Pharmacokinetics and safety of olaparib tablets as monotherapy and in combination with paclitaxel: results of a Phase I study in Chinese patients with advanced solid tumours
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Chinese patients have been enrolled in multiple Phase III trials of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza); however, the pharmacokinetic (PK) profile of olaparib has not been investigated in this population. This two-part, open-label Phase I study was, therefore, carried out to determine the PK and safety profile of olaparib (tablet formulation) in Chinese patients with advanced solid tumours as monotherapy and in combination with paclitaxel (NCT02430311).
The PK profile of olaparib 300 mg (twice daily [bid]; Cohort 1) as monotherapy after a single dose and at steady state, and 100 mg (bid; Cohort 2) as monotherapy (single dose and at steady state) and in combination (at steady state) with weekly paclitaxel (80 mg/m2) was assessed during Part A. Patients could continue to receive treatment (monotherapy, Cohort 1; combination therapy, Cohort 2) in Part B, which assessed safety and tolerability.
Twenty and 16 patients were enrolled into Cohorts 1 and 2, respectively. Steady-state olaparib exposure increased slightly less than proportionally with increasing monotherapy dose and inter-patient variability was high. A statistically significant decrease in olaparib exposure was seen when given in combination with paclitaxel. Discontinuation due to adverse events (AEs) was rare and haematological AEs were more common in patients receiving combination treatment.
The PK and safety profile of olaparib monotherapy in Chinese patients is consistent with that seen previously in Western and Japanese patients, and the recommended Phase III monotherapy tablet dose (300 mg bid) is suitable for use in this population.
KeywordsChinese patients Olaparib Paclitaxel PARP inhibitor Pharmacokinetics Safety
The authors would like to thank the patients who took part in the study and Khanh Bui for his contribution to the interpretation of the study data.
This study was sponsored by AstraZeneca and the sponsor was involved in the study design, analysis and interpretation of data, revision of the article and in the decision to submit the article for publication. Medical writing assistance was provided by Elin Pyke, MChem from Mudskipper Business Ltd, funded by AstraZeneca and Merck & Co., Inc.
Compliance with ethical standards
Conflict of interest
WB is employed by Covance Clinical Research Unit. KH was employed by AstraZeneca during manuscript development. ML is currently employed by AstraZeneca and owns stock. MZ is currently employed by AstraZeneca. All other authors report no conflicts of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 2.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 14:3916–3925CrossRefGoogle Scholar
- 3.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 105:17079–17084CrossRefGoogle Scholar
- 4.European Medicines Agency. Lynparza summary of product characteristics (2014) Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003726/WC500180151.pdf. Last accessed: 19 January 2019
- 5.FDA. Lynparza prescribing information (2017) Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208558s000lbl.pdf. Last accessed: 19 January 2019
- 6.Dent RA, Lindeman GJ, Clemons M, Wildiers H, Chan A, McCarthy NJ, Singer CF, Lowe ES, Watkins CL, Carmichael J (2013) Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer. Breast Cancer Res 15:R88CrossRefGoogle Scholar
- 7.Bang YJ, Im SA, Lee KW, Cho JY, Song EK, Lee KH, Kim YH, Park JO, Chun HG, Zang DY, Fielding A, Rowbottom J, Hodgson D, O’Connor MJ, Yin X, Kim WH (2015) Randomized, double-blind phase II trial with prospective classification by ATM protein level to evaluate the efficacy and tolerability of olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer. J Clin Oncol 33:3858–3865CrossRefGoogle Scholar
- 8.Bang YJ, Xu RH, Chin K, Lee KW, Park SH, Rha SY, Shen L, Qin S, Xu N, Im SA, Locker G, Rowe P, Shi X, Hodgson D, Liu YZ, Boku N (2017) Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 18:1637–1651CrossRefGoogle Scholar
