PMID- 31667659 OWN - NLM STAT- MEDLINE DCOM- 20210909 LR - 20210909 IS - 1573-0646 (Electronic) IS - 0167-6997 (Linking) VI - 38 IP - 4 DP - 2020 Aug TI - Phase I study of continuous olaparib capsule dosing in combination with carboplatin and/or paclitaxel (Part 1). PG - 1117-1128 LID - 10.1007/s10637-019-00856-7 [doi] AB - Background The PARP inhibitor olaparib has shown acceptable toxicity at doses of up to 400 mg twice daily (bid; capsule formulation) with encouraging signs of antitumor activity. Based on its mode of action, olaparib may sensitize tumor cells to DNA-damaging agents. This Phase I trial (NCT00516724) evaluated the safety, pharmacokinetics (PK) and preliminary efficacy of olaparib combined with carboplatin and/or paclitaxel. Methods Patients with advanced solid tumors received olaparib (capsule bid) plus carboplatin (Part A), carboplatin and paclitaxel (Part B), or paclitaxel (Part C). In each part of the study, different drug doses were given to define the most appropriate dose/drug combination to use in further studies. Safety assessments included evaluation of dose-limiting toxicities (DLTs; cycle 1 only), adverse events (AEs) and physical examinations. PK assessments of olaparib, carboplatin and paclitaxel were performed. Tumor responses (RECIST) were assessed every two cycles. Results Fifty-seven patients received treatment. DLTs were reported in two patients (both receiving olaparib 100 mg bid and carboplatin AUC 4; Part A, cohort 2): grade 1 thrombocytopenia with grade 2 neutropenia lasting for 16 days, and grade 2 neutropenia lasting for 7 days. Non-hematologic AEs were predominantly grade 1-2 and included fatigue (70%) and nausea (40%). Bone marrow suppression, mainly neutropenia (51%) and thrombocytopenia (25%), frequently led to dose modifications. Conclusions Olaparib in combination with carboplatin and/or paclitaxel resulted in increased hematologic toxicities, making it challenging to establish a dosing regimen that could be tolerated for multiple cycles without dose modifications. FAU - van der Noll, Ruud AU - van der Noll R AD - Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands. r.vd.noll@nki.nl. FAU - Jager, Agnes AU - Jager A AD - Department of Medical Oncology, Erasmus University MC Cancer Institute, PO Box 5201, 3008, AE, Rotterdam, The Netherlands. FAU - Ang, Joo Ern AU - Ang JE AD - The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Downs Road, Sutton, Surrey, SM2 5PT, UK. FAU - Marchetti, Serena AU - Marchetti S AD - Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands. FAU - Mergui-Roelvink, Marja W J AU - Mergui-Roelvink MWJ AD - Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands. FAU - Lolkema, Martijn P AU - Lolkema MP AD - Department of Medical Oncology, Erasmus University MC Cancer Institute, PO Box 5201, 3008, AE, Rotterdam, The Netherlands. AD - The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Downs Road, Sutton, Surrey, SM2 5PT, UK. FAU - de Jonge, Maja J A AU - de Jonge MJA AD - Department of Medical Oncology, Erasmus University MC Cancer Institute, PO Box 5201, 3008, AE, Rotterdam, The Netherlands. FAU - van der Biessen, Diane A AU - van der Biessen DA AD - Department of Medical Oncology, Erasmus University MC Cancer Institute, PO Box 5201, 3008, AE, Rotterdam, The Netherlands. FAU - Brunetto, Andre T AU - Brunetto AT AD - The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Downs Road, Sutton, Surrey, SM2 5PT, UK. FAU - Arkenau, Hendrik-Tobias AU - Arkenau HT AD - The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Downs Road, Sutton, Surrey, SM2 5PT, UK. FAU - Tchakov, Ilian AU - Tchakov I AD - AstraZeneca, Alderley Park, Park Estate, Macclesfield, SK10 4TF, UK. AD - Eisai, Mosquito Way, Hatfield, AL10 9SN, UK. FAU - Beijnen, Jos H AU - Beijnen JH AD - Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands. AD - Utrecht Institute of Pharmaceutical Science s (UIPS), Utrecht University, Domplein 29, 3512, JE, Utrecht, The Netherlands. FAU - de Bono, Johann S AU - de Bono JS AD - The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Downs Road, Sutton, Surrey, SM2 5PT, UK. FAU - Schellens, Jan H M AU - Schellens JHM AD - Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands. AD - Utrecht Institute of Pharmaceutical Science s (UIPS), Utrecht University, Domplein 29, 3512, JE, Utrecht, The Netherlands. LA - eng SI - ClinicalTrials.gov/NCT00516724 PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191030 PL - United States TA - Invest New Drugs JT - Investigational new drugs JID - 8309330 RN - 0 (Antineoplastic Agents) RN - 0 (Phthalazines) RN - 0 (Piperazines) RN - BG3F62OND5 (Carboplatin) RN - P88XT4IS4D (Paclitaxel) RN - WOH1JD9AR8 (olaparib) SB - IM MH - Adult MH - Aged MH - Antineoplastic Agents/*administration & dosage/adverse effects/blood/pharmacokinetics MH - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/adverse effects/pharmacokinetics MH - Carboplatin/*administration & dosage/adverse effects MH - Female MH - Humans MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Neoplasms/*drug therapy/metabolism MH - Paclitaxel/*administration & dosage/adverse effects MH - Phthalazines/*administration & dosage/adverse effects/blood/pharmacokinetics MH - Piperazines/*administration & dosage/adverse effects/blood/pharmacokinetics MH - Treatment Outcome MH - Young Adult OTO - NOTNLM OT - Carboplatin OT - Olaparib OT - PARP inhibitor OT - Paclitaxel OT - Pharmacokinetics OT - Phase I EDAT- 2019/11/02 06:00 MHDA- 2021/09/10 06:00 CRDT- 2019/11/01 06:00 PHST- 2018/12/28 00:00 [received] PHST- 2019/09/12 00:00 [accepted] PHST- 2019/11/02 06:00 [pubmed] PHST- 2021/09/10 06:00 [medline] PHST- 2019/11/01 06:00 [entrez] AID - 10.1007/s10637-019-00856-7 [pii] AID - 10.1007/s10637-019-00856-7 [doi] PST - ppublish SO - Invest New Drugs. 2020 Aug;38(4):1117-1128. doi: 10.1007/s10637-019-00856-7. Epub 2019 Oct 30.