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 own will;
2. Histologically or cytologically diagnosed with metastasis colorectal adenocarcinoma CRC (Phase IV)
3. MSS or MSI-low, MSI was assessed per local guidelines (immunohistochemistry and/or polymerase 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 including Fluorouracil, Oxaliplatin, Irinotecan and VEGF inhibitors(e.g., bevacizumab). Pre-treatment with anti-EGFR(e.g., cetuximab) were mandatory if RAS wild and left side. Failed therapies are defined as the occurance of PD or intolerable toxicities during the treatment or within 3 months after the last dose.
6. Subject must not receive any systematically anti-tumor therapies during the last 4 weeks, and never receive any vascular endothelial growth factor (VEGFR) inhibitor or Immune 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 of care 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, or hemoglobin<90g/L; blood transfusion within 1 week before enrollment for the purpose of enrollment is not allowed;
4. Serum total bilirubin>1.5×Upper Limit of Normal (ULN);Alanine transaminase(ALT) and/or Aspartate transferase (AST)>2.5×ULN (subject to the normal value at each site); or ALT and/or AST > 5×ULN for patients with liver metastases;
5. Creatinineclearancerate< 50mL/min;
6. Uncontrolled hypertension by monotherapy, i.e. systolic blood pressure >140mmHg or diastolic 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 for alopecia and ≤Grade 2 neurotoxicity caused by Oxaliplatin), not fully recovered from previous surgeries; or the time from the last anticancer therapy or surgery is less than 4 weeks;
10. Central Nervous System (CNS) metastatic disease or prior cerebral metastasis;
11. Subjects with presence of clinically detectable second primary malignant tumors at enrollment, or other malignant tumors within the last 5 years (excluding adequately treated skin basal cell carcinoma or carcinoma in situ of cervix).
12. Clinically uncontrolled active infection, such as acute pneumonia, active hepatitis B or hepatitis C(previous medical history of hepatitis B virus infection regardless of drug control, HBV DNA≥104×copynumberor ≥2000IU/mL);
13. Difficulty in swallowing or known drug malabsorption;
14. Duodenal ulcer, ulcerative colitis, intestinal obstruction, other gastrointestinal diseases or other conditions that may lead to gastrointestinal bleeding or perforation according to the investigator's judgment; or with a history of intestinal perforation or intestinal fistula, which were not fully recovered after surgery;
15. History of artery thrombosis or deep venous thrombosis within 6 months before enrollment, or have evidence or a history of bleeding tendency within 2 months before the enrollment, regardless of severity;
16. Occurrence of stroke or transient ischemic attack within 12 months before the enrollment;
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 not completely healed;
19. Acute myocardial infarction, severe/unstable angina or received coronary artery bypass surgery within 6 months prior to enrollment; or patients with cardiac insufficiency of NYHA Grade 2 or above;
20. Pregnant or lactating women Or female subjects with childbearing potentials with positive pregnancy test result before the first time of study drug treatment;
21. Any clinical or laboratory abnormalities or compliance concerns unfit to participate in 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.