医学
粘膜炎
药效学
内科学
恶心
耐受性
不利影响
胃肠病学
药代动力学
耐火材料(行星科学)
口炎
肿瘤科
实体瘤疗效评价标准
药理学
临床研究阶段
毒性
生物
天体生物学
作者
Dejan Juric,Daniel M. Anderson,Afshin Dowlati,Jordi Rodón,Iwona Ługowska,Sławomir Mańdziuk,Yuqin Song,F. J. Sherida H. Woei‐A‐Jin,Marc André,Joanna Góra‐Tybor,José‐Ángel Hernández‐Rivas,Razelle Kurzrock,Armando López‐Guillermo,David Schröder,Rafał Stec,Allison Berger,Bo Chao,Aleksander Chudnovsky,John P. Gibbs,Tao Long
出处
期刊:Cancer research communications
[American Association for Cancer Research]
日期:2025-10-24
标识
DOI:10.1158/2767-9764.crc-25-0243
摘要
Abstract Purpose: Subasumstat (TAK-981) is a first-in-class inhibitor of SUMOylation that can engage innate and adaptive immune responses in tumors by enhancing type I interferon (IFN-I) production. We conducted a phase I/II dose escalation/expansion study (NCT03648372) to investigate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of subasumstat as a single agent in patients with advanced/metastatic solid tumors and relapsed/refractory hematologic malignancies. Patients and Methods: Eligible patients received subasumstat intravenously at escalating doses twice-weekly (BIW, days 1, 4, 8, and 11) or once-weekly (days 1 and 8) in 21-day cycles until disease progression or unacceptable toxicity. Results: A total of 109 patients were enrolled (solid tumors: n = 100; lymphomas, n = 9). In phase I, four patients reported dose-limiting toxicities of grade 3 ALT/AST elevation, pneumonitis, stomatitis, and cognitive disorder; 120 mg BIW was determined as the maximum tolerated dose. The most common adverse events were fatigue (47%), nausea (41%), diarrhea (36%), and pyrexia (36%). Pharmacodynamic analyses demonstrated target engagement and SUMOylation pathway inhibition, induction of an IFN-I-regulated gene signature and cytokine production, and activation of innate and adaptive immune cells. Based on safety, pharmacokinetic, and pharmacodynamic findings, 90 mg BIW was proposed as the recommended phase II dose. Overall, three and 26 patients achieved a partial response and stable disease, respectively. Conclusions: Subasumstat had a manageable safety profile, with evidence of innate and adaptive immune response engagement in patients with advanced/metastatic solid tumors and relapsed/refractory hematologic malignancies. Further studies are needed to determine the role of subasumstat in cancer treatment.