To evaluate the efficacy and safety of trifluridine/tipiracil combined with fufuquitinib versus trifluridine/tipiracil and fufuquitinib in patients with unresectable metastatic colorectal cancer.

Inclusion Criteria:

• 1.Age 18-75 (at the time of signing the informed consent);ECOG PS score: 0-1; Expected survival time > 3 months.

  2.Patients with advanced colorectal adenocarcinoma confirmed by histopathology who had failed standard first - and second-line treatment.

  3.At least 1 measurable lesion was present according to RECIST1.1 criteria. 4.Good organ function, laboratory tests meet the following criteria:

  1. Hemoglobin ≥90g/L;Absolute count of neutrophils (ANC) ≥1.5×109/L;Platelet ≥100×109/L;

  2. ALT and AST≤2.5 upper limit of normal (ULN).ALP≤2.5 ULN;(if liver metastases ≤5 ULN);

  3. Total bilirubin (TBIL) < 1.5 ULN;

  4. Serum creatinine (CR) <1.5 ULN or creatinine clearance (CCR) ≥50ml/min;

  5. Serum albumin ≥30g/L;

  6. International Normalized ratio (INR), prothrombin time (PT), activated partial thrombin time (APTT) ≤1.5ULN;

  7. Thyrotropin (TSH) ≤ULN;If abnormal, T3 and T4 levels should be investigated, and normal levels can be included.

     5.cardiac color ultrasound: Left ventricular ejection fraction (LVEF) ≥50%. 6.Hypertension was well controlled. 7.Female participants of reproductive age should agree to use contraception during the study period and for 6 months after the study ends; Serum pregnancy test was negative within 7 days prior to study enrollment,and should be Non-lactation stage. Male subjects should agree to use contraception during the study period and for 6 months after the study ends.

     Exclusion Criteria:

• 1.Combined disease or history

  1. .Present or present with other malignancies within 3 years.

  2. .Have multiple factors affecting oral medication (such as inability to swallow, chronic diarrhea, or intestinal obstruction)

  3. .Gastrointestinal bleeding or perforation occurred during the first 4 weeks of enrollment

  4. .Patients with ulcerative colitis, Crohn's disease, and active inflammatory bowel disease during the first 4 weeks of enrollment

  5. .Uncontrolled pleural effusion, ascites, and moderate or greater pericardial effusion

  6. .Unmitigated toxic reactions above grade 1 of CTC AE due to any previous treatment, excluding alopecia.

  7. .Received major surgical treatment or significant traumatic injury within 28 days prior to enrollment

  8. .Patients with hematemesis, hematochezia, or any bleeding event ≥ CTCS AE level 3 within the previous 3 months, or with any signs of bleeding or history determined by the investigator to be ineligible for enrollment

  9. .Arteriovenous thrombosis occurred within 6 months, such as cerebrovascular accident, pulmonary embolism, etc

  10. .A history of psychotropic substance abuse and inability to abstain

  11. .Subjects with any severe and/or uncontrolled disease, including

      1. Uncontrolled hypertension
      2. Unstable angina pectoris / ≥ grade 2 cardiogenic chest pain;Myocardial infarction occurred within 12 months before randomization;≥ grade 2 heart failure;Restrictive heart disease;≥ grade 2 atrioventricular block, arrhythmia that cannot be stably controlled with drugs.
      3. Active infection
      4. Decompensated cirrhosis, active hepatitis;
      5. Renal failure requires hemodialysis or peritoneal dialysis
      6. A history of immunodeficiency, including HIV positive or other acquired, congenital immunodeficiency diseases, or a history of organ transplantation

      h.Diabetes with poorly controlled i.Urine routine showed urine protein ≥++, and 24h albuminuria quantitative > 1.0 g g.History of neurological or psychiatric disorders 2.Subjects who, in the investigator's judgment, have a concomitant medical condition that seriously endangers subjects' safety or interferes with the completion of the study, or are deemed unsuitable for enrollment for other reasons.