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Clinical Trial
. 2016 Jun;11(3):401-15.
doi: 10.1007/s11523-016-0435-8.

An Adaptive Study to Determine the Optimal Dose of the Tablet Formulation of the PARP Inhibitor Olaparib

J Mateo  1 , V Moreno  1 , A Gupta  2 , S B Kaye  1 , E Dean  3 , M R Middleton  2 , M Friedlander  4 , C Gourley  5 , R Plummer  6 , G Rustin  7 , C Sessa  8 , K Leunen  9 , J Ledermann  10 , H Swaisland  11 , A Fielding  11 , W Bannister  12 , S Nicum  2 , L R Molife  13
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Free article
Clinical Trial

An Adaptive Study to Determine the Optimal Dose of the Tablet Formulation of the PARP Inhibitor Olaparib

J Mateo et al. Target Oncol. 2016 Jun.
Free article

Abstract

Background: Olaparib is poorly soluble, requiring advanced drug delivery technologies for adequate bioavailability. Sixteen capsules/day are required for the approved 400 mg twice-daily dose; a tablet formulation was developed to reduce pill burden. This clinical trial evaluated the optimal dose and administration schedule of the tablet formulation.

Patients and methods: Two stages of sequentially enrolled cohorts: stage 1, pharmacokinetic properties of tablet and capsule formulations were compared in patients with advanced solid tumours; stage 2, tablet dose escalation with expansion cohorts at doses/schedules of interest in patients with solid tumours and BRCAm breast/ovarian cancers.

Results: Olaparib 200 mg tablets displayed similar Cmax,ss, but lower AUCss and Cmin,ss than 400 mg capsules. Following multiple dosing, steady-state exposure with tablets ≥300 mg matched or exceeded that of 400 mg capsules. After dose escalation, while 400 mg twice daily was the tablet maximum tolerated dose based on haematological toxicity, 65 % of patients in the randomized expansion phase eventually required dose reduction to 300 mg. Intermittent tablet administration did not significantly improve tolerability. Tumour shrinkage was similar for 300 and 400 mg tablet and 400 mg capsule cohorts.

Conclusions: The recommended monotherapy dose of olaparib tablet for Phase III trials was 300 mg twice daily, simplifying drug administration from 16 capsules to four tablets per day.

Clinical trial number: NCT00777582 (ClinicalTrials.gov).

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