Phase I study to determine the bioavailability and tolerability of a tablet formulation of the PARP inhibitor olaparib in patients with advanced solid tumors: Dose-escalation phase.

Abstract

3051 Background: We previously reported the comparative bioavailability of the olaparib tablet (TAB) up to 200 mg BID, with the initial capsule formulation; gmean AUC0–T following 200 mg BID TAB was ~20% lower than 400 mg BID capsule (CAP; Molife et al ASCO 2010). Olaparib 200 mg BID TAB had an acceptable tolerability profile suggesting further dose escalation might be justified. Methods: Study NCT00777582 was amended to include a dose-escalation phase, to define the maximum tolerated dose (MTD) and safety profile of the TAB, and 2 expansion phases to compare safety and efficacy of TAB doses vs 400 mg BID CAP. Expansion phase data are reported separately. Here, we report preliminary data from the dose-escalation phase where patients (pts) with advanced solid tumors, ECOG PS 0–2 and adequate organ function were assigned to treatment with increasing olaparib BID TAB doses in 28-day continuous dosing cycles. Pharmacokinetic (PK) sampling was performed on days 1, 8, 15, 29, 57. Results: 30 pts (M:F, 3:27; median age 54 yrs [range 19–70]) were enrolled in the dose-escalation phase and received treatment at 5 dose levels: 250, 300, 350, 400 and 450 mg (each dose level, n=6). Overall, the most common AEs were nausea (80%), fatigue (73%) and diarrhea (36%). The majority of AEs were mild to moderate (CTC grade [G] 1/2). Hematologic toxicity in terms of, mostly mild, anemia, neutropenia and thrombocytopenia, appeared to increase at doses of 300 mg BID or higher. Two pts had dose-limiting toxicities at 450 mg (G3 thrombocytopenia and G3 anemia); the TAB MTD was 400 mg BID. Exposure increased proportionally with increasing dose: mean exposure after 400 mg BID was double that following the previously reported 200 mg BID dose. Following 300 and 400 mg doses, gmean Cmax ss, AUC0–T and Cmin ss matched or exceeded the 400 mg BID CAP dose. Conclusions: The MTD of olaparib TAB was 400 mg BID. Based on PK analysis, the 300 and 400 mg BID doses were selected for evaluation in the MTD expansion phase to further define safety and preliminary efficacy.