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PubMed | Minority, National Cancer Institute, NCI Inc, Clinical Investigations Branch CTEP DCTD NCI and 3 more.
Type: | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016

Our preclinical studies showed the PARP inhibitor, olaparib prior to carboplatin attenuated carboplatin cytotoxicity. We evaluated sequence-specific pharmacokinetic/pharmacodynamic (PK/PD) effects, safety and activity of the combination.Eligible patients had metastatic or recurrent womens cancer. Olaparib tablets were introduced (100 or 200mg bid, days1-7) in a 3+3 dose escalation with carboplatin AUC4 or 5 q21 days, up to eight cycles, followed by olaparib maintenance. Patients were randomized to starting schedule: cohort A (olaparib days1-7, carboplatin on day8) or B (carboplatin on day1, olaparib days2-8) during cycle 1. Patients received the reversed scheme in cycle 2. Blood was collected for olaparib PK, platinum-DNA adducts, comet assay and PAR concentrations. The primary objectives were to examine schedule-dependent effects on olaparib PK and platinum-DNA adducts.77 (60 ovarian, 14 breast, and 3 uterine cancer) patients were treated. Dose limiting toxicity was thrombocytopenia and neutropenia, defining olaparib 200mg bid+carboplatin AUC4 as the MTD. Olaparib clearance was increased ~50% when carboplatin was given 24hr before olaparib. In vitro experiments demonstrated carboplatin pre-exposure increased olaparib clearance due to intracellular olaparib uptake. Quantities of platinum-DNA adducts were not statistically different as a function of the order of drug administration. Responses included 2 CR and 31 PR (46%) with a higher RR in BRCA mutation carriers compared to non-mutation carriers (68% v.19%).Tablet olaparib with carboplatin is a safe and active combination. Carboplatin pre-exposure causes intracellular olaparib accumulation reducing bioavailable olaparib, suggesting carboplatin should be administered prior to olaparib.

Loading Clinical Pharmacology Research Core and Cancer Therapeutics Branch National Cancer Institute collaborators
Loading Clinical Pharmacology Research Core and Cancer Therapeutics Branch National Cancer Institute collaborators