Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors Journal Article

Authors: Balmaña, J.; Tung, N. M.; Isakoff, S. J.; Graña, B.; Ryan, P. D.; Saura, C.; Lowe, E. S.; Frewer, P.; Winer, E.; Baselga, J.; Garber, J. E.
Article Title: Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors
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.
Keywords: adult; gene mutation; major clinical study; constipation; drug tolerability; fatigue; cisplatin; advanced cancer; cancer combination chemotherapy; diarrhea; drug dose reduction; drug efficacy; drug safety; drug withdrawal; monotherapy; side effect; solid tumor; pancreas cancer; drug megadose; low drug dose; multiple cycle treatment; ovary cancer; peritoneum cancer; breast cancer; anemia; leukopenia; nausea; thrombocytopenia; vomiting; tinnitus; cohort analysis; antineoplastic activity; asthenia; drug dose escalation; dyspnea; febrile neutropenia; lymphocytopenia; lung embolism; tumor suppressor gene; multicenter study; breast tumor; ovary tumor; drug response; headache; migraine; phase 1 clinical trial; brca1; brca2; hematologic disease; olaparib; triacylglycerol lipase; decreased appetite; enzyme blood level; brca2 gene; colony stimulating factor; human; male; female; priority journal; article
Journal Title: Annals of Oncology
Volume: 25
Issue: 8
ISSN: 0923-7534
Publisher: Oxford University Press  
Date Published: 2014-08-01
Start Page: 1656
End Page: 1663
Language: English
DOI: 10.1093/annonc/mdu187
PROVIDER: scopus
PUBMED: 24827126
Notes: Export Date: 2 September 2014 -- CODEN: ANONE -- Source: Scopus
Citation Impact
MSK Authors
  1. Jose T Baselga
    483 Baselga