A Prospective, Multicenter, Single-Arm Phase II Exploratory Study of Serplulimab Combined With Oncolytic Virus H101, Short-Course Radiotherapy, and XELOX Chemotherapy as Total Neoadjuvant Treatment for Locally Advanced (cT1-3N0M0) Rectal Cancer

A Prospective, Multicenter, Single-Arm Phase II Study of Serplulimab Combined With Oncolytic Virus H101, Short-Course Radiotherapy, and XELOX Chemotherapy as Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer (cT1-3N0M0)

This study aims to evaluate the safety and effectiveness of a combination treatment including a PD-1 inhibitor (serplulimab), oncolytic virus H101, short-course radiotherapy, and XELOX chemotherapy as total neoadjuvant therapy in patients with locally advanced low rectal cancer (cT1-3N0M0).

In this prospective, multicenter, single-arm phase II study, eligible patients will receive a standardized treatment regimen consisting of intratumoral injection of oncolytic virus H101, short-course radiotherapy, chemotherapy, and immunotherapy over multiple cycles. Tumor response will be assessed using imaging, endoscopy, and clinical evaluation after completion of treatment.

The primary objective is to determine the 1-year clinical complete response rate. Secondary outcomes include tumor response rate, organ preservation rate, survival outcomes, and treatment safety.

The results of this study may help improve treatment strategies for rectal cancer, increase the rate of complete response, and provide more opportunities for organ preservation while maintaining safety.

Rectal cancer is a common malignancy with a significant impact on patient survival and quality of life. For patients with locally advanced rectal cancer, the current standard treatment typically includes neoadjuvant chemoradiotherapy followed by surgery. Although this approach can achieve tumor control, the rate of complete response remains limited, and surgery may result in permanent stoma or impaired bowel, urinary, and sexual function. Therefore, there is a need to develop more effective treatment strategies that can improve tumor response and increase the chance of organ preservation.

Most rectal cancers are mismatch repair-proficient or microsatellite stable (pMMR/MSS), which generally show limited response to immunotherapy alone. Recent studies suggest that combination strategies may enhance treatment efficacy by modifying the tumor microenvironment and improving immune response.

This study is designed to evaluate a novel combination treatment approach that includes a PD-1 inhibitor (serplulimab), an oncolytic virus (H101), short-course radiotherapy, and XELOX chemotherapy as total neoadjuvant therapy. The oncolytic virus H101 selectively infects and destroys tumor cells while stimulating anti-tumor immune responses. Radiotherapy may further enhance immune activation by promoting tumor antigen release, and chemotherapy can improve tumor sensitivity to treatment. The combination of these therapies is expected to have a synergistic effect. :contentReference[oaicite:0]{index=0}

This is a prospective, multicenter, single-arm phase II clinical trial. Approximately 20 patients with low rectal adenocarcinoma (cT1-3N0M0) will be enrolled. All participants will receive a standardized treatment regimen consisting of intratumoral injections of H101, short-course radiotherapy, and systemic treatment with serplulimab and XELOX chemotherapy over multiple cycles. :contentReference[oaicite:1]{index=1}

Tumor response will be evaluated after completion of the total neoadjuvant therapy using imaging, endoscopy, and clinical assessments. Patients who achieve clinical complete response may enter a non-surgical management strategy with close follow-up, while others may proceed to surgery based on clinical evaluation.

The primary endpoint of this study is the 1-year clinical complete response rate. Secondary endpoints include objective response rate, organ preservation rate, tumor downstaging, recurrence-free survival, disease-free survival, overall survival, and safety outcomes. :contentReference[oaicite:2]{index=2}

The findings of this study may provide evidence for a new treatment strategy for rectal cancer that improves tumor response and increases the possibility of organ preservation while maintaining acceptable safety.

Inclusion Criteria:

- Participants must meet all of the following criteria:

1. Age 18 to 80 years, male or female.

2. Histologically confirmed low rectal adenocarcinoma, with tumor located ≤5 cm from the anal verge.

3. Clinical stage T1-3N0M0 according to AJCC staging criteria.

4. Mismatch repair-proficient (pMMR) or microsatellite stable (MSS) tumor confirmed by immunohistochemistry or genetic testing.

5. No prior anti-tumor treatment.

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, with an expected survival of at least 3 months.

7. Adequate organ function, including:

   • Absolute neutrophil count ≥1.5 × 10^9/L
   • Platelet count ≥100 × 10^9/L
   • Hemoglobin ≥9 g/dL
   • Serum albumin ≥3 g/dL
   • Total bilirubin ≤1.5 × upper limit of normal (ULN)
   • ALT and AST ≤2 × ULN
   • Serum creatinine ≤1.5 × ULN or creatinine clearance ≥60 mL/min
   • INR or PT ≤1.5 × ULN, and aPTT ≤1.5 × ULN

8. Thyroid function within normal range or adequately controlled.

9. Negative pregnancy test for women of childbearing potential.

10. Willingness to use effective contraception during the study and for 12 months after treatment.

11. Ability to understand and willingness to sign a written informed consent form.

12. Willingness and ability to comply with study procedures and follow-up.

Exclusion Criteria:

• Participants will be excluded if they meet any of the following criteria:

  1. Histology other than rectal adenocarcinoma (e.g., gastrointestinal stromal tumor, lymphoma).
  2. Prior pelvic radiotherapy.
  3. Prior treatment with PD-1, PD-L1, or CTLA-4 inhibitors.
  4. Known allergy to study drugs or their components.
  5. History of other malignancies, except adequately treated non-melanoma skin cancer, carcinoma in situ of the cervix, or papillary thyroid carcinoma.
  6. Active autoimmune disease or history of autoimmune disease requiring systemic treatment.
  7. Immunodeficiency, including HIV infection, or history of organ transplantation.
  8. History of interstitial lung disease or non-infectious pneumonitis.
  9. Active tuberculosis infection or history of untreated tuberculosis.
  10. Active hepatitis B or hepatitis C infection.
  11. Severe cardiovascular, pulmonary, or renal disease.
  12. Uncontrolled hypertension despite medication.
  13. History of substance abuse (alcohol or drugs).
  14. Active uncontrolled infection.
  15. Use of systemic immunosuppressive therapy.
  16. Pregnant or breastfeeding women.
  17. Any condition that, in the investigator's opinion, may interfere with study participation or safety.