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

Overview

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.

Interventions

• 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 fra
• 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 fractio
• 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 fractio

Primary outcome measures

• Complete Remission (CR) Rate [Time frame: At the time of surgery for pCR, and at 1 year after achieving cCR for sustained cCR]

Secondary outcome measures (5)

• 3-Year Disease-Free Survival (DFS) Rate [Time frame: Up to 3 years after randomization]
• 3-Year Overall Survival (OS) Rate [Time frame: up to 5 years]
• 3-Year Event-Free Survival (EFS) Rate [Time frame: up to 3 years from treatment]
• Objective Response Rate [Time frame: Up to 1 years]
• AE rate [Time frame: 24months]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Zhongshan hosptial, Fudan University — Shanghai

Identifiers

NCT: NCT07527520 · KY2026078

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