Phase I, multicentre, dose-escalation trial of monotherapy with milatuzumab (humanized anti-CD74 monoclonal antibody) in relapsed or refractory multiple myeloma
Phase I, multicentre, dose-escalation trial of monotherapy with milatuzumab (humanized anti-CD74 monoclonal antibody) in relapsed or refractory multiple myeloma
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DOI：
10.1111/bjh.12565
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发表时间：
2013-11-01
影响因子：
6.5
通讯作者：
Goldenberg, David M.
中科院分区：
文献类型：
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作者：
Kaufman, Jonathan L.;Niesvizky, Ruben;Goldenberg, David M.
在多发性骨髓瘤（MM）中表达的CD 74被评价为米拉珠单抗（一种人源化抗CD 74抗体）免疫治疗的靶标。在一项多中心剂量递增研究中，25例晚期MM患者接受了15（N=8）、40（N=9）、80（N=4）或16.0 mg/kg（N=4）剂量的米拉珠单抗，每周两次，共4次。他们接受了中位5次既往治疗（1次干细胞移植后17次），并且是难治性（N=7）或复发性（N=18），对末次治疗的反应通常较短（中位4.0个月）。在增加预防性药物和减缓给药后，输注耐受性良好（国家癌症研究所-通用术语标准v3毒性1-2级），在较高剂量下无剂量限制性毒性。仅1例患者出现临床意义不确定的临界阳性人抗米拉珠单抗抗体滴度。尽管米拉珠单抗从循环中快速清除，血清蓄积很少，谷水平较低，但治疗后B细胞水平中度降低（中位降低34%）。根据欧洲血液和骨髓移植组标准，没有客观缓解，但在这个经过大量预治疗且通常难治的组中完成治疗的19例患者中有5例（26%）在治疗后3个月内病情稳定（1例持续17个月）。疾病稳定和药效学活性证据支持进一步开发与其他药物联合使用或作为药物偶联物使用。（Clinicaltrials.gov标识符：NCT 00421525）
CD74, expressed in multiple myeloma (MM), was evaluated as a target for immunotherapy with milatuzumab (a humanized anti-CD74 antibody). In a multicentre dose escalation study, 25 patients with advanced MM received milatuzumab doses of 15 (N=8), 40 (N=9), 80 (N=4) or 16.0 mg/kg (N=4) administered twice weekly x 4. They had a median of 5 prior treatments (17 post 1 stem cell transplantation) and were refractory (N=7) or relapsed (N=18) with generally short-lived responses to last treatment (median 4.0 months). After increasing prophylactic medications and slowing administration, infusions were well tolerated (National Cancer Institute-Common Terminology Criteria v3 toxicity Grades 1-2) with no dose-limiting toxicity at higher doses. Only one patient developed borderline positive human anti-milatuzumab antibody titres of uncertain clinical significance. Although milatuzumab was rapidly cleared from circulation with little serum accumulation and low trough levels, B-cell levels were moderately decreased with treatment (median decrease, 34%). There were no objective responses by European Group for Blood and Marrow Transplantation criteria, but 5 of 19 patients (26%) who completed treatment in this heavily pretreated and generally refractory group had stable disease for 3 months post-treatment (one continuing for 17 months). Disease stabilization and evidence of pharmacodynamic activity support further development for use in combination with other agents or as a drug conjugate. (Clinicaltrials.gov identifier: NCT00421525)