Neoadjuvant Moderately Hypofractionated Radiotherapy Combined With Chemotherapy and Immunotherapy for High-risk pMMR/MSS Locally Advanced Rectal Cancer: A Prospective, Multi-center Randomized Control Phase II Trial

This study aims to observe and evaluate the efficacy and safety of moderately hypofractionated radiotherapy combined with chemotherapy and immunotherapy, compared with conventional neoadjuvant chemoradiotherapy, in patients with high-risk locally advanced colorectal cancer.

Study Overview

• Status: Not yet recruiting
• Conditions: Rectal Cancer; Moderately Hypofractionated Radiotherapy; Serplulimab; pMMR/MSS
• Intervention / Treatment: Drug: Serplulimab; Radiation: Moderately Hypofractionated Radiotherapy; Other: CapOx+Long-course radiotherapy

• Study Type: Interventional
• Enrollment (Estimated): 165
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Shanghai, China, 200032
    • Zhongshan hosptial, Fudan University
    • Contact: jianming XU, PhD; Phone Number: +86-13501984869; Email: xujmin@aiiyun.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years and ≤ 75 years.
• Histologically confirmed colorectal adenocarcinoma with the lower margin of the lesion ≤ 10 cm from the anal verge as assessed by MRI, and immunohistochemistry confirming pMMR, or genetic testing demonstrating MSI-L or MSS.
• Presence of at least one of the following high-risk factors as assessed by pelvic MRI: cT4a/b; N2; extramural vascular invasion (EMVI+); mesorectal fascia involvement (MRF+); enlarged lateral lymph node (longest diameter > 7 mm).
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1
• No prior surgery, radiotherapy, chemotherapy, or targeted therapy.
• Able to tolerate radiotherapy, chemotherapy, and immunotherapy: ECOG performance status score 0-2. Laboratory results: white blood cell count ≥ 4.0 × 10⁹/L, platelet count ≥ 100 × 10⁹/L, hemoglobin ≥ 80 g/L, ALT < 2 × ULN, total bilirubin < 35 μmol/L, serum creatinine < 1.5 × ULN or creatinine clearance ≥ 50 mL/min, thyroid-stimulating hormone within normal range (patients with stable thyroid function after hormone replacement therapy may be enrolled).
• Willing to participate and able to provide written informed consent.

Exclusion Criteria:

