Kantarjian Hagop M, Lioure Bruno, Kim Stella K, Atallah Ehab, Leguay Thibaut, Kelly Kevin, Marolleau Jean-Pierre, Escoffre-Barbe Martine, Thomas Xavier G, Cortes Jorge, Jabbour Elias, O'Brien Susan, Bories Pierre, Oprea Corina, Hatteville Laurence, Dombret Hervé
MD Anderson Cancer Center, Houston, TX.
CHU Hautepierre, Strasbourg, France.
Clin Lymphoma Myeloma Leuk. 2016 Mar;16(3):139-45. doi: 10.1016/j.clml.2015.12.004. Epub 2015 Dec 21.
Long-term disease-free survival in adult patients with acute lymphoblastic leukemia (ALL) remains unsatisfactory, and the treatment options are limited for those patients with relapse or a failure to respond after initial therapy. We conducted a dose-escalation/expansion phase II, multicenter, single-arm study to determine the optimal dose of coltuximab ravtansine (SAR3419), an anti-CD19 antibody-drug conjugate, in this setting.
The dose-escalation part of the study determined the selected dose of coltuximab ravtansine for the evaluation of efficacy and safety in the dose-expansion phase. Patients received coltuximab ravtansine induction therapy (≤ 8 weekly doses). The responding patients were eligible for maintenance therapy (biweekly administration for ≤ 24 weeks). Three dose levels of coltuximab ravtansine were examined: 55, 70, and 90 mg/m(2). The primary endpoint was the objective response rate (ORR). The secondary endpoints included the duration of response (DOR) and safety.
A total of 36 patients were treated: 19 during dose escalation and 17 during dose expansion. One dose-limiting toxicity was observed at 90 mg/m(2) (grade 3 peripheral motor neuropathy); therefore, 70 mg/m(2) was selected for the dose-expansion phase. Five patients discontinued therapy because of adverse events (AEs). The most common AEs were pyrexia, diarrhea, and nausea. Of the 17 evaluable patients treated at the selected dose, 4 had a disease response (estimated ORR using the Bayesian method: 25.5% (80% confidence interval, 14.2%-39.6%). The DOR was 1.9 months (range, 1-5.6 months). Because of these results, the study was prematurely discontinued.
Coltuximab ravtansine was well tolerated but was associated with a low clinical response rate in patients with relapsed or refractory ALL.
成人急性淋巴细胞白血病（ALL）患者的长期无病生存率仍不尽人意，对于那些复发或初始治疗后无反应的患者，治疗选择有限。我们开展了一项剂量递增/扩展的II期多中心单臂研究，以确定抗CD19抗体药物偶联物coltuximab ravtansine（SAR3419）在此情况下的最佳剂量。
研究的剂量递增部分确定了用于剂量扩展阶段疗效和安全性评估的coltuximab ravtansine选定剂量。患者接受coltuximab ravtansine诱导治疗（每周剂量≤8次）。有反应的患者 eligible for维持治疗（每两周给药≤24周）。检查了coltuximab ravtansine的三个剂量水平：55、70和90mg/m²。主要终点是客观缓解率（ORR）。次要终点包括缓解持续时间（DOR）和安全性。
共治疗36例患者：剂量递增阶段19例，剂量扩展阶段17例。在90mg/m²观察到1例剂量限制性毒性（3级周围运动神经病）；因此，选择70mg/m²用于剂量扩展阶段。5例患者因不良事件（AE）停药。最常见的AE是发热、腹泻和恶心。在选定剂量下接受治疗的17例可评估患者中，4例有疾病反应（使用贝叶斯方法估计的ORR：25.5%（80%置信区间，14.2%-39.6%）。DOR为1.9个月（范围，1-5.6个月）。由于这些结果，研究提前终止。
Coltuximab ravtansine耐受性良好，但复发或难治性ALL患者的临床反应率较低。
