Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer

Abstract

// Mark Yarchoan 1 , Melinda C. Myzak 1 , Burles A. Johnson III 1 , Ana De Jesus-Acosta 1 , Dung T. Le 1 , Elizabeth M. Jaffee 1 , Nilofer S. Azad 1 , Ross C. Donehower 1 , Lei Zheng 1 , Paul E. Oberstein 2 , Robert L. Fine 2 , Daniel A. Laheru 1 and Michael Goggins 1 1 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA 2 Columbia University Medical Center, New York, NY, USA Correspondence to: Michael Goggins, email: mgoggins@jhmi.edu Keywords: olaparib, pancreatic cancer, BRCA2, irinotecan, cisplatin Received: February 24, 2016     Accepted: March 13, 2017     Published: April 19, 2017 ABSTRACT Background: Olaparib is an oral inhibitor of polyadenosine 5’-diphosphoribose polymerization (PARP) that has previously shown signs of activity in patients with BRCA mutations and pancreatic ductal adenocarcinoma (PDAC). Patients and Methods: In this phase 1 dose-escalation trial in patients with unresectable PDAC, we determined the maximum tolerated dose (MTD) of olaparib (tablet formulation) in combination with irinotecan 70 mg/m 2 on days 1 and 8 and cisplatin 25 mg/m 2 on days 1 and 8 of a 28-day cycle (olaparib plus IC). We then studied the safety and tolerability of adding mitomycin C 5 mg/m 2 on day 1 to this regimen (olaparib plus ICM). Results: 18 patients with unresectable PDAC were enrolled. The MTD of olaparib plus IC was olaparib 100 mg twice-daily on days 1 and 8. The addition of mitomycin C to this dose level was not tolerated. Grade ≥3 drug-related adverse events (AEs) were encountered in 16 patients (89%). The most common grade ≥3 drug-related toxicities included neutropenia (89%), lymphopenia (72%), and anemia (22%). Two patients (11%), both of whom had remained on study for more than 12 cycles, developed drug-related myelodysplastic syndrome (MDS). The objective response rate (ORR) for all evaluable patients was 23%. One patient who carried a deleterious germline BRCA2 mutation had a durable clinical response lasting more than four years, but died from complications of treatment-related MDS. Conclusions: Olaparib had substantial toxicity when combined with IC or ICM in patients with PDAC, and this treatment combination did not have an acceptable risk/benefit profile for further study. However, durable clinical responses were observed in a subset of patients and further clinical investigation of PARP inhibitors in PDAC is warranted. Trial registration : This clinical trial was registered on ClinicalTrials.gov as NCT01296763.