Serplulimab Plus Decitabine and CAPOX Before Surgery for Locally Advanced Colorectal Cancer

A Single-Arm, Single-Center, Phase II Exploratory Clinical Study of Serplulimab Combined With Decitabine Plus CAPOX as Neoadjuvant Therapy for Locally Advanced Colorectal Cancer

Title:A Single-Arm, Single-Center, Phase II Exploratory Study of Serplulimab Combined with Decitabine plus CAPOX as Neoadjuvant Therapy for Locally Advanced Colorectal Cancer Background:Colorectal cancer is one of the most common gastrointestinal malignancies worldwide. Patients with locally advanced colorectal cancer remain at high risk of recurrence and distant metastasis after surgery. Although perioperative chemotherapy has improved clinical outcomes, the pathological complete response rate remains limited. Immune checkpoint inhibitors have shown remarkable efficacy in dMMR/MSI-H colorectal cancer; however, most pMMR/MSS tumors respond poorly to immunotherapy alone. Decitabine, a DNA methyltransferase inhibitor, may enhance tumor immunogenicity by promoting tumor antigen expression, improving antigen presentation, increasing immune cell infiltration, and reshaping the tumor immune microenvironment. CAPOX chemotherapy may further induce immunogenic cell death and enhance antitumor immune responses. Therefore, the combination of serplulimab, decitabine, and CAPOX may provide a synergistic neoadjuvant treatment strategy for locally advanced colorectal cancer.

Objective:This study aims to evaluate the efficacy and safety of serplulimab combined with decitabine plus CAPOX as neoadjuvant therapy for patients with locally advanced colorectal cancer. The primary endpoint is pathological complete response rate. Secondary endpoints include R0 resection rate, tumor downstaging, objective response rate, disease-free survival, and safety outcomes.

Methods:This is a prospective, single-center, single-arm, phase II exploratory clinical study. A total of 35 patients with previously untreated locally advanced colorectal adenocarcinoma will be enrolled. Eligible patients are adults aged ≥18 years with histologically or pathologically confirmed cT3/cT4N+M0 colorectal adenocarcinoma according to the AJCC/UICC 8th edition, at least one measurable lesion according to RECIST 1.1, ECOG performance status of 0-1, adequate organ function, and an expected survival of more than 3 months.

The study includes a safety lead-in stage and a dose-expansion stage. In the safety lead-in stage, decitabine dose escalation will follow a conventional 3+3 design, with two planned dose levels: 10 mg and 15 mg intravenously on Days 1-2 of each 3-week cycle. Serplulimab will be administered at 300 mg intravenously on Day 1 of each 3-week cycle. CAPOX consists of oxaliplatin 130 mg/m² intravenously on Day 1 and capecitabine 1000 mg/m² orally twice daily on Days 1-14 of each 3-week cycle. The maximum tolerated dose or recommended phase II dose of decitabine will be determined based on dose-limiting toxicity.

In the dose-expansion stage, patients will receive serplulimab combined with decitabine and CAPOX for four cycles as neoadjuvant therapy. Patients without distant metastasis and considered suitable for surgery will undergo radical colorectal cancer resection 2-4 weeks after completion of neoadjuvant treatment. Postoperative adjuvant therapy will be determined by the investigator according to pathological findings and clinical practice.

Endpoints and Analysis:The primary endpoint is pathological complete response, defined as the absence of residual viable tumor cells in the primary tumor and resected lymph nodes after neoadjuvant therapy. Secondary endpoints include R0 resection rate, tumor downstaging rate, objective response rate assessed by RECIST 1.1, and disease-free survival. Safety assessments include adverse events, serious adverse events, immune-related adverse events, laboratory abnormalities, vital signs, 12-lead ECG, ECOG performance status, thyroid function, and physical examination findings. Adverse events will be graded according to NCI-CTCAE version 5.0.

Descriptive statistics will be used for analysis. Continuous variables will be summarized by mean, standard deviation, median, minimum, and maximum. Categorical variables will be summarized by frequency and percentage. Time-to-event outcomes will be analyzed using the Kaplan-Meier method.

Expected Significance:This study will explore whether the combination of PD-1 blockade, epigenetic modulation, and CAPOX chemotherapy can improve pathological response while maintaining acceptable safety in locally advanced colorectal cancer. The results may provide preliminary evidence for a new neoadjuvant treatment strategy and support future multicenter clinical studies.

