Oral Inulin in Combination With Fruquintinib Plus Sintilimab as Third- or Further-line Treatment in Metastatic Colorectal Cancer

Inclusion Criteria:

• Have been fully informed about the study and have voluntarily signed an informedconsent form;
• Aged 18-75 years (inclusive of 18 and 75 years);
• Pathologically determined unresectable advanced metastatic colorectal cancer;
• Failure of prior second- and back-line standard therapy;
• pMMR or MSS;
• ECOG physical status score of 0-2;
• Expected survival ≥ 6 months;
• Need to have at least one measurable lesion with a maximum diameter of at least 10 mmas determined by spiral CT scanning and at least 20 mm as determined by conventionalCT scanning (Criteria for Evaluation of Efficacy in Solid Tumors, i.e., RECIST version 1.1);
• The function of vital organs meets the following requirements (the use of any bloodcomponents and cell growth factors is not permitted within *14d prior to enrollment):absolute neutrophil count ≥1.5×10^9/L; platelets ≥75×10^9/L; hemoglobin ≥90g/L; totalbilirubin <1.5 times ULN; ALT and/or AST <1.5 times ULN, and for patients with livermetastases <3 times ULN; serum creatinine <1.5 times ULN; endogenous creatinineclearance ≥50 ml/min;
• Men and women of childbearing age need to use effective contraception;
• Not allergic to inulin;
• Subjects agree to provide sufficient blood and fecal samples for immune function andintestinal microbiology testing.

Exclusion Criteria:

• Inability to comply with the study protocol or study procedures;
• Prior treatment with a vascular endothelial growth factor receptor (VEGFR) inhibitoror prior treatment with an immune checkpoint inhibitor;
• Other malignancy within the past 5 years, except for basal or squamous cell carcinomaof the skin after radical surgery, or carcinoma in situ of the cervix;
• The presence of central nervous system (CNS) metastases or previous brain metastasesprior to enrollment
• autoimmune disease or history of autoimmune disease within 4 weeks prior to enrollment
• Previous allogeneic bone marrow transplantation or organ transplantation;
• Uncontrolled malignant ascites (defined as ascites that, in the judgment of theinvestigator, cannot be controlled by means of diuretics or puncture);
• Severe cardiovascular disease, including unstable angina or myocardial infarction,within 6 months prior to initiation of study treatment, clinically significantcardiovascular disease, including unstable angina or myocardial infarction, within 6months prior to initiation of study treatment, including, but not limited to, acutemyocardial infarction, severe/unstable angina, or coronary artery bypass graftingwithin 6 months prior to enrollment; congestive Heart failure New York HeartAssociation (NYHA) classification >2; Ventricular arrhythmia requiring pharmacologictreatment; LVEF (left ventricular ejection fraction) <50%;
• Subjects with hypersensitivity to the study drug or any of its adjuvants;
• Have participated in a clinical trial of another drug not yet approved or marketed inChina within 4 weeks prior to enrollment and have been treated with the correspondingtrial drug;
• Electrolyte abnormalities of clinical significance as determined by the investigator;
• Pre-existing medically uncontrolled hypertension, defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg;
• The presence of poorly controlled diabetes mellitus (fasting glucose concentration ≥CTCAE grade 2 after regular treatment) prior to enrollment;
• Any disease or condition that interferes with drug absorption prior to enrollment orthe patient is unable to take Fruquintinib orally;
• The presence of gastrointestinal diseases such as active gastric and duodenal ulcers,ulcerative colitis, or active bleeding from unresected tumors prior to enrollment, orother conditions that may cause gastrointestinal bleeding or perforation, asdetermined by the investigator;
• Patients with evidence or history of significant bleeding tendency within 3 monthsprior to enrollment (bleeding >30 mL within 3 months, vomiting blood, black stool,blood in stool), hemoptysis (>5 mL of fresh blood within 4 weeks), or a thromboembolicevent (including stroke events and/or transient ischemic attack) within 12 months;
• Active or uncontrolled serious infection (≥ CTCAE v5.0 grade 2 infection);
• Known human immunodeficiency virus (HIV) infection. Known history of clinicallysignificant liver disease, including viral hepatitis [known hepatitis B virus (HBV)carriers must be excluded from active HBV infection, i.e., HBV DNA-positive (>1×10^4copies/mL or >2000 IU/ml); known hepatitis C virus infection (HCV) and HCVRNA-positive (>1×10^3 copies/mL)];
• Unresolved toxic reactions above CTCAE v5.0 Grade 1 or higher due to any prioranticancer therapy, excluding alopecia, lymphopenia, and neurotoxicity ≤ Grade 2 dueto oxaliplatin;
• Females who are pregnant (positive pregnancy test prior to dosing) or breastfeeding;
• Transfusion therapy, blood products, and hematopoietic factors, such as albumin andgranulocyte colony-stimulating factor (G-CSF), received within 14 days prior toenrollment;
• Any other disease with clinically significant metabolic abnormalities, physicalexamination abnormalities, or laboratory test abnormalities that, in the judgment ofthe investigator, give reason to suspect that the patient has a disease or conditionfor which the use of the study medication is inappropriate (e.g., has epilepticseizures that require treatment), or that would interfere with the interpretation ofthe study results, or that would place the patient at a high level of risk
• Those with routine urinalysis suggestive of urinary protein ≥2+ and a 24-hour urineprotein volume >1.0 g;
• Complications requiring long-term immunosuppressive therapy or requiring systemic ortopical immunosuppressive corticosteroids (>10 mg/day prednisone or other therapeutichormones);
• Use of antibiotics or probiotic preparations (probiotic candies, powders, pills,probiotic juices, probiotic yogurts, oligosaccharides, etc.) within the last month
• Patients who, in the opinion of the investigator, are not suitable for enrollment inthis study.