MAK683（EED抑制剂）在晚期恶性肿瘤患者中的首次人体1/2期剂量递增研究。
A first-in-human phase 1/2 dose-escalation study of MAK683 (EED inhibitor) in patients with advanced malignancies.
作者信息
Ribrag Vincent, Iglesias Lara, De Braud Filippo, Ma Brigette, Yokota Tomoya, Zander Thomas, Spreafico Anna, Subbiah Vivek, Illert Anna L, Tan Daniel, Santoro Armando, Munster Pamela N, Suehiro Youko, Wang Yongsheng, Ji Dong-Mei, Chen Shuqi, Beltz Karen, Suenaga Naoko, Ramkumar Thiruvamoor, Luo Fangjun, Lai Clinton, Wainberg Zev A
机构信息
Gustave Roussy, Villejuif, France.
Hospital Universitario 12 de Octubre, Madrid, Spain.
出版信息
Eur J Cancer. 2025 Feb 5;216:115122. doi: 10.1016/j.ejca.2024.115122. Epub 2024 Nov 16.
PURPOSE
MAK683, a first-in-class and highly selective allosteric inhibitor of the embryonic ectoderm development subunit of polycomb repressive complex 2, has shown sustained antitumor activity in tumor xenograft models. This first-in-human phase 1/2 study evaluated the safety, pharmacokinetics (PK), and clinical activity of single-agent MAK683 in advanced malignancies.
METHODS
MAK683 was administered fasted once daily or twice daily continuously in 28-day treatment cycles. Safety assessments included the nature of dose-limiting toxicities (DLTs) and the incidence and severity of adverse events (AEs) and serious AEs. The PK profile of MAK683 was assessed in sequential blood samples of cycles 1-6, and pharmacodynamic profiles were measured by H3K27me3 changes from baseline.
RESULTS
Overall, 139 patients (clear cell carcinoma of the ovary [CCCO], 9 [6.5%]; castration-resistant prostate cancer [CRPC], 22 [15.8 %]; diffuse large B-cell lymphoma [DLBCL], 31 [22.3%]; epithelioid sarcoma [ES], 17 [12.2 %]; gastric cancer [GC], 37 [26.6 %]; nasopharyngeal carcinoma [NPC], 17 [12.2 %]; SWI/SNF-mutated sarcoma, 6 [4.3 %]) received MAK683. Median duration of exposure was 57 days (range: 4-1006). Fifteen patients experienced 22 DLTs including thrombocytopenia (4.9 %) and febrile neutropenia (3.3 %). MAK683-related AEs were reported in 98 patients (70.5 %); 43 patients had grade 3/4 drug-related AEs, including neutropenia, thrombocytopenia, and anemia. MAK683 was quickly absorbed, with peak plasma concentrations ranging from 0.975 to 4.08 h. Median progression-free survival was 1.9 months (90 % confidence interval [CI]: 1.8-2.3), and overall response rate was 5.8 % (90 % CI: 2.52-11.03 %). Clinical activity was observed in patients with advanced DLBCL and ES.
CONCLUSION
Overall, MAK683 treatment was well tolerated, and clinical activity was observed in patients with advanced DLBCL and ES.
CLINICAL TRIAL INFORMATION
NCT02900651.
目的
MAK683是一种一流的、高度选择性的多梳抑制复合物2胚胎外胚层发育亚基的变构抑制剂，已在肿瘤异种移植模型中显示出持续的抗肿瘤活性。这项首次人体1/2期研究评估了单药MAK683在晚期恶性肿瘤中的安全性、药代动力学（PK）和临床活性。
方法
MAK683在28天的治疗周期中，空腹每日给药一次或每日给药两次。安全性评估包括剂量限制毒性（DLT）的性质、不良事件（AE）和严重不良事件的发生率及严重程度。在第1 - 6周期的连续血样中评估MAK683的PK特征，并通过与基线相比H3K27me3的变化来测量药效学特征。
结果
总体而言，139例患者（卵巢透明细胞癌[CCCO]，9例[6.5%]；去势抵抗性前列腺癌[CRPC]，22例[15.8%]；弥漫性大B细胞淋巴瘤[DLBCL]，31例[22.3%]；上皮样肉瘤[ES]，17例[12.2%]；胃癌[GC]，37例[26.6%]；鼻咽癌[NPC]，17例[12.2%]；SWI/SNF突变肉瘤，6例[4.3%]）接受了MAK683治疗。中位暴露持续时间为57天（范围：4 - 1006天）。15例患者发生22次DLT，包括血小板减少（4.9%）和发热性中性粒细胞减少（3.3%）。98例患者（70.5%）报告了与MAK683相关的AE；43例患者发生3/4级药物相关AE，包括中性粒细胞减少、血小板减少和贫血。MAK683吸收迅速，血浆峰浓度出现在0.975至4.08小时之间。中位无进展生存期为1.9个月（90%置信区间[CI]：1.8 - 2.3），总缓解率为5.8%（90% CI：2.52 - 11.03%）。在晚期DLBCL和ES患者中观察到临床活性。
结论
总体而言，MAK683治疗耐受性良好，在晚期DLBCL和ES患者中观察到临床活性。
临床试验信息
NCT02900651。
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