| Abstract: |
Background: To establish the maximum tolerated dose, determine safety/tolerability and evaluate the pharmacokinetics and preliminary efficacy of olaparib in combination with cisplatin in patients with advanced solid tumors. Patients and methods: Patients aged ≥18 years with advanced solid tumors, who had progressed on standard treatment, were assigned to a treatment cohort and received oral olaparib [50-200 mg twice daily (bid); 21-day cycle] continuously or intermittently (days 1-5 or 1-10) in combination with cisplatin (60-75 mg/m2 intravenously) on day 1 of each cycle. Results: Dose-limiting toxicities (DLTs) of grade 3 neutropenia (cisplatin 75 mg/m2 with continuous olaparib 100 mg bid or 200 mg bid; n = 1 each) and grade 3 lipase elevation (cisplatin 75 mg/m2 with olaparib 100 mg bid days 1-10 or 50 mg bid days 1-5; n = 1 each) were reported. Olaparib and cisplatin doses were subsequently reduced to 50 mg bid days 1-5 and 60 mg/m2, respectively; no DLTs were reported for patients receiving this regimen. The most frequent grade ≥3 adverse events were neutropenia (16.7%), anemia (9.3%) and leucopenia (9.3%). Thirty patients (55.6%) received colonystimulating factors for hematologic support. The overall objective response rate was 41% for patients with measurable disease, and 43% and 71% among patients with a BRCA1/2 mutation who had ovarian and breast cancer, respectively. Conclusions: Olaparib in combination with cisplatin 75 mg/m2 was not considered tolerable; intermittent olaparib (50 mg bid, days 1-5) with cisplatin 60 mg/m2 improved tolerability. Promising antitumor activity in patients with germline BRCA1/2 mutations was observed and warrants further investigation. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. |
