Pharmacokinetic Effects and Safety of Olaparib Administered with Endocrine Therapy: A Phase I Study in Patients with Advanced Solid Tumours |
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| Authors: | Ruth Plummer Henk M Verheul Filip Y F L De Vos Karin Leunen L Rhoda Molife Christian Rolfo Peter Grundtvig-Sørensen Jacques De Grève Sylvie Rottey Guy Jerusalem Antoine Italiano James Spicer Luc Dirix Carsten Goessl Joseph Birkett Stuart Spencer Maria Learoyd Christopher Bailey Emma Dean |
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| Institution: | 1.Northern Centre for Cancer Care, Newcastle University,Newcastle upon Tyne,UK;2.Department of Medical Oncology, Cancer Center Amsterdam,VU University Medical Center,Amsterdam,The Netherlands;3.University Medical Center Utrecht,University of Utrecht,Utrecht,The Netherlands;4.Universitair Ziekenhuis Leuven,Leuven,Belgium;5.The Royal Marsden and Institute of Cancer Research,Sutton,UK;6.Universitair Ziekenhuis Antwerpen,Antwerp,Belgium;7.Herlev Hospital,University of Copenhagen,Herlev,Denmark;8.Department of Medical Oncology, Oncologisch Centrum,Universitair Ziekenhuis Brussel,Brussels,Belgium;9.Universitair Ziekenhuis Gent,Ghent,Belgium;10.CHU Sart-Tilman Liege,Liege University,Liege,Belgium;11.Department of Medical Oncology,Institut Bergonié, Comprehensive Cancer Centre Bordeaux,Bordeaux,France;12.King’s College London,Guy’s Hospital,London,UK;13.Campus Sint-Augustinus,GZA Ziekenhuizen,Antwerp,Belgium;14.AstraZeneca,Gaithersburg,USA;15.AstraZeneca,Macclesfield,UK;16.AstraZeneca,Cambridge,UK;17.The Christie NHS Foundation Trust,University of Manchester,Manchester,UK |
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| Abstract: | IntroductionThe PARP inhibitor olaparib is efficacious as monotherapy and has potential application in combination with endocrine therapy for the treatment of breast cancer. This phase I study assessed the safety and pharmacokinetic (PK) profiles of olaparib combined with tamoxifen, anastrozole or letrozole in patients with advanced solid tumours.MethodsDuring part A, PK profiles were assessed in three consecutive treatment periods: (1) olaparib (tablet) 300 mg bid, days 1–5 followed by a 4-day washout; (2) cohort 1, tamoxifen 60 mg loading dose qd days 10–13, 20 mg qd days 14–26; cohort 2, anastrozole 1 mg qd days 10–19; cohort 3, letrozole 2.5 mg qd days 10–38; (3) as for period 2, with concomitant olaparib 300 mg bid for 5 days. Patients could then enter part B and receive olaparib monotherapy (300 mg bid continuously). Safety was assessed in parts A and B until 12 months after the last patient entered part B.ResultsSeventy-nine patients (20.3% with breast cancer) received treatment in part A; 72 completed part A and 69 entered part B. Anastrozole and letrozole had no effect on the PK profile of olaparib and vice versa. Co-administration with tamoxifen produced a modest decrease in exposure to olaparib geometric least-squares mean (GLSmean) Cmax,ss and AUC0–τ decreased by 20% (90% CI 0.71–0.90) and 27% (0.63–0.84), respectively]. Exposure to tamoxifen was slightly increased when combined with olaparib GLSmean Cmax,ss and AUC0–τ increased by 13% (1.06–1.22) and 16% (1.11–1.21), respectively]; however, the 90% CI fell within the 0.7–1.43 boundary and there were no changes in exposure to tamoxifen metabolites. The safety profile for olaparib alone and in combination with the antihormonal therapies was acceptable.ConclusionsThe combination of olaparib and either anastrozole, letrozole or tamoxifen was generally well tolerated, with no clinically relevant PK interactions identified.FundingAstraZeneca.Clinical Trial RegistrationNCT02093351. |
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