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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 4/2016

01-10-2016 | Original Article

Olaparib does not cause clinically relevant QT/QTc interval prolongation in patients with advanced solid tumours: results from two phase I studies

Authors: Helen Swaisland, Ruth Plummer, Karen So, Sally Garnett, Wendy Bannister, Marc-Antoine Fabre, Corina Dota, Anitra Fielding

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2016

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Abstract

Background

Some therapeutic agents in oncology can be causally associated with specific cardiovascular events including QT/QTc interval prolongation. We investigated the effect of multiple dosing of the oral poly (ADP-ribose)-polymerase (PARP) inhibitor, olaparib (tablet formulation) on QT/QTc interval.

Methods

Two phase I, open-label, three-part studies (NCT01921140 [study 4] and NCT01900028 [study 7]) were conducted in adults with refractory/resistant advanced solid tumours. In both studies, parts A and B assessed the QT/QTc interval effects of single-dose oral olaparib 100 (study 4) or 300 (study 7) mg and multiple-dose olaparib 300 mg bid for 5 days, respectively, while part C evaluated continued access to olaparib for additional safety analyses. An ANCOVA model tested the primary objective of multiple-dose effects of olaparib on QT interval corrected using Fridericia’s formula (QTcF).

Results

Data from 119 and 109 patients were pooled from parts A and B, respectively, for QT/QTc analysis. At pre-dose and up to 12 h post-dose, the upper limits of the 90 % confidence intervals (CIs) for the difference in QTcF least squares means after olaparib multiple dosing versus control (day −1) were <10 ms, suggesting a lack of clinically relevant effect on cardiac repolarization. A slight shortening of QTcF was observed at most time points versus control. QTcF results for the individual studies and single-dose olaparib paralleled the primary multiple-dose pooled analysis, with upper limits of the 90 % CIs < 10 ms.

