A pharmacokinetics/pharmacodynamics study of sequence specificity of the PARP inhibitor olaparib with carboplatin in refractory/recurrent women’s cancers: NCT01237067.

Abstract

TPS158 Background: The combination of carboplatin, C, and the PARP inhibitor olaparib, O, has activity in BRCA1/2mut or BRCA-like breast and ovarian cancers (Br/OvCa). The role of sequence specificity affecting DNA damage and cell injury and death is unknown. We modeled exposure to C and O in Br/OvCa cell lines, including BRCA1mut+ cells. Results indicated exposure to O prior to C (C>O) reduced double stranded DNA damage and cell loss, compared with exposure to C followed by O (O>C) or concomitant treatment. Our trial tests the hypothesis that C>O is more effective. Women will be randomized to receive either Ox7 days followed by C (O>C) or C followed by Ox7 days (C>O) with schedule flip on cycle 2, allowing both intra-patient and inter-cohort examination of PK/PD endpoints. Pts will receive O days 1-7 with C on d1 or 2 on subsequent cycles, following our current schedule (NCTNCT00647062). PMBCs will be collected C1 and 2 for measures of platination and DNA damage/repair. Clinical endpoints of frequency and duration of response, and AEs will follow standard phase II definitions. Objectives: To determine the safe q12h dose of O tablet formulation given with C AUC4; To estimate the PK and PD effects of two schedules of O and C using PBMCs; To determine the schedule-associated safety of O and C in women’s cancers. Eligibility: Women with histologically documented recurrent women’s cancers (e.g. Br, gynecologic cancers) for whom standard curative therapies do not exist or are no longer effective; No platinum compound for 6 months; Evaluable disease and good end organ function. Methods: A 3+3 safety run-in will examine the new O tablet formulation and will precede and inform the randomized PK/PD portion of the study. All women will receive C AUC4 with no more than 8 C-containing cycles given; subsequent cycles will consist of daily oral O. O will be continued in all patients until progression or recurrence of disease. PBMCs will be collected prior to and during C1 and 2 for PD and PK analyses. Clinical benefit will be reassessed every other cycle. Biopsy at progression of disease will be requested of mutation carriers to evaluate development of BRCA1/2 re-expression mutations.