Oncotarget

Research Papers:

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

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

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Oncotarget. 2017; 8:44073-44081. https://doi.org/10.18632/oncotarget.17237

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Abstract

Mark Yarchoan1, Melinda C. Myzak1, Burles A. Johnson III1, Ana De Jesus-Acosta1, Dung T. Le1, Elizabeth M. Jaffee1, Nilofer S. Azad1, Ross C. Donehower1, Lei Zheng1, Paul E. Oberstein2, Robert L. Fine2, Daniel A. Laheru1 and Michael Goggins1

1The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

2Columbia University Medical Center, New York, NY, USA

Correspondence to:

Michael Goggins, email: [email protected]

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/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).

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.


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