Safety, Efficacy and Pharmacokinetics of Neratinib (HKI-272) in Japanese Patients with Advanced Solid Tumors: A Phase 1 Dose-escalation Study
Safety, Efficacy and Pharmacokinetics of Neratinib (HKI-272) in Japanese Patients with Advanced Solid Tumors: A Phase 1 Dose-escalation Study
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DOI：
10.1093/jjco/hys012
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发表时间：
2012-04-01
影响因子：
2.4
通讯作者：
Boku, Narikazu
中科院分区：
文献类型：
--
作者：
Ito, Yoshinori;Suenaga, Mitsukuni;Boku, Narikazu
Neratinib （HKI-272）是一种有效的、不可逆的、小分子、口服的泛erbb抑制剂，通过抑制三种表皮生长因子受体[ErbB1、ErbB2 （Her2）和ErbB4]来阻断信号转导，目前正在开发用于治疗包括乳腺癌在内的实体肿瘤。这项1期剂量递增研究评估了奈拉替尼在日本晚期实体瘤患者中的安全性、耐受性、最大耐受剂量、抗肿瘤活性和药代动力学。患者口服奈拉替尼80、160、240或320 mg；每个患者只入组一个剂量队列。患者在第1周接受单剂量，随后每天连续给药。分别于第1天和第21天采集血样进行药代动力学分析。21例患者入组，其中乳腺癌3例，结直肠癌17例，胃癌1例。neratinib相关不良事件（所有级别）包括腹泻（20例）、疲劳（14例）、恶心和腹痛（各9例）和厌食症（8例）。2例或更多患者的epsilon 3级neratinib相关不良事件为腹泻和厌食症（各2例）。剂量限制性毒性为腹泻和厌食（2例，剂量为320 mg）。最大耐受剂量和推荐剂量为neratinib 240 mg，每日一次。在21名可评估的患者中，2名乳腺癌患者有部分缓解，3名在24周内病情稳定，7名在16周内病情稳定，9名病情进展。药代动力学分析表明，纳拉替尼暴露量随剂量增加而增加。neratinib的安全性、有效性和药代动力学特征与非日本患者的报道一致，值得进一步研究neratinib在日本实体瘤患者中的应用。
Neratinib (HKI-272), a potent, irreversible, small-molecule, orally administered, pan-ErbB inhibitor that blocks signal transduction via inhibition of three epidermal growth factor receptors [ErbB1, ErbB2 (Her2) and ErbB4], is being developed for the treatment of solid tumors, including breast cancer. This Phase 1 dose-escalation study assessed the safety, tolerability, maximum-tolerated dose, antitumor activity and pharmacokinetics of neratinib in Japanese patients with advanced solid tumors.Patients received neratinib 80, 160, 240 or 320 mg orally; each patient enrolled in only one dose cohort. Patients received a single dose in week 1, followed by daily continuous doses. Blood samples collected were on days 1 and 21 for pharmacokinetic analyses.Twenty-one patients were enrolled (3 breast cancer; 17 colorectal cancer; 1 gastric cancer). Neratinib-related adverse events (all grades) included diarrhea (20 patients), fatigue (14 patients), nausea and abdominal pain (9 patients each) and anorexia (8 patients). Grade epsilon 3 neratinib-related adverse events in two or more patients were diarrhea and anorexia (two patients each). Dose-limiting toxicities were diarrhea and anorexia (two patients, 320 mg dose). The maximum-tolerated dose and recommended dose was neratinib 240 mg once daily. Of 21 evaluable patients, 2 with breast cancer had partial response, 3 had stable disease epsilon 24 weeks, 7 had stable disease epsilon 16 weeks and 9 had progressive disease. Pharmacokinetic analyses indicated that neratinib exposures increased with dose.The safety, efficacy and pharmacokinetic profiles of neratinib are consistent with those reported for non-Japanese patients and warrant further investigation of neratinib in Japanese patients with solid tumors.