for hormone therapy) or radiation therapy (2 weeks for limited field palliative
radiation to the bone)

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Patients with treated brain metastases and life expectancy of greater than 3 months

- Patients with known Gilbert syndrome with abnormal unconjugated bilirubin will be
eligible

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic acid transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 X institutional upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- No prior therapy with veliparib for metastatic disease will be allowed

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
the duration of study participation; should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician
immediately

- Ability to understand and the willingness to sign a written informed consent document

- Patients must be able to swallow pills

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier

- Patients may not be receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to veliparib or other agents used in study

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with veliparib

- Known human immunodeficiency virus (HIV)-infected patients on protease inhibitors are
ineligible; HIV-infected patients with adequate cluster of differentiation (CD)4
counts (> 500) and not on protease inhibitors are eligible

- Patients with active seizure or a history of seizures are not eligible

- Patients with uncontrolled central nervous system (CNS) metastasis are not eligible;
patients with CNS metastases must be stable after therapy for > 3 months and off
steroid treatment prior to study enrollment