A First-in-Human Study of Conatumumab in Adult Patients with Advanced Solid Tumors
A First-in-Human Study of Conatumumab in Adult Patients with Advanced Solid Tumors
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DOI：
10.1158/1078-0432.ccr-10-0631
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发表时间：
2010-12-01
影响因子：
11.5
通讯作者：
LoRusso, Patricia M.
中科院分区：
文献类型：
--
作者：
Herbst, Roy S.;Kurzrock, Razelle;LoRusso, Patricia M.
目的：为了确定conatumumab（一种针对人死亡受体5的研究性全人源单克隆激动剂抗体）在晚期实体瘤患者中的安全性、耐受性、药代动力学和最大耐受剂量（MTD）。在剂量递增阶段，患者每2周一次接受递增剂量的conatumumab静脉给药（0.3、1、3、10或20 mg/kg，每个队列3-9例）。在剂量扩展阶段，10例结直肠癌（CRC）和7例非小细胞肺癌（NSCLC）患者接受20 mg/kg的conatumumab，每2 weeks.Results：37例患者接受1剂或多剂conatumumab。Conatumumab似乎耐受良好;没有剂量限制性毒性。在可能与治疗相关的不良事件中，仅3例患者（8%）发生3级事件（疲乏和/或脂肪酶升高），未检测到抗conatumumab抗体。未达到MTD。Conatumumab在3 - 20 mg/kg剂量范围内表现出剂量线性动力学，平均终末半衰期为13 - 19天。1例NSCLC患者（0.3 mg/kg）在第32周时确认部分缓解（PR）（肿瘤大小缩小38%），到第96周时进一步缩小（48%）;该患者在4.2年后仍接受conatumumab治疗，持续PR。14例患者的最佳缓解为疾病稳定，2例持续32周或以上。1例CRC患者（0.3 mg/kg）病情稳定24周，根据RECIST（实体瘤疗效评价标准），肿瘤大小减小24%，通过[18 F]氟脱氧葡萄糖正电子发射断层扫描测量的所有病灶的标准化摄取值总和减小35%。活化的caspase-3的肿瘤水平的变化似乎与肿瘤responsibility.Conclusions：Conatumumab可以安全地给药至每2周20 mg/kg的目标剂量。临床癌症研究; 16（23）; 5883-91。（C）2010年AACR。
Purpose: To determine the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of conatumumab, an investigational, fully human monoclonal agonist antibody against human death receptor 5, in patients with advanced solid tumors.Experimental Design: In the dose-escalation phase, patients received escalating intravenous doses of conatumumab (0.3, 1, 3, 10, or 20 mg/kg, 3-9 per cohort) every 2 weeks. In the dose-expansion phase, 10 patients with colorectal cancer (CRC) and 7 with non-small cell lung cancer (NSCLC) received 20 mg/kg of conatumumab every 2 weeks.Results: Thirty-seven patients received 1 or more doses of conatumumab. Conatumumab seemed to be well tolerated; there were no dose-limiting toxicities. Of adverse events possibly related to treatment, only 3 patients (8%) had a grade 3 event (fatigue and/or elevated lipase), and no anticonatumumab antibodies were detected. An MTD was not reached. Conatumumab exhibited dose linear kinetics from 3 to 20 mg/kg, with a mean terminal half-life of 13 to 19 days. One patient with NSCLC (0.3 mg/kg) had a confirmed partial response (PR) at week 32 (38% reduction in tumor size), with further reduction (48%) by week 96; this patient remains on conatumumab after 4.2 years with a sustained PR. Fourteen patients had a best response of stable disease, 2 for 32 weeks or more. One patient with CRC (0.3 mg/kg) and stable disease for 24 weeks had a 24% reduction in tumor size by RECIST (Response Evaluation Criteria in Solid Tumors) and a 35% reduction in the sum of standardized uptake values of all lesions measured by [18F] fluorodeoxyglucose positron emission tomographic scan. Changes in tumor levels of activated caspase-3 did not appear to be associated with tumor response.Conclusions: Conatumumab can be administered safely up to the target dose of 20 mg/kg every 2 weeks. Clin Cancer Res; 16(23); 5883-91. (C)2010 AACR.