Sequence-Specific Pharmacokinetic and Pharmacodynamic Phase I/Ib Study of Olaparib Tablets and Carboplatin in Women's Cancer.
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 vitroexperiments 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 inBRCAmutation 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.Clin Cancer Res; 23(6); 1397-406. ©2016 AACR.
Women's Malignancies Branch, Center for Cancer Research, NCI, Bethesda, Maryland. leej6@mail.nih.gov.
Jung-Min
JM
Lee
Clinical Pharmacology Program, Center for Cancer Research, NCI, Bethesda, Maryland.
Cody J
CJ
Peer
Women's Malignancies Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
Minshu
M
Yu
National Institute on Minority Health and Health Disparities, Bethesda, Maryland.
Lauren
L
Amable
Women's Malignancies Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
Nicolas
N
Gordon
Women's Malignancies Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
Christina M
CM
Annunziata
Women's Malignancies Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
Nicole
N
Houston
Clinical Pharmacology Program, Center for Cancer Research, NCI, Bethesda, Maryland.
Andrew K L
AK
Goey
Clinical Pharmacology Program, Center for Cancer Research, NCI, Bethesda, Maryland.
Tristan M
TM
Sissung
Women's Malignancies Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
Bernard
B
Parker
Women's Malignancies Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
Lori
L
Minasian
Women's Malignancies Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
Victoria L
VL
Chiou
Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
Robert F
RF
Murphy
Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
Brigitte C
BC
Widemann
Clinical Pharmacology Program, Center for Cancer Research, NCI, Bethesda, Maryland.
William D
WD
Figg
Women's Malignancies Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
Elise C
EC
Kohn
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D016190:Carboplatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018736:DNA Adducts / Q000097:blood; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions / Q000097:blood / Q000473:pathology; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000473:pathology; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000473:pathology; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D010793:Phthalazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D014594:Uterine Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology
D018736:DNA Adducts; D010793:Phthalazines; D010879:Piperazines; D016190:Carboplatin; C531550:olaparib
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