Yonemori Kan, Tamura Kenji, Kodaira Makoto, Fujikawa Koshi, Sagawa Tamotsu, Esaki Taito, Shirakawa Tsuyoshi, Hirai Fumihiko, Yokoi Yuki, Kawata Toshio, Hatano Ben, Takahashi Yasuo
Department of Breast and Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
Department of Gastroenterology, National Hospital Organization Hokkaido Cancer Center, Hokkaido, Japan.
Cancer Chemother Pharmacol. 2016 Sep;78(3):525-31. doi: 10.1007/s00280-016-3106-7. Epub 2016 Jul 15.
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.
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.
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.
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.
NCT01813474.
这是第一项评估口服聚（ADP - 核糖）聚合酶抑制剂奥拉帕利（Lynparza™）片剂在日本晚期实体瘤患者中的安全性和耐受性的I期研究。同时还评估了奥拉帕利片剂的药代动力学特征和抗肿瘤活性。
在这项开放标签、多中心研究（D081BC00001；NCT01813474）中，于第1天给予单剂量奥拉帕利（200或300mg，片剂），48小时后开始多次给药（200或300mg，每日两次 [bid]），为期28天的周期。剂量在连续的队列中逐步递增，在剂量递增期间确认可耐受的最高剂量处纳入一个扩展队列。
共入组28例患者，23例接受治疗（分别为200mg bid组4例、300mg bid组7例和300mg [扩展] bid组12例）。无患者发生剂量限制性毒性，因此未确定最大耐受剂量。最常见的不良事件为恶心（43.5%）、食欲减退（30.4%）、贫血（26.1%）和便秘（26.1%）。无患者减少剂量，2例患者中断剂量，2例因不良事件停止治疗。单剂量和多剂量给药后奥拉帕利吸收迅速，单剂量给药后血浆浓度呈双相下降。无患者有确证的抗肿瘤反应。
200mg和300mg bid的奥拉帕利片剂剂量在日本晚期实体瘤患者中被认为是可耐受的。与全球奥拉帕利研究项目一致，选择300mg bid作为未来研究的推荐片剂剂量。
NCT01813474。
