A Phase Ib/II Trial of the First-in-Class Anti-CXCR4 Antibody Ulocuplumab in Combination with Lenalidomide or Bortezomib Plus Dexamethasone in Relapsed Multiple Myeloma
A Phase Ib/II Trial of the First-in-Class Anti-CXCR4 Antibody Ulocuplumab in Combination with Lenalidomide or Bortezomib Plus Dexamethasone in Relapsed Multiple Myeloma
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DOI：
10.1158/1078-0432.ccr-19-0647
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发表时间：
2020-01-15
影响因子：
11.5
通讯作者：
Becker, Pamela S.
中科院分区：
文献类型：
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作者：
Ghobrial, Irene M.;Liu, Chia-Jen;Becker, Pamela S.
目的：乌洛溴单抗(BMS-936564)是一种能抑制CXCR4与CXCL12结合的一类全人抗CXCR4单抗。患者和方法：本Ib/II期研究旨在确定乌洛库单抗与来那度胺和地塞米松(A组)或硼替佐米和地塞米松(B组)联合应用治疗复发性/难治性多发性骨髓瘤的安全性和耐受性。既往治疗的中位数为3次(范围1-11)，70%的受试者接受过3次治疗。这项试验有剂量递增和剂量扩大部分。在试验的两个手臂上采用3+3设计，乌洛库单抗的剂量增加到最大10毫克/公斤，但没有达到MTD。最常见的治疗相关不良事件(AE)是A组的中性粒细胞减少(13例，43.3%)和B组的血小板减少(6例，37.5%)，没有发生与研究药物相关的死亡。乌洛库单抗联合来那度胺和地塞米松的有效率(PR)为55.2%，临床受益率为72，4%。结论：乌鲁库单抗阻断CXCR4-CXCL12轴是安全的，不良反应可接受，联合应用来那度胺和地塞米松治疗复发性/难治性骨髓瘤有较高的有效率，CXCR4抑制剂是一类有希望的抗骨髓瘤药物，值得在临床试验和研究中进一步探索。
Purpose: Ulocuplumab (BMS-936564) is a first-in-class fully human lgG4 monoclonal anti-CXCR4 antibody that inhibits the binding of CXCR4 to CXCL12.Patients and Methods: This phase Ib/II study aimed to determine the safety and tolerability of ulocuplumab alone and in combination with lenalidomide and dexamethasone (Arm A), or bortezomib and dexamethasone (Arm B), in patients with relapsed/refractory multiple myeloma.Results: Forty-sec patients were evaluated (median age, 60 years; range, 53-67). The median number of prior therapies was 3 (range, 1-11), with 70% of subjects having received >= 3. This trial had a dose-escalation and a dose-expansion part. Using a 3+3 design on both arms of the trial, ulocuplumab's dose was escalated to a maximum of 10 mg/kg without reaching MTD. The most common treatment-related adverse events (AE) were neutropenia (13 patients, 43.3%) in Arm A and thrombocytopenia (6 patients, 37.5%) in Arm B. No deaths related to study drugs occurred. The combination of ulocuplumab with lenalidomide and dexamethasone showed a high response rate (PR or better) of 55,2% and a clinical benefit rate of 72,4%, even in patients who had been previously treated with immunomodulatory agents (1MiD).Conclusions: This study showed that blockade of the CXCR4-CXCL12 axis by ulocuplumab is safe with acceptable AEs and leads to a high response rate in combination with lenalidomide and dexamethasone in patients with relapsed/refractory myelorna, making CXCR4 inhibitors a promising class of antimyeloma drugs that should be further explored in clinical trials,