Conclusion

Olaparib tablets administered as multiple or single doses had no clinically significant effect on QT/QTc interval.
Appendix
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Literature
1.
Evers B, Drost R, Schut E, de Bruin M, van der Burg E, Derksen PW, Holstege H, Liu X, van Drunen E, Beverloo HB, Smith GC, Martin NM, Lau A, O’Connor MJ, Jonkers J (2008) Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin. Clin Cancer Res 14:3916–3925CrossRefPubMed
2.
Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, Derksen PW, de Bruin M, Zevenhoven J, Lau A, Boulter R, Cranston A, O’Connor MJ, Martin NM, Borst P, Jonkers J (2008) High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci USA 105:17079–17084CrossRefPubMedPubMedCentral
3.
Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, Scott C, Weitzel JN, Oaknin A, Loman N, Lu K, Schmutzler RK, Matulonis U, Wickens M, Tutt A (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 376:245–251CrossRefPubMed
4.
Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, Friedlander M, Arun B, Loman N, Schmutzler RK, Wardley A, Mitchell G, Earl H, Wickens M, Carmichael J (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376:235–244CrossRefPubMed
5.
Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, Hirte H, Huntsman D, Clemons M, Gilks B, Yerushalmi R, MacPherson E, Carmichael J, Oza A (2011) Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 12:852–861CrossRefPubMed
6.
Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, Meier W, Shapira Frommer R, Safra T, Matei D, MacPherson E, Watkins C, Carmichael J, Matulonis U (2012) Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 366:1382–1392CrossRefPubMed
7.
Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott CL, Meier W, Shapira-Frommer R, Safra T, Matei D, Fielding A, Spencer S, Dougherty B, Orr M, Hodgson D, Barrett JC, Matulonis U (2014) Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 15:852–861CrossRefPubMed
8.
Mateo J, Friedlander M, Sessa C, Leunen K, Nicum S, Gourley C, Fielding A, Bowen K, Kaye S, Molife LR (2013) Administration of continuous/intermittent olaparib in ovarian cancer patients with a germline BRCA1/2 mutation to determine an optimal dosing schedule for the tablet formulation. Eur J Cancer 49(Suppl 2):abst 801
9.
Molife LR, Mateo J, McGoldrick T, Krebs M, Drew Y, Banerjee SN, Nicum S, Ranson M, Rustin GJ, Sessa C, Plummer R, Leunen K, Friedlander M, Swaisland H, Burke W, McCormack P, Pemberton K, Tchakov I, Kaye SB, Gourley C (2012) Safety and efficacy results from two randomized expansions of a phase I study of a tablet formulation of the PARP inhibitor, olaparib, in ovarian and breast cancer patients with BRCA1/2 mutations. J Clin Oncol 30(15S):abst 3048
10.
11.
Bagnes C, Panchuk PN, Recondo G (2010) Antineoplastic chemotherapy induced QTc prolongation. Curr Drug Saf 5:93–96CrossRefPubMed
12.
13.
Rock EP, Finkle J, Fingert HJ, Booth BP, Garnett CE, Grant S, Justice RL, Kovacs RJ, Kowey PR, Rodriguez I, Sanhai WR, Strnadova C, Targum SL, Tsong Y, Uhl K, Stockbridge N (2009) Assessing proarrhythmic potential of drugs when optimal studies are infeasible. Am Heart J 157(827–36):836
14.
Plummer R, Swaisland H, Leunen K, van Herpen CM, Jerusalem G, De Grève J, Lolkema MP, Soetekouw P, Mau-Sorensen M, Nielsen D, Spicer J, Fielding A, So K, Bannister W, Molife LR (2015) Olaparib tablet formulation: effect of food on the pharmacokinetics after oral dosing in patients with advanced solid tumours. Cancer Chemother Pharmacol 76:723–729CrossRefPubMed
15.
Plummer R, Verheul H, Rottey S, Leunen K, Jerusalem G, Rolfo C, Nielsen D, Molife R, Kristeleit R, de Vos-Geelen J, Mau-Sørensen M, Soetekouw P, van Herpen C, Swaisland H, Fielding A, So K, Bannister W, Dirix L (2015) Effect of itraconazole and rifampin on the pharmacokinetics of olaparib tablet formulation in patients with advanced solid tumours: a Phase 1 open label study. J Clin Oncol 33(Suppl):abst 2565
16.
17.
Piotrovsky V (2005) Pharmacokinetic-pharmacodynamic modeling in the data analysis and interpretation of drug-induced QT/QTc prolongation. AAPS J 7:E609–E624CrossRefPubMedPubMedCentral
18.
Garnett CE, Beasley N, Bhattaram VA, Jadhav PR, Madabushi R, Stockbridge N, Tornøe CW, Wang Y, Zhu H, Gobburu JV (2008) Concentration–QT relationships play a key role in the evaluation of proarrhythmic risk during regulatory review. J Clin Pharmacol 48:13–18CrossRefPubMed
19.
Taubel J, Wong AH, Naseem A, Ferber G, Camm AJ (2012) Shortening of the QT interval after food can be used to demonstrate assay sensitivity in thorough QT studies. J Clin Pharmacol 52:1558–1565CrossRefPubMed
20.
Iribarren C, Round AD, Peng JA, Lu M, Zaroff JG, Holve TJ, Prasad A, Stang P (2013) Validation of a population-based method to assess drug-induced alterations in the QT interval: a self-controlled crossover study. Pharmacoepidemiol Drug Saf 22:1222–1232CrossRefPubMed
21.
Bedford TA, Rowbotham DJ (1996) Cisapride. Drug interactions of clinical significance. Drug Saf 15:167–175CrossRefPubMed
22.
Honig PK, Wortham DC, Hull R, Zamani K, Smith JE, Cantilena LR (1993) Itraconazole affects single-dose terfenadine pharmacokinetics and cardiac repolarization pharmacodynamics. J Clin Pharmacol 33:1201–1206CrossRefPubMed
23.
Cruccu V, Pedretti D, Confalonieri F (1995) A case of pulmonary aspergillosis effectively treated with itraconazole. Possible interaction of the antimycotic agent with hydroquinidine. Clin Ter 146:383–389
24.
Metadata
Title
Olaparib does not cause clinically relevant QT/QTc interval prolongation in patients with advanced solid tumours: results from two phase I studies
Authors
Helen Swaisland
Ruth Plummer
Karen So
Sally Garnett
Wendy Bannister
Marc-Antoine Fabre
Corina Dota
Anitra Fielding
Publication date
01-10-2016
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 4/2016
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-016-3124-5

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