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Ann Oncol. 2015 Apr;26(4):804-11. doi: 10.1093/annonc/mdu581. Epub 2015 Jan 7.

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.

Author information

1
Drug Development Unit, Sarah Cannon Research Institute/Tennessee Oncology, Nashville jbendell@tnonc.com.
2
Memorial Sloan Kettering Cancer Center, New York, USA.
3
Department of Oncology, University of Oxford, Oxford.
4
Department of Medicine, Royal Marsden Hospital, Sutton, UK.
5
Yale Cancer Center, Yale School of Medicine, New Haven, USA.
6
Global Medicines Development, AstraZeneca.
7
Clinical Pharmacology, AstraZeneca, Macclesfield, UK.
8
Drug Development Unit, Sarah Cannon Research Institute/Tennessee Oncology, Nashville.

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/m(2); 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/m(2)). 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/m(2)).

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/m(2) and olaparib 100 mg o.d. tablet (intermittently, days 1-14) plus gemcitabine 600 mg/m(2). 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/m(2) is tolerated in advanced solid tumour patients, with no unmanageable/unexpected toxicities. Continuous dosing of olaparib or combination with gemcitabine at doses >600 mg/m(2) was not considered to have an acceptable tolerability profile for further study.

CLINICALTRIALSGOV:

NCT00515866.

KEYWORDS:

gemcitabine; olaparib; pancreatic cancer

PMID:
25573533
DOI:
10.1093/annonc/mdu581
[Indexed for MEDLINE]

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