Safety and tolerability of the olaparib tablet formulation in Japanese patients with advanced solid tumours

Kan Yonemori, Kenji Tamura, Makoto Kodaira, Koshi Fujikawa, Tamotsu Sagawa, Taito Esaki, Tsuyoshi Shirakawa, Fumihiko Hirai, Yuki Yokoi, Toshio Kawata, Ben Hatano, Yasuo Takahashi

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Abstract

Purpose: This was the first Phase I study to assess the safety and tolerability of the tablet formulation of olaparib (Lynparza™), an oral poly(ADP-ribose) polymerase inhibitor, in Japanese patients with advanced solid tumours. The pharmacokinetic profile and antitumour activity of olaparib tablets were also assessed. Methods: In this open-label, multicentre study (D081BC00001; NCT01813474), a single dose of olaparib (200 or 300 mg, tablets) was administered on day 1, followed 48 h afterwards by multiple dosing (200 or 300 mg twice daily [bid]) for 28-day cycles. Doses were escalated in successive cohorts, with an expansion cohort enrolled at the highest dose that was confirmed to be tolerable during dose escalation. Results: Twenty-eight patients were enrolled and 23 were treated (n = 4, 7 and 12 at 200, 300 and 300 [expansion] mg bid, respectively). No patients experienced a dose-limiting toxicity, so the maximum tolerated dose was not defined. The most frequent adverse events were nausea (43.5 %), decreased appetite (30.4 %), anaemia (26.1 %) and constipation (26.1 %). No patient had dose reductions, two had dose interruptions, and two discontinued treatment because of adverse events. Absorption of olaparib was rapid following single and multiple dosing, and plasma concentrations declined biphasically after single dosing. No patients had a confirmed antitumour response. Conclusions: Olaparib tablet doses of 200 and 300 mg bid were considered tolerable in Japanese patients with advanced solid tumours. Consistent with the global olaparib programme, 300 mg bid was selected as the recommended tablet dose for future studies. Clinical trial registration number: NCT01813474.

Original languageEnglish
Pages (from-to)525-531
Number of pages7
JournalCancer chemotherapy and pharmacology
Volume78
Issue number3
DOIs
Publication statusPublished - Sep 1 2016

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Tablets
Tumors
Safety
Neoplasms
Pharmacokinetics
Maximum Tolerated Dose
Appetite
Constipation
olaparib
Nausea
Multicenter Studies
Toxicity
Labels
Anemia
Clinical Trials
Plasmas

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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Safety and tolerability of the olaparib tablet formulation in Japanese patients with advanced solid tumours. / Yonemori, Kan; Tamura, Kenji; Kodaira, Makoto; Fujikawa, Koshi; Sagawa, Tamotsu; Esaki, Taito; Shirakawa, Tsuyoshi; Hirai, Fumihiko; Yokoi, Yuki; Kawata, Toshio; Hatano, Ben; Takahashi, Yasuo.

In: Cancer chemotherapy and pharmacology, Vol. 78, No. 3, 01.09.2016, p. 525-531.

Research output: Contribution to journalArticle

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 chemotherapy and pharmacology, vol. 78, no. 3, pp. 525-531. https://doi.org/10.1007/s00280-016-3106-7
Yonemori, Kan ; Tamura, Kenji ; Kodaira, Makoto ; Fujikawa, Koshi ; Sagawa, Tamotsu ; Esaki, Taito ; Shirakawa, Tsuyoshi ; Hirai, Fumihiko ; Yokoi, Yuki ; Kawata, Toshio ; Hatano, Ben ; Takahashi, Yasuo. / Safety and tolerability of the olaparib tablet formulation in Japanese patients with advanced solid tumours. In: Cancer chemotherapy and pharmacology. 2016 ; Vol. 78, No. 3. pp. 525-531.
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AU - Kodaira, Makoto

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AU - Sagawa, Tamotsu

AU - Esaki, Taito

AU - Shirakawa, Tsuyoshi

AU - Hirai, Fumihiko

AU - Yokoi, Yuki

AU - Kawata, Toshio

AU - Hatano, Ben

AU - Takahashi, Yasuo

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N2 - Purpose: This was the first Phase I study to assess the safety and tolerability of the tablet formulation of olaparib (Lynparza™), an oral poly(ADP-ribose) polymerase inhibitor, in Japanese patients with advanced solid tumours. The pharmacokinetic profile and antitumour activity of olaparib tablets were also assessed. Methods: In this open-label, multicentre study (D081BC00001; NCT01813474), a single dose of olaparib (200 or 300 mg, tablets) was administered on day 1, followed 48 h afterwards by multiple dosing (200 or 300 mg twice daily [bid]) for 28-day cycles. Doses were escalated in successive cohorts, with an expansion cohort enrolled at the highest dose that was confirmed to be tolerable during dose escalation. Results: Twenty-eight patients were enrolled and 23 were treated (n = 4, 7 and 12 at 200, 300 and 300 [expansion] mg bid, respectively). No patients experienced a dose-limiting toxicity, so the maximum tolerated dose was not defined. The most frequent adverse events were nausea (43.5 %), decreased appetite (30.4 %), anaemia (26.1 %) and constipation (26.1 %). No patient had dose reductions, two had dose interruptions, and two discontinued treatment because of adverse events. Absorption of olaparib was rapid following single and multiple dosing, and plasma concentrations declined biphasically after single dosing. No patients had a confirmed antitumour response. Conclusions: Olaparib tablet doses of 200 and 300 mg bid were considered tolerable in Japanese patients with advanced solid tumours. Consistent with the global olaparib programme, 300 mg bid was selected as the recommended tablet dose for future studies. Clinical trial registration number: NCT01813474.

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