TY - JOUR
T1 - Sequence-specific pharmacokinetic and pharmacodynamic phase I/Ib study of olaparib tablets and carboplatin in women's cancer
AU - Lee, Jung Min
AU - Peer, Cody J.
AU - Yu, Minshu
AU - Amable, Lauren
AU - Gordon, Nicolas
AU - Annunziata, Christina M.
AU - Houston, Nicole
AU - Goey, Andrew K.L.
AU - Sissung, Tristan M.
AU - Parker, Bernard
AU - Minasian, Lori
AU - Chiou, Victoria L.
AU - Murphy, Robert F.
AU - Widemann, Brigitte C.
AU - Figg, William D.
AU - Kohn, Elise C.
N1 - Funding Information:
This work was funded in part by the 2011 Jane C. Wright MD ASCO Young Investigator Award from Conquer Cancer Foundation (to J.-M. Lee) and by the Intramural Program of the Center for Cancer Research, NCI and NIMHD, NIH.
Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2017/3/15
Y1 - 2017/3/15
N2 - Purpose: Our preclinical studies showed that the PARP inhibitor, olaparib, prior to carboplatin attenuated carboplatin cytotoxicity. We evaluated sequence-specific pharmacokinetic and pharmacodynamic effects, safety, and activity of the combination. Experimental Design: Eligible patients had metastatic or recurrent women's cancer. Olaparib tablets were introduced (100 or 200 mg twice daily, days 1-7) in a 3 + 3 dose escalation with carboplatin AUC4 or 5 every 21 days, up to eight cycles, followed by olaparib 300 mg twice daily maintenance. Patients were randomly assigned to starting schedule: cohort A (olaparib days 1-7, carboplatin on day 8) or B (carboplatin on day 1, olaparib days 2-8) during cycle 1. Patients received the reversed scheme in cycle 2. Blood was collected for olaparib pharmacokinetics, platinum- DNA adducts, comet assay, and PAR concentrations. The primary objectives were to examine schedule-dependent effects on olaparib pharmacokinetics and platinum-DNA adducts. Results: A total of 77 (60 ovarian, 14 breast, and 3 uterine cancer) patients were treated. Dose-limiting toxicity was thrombocytopenia and neutropenia, defining olaparib 200 mg twice daily + carboplatin AUC4 as the MTD. Olaparib clearance was increased approximately 50% when carboplatin was given 24 hours before olaparib. In vitro experiments demonstrated carboplatin preexposure increased olaparib clearance due to intracellular olaparib uptake. Quantities of platinum-DNA adducts were not different as a function of the order of drug administration. Responses included 2 CRs and 31 PRs (46%) with a higher RR in BRCA mutation carriers compared with nonmutation carriers (68% vs. 19%). Conclusions: Tablet olaparib with carboplatin is a safe and active combination. Carboplatin preexposure causes intracellular olaparib accumulation reducing bioavailable olaparib, suggesting carboplatin should be administered prior to olaparib.
AB - Purpose: Our preclinical studies showed that the PARP inhibitor, olaparib, prior to carboplatin attenuated carboplatin cytotoxicity. We evaluated sequence-specific pharmacokinetic and pharmacodynamic effects, safety, and activity of the combination. Experimental Design: Eligible patients had metastatic or recurrent women's cancer. Olaparib tablets were introduced (100 or 200 mg twice daily, days 1-7) in a 3 + 3 dose escalation with carboplatin AUC4 or 5 every 21 days, up to eight cycles, followed by olaparib 300 mg twice daily maintenance. Patients were randomly assigned to starting schedule: cohort A (olaparib days 1-7, carboplatin on day 8) or B (carboplatin on day 1, olaparib days 2-8) during cycle 1. Patients received the reversed scheme in cycle 2. Blood was collected for olaparib pharmacokinetics, platinum- DNA adducts, comet assay, and PAR concentrations. The primary objectives were to examine schedule-dependent effects on olaparib pharmacokinetics and platinum-DNA adducts. Results: A total of 77 (60 ovarian, 14 breast, and 3 uterine cancer) patients were treated. Dose-limiting toxicity was thrombocytopenia and neutropenia, defining olaparib 200 mg twice daily + carboplatin AUC4 as the MTD. Olaparib clearance was increased approximately 50% when carboplatin was given 24 hours before olaparib. In vitro experiments demonstrated carboplatin preexposure increased olaparib clearance due to intracellular olaparib uptake. Quantities of platinum-DNA adducts were not different as a function of the order of drug administration. Responses included 2 CRs and 31 PRs (46%) with a higher RR in BRCA mutation carriers compared with nonmutation carriers (68% vs. 19%). Conclusions: Tablet olaparib with carboplatin is a safe and active combination. Carboplatin preexposure causes intracellular olaparib accumulation reducing bioavailable olaparib, suggesting carboplatin should be administered prior to olaparib.
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U2 - 10.1158/1078-0432.CCR-16-1546
DO - 10.1158/1078-0432.CCR-16-1546
M3 - Article
C2 - 27663600
AN - SCOPUS:85016153695
SN - 1078-0432
VL - 23
SP - 1397
EP - 1406
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 6
ER -