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

We identified olaparib 100 mg b.i.d. (intermittent) with gemcitabine 600 mg/m² as a tolerated dose combination, which could be considered for future evaluation. Given the encouraging response observed in patients with aBRCAm in previous olaparib trials, further investigation of clinical benefit in this patient subset compared with chemotherapy alone is warranted.BackgroundOlaparib (Lynparza™) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that induces synthetic lethality in cancers with homologous recombination defects.Patients and methodsIn 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).ResultsSixty-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.ConclusionsOlaparib 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.ClinicalTrials.govNCT00515866.