Huang Mengqian, Kang Zhuang, Li Shenglan, Zhang Botao, Xiao Yantao, Li Shangwei, Li Wenbin
Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China.
Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China.
Neoplasia. 2025 Mar;61:101141. doi: 10.1016/j.neo.2025.101141. Epub 2025 Feb 18.
Despite a standard of care, the mortality of recurrent high-grade gliomas (HGGs) remains high. SM-1 is a novel molecular activator that has shown to target procaspase-3, which is overexpressed in HGGs. A phase I clinical trial was conducted to evaluate the safety, pharmacokinetics, and primary clinical efficacy of SM-1 plus TMZ. Participants received escalating doses of daily oral SM-1 (450, 600, and 800 mg) plus standard TMZ therapy.
In the preclinical study, the synergistic effects of SM-1 and temozolomide (TMZ) in rodent models were evaluated. In the clinical study, adult patients received SM-1 therapy in various doses in combination with a standard TMZ dosing. The tolerability and pharmacokinetics data of the combination therapy were tested. The primary efficacy was measured by tumor response in accordance with the RANO criteria.
A total of 13 patients with recurrent HGG were enrolled, with 11 patients completed ≥ two cycles of therapy and received tumor assessment. Among them, one patient had complete response, whereas two patients had partial response for the best change from baseline. No dose-limited toxicities were observed, and no maximum tolerated dose was reached.
SM-1 has the potential to enhance antitumor activity while alleviating the side effects of TMZ. SM-1 exhibited mild toxicity in patients with recurrent HGG. The combination of SM-1 and TMZ warrants further investigation, with promising clinical outcomes. The monotherapy phase and expansion phase of SM-1 are still ongoing. (ClinicalTrials.gov number, CTR20221641).
尽管有标准治疗方案，但复发性高级别胶质瘤（HGG）的死亡率仍然很高。SM-1是一种新型分子激活剂，已显示可靶向在HGG中过表达的procaspase-3。进行了一项I期临床试验，以评估SM-1联合替莫唑胺（TMZ）的安全性、药代动力学和主要临床疗效。参与者接受递增剂量的每日口服SM-1（450、600和800毫克）加标准TMZ治疗。
在临床前研究中，评估了SM-1和替莫唑胺（TMZ）在啮齿动物模型中的协同作用。在临床研究中，成年患者接受不同剂量的SM-1治疗，并与标准TMZ给药联合使用。测试了联合治疗的耐受性和药代动力学数据。主要疗效根据RANO标准通过肿瘤反应来衡量。
共纳入13例复发性HGG患者，11例患者完成了≥两个周期的治疗并接受了肿瘤评估。其中，1例患者完全缓解，2例患者部分缓解，为自基线以来的最佳变化。未观察到剂量限制毒性，也未达到最大耐受剂量。
SM-1有潜力增强抗肿瘤活性，同时减轻TMZ的副作用。SM-1在复发性HGG患者中表现出轻度毒性。SM-1与TMZ的联合值得进一步研究，临床结果有望良好。SM-1的单药治疗阶段和扩展阶段仍在进行中。（ClinicalTrials.gov编号，CTR20221641）
