TPS106 Background: Preclinical and clinical data demonstrate the promising activity of PARP inhibitors (PARPi) in triple negative (TN) and BRCA-1 deficient breast cancers. BRCA 1/2 are part of the Fanconi Anemia (FA) network of proteins that function in DNA damage response to maintain genomic integrity. Investigators at our institution have shown that defect in FA pathway sensitizes cells to DNA damaging agents and PARPi. We propose here to combine carboplatin and oral PARPi (ABT 888) to determine the maximum tolerated dose (MTD) on 2 differing schedules of 7 and 14 days in patients with MBC that are either TN or ER and/or PR +(HR +ve) with FA defect.
METHODS
Objectives: 1. To determine the MTD, toxicity and preliminary efficacy of ABT 888 in combination with carboplatin 2. To determine the biological dose-response to varying dose/schedule of ABT 888, we propose to use A. the novel imaging 3'-[F-18]Fluoro-3'-deoxythymidine Positron Emission Tomography (FLT-PET), B. obtain circulating tumor cells (CTCs) to assess induction of gamma H2Ax, and C. determine PAR levels in PBMC 3. Evaluate biomarkers in primary tumor that could predict response to PARPi such as BRCA-1/2, FANCD2 nuclear foci formation (using the FA Triple Stain Immunofluroscence test/FATSI) and expression of miR 155 (oncogenic miR that targets DNA repair genes). Eligibility: Patients with Her 2 negative MBC that are either ER/PR negative (triple negative) or HR+ with a defective FA pathway who have received no more than 3 prior chemotherapy regimens, and ECOG PS 0-2 are eligible. Prior platinum therapy is allowed.
STUDY DESIGN
Patients with HR+ve MBC will sign a screening consent form to obtain archival tumor to test for absence of nuclear FANCD2 by FATSI and if confirmed, will be potentially eligible. All eligible patients will receive carboplatin at AUC of 6 on day 1 of a 21 day cycle and ABT 888 BID for 7 or 14 days depending on dose level. Dose-escalation: Standard 3+3 phase I trial design will be used for dose escalation and to identify MTD for -7 and 14 day schedule. Correlatives: FLT-PET scan and peripheral blood for CTCs and PAR immunoassay will be obtained at baseline and multiple time-points during the study. Funded by U01 -CA 76576.