Phase I clinical trial of a novel procaspase-3 activator SM-1 with temozolomide in recurrent high-grade gliomas
Objective: 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 pr...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-03-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S147655862500020X |
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| author | Mengqian Huang Zhuang Kang Shenglan Li Botao Zhang Yantao Xiao Shangwei Li Wenbin Li |
| author_facet | Mengqian Huang Zhuang Kang Shenglan Li Botao Zhang Yantao Xiao Shangwei Li Wenbin Li |
| author_sort | Mengqian Huang |
| collection | DOAJ |
| description | Objective: 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. Methods: 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. Results: 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. Conclusion: 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). |
| format | Article |
| id | doaj-art-d8a4ee338a2246199717a1ab29bb19e7 |
| institution | OA Journals |
| issn | 1476-5586 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj-art-d8a4ee338a2246199717a1ab29bb19e72025-08-20T02:00:45ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862025-03-016110114110.1016/j.neo.2025.101141Phase I clinical trial of a novel procaspase-3 activator SM-1 with temozolomide in recurrent high-grade gliomasMengqian Huang0Zhuang Kang1Shenglan Li2Botao Zhang3Yantao Xiao4Shangwei Li5Wenbin Li6Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR ChinaCancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR ChinaCancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR ChinaCancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR ChinaClinical R&D Department, Shenzhen Zhenxing Pharmaceutical Technology Co., Ltd. , PR ChinaClinical R&D Department, Shenzhen Zhenxing Pharmaceutical Technology Co., Ltd. , PR ChinaCancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China; Corresponding author at: Cancer Center, Beijing Tiantan Hospital, Capital Medical University, No.119, Nansihuan West Road, Fengtai District, Beijing 100070, PR China.Objective: 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. Methods: 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. Results: 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. Conclusion: 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).http://www.sciencedirect.com/science/article/pii/S147655862500020XGlioblastomaProcaspase-3High-grade gliomaTemozolomideTargeted therapy |
| spellingShingle | Mengqian Huang Zhuang Kang Shenglan Li Botao Zhang Yantao Xiao Shangwei Li Wenbin Li Phase I clinical trial of a novel procaspase-3 activator SM-1 with temozolomide in recurrent high-grade gliomas Neoplasia: An International Journal for Oncology Research Glioblastoma Procaspase-3 High-grade glioma Temozolomide Targeted therapy |
| title | Phase I clinical trial of a novel procaspase-3 activator SM-1 with temozolomide in recurrent high-grade gliomas |
| title_full | Phase I clinical trial of a novel procaspase-3 activator SM-1 with temozolomide in recurrent high-grade gliomas |
| title_fullStr | Phase I clinical trial of a novel procaspase-3 activator SM-1 with temozolomide in recurrent high-grade gliomas |
| title_full_unstemmed | Phase I clinical trial of a novel procaspase-3 activator SM-1 with temozolomide in recurrent high-grade gliomas |
| title_short | Phase I clinical trial of a novel procaspase-3 activator SM-1 with temozolomide in recurrent high-grade gliomas |
| title_sort | phase i clinical trial of a novel procaspase 3 activator sm 1 with temozolomide in recurrent high grade gliomas |
| topic | Glioblastoma Procaspase-3 High-grade glioma Temozolomide Targeted therapy |
| url | http://www.sciencedirect.com/science/article/pii/S147655862500020X |
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