Inclusion Criteria:

• Voluntarily signs written informed consent before screening.
• Male or female, aged 18 years or older.
• Has at least one measurable lesion according to RECIST version 1.1.
• ECOG performance status score of 0 to 1.
• Histologically or pathologically confirmed colorectal adenocarcinoma with no prior antitumor treatment, staged as cT3/cT4N+M0 locally advanced colorectal cancer according to the AJCC/UICC 8th edition based on contrast-enhanced CT or MRI, with colonoscopy and/or diagnostic laparoscopy if clinically indicated.
• Planned to undergo surgery after neoadjuvant therapy according to clinical staging.
• Expected survival of more than 3 months.
• Adequate major organ function, meeting all of the following criteria:
• Hematology: neutrophil count ≥1.5 × 10^9/L, platelet count ≥100 × 10^9/L, hemoglobin ≥90 g/L, and white blood cell count ≥3.5 × 10^9/L, without blood transfusion, granulocyte colony-stimulating factor, or other hematopoietic growth factors within 14 days before screening.
• Hepatic function: ALT and AST ≤2.5 × upper limit of normal, and total bilirubin ≤1.5 × upper limit of normal, or ≤3 × upper limit of normal for patients with Gilbert syndrome.
• Renal function: serum creatinine ≤1.5 × upper limit of normal or creatinine clearance ≥60 mL/min.
• Coagulation function: activated partial thromboplastin time, international normalized ratio, and prothrombin time ≤1.5 × upper limit of normal.

Exclusion Criteria:

• Prior treatment with any antitumor therapy, including chemotherapy, radiotherapy, hormonal therapy, or molecular targeted therapy.
• Prior immunotherapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4 antibody, or any other antibody or drug targeting T-cell co-stimulation or immune checkpoint pathways.
• History of another malignancy within 5 years or concurrent malignancy, except cured carcinoma in situ of the cervix, non-melanoma skin cancer, or other malignancy treated with curative intent with no evidence of disease for at least 5 years.
• Pre-existing peripheral neuropathy of grade 2 or higher according to NCI-CTCAE version 5.0.
• Known active central nervous system metastasis and/or carcinomatous meningitis.
• History of severe hypersensitivity reaction to any component of a product or formulation similar to the study PD-1 antibody, or known severe hypersensitivity reaction to other monoclonal antibodies, oxaliplatin, capecitabine, or related compounds, defined as NCI-CTCAE version 5.0 grade 3 or higher.
• Known history of hereditary bleeding disorder or coagulation disorder associated with bleeding risk.
• Major surgery within 4 weeks before enrollment.
• Has not recovered from complications of prior surgery to grade 1 or lower according to CTCAE version 5.0, except alopecia and fatigue.
• Requires immunosuppressive medication within 2 weeks before enrollment or during the study, except intranasal, inhaled, topical, or local steroid injections; systemic corticosteroids at physiological doses equivalent to prednisone ≤10 mg/day; or short-term use of steroids for prevention or treatment of non-autoimmune allergic conditions for no more than 7 days.
• Active autoimmune disease or history of autoimmune disease with potential recurrence.
• Known history of interstitial lung disease or non-infectious pneumonitis.
• Known history of active tuberculosis.
• History of human immunodeficiency virus infection, other acquired or congenital immunodeficiency disease, organ transplantation, or stem cell transplantation.
• Positive hepatitis B surface antigen with HBV DNA ≥10^4 copies/mL or ≥2000 IU/mL at screening, or active hepatitis C defined as positive HCV antibody with HCV RNA above the lower limit of detection.
• Active or uncontrolled infection requiring systemic treatment within 2 weeks before enrollment.
• Receipt of a live viral vaccine within 4 weeks before enrollment.
• Intestinal obstruction, inflammatory bowel disease, extensive intestinal resection with chronic diarrhea, Crohn's disease, ulcerative colitis, or chronic diarrhea.
• Breastfeeding, or planning pregnancy during treatment and within 6 months after completion of treatment.
• Unwillingness to use effective contraception during treatment and within 6 months after completion of treatment, including male participants capable of fathering a child, female participants, and their male partners.
• Any other condition that, in the investigator's judgment, may affect protocol compliance or assessment of study endpoints and makes the participant unsuitable for this study.