Phase I and pharmacokinetic study of dacomitinib (PF-00299804), an oral irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases, in Japanese patients with advanced solid tumors.
Phase I and pharmacokinetic study of dacomitinib (PF-00299804), an oral irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases, in Japanese patients with advanced solid tumors.
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DOI：
10.1007/s10637-011-9789-z
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发表时间：
2012-12
影响因子：
3.4
通讯作者：
Yamamoto, Nobuyuki
中科院分区：
文献类型：
--
作者：
Takahashi, Toshiaki;Boku, Narikazu;Murakami, Haruyasu;Naito, Tateaki;Tsuya, Asuka;Nakamura, Yukiko;Ono, Akira;Machida, Nozomu;Yamazaki, Kentaro;Watanabe, Junichiro;Ruiz-Garcia, Ana;Imai, Keiji;Ohki, Emiko;Yamamoto, Nobuyuki
关键词：
背景Dacomitinib（PF-00299804）是一种口服、不可逆的人表皮生长因子受体-1、-2和-4酪氨酸激酶小分子抑制剂。方法这项I期、开放标签、剂量递增研究（clinicaltrials.gov：NCT 00783328）主要通过剂量限制性毒性（DLT）评估dacomitinib的安全性和耐受性，并确定日本晚期实体瘤患者的临床推荐II期剂量（RP 2D）。Dacomitinib以3个剂量水平（15、30或45 mg每日一次[QD]）口服给药。患者最初接受单次给药，9天随访后，连续QD，21天为一个周期。终点包括药代动力学（PK）和抗肿瘤活性。结果13例患者按照传统的“3 + 3”设计被分配到3个剂量水平（15 mg队列：n = 3; 30 mg队列：n = 3; 45 mg队列：n = 7）。接受治疗的患者均未发生DLT。毒性是可管理的，并且与其他研究中观察到的毒性类型相似。在评价的范围内，PK浓度参数随剂量增加而增加，无随时间蓄积的证据。在13例可评价患者中，1例NSCLC（腺癌）患者部分缓解，9例患者病情稳定。结论Dacomitinib 45 mg QD定义为RP 2D，在日本晚期实体瘤患者中表现出初步活性。
Background Dacomitinib (PF-00299804) is an oral, irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases. Methods This phase I, open-label, dose-escalation study (clinicaltrials.gov: NCT00783328) primarily evaluated the safety and tolerability of dacomitinib by dose-limiting toxicity (DLT), and determined the clinically recommended phase II dose (RP2D) in Japanese patients with advanced solid tumors. Dacomitinib was administered orally at three dose levels (15, 30, or 45 mg once daily [QD]). Patients initially received a single dose, and after 9 days of follow-up, continuously QD in 21-day cycles. Endpoints included pharmacokinetics (PK) and antitumor activity. Results Thirteen patients were assigned to the three dose levels (15 mg cohort: n = 3; 30 mg cohort: n = 3; 45 mg cohort: n = 7) according to a traditional ‘3 + 3’ design. None of the treated patients experienced a DLT. Toxicities were manageable and similar in type to those observed in other studies. PK concentration parameters increased with dose over the range evaluated, with no evidence of accumulation over time. Of 13 evaluable patients, one with NSCLC (adenocarcinoma) had a partial response and nine patients had stable disease. Conclusions Dacomitinib 45 mg QD was defined as the RP2D and demonstrated preliminary activity in Japanese patients with advanced solid tumors.
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影响因子：
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