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01-06-2016 | Original Research Article

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

Authors: J. Mateo, V. Moreno, A. Gupta, S. B. Kaye, E. Dean, M. R. Middleton, M. Friedlander, C. Gourley, R. Plummer, G. Rustin, C. Sessa, K. Leunen, J. Ledermann, H. Swaisland, A. Fielding, W. Bannister, S. Nicum, L. R. Molife

Published in: Targeted Oncology | Issue 3/2016

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 C_max,ss, but lower AUC_ss and C_min,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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Title: An Adaptive Study to Determine the Optimal Dose of the Tablet Formulation of the PARP Inhibitor Olaparib
Authors: J. Mateo
V. Moreno
A. Gupta
S. B. Kaye
E. Dean
M. R. Middleton
M. Friedlander
C. Gourley
R. Plummer
G. Rustin
C. Sessa
K. Leunen
J. Ledermann
H. Swaisland
A. Fielding
W. Bannister
S. Nicum
L. R. Molife
Publication date: 01-06-2016
Publisher: Springer International Publishing
Published in: Targeted Oncology / Issue 3/2016
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI: https://doi.org/10.1007/s11523-016-0435-8

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Abstract

Background

Patients and Methods

Results

Conclusions

Clinical Trial Number

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