A Phase II Randomized Trial of Serplulimab With Second-Line Chemo/Targeted Therapy for Early Relapse Colorectal Cancer After Adjuvant Chemotherapy

Inclusion criteria

Age ≥18 years, male or female. Histologically confirmed early relapse (within 1 year after surgery, UICC stage IV) of colorectal cancer after adjuvant chemotherapy, with initially unresectable metastatic lesions or refusal of surgery.

Have received standard postoperative adjuvant chemotherapy (XELOX or FOLFOX). Before enrollment, tumor tissue tested by immunohistochemistry as pMMR, or by PCR or NGS as MSS or MSI-L.

At least one measurable tumor lesion according to RECIST 1.1 criteria. ECOG performance status 0-1. Life expectancy ≥3 months.

Adequate organ function:

• Neutrophils ≥1.5 × 10⁹/L; platelets ≥100 × 10⁹/L; hemoglobin ≥9 g/dL; serum albumin ≥3 g/dL.
• Thyroid-stimulating hormone (TSH) ≤ upper limit of normal (ULN), with T3 and T4 within normal range.
• Bilirubin ≤1.5 × ULN; ALT and AST ≤2 × ULN.
• Serum creatinine ≤1.5 × ULN, creatinine clearance ≥60 mL/min.
• International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN, unless the patient is receiving anticoagulant therapy and PT is within the expected therapeutic range for anticoagulation.
• Activated partial thromboplastin time (aPTT) ≤1.5 × ULN. Female patients of childbearing potential must have a negative pregnancy test. Female patients not of childbearing potential, fertile male patients, and female patients of childbearing potential at risk of pregnancy must agree to use adequate contraception throughout the study and for 12 months after the last dose of study treatment.

Signed and dated written informed consent indicating that the patient has been informed of all relevant aspects of the study.

Willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

Exclusion criteria

Pathologically diagnosed other intestinal tumors, such as gastrointestinal stromal tumors.

RAS mutation status not tested. Tumor tissue tested by immunohistochemistry as dMMR, or by PCR or NGS as MSI-H. Metastatic lesions are resectable, or the patient wishes to undergo metastasectomy.

Uncontrolled active bleeding from the primary tumor or intestinal obstruction. Contraindications to immune checkpoint inhibitor therapy. Hypersensitivity to study drugs or their excipients. Prior or concurrent other malignancy, except for adequately treated non-melanoma skin cancer, cervical carcinoma in situ, and papillary thyroid carcinoma.

Active autoimmune disease or history of autoimmune disease (e.g., interstitial pneumonia, colitis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism, including but not limited to these diseases or syndromes); excluding autoimmune-mediated hypothyroidism treated with stable doses of thyroid replacement hormone, type I diabetes mellitus treated with stable doses of insulin, vitiligo, or childhood asthma/allergy that has resolved and requires no intervention in adulthood.

History of immunodeficiency, including HIV positivity, or other acquired or congenital immunodeficiency diseases, or history of organ transplantation or allogeneic bone marrow transplantation.

History of interstitial lung disease or non-infectious pneumonitis. Active pulmonary tuberculosis infection by history or CT scan, or history of active pulmonary tuberculosis infection within 1 year before enrollment, or history of active pulmonary tuberculosis infection more than 1 year prior without adequate treatment.

Active hepatitis B (HBV DNA ≥2000 IU/mL or 10⁴ copies/mL) or hepatitis C (positive HCV antibody with HCV-RNA above the lower limit of detection of the assay).

Severe cardiac, pulmonary, renal, or hepatic dysfunction. Hypertension that cannot be adequately controlled with antihypertensive medication (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg).

History of psychotropic substance abuse, alcoholism, or drug addiction. Other factors that may affect patient safety or trial compliance as judged by the investigator, such as serious diseases requiring concomitant treatment (including psychiatric disorders), serious laboratory abnormalities, or other family or social factors.