Safety and Efficacy of Canagliflozin in Patients With Metastatic High Microsatellite Instability (MSI-H) Colorectal Cancer
Trial Parameters
Brief Summary
Colorectal cancer (CRC), ranking third in incidence among men and second in women globally with third-highest mortality in the US, remains a major health challenge despite multimodal therapies, particularly for advanced-stage patients with poor prognosis where immune checkpoint inhibitors (ICIs) like PD-1/PD-L1 blockers have emerged as transformative agents by reinvigorating anti-tumor immunity through PD-1/PD-L1 pathway inhibition. While MSI-H CRC's high mutational burden renders it susceptible to immunotherapy, clinical trials demonstrate durable responses with domestic ICIs such as tislelizumab showing 41.2% ORR, 14.4-month PFS, and 28.7-month OS in metastatic MSI-H CRC, yet unmet needs persist. Intriguingly, SGLT-2 inhibitor exhibit promising oncolytic potential, particularly when combined with ICIs, as evidenced by observational studies revealing enhanced tumor control in pancreatic ductal adenocarcinoma through metabolic-immunologic crosstalk and our preclinical data showing synergistic CRC growth suppression with the SGLT-2 inhibitor canagliflozin plus PD-1 blockade. This phase II trial investigates the safety and efficacy of canagliflozin-tislelizumab combination in metastatic MSI-H CRC, evaluating its impact on PFS, OS, and ORR while dissecting tumor microenvironment modulation mechanisms, thereby pioneering a novel metabolic-immunotherapy paradigm that could redefine treatment paradigms through dual metabolic-immune regulation.
Eligibility Criteria
Inclusion Criteria: 1. Aged ≥18 years and ≤80 years old at the time of signing the written informed consent form, regardless of gender. 2. Patients with histologically or cytologically confirmed colorectal cancer, including: 1. Patients with unresectable locally advanced, recurrent, or distant metastatic colorectal cancer. 2. Patients with wild-type RAS/RAF and BRAF V600E genotypes in tumor tissues. 3. Patients with microsatellite instability-high (MSI-H) colorectal cancer confirmed by MSI testing. 4. Patients who have experienced disease progression after receiving at least two lines of standard treatment, or who cannot tolerate the toxic side effects. 3. According to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1), patients must have at least one target lesion with measurable diameters (tumor lesions with a long diameter ≥10 mm on CT scan, lymph node lesions with a short diameter ≥10 mm on CT scan, and a scan slice thickness of no more than 5 mm). Lesions that have rece