This is a single-center exploratory clinical study to explore the efficacy and safety of Oral Inulin in Combination With Fruquintinib Plus Sintilimab as Third- or Further-line Treatment in Metastatic Colorectal Cancer.

This was a prospective, two-arm, single-center, exploratory phase I study, randomized 2: 1 into an intervention group (Fruquintinib combined with Sintilimab and inulin group) and a control group (Fruquintinib combined with Sintilimab group). Fruquintinib: 4 mg/d, QD po, administered continuously for 2 weeks with a 1-week discontinuation; Sintilimab 200 mg, I.V., D1, administered every 3 weeks; Inulin: 5 g/d, qd po, in the first week, and 10 g/d, bid po, starting in the second week; Combination therapy was administered every 3 weeks as a treatment cycle. Combination therapy was administered until disease progression, death, or intolerable toxicity.

The study was divided into 3 phases: a screening phase, a treatment phase, and a follow-up phase. Tumor status was assessed using imaging methods every 6 weeks (±7 days) until disease progression (RECIST 1.1) or death (during patient treatment) or intolerable toxicity, and tumor treatment and survival status after disease progression were recorded. Safety observations included changes in AE, laboratory test values, vital signs, and electrocardiographic changes.

Inclusion Criteria:

• Have been fully informed about the study and have voluntarily signed an informed consent 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 mm as determined by spiral CT scanning and at least 20 mm as determined by conventional CT 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 blood components 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; total bilirubin <1.5 times ULN; ALT and/or AST <1.5 times ULN, and for patients with liver metastases <3 times ULN; serum creatinine <1.5 times ULN; endogenous creatinine clearance ≥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 and intestinal microbiology testing.

Exclusion Criteria:

• Inability to comply with the study protocol or study procedures;
• Prior treatment with a vascular endothelial growth factor receptor (VEGFR) inhibitor or prior treatment with an immune checkpoint inhibitor;
• Other malignancy within the past 5 years, except for basal or squamous cell carcinoma of the skin after radical surgery, or carcinoma in situ of the cervix;
• The presence of central nervous system (CNS) metastases or previous brain metastases prior 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 the investigator, 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 significant cardiovascular disease, including unstable angina or myocardial infarction, within 6 months prior to initiation of study treatment, including, but not limited to, acute myocardial infarction, severe/unstable angina, or coronary artery bypass grafting within 6 months prior to enrollment; congestive Heart failure New York Heart Association (NYHA) classification >2; Ventricular arrhythmia requiring pharmacologic treatment; 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 in China within 4 weeks prior to enrollment and have been treated with the corresponding trial 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 or the 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, or other conditions that may cause gastrointestinal bleeding or perforation, as determined by the investigator;
• Patients with evidence or history of significant bleeding tendency within 3 months prior 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 thromboembolic event (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 clinically significant liver disease, including viral hepatitis [known hepatitis B virus (HBV) carriers must be excluded from active HBV infection, i.e., HBV DNA-positive (>1×10^4 copies/mL or >2000 IU/ml); known hepatitis C virus infection (HCV) and HCV RNA-positive (>1×10^3 copies/mL)];
• Unresolved toxic reactions above CTCAE v5.0 Grade 1 or higher due to any prior anticancer therapy, excluding alopecia, lymphopenia, and neurotoxicity ≤ Grade 2 due to oxaliplatin;
• Females who are pregnant (positive pregnancy test prior to dosing) or breastfeeding;
• Transfusion therapy, blood products, and hematopoietic factors, such as albumin and granulocyte colony-stimulating factor (G-CSF), received within 14 days prior to enrollment;
• Any other disease with clinically significant metabolic abnormalities, physical examination abnormalities, or laboratory test abnormalities that, in the judgment of the investigator, give reason to suspect that the patient has a disease or condition for which the use of the study medication is inappropriate (e.g., has epileptic seizures that require treatment), or that would interfere with the interpretation of the 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 urine protein volume >1.0 g;
• Complications requiring long-term immunosuppressive therapy or requiring systemic or topical immunosuppressive corticosteroids (>10 mg/day prednisone or other therapeutic hormones);
• 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 in this study.