I. To evaluate the efficacy of single agent ABT-888 (veliparib) (NSC 737664) in BRCA carriers with metastatic breast cancer based on response rate (RECIST criteria).
I. To conduct subset analysis on BRCA1 vs. BRCA2 and hormone receptor status. II. To evaluate progression-free survival of patients on single-agent ABT-888. III. To further describe the safety and tolerability of ABT-888 (NSC 737664) as a single agent and in combination with carboplatin for BRCA-associated breast cancer.
IV. To evaluate the pharmacokinetics of ABT-888 (NSC 737664) alone and in combination with carboplatin.
V. To assess the relationship between the level of PARP inhibition by ABT-888 and biomarkers of DNA damage in PBMC's and in tumor VI. To explore the relationship between biomarkers of drug effect and progression-free survival.
VII. To evaluate the efficacy and safety of the combination of carboplatin and ABT-888 in patients who have failed single agent ABT-888.
VIII. To conduct subset analysis on BRCA1 vs. BRCA2 and hormone receptor status.
OUTLINE: This is a multicenter study. Patients are stratified according to ECOG performance status (0-1 vs 2), and hormone status (estrogen receptor [ER]- and/or progesterone receptor [PR]-positive vs ER- and/or PR-negative). Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive oral veliparib twice daily on days 1-21.
ARM II: Patients receive carboplatin IV over 30 minutes on day 1 and veliparib as in arm I.
In both arms, treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood and hair follicle sample collection for pharmacokinetics and other laboratory studies.
After completion of study therapy, patients are followed up every 3-6 months.
- Histologically confirmed breast cancer
- Metastatic or locally advanced disease
- Disease not amenable to surgery
- Standard curative measures do not exist or are no longer effective
- Patient must have a known deleterious BRCA mutation confirmed by report from a CLIA certified laboratory
- Measurable disease by RECIST criteria
- At least 3 weeks since prior chemotherapy
- Hormone receptor status known
- ECOG performance status 0-2
- Life expectancy > 4 months
- ANC ≥ 1,500/mm^3
- Platelet count ≥ 100,000/mm^3
- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
- AST and ALT ≤ 2.5 times ULN (≤ 5 times ULN if there is evidence of liver metastasis)
- Creatinine normal OR creatinine clearance ≥ 60 mL/min
- Negative pregnancy test
- Fertile patients must agree to use effective contraception before, during, and for 3 months after completion of study therapy
- Ability to understand and the willingness to sign a written informed consent document
- No prior therapy with platinum agents or PARP inhibitors
- Prior adjuvant platinum agents within the past 12 months allowed
- No other concurrent investigational agents
- No known CNS metastases with active symptomatology, or requiring anticonvulsant medications or steroids
- Patients on anticonvulsant medications prescribed for reasons other than CNS metastases, not on steroids and without active symptomatology allowed
- Patients with active seizure or a history of seizure; patients with CNS metastases must be stable after therapy for > 3 months and off steroid treatment prior to study enrollment
- No history of allergic reactions attributed to compounds of similar chemical or biological composition to veliparib or PARP Inhibitors
- No contraindications to platinum agents
- More than 5 years since prior and no concurrent non-breast malignancy except nonmelanoma skin cancer or resected stage I ovarian cancer
- No intercurrent illness (e.g., cardiovascular, pulmonary, or central nervous system) that is either poorly controlled with currently available treatment or that, in the opinion of the investigator, is deemed unwise to enter the patient on the protocol
- Not pregnant or nursing
- Patients unable to swallow the ABT-888 tablets whole are ineligible; (the tablets cannot be crushed or broken)
- No active severe infection, including known infection with HIV or hepatitis B or C virus
Last updated: 01/11/2013
NCT ID: NCT01149083