• Presence of distant metastasis.
• Patients with stage I or II rectal cancer who do not require preoperative neoadjuvant therapy.
• Severe diseases involving the heart, lung, brain, kidney, gastrointestinal tract, or other systemic conditions.
• Untreated chronic hepatitis B or HBV carriers with HBV DNA > 500 IU/mL, or patients positive for HCV RNA. Patients with inactive hepatitis B surface antigen (HBsAg) carriers, those with hepatitis B who have been treated and are stable (HBV DNA < 500 IU/mL), and those who have been cured of hepatitis C may be enrolled.
• Active autoimmune disease or history of autoimmune disease with potential for relapse.
• Receipt of corticosteroids (at a dose equivalent to prednisone > 10 mg/day) or other immunosuppressive therapy within 2 weeks prior to study drug administration.
• History of thyroid dysfunction.
• Severe chronic or active infection requiring systemic antifungal or antiviral therapy, including tuberculosis infection.
• History of allergic constitution or allergy to multiple drugs.
• History of prior pelvic radiotherapy.
• History of inflammatory bowel disease.
• Unwillingness to participate or inability to provide written informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental group A; CapOx+Serplulimab+Moderately Hypofractionated Radiotherapy	Drug: Serplulimab; CapOx Regimen Recommended Dose：Capecitabine: 1000 mg/m² orally twice daily on days 1-14 of each 21-day cycle.Oxaliplatin: 130 mg/m² intravenously on day 1 of each 21-day cycle. Serplulimab: 300 mg intravenously on day 1 of each 21-day cycle. Long-course Concurrent Chemoradiotherapy：Delivered using a conventional fractionation schedule.Gross tumor volume (GTV): 1.8-2.0 Gy per fraction, total dose 50-50.4 Gy.Clinical target volume (CTV): 1.8 Gy per fraction, total dose 45 Gy.Once daily, 5 fractions per week.GTV receives 25-28 fractions; CTV receives 25 fractions.
Experimental: Experimental group B; CapOx+Serplulimab+Long-course radiotherapy	Radiation: Moderately Hypofractionated Radiotherapy; CapOx Regimen Recommended Dose：Capecitabine: 1000 mg/m² orally twice daily on days 1-14 of each 21-day cycle.Oxaliplatin: 130 mg/m² intravenously on day 1 of each 21-day cycle. Serplulimab: 300 mg intravenously on day 1 of each 21-day cycle. Moderately Hypofractionated Radiotherapy：Delivered using a simultaneous integrated boost (SIB) technique.Gross tumor volume (GTV): 3.5 Gy per fraction; clinical target volume (CTV): 3.0 Gy per fraction.Once daily, 5 fractions per week, for a total of 10 fractions.Total dose: GTV 35 Gy, CTV 30 Gy.
Active Comparator: Control arm; CapOx+Long-course radiotherapy	Other: CapOx+Long-course radiotherapy; CapOx Regimen Recommended Dose：Capecitabine: 1000 mg/m² orally twice daily on days 1-14 of each 21-day cycle.Oxaliplatin: 130 mg/m² intravenously on day 1 of each 21-day cycle. Long-course Concurrent Chemoradiotherapy：Delivered using a conventional fractionation schedule.Gross tumor volume (GTV): 1.8-2.0 Gy per fraction, total dose 50-50.4 Gy.Clinical target volume (CTV): 1.8 Gy per fraction, total dose 45 Gy.Once daily, 5 fractions per week.GTV receives 25-28 fractions; CTV receives 25 fractions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Remission (CR) Rate	Definition: The proportion of participants achieving complete remission, defined as: Pathologic complete response (pCR): No residual viable tumor cells detected in the resected specimen after neoadjuvant treatment (ypT0N0) Sustained clinical complete response (cCR): No evidence of residual tumor on digital rectal examination, endoscopy, and MRI, maintained for more than 1 year without surgery Assessment Method: Evaluated by investigators based on imaging, endoscopic findings, pathology (for surgical cases), and clinical examination	At the time of surgery for pCR, and at 1 year after achieving cCR for sustained cCR

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AE rate	Adverse event incidence rate	24months
3-Year Disease-Free Survival (DFS) Rate	Time from randomization to evidence of disease recurrence within 3 years	Up to 3 years after randomization
3-Year Overall Survival (OS) Rate	Time from randomization to death from any cause.	up to 5 years
3-Year Event-Free Survival (EFS) Rate	Defined as the time from the start of treatment to the occurrence of any of the following events, whichever occurs first: disease progression that precludes surgery, postoperative disease progression or recurrence (per RECIST v1.1), or death from any cause.	up to 3 years from treatment
Objective Response Rate	The rate of participants that achieve either a complete response (CR) or a partial response (PR).	Up to 1 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of life (QoL)	Quality of life will be evaluated using the European O-rganization for Reasearch and Treatment of Cancer Quality of Life Questionnaire-C30（EORTC QLQ-C30） (range 0-100). It evaluates the quality of life from 30 aspects, including appetite, mental status, sleep quality, fatigue, etc. The higher scores mean a better quality of life.	From date of randomization until the date of death from any cause, assessed up to 10 years

Collaborators and Investigators

• Sponsor: Fudan University

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): June 1, 2031

Study Registration Dates

• First Submitted: April 7, 2026
• First Submitted That Met QC Criteria: April 7, 2026
• First Posted (Actual): April 14, 2026

Study Record Updates

• Last Update Posted (Actual): April 14, 2026
• Last Update Submitted That Met QC Criteria: April 7, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Rectal Diseases; Rectal Neoplasms
• Other Study ID Numbers: KY2026078

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No