tislelizumab combined with fruquintinib for metastatic pmmr/mss colorectal cancer

Conditions: Metastatic Colorectal Cancer; mCRC

Summary: this is an open-label phase ii study, with the aim of investigating the efficacy and safety of tislelizumab + fruquintinib combination therapy in arid1a-mutated pmmr/mss metastatic colorectal cancer who have been treated with standard chemotherapy that includes fluoropyrimidine, oxaliplatin, and irinotecan. patients with hypermutated crc that carries pole/pold1 mutations cannot be included.

in this open-label phase ii study, patients with arid1a-mutated pmmr/mss metastatic colorectal cancer who have been treated with standard chemotherapy that includes fluoropyrimidine, oxaliplatin, and irinotecan, will be scheduled for tislelizumab (200mg ivdrip q3w day1) + fruquintinib (5mg/day q3w day1-14) until intolerable toxicity, disease progression or death. primary endpoint of this study is orr and secondary endpoints are os, pfs, dcr and safety.

Eligibility criteria:
inclusion criteria: * 18-80 years old (including 18 and 80); * histologically confirmed colorectal adenocarcinoma and biopsy pathology confirmed mss/pmmr; * gene testing confirmed arid1a gene mutation (nonsynonymous); * no signs of intestinal obstruction; or intestinal obstruction has been relieved after proximal colostomy; * has received and failed ≥ 2 line of chemotherapy or progressed on or intolerable to oxaliplatin, irinotecan and fluorouracil chemotherapy after diagnosed with mcrc; * ecog ps 0-2; * able to swallow tablets; * life expectancy of greater than 3 months; * adequate bone marrow and organ function; * if female and of childbearing potential, must: * have a negative pregnancy test ≤14 days prior to initiating study treatment * agree to avoid pregnancy during and for 3 months after study treatment if male with a partner of childbearing potential, must: * agree to use adequate, medically approved, contraceptive precautions during and for 3 months after the last dose of study treatment. * able and willing to provide written informed consent for the study. exclusion criteria: * any active autoimmune disease or history of autoimmune disease; * those who are using immunosuppressive agents, or systemic or absorbable local hormone therapy to achieve immunosuppressive purpose, and continue to use within 2 weeks before enrollment; * severe allergic reaction to other monoclonal antibodies; * subjects with clinical symptoms of untreated active brain metastasis or meningeal metastasis; * have received other pd-1 antibody therapy or other immunotherapy targeting pd-1/pd-l1 in the past; * patients with high tmb (≥ 30muts/mb) and germline or somatic pole/pold1 gene mutations in the exonuclease domain; * there are clinical symptoms or diseases of heart that are not well controlled, such as: (a) heart failure of nyha level 2 or above (b) unstable angina pectoris (c) myocardial infarction occurred within 1 year (d) clinically significant supraventricular or ventricular arrhythmia needs treatment or intervention; * known hereditary or acquired bleeding and thrombophilia or being treated with thrombolysis or anticoagulation; * urinary protein ≥ ++, or the 24-hour urine protein quantification greater than 1.0g; * clinically significant bleeding symptoms or clear bleeding tendency within 3 months before enrollment; * subjects with active infection; * congenital or acquired immune deficiency (such as hiv infected persons), or active hepatitis (hepatitis b: hbsag positive and hbv dna ≥ 10\^4 copies/ml; hepatitis c: hcv antibody positive); * other advanced malignant tumors within 5 years (except cured skin basal cell carcinoma, cervical carcinoma in situ, ovarian cancer, thyroid cancer and breast cancer); * live vaccine may be inoculated less than 4 weeks before the study medication or during the study period; * known or suspected to be allergic to the study drug or to any drug given in this trial; * have any other disease, metabolic disorder, physical examination anomaly, abnormal laboratory result, or any other conditions that makes the subject not eligible according to the judgment of the investigator.