Tislelizumab Combined With Fruquintinib for Metastatic pMMR/MSS Colorectal Cancer

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.