Safety and Efficacy of Canagliflozin in Patients With Metastatic High Microsatellite Instability (MSI-H) Colorectal Cancer: a Phase I Trial
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.
• Aged ≥18 years and ≤80 years old at the time of signing the written informed consent form, regardless of gender.
• Patients with histologically or cytologically confirmed colorectal cancer, including:
∙ Patients with unresectable locally advanced, recurrent, or distant metastatic colorectal cancer.
‣ Patients with wild-type RAS/RAF and BRAF V600E genotypes in tumor tissues.
‣ Patients with microsatellite instability-high (MSI-H) colorectal cancer confirmed by MSI testing.
‣ Patients who have experienced disease progression after receiving at least two lines of standard treatment, or who cannot tolerate the toxic side effects.
• 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 received local treatments such as radiotherapy can be used as target lesions after clear progression is confirmed.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 1, with an expected survival period of ≥3 months.
• Patients must be type 2 diabetes mellitus (T2DM) patients and meet the indications for canagliflozin; or patients have no diagnosis of diabetes, no history of type 1 diabetes or diabetic ketoacidosis.
• The diagnosis of type 2 diabetes mellitus is defined as typical diabetic symptoms plus random blood glucose ≥11.1 mmol/L, or plus fasting blood glucose ≥7.0 mmol/L, or plus 2-hour post-load blood glucose in oral glucose tolerance test (OGTT) ≥11.1 mmol/L, or plus HbA1c ≥6.5%. For those without typical diabetic symptoms, reexamination on another day is required for confirmation (excluding random blood glucose).
• Good function of major organs, that is, the relevant examination indicators within 14 days before randomization meet the following requirements (without blood or blood product transfusion, without the use of hematopoietic stimulating factors, and without the use of albumin or blood products):
‣ Routine blood test: Hemoglobin ≥80 g/L; neutrophil count \>1.5×10⁹/L; platelet count ≥90×10⁹/L.
⁃ Biochemical test: Total bilirubin ≤1.5×ULN (upper limit of normal value); serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤2.5×ULN; serum creatinine (SCr) ≤1.5×ULN or creatinine clearance rate ≥50 mL/min (Cockcroft-Gault formula).
⁃ Prothrombin time (PT), international normalized ratio (INR) ≤1.5×ULN (unless warfarin anticoagulation is being used).
⁃ Cardiac Doppler ultrasound evaluation: Left ventricular ejection fraction (LVEF) ≥50%.
⁃ Renal function: eGFR ≥60 mL/min/1.73 m².
⁃ Blood glucose: HbA1c ≤9%.
• Patients of childbearing potential (both male and female) must use effective medical contraceptive measures during the study period and within 6 months after the end of drug administration.
• Body mass index (BMI) ≥18.5 kg/m² during the study screening period.
• If complicated with hypertension, blood pressure must be controlled to a stable level with other medications.
⁃ No history of peripheral vascular disease, neuropathy, or diabetic foot ulcers.
⁃ Patients voluntarily join this study, sign the informed consent form, have good compliance, and patients and their families agree to cooperate with survival follow-up.