Phase I study of olaparib plus gemcitabine in patients with advanced solid tumours and comparison with gemcitabine alone in patients with locally advanced/metastatic pancreatic cancer Journal Article


Authors: Bendell, J.; O'Reilly, E. M.; Middleton, M. R.; Chau, I.; Hochster, H.; Fielding, A.; Burke, W.; Burris, H. 3rd
Article Title: Phase I study of olaparib plus gemcitabine in patients with advanced solid tumours and comparison with gemcitabine alone in patients with locally advanced/metastatic pancreatic cancer
Abstract: Background: Olaparib (Lynparza™) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that induces synthetic lethality in cancers with homologous recombination defects. Patients and methods: In this phase I, dose-escalation trial, patients with advanced solid tumours received olaparib (50-200 mg capsules b.i.d.) continuously or intermittently (days 1-14, per 28-day cycle) plus gemcitabine [i.v. 600-800 mg/m2; days 1, 8, 15, and 22 (cycle 1), days 1, 8, and 15 (subsequent cycles)] to establish the maximum tolerated dose. A separate dose-escalation phase evaluated olaparib in tablet formulation (100 mg o.d./b.i.d.; days 1-14) plus gemcitabine (600 mg/m2). In an expansion phase, patients with genetically unselected locally advanced or metastatic pancreatic cancer were randomised 2 : 1 to the tolerated olaparib capsule combination dose or gemcitabine alone (1000 mg/m2). Results: Sixty-six patients were treated [dose-escalation phase, n = 44 (tablet cohort, n = 12); dose-expansion phase, n = 22 (olaparib plus gemcitabine, n = 15; gemcitabine alone, n = 7)]. In the dose-escalation phase, four patients (6%) experienced dose-limiting toxicities (raised alanine aminotransferase, n = 2; neutropenia, n = 1; febrile neutropenia, n = 1). Grade ≥3 adverse events were reported in 38/47 patients (81%) treated with olaparib capsules plus gemcitabine; most common were haematological toxicities (55%). Tolerated combinations were olaparib 100 mg b.i.d. capsule (intermittently, days 1-14) plus gemcitabine 600 mg/m2 and olaparib 100 mg o.d. tablet (intermittently, days 1-14) plus gemcitabine 600 mg/m2. There were no differences in efficacy observed during the dose-expansion phase. Conclusions: Olaparib 100 mg b.i.d. (intermittent dosing; capsules) plus gemcitabine 600 mg/m2 is tolerated in advanced solid tumour patients, with no unmanageable/unexpected toxicities. Continuous dosing of olaparib or combination with gemcitabine at doses >600 mg/m2 was not considered to have an acceptable tolerability profile for further study. © The Author 2015.
Keywords: gemcitabine; pancreatic cancer; olaparib
Journal Title: Annals of Oncology
Volume: 26
Issue: 4
ISSN: 0923-7534
Publisher: Oxford University Press  
Date Published: 2015-04-01
Start Page: 804
End Page: 811
Language: English
DOI: 10.1093/annonc/mdu581
PROVIDER: scopus
PUBMED: 25573533
DOI/URL:
Notes: Export Date: 4 May 2015 -- Source: Scopus
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  1. Eileen O'Reilly
    596 O'Reilly