Seto Takashi, Hirai Fumihiko, Saka Hideo, Kogure Yoshihito, Yoh Kiyotaka, Niho Seiji, Fukase Kenjiro, Shimada Hitoshi, Sasai Michitaka, Fukino Koichi
Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka.
Department of Medical Oncology and Respiratory Medicine, National Hospital Organisation Nagoya Medical Centre, Nagoya.
Jpn J Clin Oncol. 2018 Jan 1;48(1):31-42. doi: 10.1093/jjco/hyx144.
This Phase I study (NCT01605916) investigated the safety, tolerability and pharmacokinetic profile of selumetinib plus docetaxel as second-line therapy in Japanese patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), or selumetinib monotherapy in Japanese patients with advanced solid malignancies.
All enrolled patients received single-dose selumetinib 25, 50 or 75 mg, followed by a 3-day washout. Combination therapy cohorts then started a 21-day cycle of docetaxel 60 mg/m2 plus selumetinib 25 or 75 mg twice-daily (BID) on Day 1. Thereafter, selumetinib BID continued for 20 days; patients received ≤6 cycles. Following single-dosing, monotherapy cohorts underwent a 21-day cycle of selumetinib 25, 50 or 75 mg BID.
Thirty-three patients were enrolled and 25 assigned to treatment (combination, n = 8; monotherapy, n = 17). Most frequent adverse events (AEs) included: vomiting, decreased appetite, diarrhea, nausea and stomatitis (combination cohorts); gastrointestinal disorders, skin and subcutaneous tissue disorders (monotherapy cohorts). Grade 3 dose-limiting toxicities: febrile neutropenia, causally related to combination therapy (n = 3); pneumonitis, selumetinib 50 mg monotherapy (n = 1). Selumetinib 75 mg monotherapy and selumetinib 25 mg plus docetaxel 60 mg/m2 were tolerated; selumetinib 75 mg plus docetaxel 60 mg/m2 was not tolerated. Selumetinib pharmacokinetic profile was similar when administered as a monotherapy or in combination with docetaxel.
Selumetinib 75 mg monotherapy was tolerated in Japanese patients with NSCLC. Due to the overall selumetinib AE profile, the maximum tolerated dose was not determined for combination therapy or monotherapy. Selumetinib 75 mg BID plus docetaxel 60 mg/m2 was not tolerated in this patient population.
本I期研究（NCT01605916）调查了司美替尼联合多西他赛作为日本局部晚期或转移性非小细胞肺癌（NSCLC）患者二线治疗方案的安全性、耐受性和药代动力学特征，以及司美替尼单药治疗日本晚期实体瘤患者的情况。
所有入组患者接受单剂量25、50或75mg司美替尼治疗，随后进行3天的洗脱期。联合治疗组在第1天开始为期21天的周期，多西他赛60mg/m²加司美替尼25或75mg，每日两次（BID）。此后，司美替尼每日两次持续给药20天；患者接受≤6个周期的治疗。单剂量给药后，单药治疗组进行为期21天的周期，司美替尼25、50或75mg，每日两次。
共入组33例患者，25例接受治疗（联合治疗组，n = 8；单药治疗组，n = 17）。最常见的不良事件（AE）包括：呕吐、食欲下降、腹泻、恶心和口腔炎（联合治疗组）；胃肠道疾病、皮肤和皮下组织疾病（单药治疗组）。3级剂量限制性毒性：发热性中性粒细胞减少症，与联合治疗因果相关（n = 3）；肺炎，司美替尼50mg单药治疗（n = 1）。司美替尼75mg单药治疗和司美替尼25mg加60mg/m²多西他赛可耐受；司美替尼75mg加60mg/m²多西他赛不可耐受。司美替尼单药治疗或与多西他赛联合给药时，药代动力学特征相似。
司美替尼75mg单药治疗对日本NSCLC患者可耐受。由于司美替尼总体不良事件情况，联合治疗或单药治疗的最大耐受剂量未确定。司美替尼75mg每日两次加60mg/m²多西他赛在该患者群体中不可耐受。
