Masuda Norikazu, Iwata Hiroji, Aogi Kenjiro, Xu Yihuan, Ibrahim Ayman, Gao Ling, Dalal Rita, Yoshikawa Reigetsu, Sasaki Yasutsuna
Department of Surgery, Breast Oncology, National Hospital Organization, Osaka National Hospital, Osaka
Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya.
Jpn J Clin Oncol. 2016 Dec;46(12):1088-1094. doi: 10.1093/jjco/hyw127. Epub 2016 Sep 8.
The primary objective of this study was to investigate the safety and tolerability and to confirm the recommended dose of the anti-vascular endothelial growth factor receptor 2 monoclonal antibody ramucirumab in combination with docetaxel in Japanese patients with metastatic/locally advanced breast cancer.
In this multicenter, single-arm, Phase Ib trial, eligibility criteria included: 20 years or older, Eastern Cooperative Oncology Group performance status of 0/1 and confirmed diagnosis of human epidermal growth factor receptor 2-negative metastatic/locally recurrent inoperable breast adenocarcinoma. Patients received docetaxel (75 mg/m) followed by ramucirumab (10 mg/kg) on Day 1 of 21-day cycles. Recommended dose was defined as <33% dose-limiting toxicities in dose-limiting toxicity-evaluable patients in Cycle 1. The safety, pharmacokinetics, immunogenicity and antitumor activity were examined.
Seven patients were treated. Most adverse events were mild to moderate. Two patients during Cycle 1 experienced a dose-limiting toxicity; one patient each experienced Grade 3 febrile neutropenia and Grade 3 gingivitis. Both dose-limiting toxicities subsequently resolved. No patients discontinued study therapies during Cycle 1. Four serious adverse events were possibly related to ramucirumab in combination with docetaxel. Anti-ramucirumab antibodies were not detected. Pharmacokinetic analysis revealed low total body clearance and long apparent terminal elimination half-life (~7-12 days). Partial response was reported in four patients.
The combination of ramucirumab and docetaxel was tolerable in female Japanese patients with breast cancer. Ramucirumab 10 mg/kg in combination with docetaxel (75 mg/m) was confirmed as the recommended dose among Japanese patients, supporting its use in future studies.
本研究的主要目的是调查抗血管内皮生长因子受体2单克隆抗体雷莫西尤单抗联合多西他赛用于日本转移性/局部晚期乳腺癌患者的安全性和耐受性，并确定推荐剂量。
在这项多中心、单臂Ib期试验中，纳入标准包括：年龄20岁及以上，东部肿瘤协作组体能状态为0/1，确诊为人表皮生长因子受体2阴性的转移性/局部复发性不可手术乳腺癌。患者接受多西他赛（75mg/m²），随后在每21天周期的第1天接受雷莫西尤单抗（10mg/kg）。推荐剂量定义为在第1周期中可评估剂量限制性毒性的患者中剂量限制性毒性发生率<33%。对安全性、药代动力学、免疫原性和抗肿瘤活性进行了检查。
7例患者接受了治疗。大多数不良事件为轻度至中度。2例患者在第1周期出现剂量限制性毒性；1例患者分别出现3级发热性中性粒细胞减少和3级牙龈炎。两种剂量限制性毒性随后均得到缓解。第1周期无患者停止研究治疗。4例严重不良事件可能与雷莫西尤单抗联合多西他赛有关。未检测到抗雷莫西尤单抗抗体。药代动力学分析显示总体清除率低，表观终末消除半衰期长（约7 - 12天）。4例患者报告有部分缓解。
雷莫西尤单抗和多西他赛联合用药在日本女性乳腺癌患者中耐受性良好。雷莫西尤单抗10mg/kg联合多西他赛（75mg/m²）被确认为日本患者的推荐剂量，支持其在未来研究中的应用。