- 10.Mateo J, Moreno V, Gupta A, Kaye SB, Dean E, Middleton MR, Friedlander M, Gourley C, Plummer R, Rustin G, Sessa C, Leunen K, Ledermann J, Swaisland H, Fielding A, Bannister W, Nicum S, Molife LR (2016) An adaptive study to determine the optimal dose of the tablet formulation of the PARP inhibitor olaparib. Target Oncol 11:401–415CrossRefGoogle Scholar
- 11.Yonemori K, Tamura K, Kodaira M, Fujikawa K, Sagawa T, Esaki T, Shirakawa T, Hirai F, Yokoi Y, Kawata T, Hatano B, Takahashi Y (2016) Safety and tolerability of the olaparib tablet formulation in Japanese patients with advanced solid tumours. Cancer Chemother Pharmacol 78:525–531CrossRefGoogle Scholar
- 12.Dirix L, Swaisland H, Verheul HM, Rottey S, Leunen K, Jerusalem G, Rolfo C, Nielsen D, Molife LR, Kristeleit R, Vos-Geelen J, Mau-Sørensen M, Soetekouw P, van Herpen C, Fielding A, So K, Bannister W, Plummer R (2016) Effect of itraconazole and rifampin on the pharmacokinetics of olaparib in patients with advanced solid tumors: results of two Phase I open-label studies. Clin Ther 38(10):2286–2299CrossRefGoogle Scholar
- 15.Moore KN, DiSilvestro P, Lowe ES, Garnett S, Pujade-Lauraine E (2014) SOLO1 and SOLO2: randomized Phase III trials of olaparib in patients (pts) with ovarian cancer and a BRCA1/2 mutation (BRCAm). J Clin Oncol 32(15 Suppl):abst TPS5616Google Scholar
- 16.Tutt A, Balmana J, Robson M, Garber J, Kaufman B, Geyer C, Saini K, Stuart M, Mann H, Fasching PA, Fashoyin-Aje I (2014) OlympiA, Neo-Olympia and OlympiAD: Randomized Phase III trials of olaparib in patients (pts) with breast cancer (BC) and a germline BRCA1/2 mutation (gBRCAm). Ann Oncol 25:iv85–iv109Google Scholar
- 17.AstraZeneca. Global policy: bioethics (2016) Available at: https://www.astrazeneca.com/content/dam/az/PDF/Bioethics_policy.pdf
- 18.Rolfo C, Swaisland H, Leunen K, Rutten A, Soetekouw P, Slater S, Verheul HM, Fielding A, So K, Bannister W, Dean E (2015) Effect of food on the pharmacokinetics of olaparib after oral dosing of the capsule formulation in patients with advanced solid tumors. Adv Ther 32(6):510–522CrossRefGoogle Scholar
- 19.China State Food and Drug Administration (2005) Technical guideline for clinical pharmacokinetic study of chemical drugs 2005. China State FDA, Beijing [H] GCL. pp. 1–2Google Scholar
- 20.Plummer R, Verheul HMW, Langenberg MHG, Leunen K, Molife RL, Rolfo CD, Grundtvig Soerensen P, de Greve J, Rottey S, Jerusalem GHM, Italiano A, Spicer JF, Dirix LY, Goessl CD, Birkett J, Spencer S, Learoyd M, Dean EJ (2016) Pharmacokinetic (PK) effects and safety of olaparib in combination with tamoxifen, anastrozole, or letrozole: Phase I study. J Clin Oncol 34(15_suppl):abst 2562CrossRefGoogle Scholar
- 22.Plummer R, Swaisland H, Leunen K, van Herpen CM, Jerusalem G, De Grève J, Lolkema MP, Soetekouw P, Mau-Sørensen 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(4):723–729CrossRefGoogle Scholar
- 28.Shono Y, Nishihara H, Matsuda Y, Furukawa S, Okada N, Fujita T, Yamamoto A (2004) Modulation of intestinal P-glycoprotein function by cremophor EL and other surfactants by an in vitro diffusion chamber method using the isolated rat intestinal membranes. J Pharm Sci 93(4):877–885CrossRefGoogle Scholar
- 31.Pujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT, Oza AM, Korach J, Huzarski T, Poveda A, Pignata S, Friedlander M, Colombo N, Harter P, Fujiwara K, Ray-Coquard I, Banerjee S, Liu J, Lowe ES, Bloomfield R, Pautier P (2017) Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 18:1274–1284CrossRefGoogle Scholar
- 33.FDA. Taxol (paclitaxel) injection (2011) Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020262s049lbl.pdf
- 34.de Bono JS, Hussain M, Thiery-Vuillemin A, Mateo J, Sartor AO, Chi KN (2017) PROfound: a randomized phase III trial evaluating olaparib in patients with metastatic castration-resistant prostate cancer and a deleterious homologous recombination DNA repair aberration. J Clin Oncol 35(15 Suppl):abst TPS5091Google Scholar