Phase I trial of the prostate-specific membrane antigen directed immunoconjugate MLN2704 in patients with progressive metastatic castration-resistant prostate cancer
Phase I trial of the prostate-specific membrane antigen directed immunoconjugate MLN2704 in patients with progressive metastatic castration-resistant prostate cancer
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DOI：
10.1200/jco.2007.15.0532
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发表时间：
2008-05-01
影响因子：
45.3
通讯作者：
Scher, Howard I.
中科院分区：
文献类型：
--
作者：
Galsky, Matthew D.;Eisenberger, Mario;Scher, Howard I.
emln2704是一种免疫偶联物，旨在通过PSMA靶向单克隆抗体MLN591将美坦素类抗微管药物美坦素-1直接递送到表达PSMA的细胞中。这种新型免疫偶联物显示出抗前列腺癌的细胞毒性活性。本研究考察了MLN2704的安全性、药代动力学、免疫原性和初步的抗肿瘤活性。患者和方法进行性、转移性、去势抵抗性前列腺癌患者静脉注射MLN2704超过2.5小时。评估了剂量限制毒性（DLT）、最大耐受剂量（MTD）、药代动力学、免疫原性和抗肿瘤活性。结果23例患者接受MLN2704治疗，剂量为18 ~ 343 mg/m(2)。其中18名患者每隔4周接受>= 3次剂量。药代动力学与剂量成正比。清除率与体表面积无相关性。MLN2704无免疫原性。研究药物相关的3级毒性发生在23例患者中的3例（13%），包括1例患者无并发症发热性中性粒细胞减少症（唯一的DLT）、可逆性肝转氨酶升高、白细胞减少症和淋巴细胞减少症。未观察到4级毒性。最常见的1级或2级毒性包括疲劳、恶心和腹泻。23例患者中有8例（35%）发生神经病变，包括343 mg/m治疗的6例患者中的5例(2)。在接受264或343 mg/m(2)治疗的9名患者中，有2名（22%）的前列腺特异性抗原与基线相比下降了50%以上，同时在接受264 mg/m治疗的患者中出现了可测量的肿瘤消退。结论MLN2704治疗剂量可安全重复给药。没有定义MTD。在正在进行的试验中，以更频繁的间隔给药MLN2704，以确定最佳给药方案。
PurposeMLN2704 is an immunoconjugate designed to deliver the maytansinoid antimicrotubule agent drug maytansinoid-1 directly to prostate-specific membrane antigen ( PSMA) -expressing cells via the PSMA-targeted monoclonal antibody MLN591. This novel immunoconjugate has shown cytotoxic anti-prostate cancer activity. This study investigated the safety profile, pharmacokinetics, immunogenicity, and preliminary antitumor activity of MLN2704.Patients and MethodsPatients with progressive, metastatic, castration-resistant prostate cancer received MLN2704 intravenously over 2.5 hours. Dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics, immunogenicity, and antitumor activity were assessed.ResultsTwenty-three patients received MLN2704 at doses of 18 to 343 mg/m(2). Eighteen of these patients received >= three doses at 4-week intervals. Pharmacokinetics of conjugate levels were dose proportional. There was no correlation between clearance and body-surface area. MLN2704 was nonimmunogenic. Study drug-related grade 3 toxicities occurred in three (13%) of 23 patients, including uncomplicated febrile neutropenia ( the only DLT) in one patient, reversible elevations in hepatic transaminases, leukopenia, and lymphopenia. No grade 4 toxicities were observed. The most frequent grade 1 or 2 toxicities included fatigue, nausea, and diarrhea. Neuropathy occurred in eight (35%) of 23 patients, including five of six patients treated at 343 mg/m(2). Two (22%) of the nine patients treated at 264 or 343 mg/m(2) had sustained a more than 50% decrease in prostate-specific antigen versus baseline, accompanied by measurable tumor regression in the patient treated at 264 mg/m(2).ConclusionTherapeutic doses of MLN2704 can be administered safely on a repetitive basis. An MTD was not defined. MLN2704 is being administered at more frequent intervals in ongoing trials to determine an optimal dosing schedule.