A phase I combination study of olaparib with cisplatin and gemcitabine in adults with solid tumors

Arun Rajan, Corey A. Carter, Ronan J. Kelly, Martin Gutierrez, Shivaani Kummar, Eva Szabo, Mary Ann Yancey, Uping Ji, Baskar Mannargudi, Sukyung Woo, Shawn Spencer, William Douglas Figg, Giuseppe Giaccone*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

139 Scopus citations


Purpose: To determine the safety and tolerability of olaparib with cisplatin and gemcitabine, establish the maximum tolerated dose (MTD), and evaluate the pharmacodynamic and pharmacokinetic profile of the combination. Experimental Design: We conducted a phase I study of olaparib with cisplatin and gemcitabine in patients with advanced solid tumors. Treatment at dose level 1 (DL1) consisted of olaparib 100 mg orally every 12 hours on days 1 to 4, gemcitabine 500 mg/m 2 on days 3 and 10, and cisplatin 60 mg/m 2 on day 3. PAR levels were measured in peripheral blood mononuclear cells (PBMC). Results: Dose-limiting toxicities (DLT) in two of three patients at DL1 included thrombocytopenia and febrile neutropenia. The protocol was amended to enroll patients treated with ≤2 prior severely myelosuppressive chemotherapy regimens and treated with olaparib 100mgonce daily on days 1 to 4 (DL-1).No DLTs were seen in six patients at DL-1. Because of persistent thrombocytopenia and neutropenia following a return to DL1, patients received 100 mg olaparib every 12 hours on day 1 only. No hematologic DLTs were observed; nonhematologic DLTs included gastrointestinal bleed, syncope, and hypoxia. Of 21 patients evaluable for response, two had partial response. Olaparib inhibited PARP in PBMCs and tumor tissue, although PAR levels were less effectively inhibited when olaparib was used for a short duration. Conclusions: Olaparib in combination with cisplatin and gemcitabine is associated with myelosuppression even at relatively low doses. Modified schedules of olaparib in chemotherapy naive patients will have to be explored with standard doses of chemotherapy.

Original languageEnglish
Pages (from-to)2344-2351
Number of pages8
JournalClinical Cancer Research
Issue number8
StatePublished - 15 Apr 2012
Externally publishedYes


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