Phase 1, open-label, dose escalation, safety, and pharmacokinetics study of ME-344 as a single agent in patients with refractory solid tumors.
Phase 1, open-label, dose escalation, safety, and pharmacokinetics study of ME-344 as a single agent in patients with refractory solid tumors.
复制标题
DOI：
10.1002/cncr.29155
复制
发表时间：
2015-04-01
期刊：
影响因子：
6.2
通讯作者：
Moore, Kathleen N.
中科院分区：
文献类型：
--
作者：
Bendell, Johanna C.;Patel, Manish R.;Infante, Jeffrey R.;Kurkjian, Carla D.;Jones, Suzanne F.;Pant, Shubham;Burris, Howard A., III;Moreno, Ofir;Esquibel, Vanessa;Levin, Wendy;Moore, Kathleen N.
关键词：
目前的第1阶段开放标记剂量递增研究旨在确定新型线粒体抑制剂ME-344在难治性实体肿瘤患者中的安全性、耐受性、药代动力学特征和初步抗肿瘤活性。难治性实体瘤患者按3 + 3剂量递增设计进行治疗。ME-344在第一个28天周期的第1、8和15天静脉滴注，此后每周给药一次。在第一周期的第1天和第15天进行药代动力学评估。共有30名患者(中位年龄65岁，其中67%是女性)接受ME-344治疗。有5种剂量限制毒性的报道。4名患者发展为3级神经病变(剂量分别为15 mg/kg和20 mg/kg的2名患者)，1名接受10 mg/kg治疗的患者发展为3级急性心肌梗死(毒性根据国家癌症研究所不良事件通用术语标准[版本4.03]进行分级)。最大耐受量(MTD)定义为每周10 mg/kg。最常见的不良反应是恶心、头晕和疲劳。在MTD为10 mg/kg时，最大血药浓度(Cmax)为25.8微克/毫升，药时曲线下面积为25.9小时*微克/毫升。1例小细胞肺癌患者在≥治疗52周后部分缓解。有4名患者病情长期稳定(1名患者分别患有尿路上皮癌[47周]、类癌[≥40周]、宫颈平滑肌肉瘤[39周]和宫颈癌[≥31周])。在目前的研究中，每周给药一次的ME-344总体上耐受性良好，这是一项首次在人类进行的研究；注意到了剂量限制性神经病变，但在MTD中没有。暴露在10毫克/公斤剂量水平表明有足够的治疗指数。作为单一疗法的初步临床活性支持ME-344与化疗相结合的进一步临床开发。目前的第一阶段，开放标签，剂量递增，在人类中第一次对ME-344在难治性实体肿瘤患者中的研究发现，每周一次的最大耐受量10毫克/公斤的药物通常耐受性良好。作为单一疗法的初步临床活性支持ME-344与化疗相结合的进一步临床开发。
The current phase 1, open-label, dose escalation study was conducted to establish the safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity of the novel mitochondrial inhibitor ME-344 in patients with refractory solid tumors. Patients with refractory solid tumors were treated in a 3 + 3 dose escalation design. ME-344 was administered via intravenous infusion on days 1, 8, and 15 of the first 28-day cycle and weekly thereafter. Pharmacokinetics was assessed on days 1 and 15 of the first cycle. A total of 30 patients (median age, 65 years; 67% of whom were female) received ME-344. There were 5 dose-limiting toxicities reported. Four patients developed grade 3 neuropathy (2 patients each at doses of 15 mg/kg and 20 mg/kg) and 1 patient treated at a dose of 10 mg/kg developed a grade 3 acute myocardial infarction (toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]). The maximum tolerated dose (MTD) was defined as 10 mg/kg weekly. The most common adverse events were nausea, dizziness, and fatigue. At the MTD of 10 mg/kg, the maximal plasma concentration (Cmax) was 25.8 µg/mL and the area under the concentration curve from time zero to infinity was 25.9 hour*µg/mL. One patient with small cell lung cancer achieved a partial response for ≥52 weeks. Four patients had prolonged stable disease (1 patient each with urothelial carcinoma [47 weeks], carcinoid tumor [≥40 weeks], cervical leiomyosarcoma [39 weeks], and cervical cancer [≥31 weeks]). The once-weekly administration of ME-344 was generally well tolerated in the current study, a first-in-human study; dose-limiting neuropathy was noted, but not at the MTD. Exposures at the 10-mg/kg dose level suggest a sufficient therapeutic index. The preliminary clinical activity as a monotherapy supports the further clinical development of ME-344 in combination with chemotherapy. The current phase 1, open-label, dose escalating, first-in human study of ME-344 in patients with refractory solid tumors found that the maximum tolerated dose of once-weekly 10-mg/kg administration of the drug was generally well tolerated. The preliminary clinical activity as a monotherapy supports the further clinical development of ME-344 in combination with chemotherapy.
登录
查看更多内容
影响因子：
6.2
作者：
Alvero, Ayesha B.;Montagna, Michele K.;Chen, Rui;Kim, Ki Hyung;Kyungjin, Kim;Visintin, Irene;Fu, Han-Hsuan;Brown, David;Mor, Gil
通讯作者：
Mor, Gil
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
20.3
作者：
Valentin-Vega, Yasmine A.;MacLean, Kirsteen H.;Kastan, Michael B.
通讯作者：
Kastan, Michael B.
影响因子：
11.4
作者：
Areti A;Yerra VG;Naidu V;Kumar A
通讯作者：
Kumar A
影响因子：
7.4
作者：
Xiao WH;Bennett GJ
通讯作者：
Bennett GJ