Phase I study of IMGN901, a CD56-targeting antibody-drug conjugate, in patients with CD56-positive solid tumors.
Phase I study of IMGN901, a CD56-targeting antibody-drug conjugate, in patients with CD56-positive solid tumors.
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IMGN901（一种针对CD56靶向抗体 - 药物结合物）对CD56阳性实体瘤患者的I期研究。
DOI：
10.1007/s10637-016-0336-9
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发表时间：
2016-06
影响因子：
3.4
通讯作者：
Woll PJ
中科院分区：
文献类型：
--
作者：
Shah MH;Lorigan P;O'Brien ME;Fossella FV;Moore KN;Bhatia S;Kirby M;Woll PJ
背景IMGN 901是一种靶向CD 56的抗体-药物偶联物，旨在肿瘤选择性递送细胞毒性美登木素生物碱DM 1。这项1期研究调查了顶GN 901在表达CD 56的实体瘤患者中的安全性、耐受性、药代动力学和初步活性。方法将患者纳入递增IMGN 901剂量的队列，静脉内施用，每21天连续3天。剂量扩展阶段增加了患有小细胞肺癌（SCLC）、默克尔细胞癌（MCC）或卵巢癌的患者。结果52例患者接受了剂量从4至94 mg/m2/d的治疗。最大耐受剂量（MTD）确定为75 mg/m2。剂量限制性毒性包括疲劳、神经病变、头痛或脑膜炎样症状、胸痛、呼吸困难和肌痛。在剂量扩展阶段（n = 45），7例患者接受75 mg/m2，38例患者接受60 mg/m2，最多21个周期。在剂量扩展期间，将推荐的II期剂量（RP 2D）确定为60 mg/m2。总体而言，96.9%的患者发生了治疗后出现的不良事件（TEAE），其中大多数为1级或2级。最常报告的3级或4级TEAE为低钠血症和呼吸困难（各8.2%）。缓解包括MCC中1例完全缓解（CR）、1例临床CR和1例未经证实的部分缓解（PR）; SCLC中1例未经证实的PR。在接受剂量≥60 mg/m2的所有可评价患者中，25%的患者病情稳定。结论60 mg/m2 IMGN 901的RP 2D每3周连续3天给药与可接受的耐受性特征相关。在晚期CD 56+癌症患者中观察到客观缓解。
Background IMGN901 is a CD56-targeting antibody-drug conjugate designed for tumor-selective delivery of the cytotoxic maytansinoid DM1. This phase 1 study investigated the safety, tolerability, pharmacokinetics, and preliminary activity of IMGN901 in patients with CD56-expressing solid tumors. Methods Patients were enrolled in cohorts of escalating IMGN901 doses, administered intravenously, on 3 consecutive days every 21 days. A dose-expansion phase accrued patients with small cell lung cancer (SCLC), Merkel cell carcinoma (MCC), or ovarian cancer. Results Fifty-two patients were treated at doses escalating from 4 to 94 mg/m2/day. The maximum tolerated dose (MTD) was determined to be 75 mg/m2. Dose-limiting toxicities included fatigue, neuropathy, headache or meningitis-like symptoms, chest pain, dyspnea, and myalgias. In the dose-expansion phase (n = 45), seven patients received 75 mg/m2 and 38 received 60 mg/m2 for up to 21 cycles. The recommended phase 2 dose (RP2D) was established at 60 mg/m2 during dose expansion. Overall, treatment-emergent adverse events (TEAEs) were experienced by 96.9 % of all patients, the majority of which were Grade 1 or 2. The most commonly reported Grade 3 or 4 TEAEs were hyponatremia and dyspnea (each 8.2 %). Responses included 1 complete response (CR), 1 clinical CR, and 1 unconfirmed partial response (PR) in MCC; and 1 unconfirmed PR in SCLC. Stable disease was seen for 25 % of all evaluable patients who received doses ≥60 mg/m2. Conclusions The RP2D for IMGN901 of 60 mg/m2 administered for 3 consecutive days every 3 weeks was associated with an acceptable tolerability profile. Objective responses were observed in patients with advanced CD56+ cancers.