Sequence-Specific Pharmacokinetic and Pharmacodynamic Phase I/Ib Study of Olaparib Tablets and Carboplatin in Women's Cancer
| العنوان: | Sequence-Specific Pharmacokinetic and Pharmacodynamic Phase I/Ib Study of Olaparib Tablets and Carboplatin in Women's Cancer |
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| المؤلفون: | Jung-Min Lee, Andrew K. L. Goey, Lori M. Minasian, Victoria L. Chiou, Bernard Parker, Nicolas Gordon, Cody J. Peer, Robert F. Murphy, Nicole D. Houston, Tristan M. Sissung, William D. Figg, Minshu Yu, Lauren Amable, Elise C. Kohn, Christina M. Annunziata, Brigitte C. Widemann |
| المصدر: | Clinical Cancer Research. 23:1397-1406 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Adult, 0301 basic medicine, Cancer Research, Drug-Related Side Effects and Adverse Reactions, Maximum Tolerated Dose, endocrine system diseases, Breast Neoplasms, Pharmacology, Neutropenia, Article, Drug Administration Schedule, Piperazines, Carboplatin, Olaparib, DNA Adducts, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Pharmacokinetics, medicine, Humans, Aged, Ovarian Neoplasms, business.industry, BRCA mutation, Cancer, Middle Aged, medicine.disease, female genital diseases and pregnancy complications, 030104 developmental biology, Oncology, chemistry, 030220 oncology & carcinogenesis, Pharmacodynamics, Uterine Neoplasms, PARP inhibitor, Leukocytes, Mononuclear, Phthalazines, Female, Neoplasm Recurrence, Local, business |
| الوصف: | 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. Clin Cancer Res; 23(6); 1397–406. ©2016 AACR. |
| تدمد: | 1557-3265 1078-0432 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::96e011272634c437c2b00bf1d605f66d https://doi.org/10.1158/1078-0432.ccr-16-1546 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....96e011272634c437c2b00bf1d605f66d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15573265 10780432 |
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