Abstract 1754: A pharmacokinetics/pharmacodynamics study of sequence specificity of the PARP inhibitor, olaparib (O) with carboplatin (C) in recurrent women's cancers NCT01237067

Background: C, O, and C+O have documented activity in BRCA1/2 mut+ or BRCA-like breast and ovarian cancers (Br/OvCa). The effect of drug sequence on DNA damage and cell death is unknown. Our in vitro modeling suggests that exposure to O prior to C (O>C) reduced double stranded DNA damage and cell loss. Our trial tests the hypothesis that C>O causes more cellular injury. Methods: Eligible pts have recurrent women9s cancers, good end organ function, and evaluable disease. A 3+3 dose escalation run-in defined the O tablet dose in combination with C (AUC 4). The study will now randomize pts to schedule A or B (below), allowing intra-pt and inter-cohort analysis of PK/PD endpoints. PBMCs will be collected C1/2 for measurement of platination and DNA damage/repair; DNA repair protein integrity will be assessed on archival tissues. Clinical benefit, response frequency and duration, and toxicity will be ascertained. Mutation carriers will undergo progression biopsy for analysis of BRCA1/2 re-expression mutations. Results: The phase I portion is complete. 12 women (8Ov/3Br/1Endometrial[En]) have been accrued on 3 dose levels (DLs). Median prior number of regimens was 5. No DLT have been seen in 5 evaluable pts on DL3 (O tablet 200mg q12h/C AUC4 [1 pt pending]). Gr3 AEs included neutropenia (44%), and gr2 were anemia (56%), fatigue (22 %), C hypersensitivity (22%), thrombocytopenia (11%), and nausea (11%). 1 pt (DL2; stable disease) died of unrelated bleeding during C4. Clinical benefit has been observed in 8 evaluable pts with PR in 2 BRCA1 mut+ OvCa (9 + , 11 + mo), stabilization > 4mo in 6 pts (4OvCa,1BrCa, 1EnCa), and 3 are TETE. Conclusions: O in tablet formulation at 200mg q12h x 7d with C AUC4 q21d is active and tolerable, with observed interactive marrow suppression. Subsequent women will be randomized to examine schedule dependence of activity and toxicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1754. doi:1538-7445.AM2012-1754