To evaluate the safety and efficacy of SHR-3821 combined with fruquintinib in the advanced colorectal cancer after failure of standard therapy

This is a single-center, open-label, exploratory phase II clinical trial designed to investigate the efficacy and safety of SHR-3821 in combination with fruquintinib for the treatment of metastatic colorectal cancer.

Inclusion Criteria:

1. Histologically or cytologically confirmed unresectable recurrent or metastatic colorectal cancer.

2. Aged 18-75 years, male or female.

3. Failure of ≥2 lines of prior standard systemic therapy, which should have included oxaliplatin, irinotecan, and fluoropyrimidine-based chemotherapy. Subjects who failed first-line therapy are eligible if the first-line regimen contained all three chemotherapeutic agents, or if they exhibited intolerance or lack of response to oxaliplatin during adjuvant therapy. Subjects with dMMR/MSI-H tumors must also have failed anti-PD-1/PD-L1 antibody therapy.

4. Life expectancy ≥3 months.

5. Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0-1.

6. At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).

7. Adequate organ and bone marrow function within 7 days prior to the first dose, as defined below:

   1. Hematology (without transfusion or growth factor support within 14 days): hemoglobin ≥90 g/L; platelet count ≥100×10^9/L; white blood cell count ≥3.5×10^9/L; absolute neutrophil count ≥1.5×10^9/L.
   2. Liver function: total bilirubin ≤1.5 × upper limit of normal (ULN); aspartate aminotransferase and alanine aminotransferase ≤2.5 × ULN (≤5 × ULN if liver metastases are present).
   3. Renal function: serum creatinine ≤1.5 × ULN or calculated creatinine clearance ≥60 mL/min (using the Cockcroft-Gault formula).
   4. Coagulation: international normalized ratio ≤1.5 × ULN (or between 2.0 and 3.0 if on stable warfarin therapy); activated partial thromboplastin time and prothrombin time ≤1.5 × ULN.

8. Male patients and female patients of childbearing potential must use highly effective contraception during the study and for 12 months after the last dose. Female patients must be non-lactating and have a negative serum pregnancy test within 7 days before the first dose.

9. Voluntary participation, signed informed consent, good compliance, and willingness to cooperate with follow-up.

Exclusion Criteria:

1. Presence of concurrent active malignancies other than the primary tumor (except cured basal cell carcinoma of the skin, carcinoma in situ of the cervix, superficial bladder cancer, ductal carcinoma in situ of the breast, papillary thyroid carcinoma, and gastrointestinal tumors confirmed cured by endoscopic mucosal resection). History of prior malignancy is allowed if the disease has been cured for ≥2 years.

2. Patients with untreated or active central nervous system (CNS) metastases or leptomeningeal metastasis. Patients are eligible if they have received local therapy, have stable neurological symptoms for at least 2 weeks prior to the first dose, and do not require corticosteroids or require ≤10 mg/day of prednisone (or equivalent).

3. Presence of severe complications at the primary site (e.g., perforation, obstruction, uncontrollable massive hemorrhage).

4. Uncontrolled or moderate-to-large pleural effusion or pericardial effusion. Clinically symptomatic moderate or severe ascites (patients with small ascites detected only by imaging without clinical symptoms are eligible).

5. Toxicities and/or complications from prior interventions have not recovered to ≤ Grade 1 per NCI CTCAE or to levels specified in the inclusion/exclusion criteria (except for toxicities judged by the investigator as safe and controllable, such as alopecia, ≤ Grade 2 peripheral neuropathy).

6. Uncontrolled hypertension or history of hypertensive crisis.

7. Significant cardiovascular or cerebrovascular diseases, including but not limited to:

   1. Left ventricular ejection fraction (LVEF) <50% within 28 days prior to the first dose.
   2. Severe cardiac arrhythmia or conduction abnormalities, such as ventricular arrhythmias requiring clinical intervention, grade ii-iii atrioventricular block.
   3. Acute coronary syndrome, congestive heart failure (new york heart association (NYHA) class ≥II), aortic dissection, stroke, or other grade 3 or higher cardiovascular/cerebrovascular events within 6 months prior to the first dose.
   4. Average QTc interval ≥450 ms for males and ≥470 ms for females based on two electrocardiogram (ECG) measurements (QTcF=QT/RR^0.33).
   5. Arterial/venous thrombotic events, such as cerebrovascular accident, deep vein thrombosis, or pulmonary embolism, within 6 months prior to the first dose.

8. Major surgery (defined as surgery requiring general anesthesia and a recovery period of at least 3 weeks) within 28 days prior to the first dose of study drug (diagnostic biopsy is allowed).

9. Active tuberculosis or history of active tuberculosis infection within ≤48 weeks prior to screening, regardless of treatment.

10. History of interstitial lung disease (ILD), or radiographic findings suggestive of or cannot rule out ild at screening; or other moderate-to-severe pulmonary diseases that significantly impair lung function.

11. Active hepatitis b or active hepatitis c (HBV DNA≥1x10^3).

12. History of immunodeficiency, including positive HIV test, other acquired or congenital immunodeficiency diseases, or history of organ transplantation.

13. Severe infection within 4 weeks prior to the first dose, including but not limited to bacteremia or severe pneumonia requiring hospitalization; or active infection of CTCAE grade ≥2 requiring systemic antibiotic therapy within 2 weeks prior to the first dose.

14. Any significant clinical or laboratory abnormality that, in the investigator's judgment, may affect safety evaluation (e.g., uncontrolled diabetes, chronic kidney disease, thyroid dysfunction, poorly controlled hypercholesterolemia).

15. Known history of hypersensitivity to any component of the investigational agents.

16. Inability to swallow study drugs, or conditions affecting drug administration and absorption (e.g., chronic diarrhea [including but not limited to irritable bowel syndrome, Crohn's disease, ulcerative colitis], intestinal obstruction).

17. Pregnant or lactating women, or patients of childbearing potential (men or women with less than 1 year since last menstruation) unwilling to use effective contraception.

18. Any other condition that, in the investigator's judgment, may increase the risk associated with study participation, interfere with the interpretation of study results, or make the patient unsuitable for the study.