Phase II Trial of Fruquintinib With Sintilimab in Treating Selected Refractory Metastatic Colorectal Cancer Patients

Inclusion Criteria:

1. Fully understand the study and signed the Informed Consent Form (ICF) out of their ownwill;
2. Histologically or cytologically diagnosed with metastasis colorectal adenocarcinomaCRC (Phase IV)
3. MSS or MSI-low, MSI was assessed per local guidelines (immunohistochemistry and/orpolymerase chain reaction [PCR]) prior to screening. Tumor samples with instability in 0 or 1 marker were identified as microsatellite-stable and MSI-low, respectively.
4. TMB≥5 mutations/Mb, TMB was performed on plasma samples by NGS.
5. Subjects who failed at least second line standard chemotherapies includingFluorouracil, Oxaliplatin, Irinotecan and VEGF inhibitors(e.g., bevacizumab).Pre-treatment with anti-EGFR(e.g., cetuximab) were mandatory if RAS wild and leftside. Failed therapies are defined as the occurance of PD or intolerable toxicitiesduring the treatment or within 3 months after the last dose.
6. Subject must not receive any systematically anti-tumor therapies during the last 4weeks, and never receive any vascular endothelial growth factor (VEGFR) inhibitor orImmune checkpoint blockade.
7. 18-75 years of age (inclusive)
8. Body weight≥40Kg
9. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
10. Patients capable of taking oral medication
11. Patients with evaluable or measurable lesions as per RECIST version 1.1
12. Expected survival >12 weeks

Exclusion Criteria:

1. with MSI-H colorectal adenocarcinoma as defined per local assessment using standard ofcare testing
2. Previous treatment with Fruquintinib or immune checkpoint inhibitors
3. Absolute neutrophil count (ANC)<1.5×109/L, or blood platelet count (PLT)<100×109/L, orhemoglobin<90g/L; blood transfusion within 1 week before enrollment for the purpose ofenrollment is not allowed;
4. Serum total bilirubin>1.5×Upper Limit of Normal (ULN);Alanine transaminase(ALT) and/orAspartate transferase (AST)>2.5×ULN (subject to the normal value at each site); or ALTand/or AST > 5×ULN for patients with liver metastases;
5. Creatinineclearancerate< 50mL/min;
6. Uncontrolled hypertension by monotherapy, i.e. systolic blood pressure >140mmHg ordiastolic blood pressure >90mmHg after monotherapy treatment.
7. Clinical significant electrolyte abnormality;
8. Results of urine protein detection with 2+ or above, or urinary protein quantity ≥1.0g/24h;
9. Unrecovered toxicity fromprevious anticancer therapies(NCI CTC AE>Grade 1, except foralopecia and ≤Grade 2 neurotoxicity caused by Oxaliplatin), not fully recovered fromprevious surgeries; or the time from the last anticancer therapy or surgery is lessthan 4 weeks;
10. Central Nervous System (CNS) metastatic disease or prior cerebral metastasis;
11. Subjects with presence of clinically detectable second primary malignant tumors atenrollment, or other malignant tumors within the last 5 years (excluding adequatelytreated skin basal cell carcinoma or carcinoma in situ of cervix).
12. Clinically uncontrolled active infection, such as acute pneumonia, active hepatitis Bor hepatitis C(previous medical history of hepatitis B virus infection regardless ofdrug control, HBV DNA≥104×copynumberor ≥2000IU/mL);
13. Difficulty in swallowing or known drug malabsorption;
14. Duodenal ulcer, ulcerative colitis, intestinal obstruction, other gastrointestinaldiseases or other conditions that may lead to gastrointestinal bleeding or perforationaccording to the investigator's judgment; or with a history of intestinal perforationor intestinal fistula, which were not fully recovered after surgery;
15. History of artery thrombosis or deep venous thrombosis within 6 months beforeenrollment, or have evidence or a history of bleeding tendency within 2 months beforethe enrollment, regardless of severity;
16. Occurrence of stroke or transient ischemic attack within 12 months before theenrollment;
17. Activated Partial Thromboplastin Time (APTT) and/or prothrombin time (PT) > 1.5×ULN (subject to the normal range at each site);
18. Skin wounds, surgical site, trauma site, severe mucosal ulcers or fracture notcompletely healed;
19. Acute myocardial infarction, severe/unstable angina or received coronary artery bypasssurgery within 6 months prior to enrollment; or patients with cardiac insufficiency ofNYHA Grade 2 or above;
20. Pregnant or lactating women Or female subjects with childbearing potentials withpositive pregnancy test result before the first time of study drug treatment;
21. Any clinical or laboratory abnormalities or compliance concerns unfit to participatein this clinical trial according to the investigator's judgment;
22. Serious psychological or psychiatric disorders;
23. Contraindications of immune checkpoint inhibitors
24. Participated in any other drug clinical trial during the last 4 weeks.