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

Mark Yarchoan,Robert L Fine,Burles A Johnson,Michael Goggins,Nilofer S Azad,Lei Zheng,Ana De Jesus-Acosta,Paul E Oberstein,Ross C Donehower,Daniel A Laheru,Dung T Le,Melinda C Myzak,Elizabeth M Jaffee

doi:10.18632/oncotarget.17237

Abstract

BackgroundOlaparib 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 MethodsIn 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/m2 on days 1 and 8 and cisplatin 25 mg/m2 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/m2 on day 1 to this regimen (olaparib plus ICM).Results18 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.ConclusionsOlaparib 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 registrationThis clinical trial was registered on ClinicalTrials.gov as NCT01296763.

Highlights

Pancreatic ductal adenocarcinoma is an aggressive malignancy and the fourth most common cause of cancerrelated deaths in the United States [1, 2]
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 myelodysplastic syndrome (MDS)
Olaparib had substantial toxicity when combined with irinotecan plus cisplatin (IC) or ICM in patients with pancreatic ductal adenocarcinoma (PDAC), and this treatment combination did not have an acceptable risk/ benefit profile for further study

Summary

Introduction

Pancreatic ductal adenocarcinoma is an aggressive malignancy and the fourth most common cause of cancerrelated deaths in the United States [1, 2]. Despite the recent development of novel gemcitabine or 5-FU-based combination chemotherapy regimens, the median overall www.impactjournals.com/oncotarget survival for patients with metastatic disease is less than one year [5, 6]. This highlights the continued need for novel and effective therapies for pancreatic ductal adenocarcinoma. PARP inhibitors have clinical activity in cancers without known defects in homologous DNA repair, preclinical and clinical trials have shown higher clinical response rates in patients with tumors harboring such defects [12, 13]. 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)

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