A first-in-human Phase I trial of the oral p-STAT3 inhibitor WP1066 in patients with recurrent malignant glioma.

IF 2 2区 化学 Q2 CRYSTALLOGRAPHY Crystallography Reviews Pub Date : 2022-06-01 Epub Date: 2022-05-16 DOI:10.2217/cns-2022-0005
John de Groot, Martina Ott, Jun Wei, Cynthia Kassab, Dexing Fang, Hinda Najem, Barbara O'Brien, Shiao-Pei Weathers, Carlos Kamiya Matsouka, Nazanin K Majd, Rebecca A Harrison, Gregory N Fuller, Jason T Huse, James P Long, Raymond Sawaya, Ganesh Rao, Tobey J MacDonald, Waldemar Priebe, Michael DeCuypere, Amy B Heimberger
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Abstract

Aim: To ascertain the maximum tolerated dose (MTD)/maximum feasible dose (MFD) of WP1066 and p-STAT3 target engagement within recurrent glioblastoma (GBM) patients. Patients & methods: In a first-in-human open-label, single-center, single-arm 3 + 3 design Phase I clinical trial, eight patients were treated with WP1066 until disease progression or unacceptable toxicities. Results: In the absence of significant toxicity, the MFD was identified to be 8 mg/kg. The most common adverse event was grade 1 nausea and diarrhea in 50% of patients. No treatment-related deaths occurred; 6 of 8 patients died from disease progression and one was lost to follow-up. Of 8 patients with radiographic follow-up, all had progressive disease. The longest response duration exceeded 3.25 months. The median progression-free survival (PFS) time was 2.3 months (95% CI: 1.7 months-NA months), and 6-month PFS (PFS6) rate was 0%. The median overall survival (OS) rate was 25 months (95% CI: 22.5 months-NA months), with an estimated 1-year OS rate of 100%. Pharmacokinetic (PK) data demonstrated that at 8 mg/kg, the T1/2 was 2-3 h with a dose dependent increase in the Cmax. Immune monitoring of the peripheral blood demonstrated that there was p-STAT3 suppression starting at a dose of 1 mg/kg. Conclusion: Immune analyses indicated that WP1066 inhibited systemic immune p-STAT3. WP1066 had an MFD identified at 8 mg/kg which is the target allometric dose based on prior preclinical modeling in combination with radiation therapy and a Phase II study is being planned for newly diagnosed MGMT promoter unmethylated glioblastoma patients.

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口服 p-STAT3 抑制剂 WP1066 治疗复发性恶性胶质瘤患者的首次人体 I 期试验。
目的:确定WP1066的最大耐受剂量(MTD)/最大可行剂量(MFD)以及p-STAT3在复发性胶质母细胞瘤(GBM)患者中的靶向参与度。患者与方法:在一项首次人体开放标签、单中心、单臂 3 + 3 设计 I 期临床试验中,8 名患者接受了 WP1066 治疗,直至疾病进展或出现不可接受的毒性反应。试验结果在无明显毒性的情况下,确定最大剂量为 8 毫克/千克。最常见的不良反应是一级恶心和腹泻,50%的患者有此症状。没有发生与治疗相关的死亡病例;8 名患者中有 6 人死于疾病进展,1 人失去随访机会。在接受放射学随访的 8 名患者中,所有患者的病情都在进展。最长的反应持续时间超过 3.25 个月。中位无进展生存期(PFS)为2.3个月(95% CI:1.7个月-NA个月),6个月PFS(PFS6)率为0%。中位总生存期(OS)为25个月(95% CI:22.5个月-NA个月),预计1年OS率为100%。药代动力学(PK)数据显示,8毫克/千克时,T1/2为2-3小时,Cmax随剂量增加而增加。外周血免疫监测显示,从 1 毫克/公斤的剂量开始,p-STAT3 受到抑制。结论免疫分析表明,WP1066 可抑制全身免疫 p-STAT3。WP1066的MFD确定为8毫克/千克,这是根据先前的临床前模型确定的与放射治疗联合使用的目标异构剂量,目前正计划对新诊断的MGMT启动子未甲基化胶质母细胞瘤患者进行II期研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Crystallography Reviews
Crystallography Reviews CRYSTALLOGRAPHY-
CiteScore
3.70
自引率
0.00%
发文量
16
审稿时长
>12 weeks
期刊介绍: Crystallography Reviews publishes English language reviews on topics in crystallography and crystal growth, covering all theoretical and applied aspects of biological, chemical, industrial, mineralogical and physical crystallography. The intended readership is the crystallographic community at large, as well as scientists working in related fields of interest. It is hoped that the articles will be accessible to all these, and not just specialists in each topic. Full reviews are typically 20 to 80 journal pages long with hundreds of references and the journal also welcomes shorter topical, book, historical, evaluation, biographical, data and key issues reviews.
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