A Clinical Trial Comparing Long-Course Versus Short-Course Radiotherapy Followed by Immunotherapy Combined With Total Neoadjuvant Therapy (TNT) to Long-Course Radiotherapy Followed by TNT in High-Risk Locally Advanced Rectal Cancer

Not Applicable

Not yet recruiting

• Conditions: Rectal Cancer; Radiotherapy; Immunotherapy; Total Neoadjuvant Therapy
• Interventions: Radiation: Long-course radiotherapy; Radiation: Short-course radiotherapy; Drug: Capecitabine; Drug: Oxaliplatin; Drug: Camrelizumab; Procedure: TME surgery

• Registration Number: NCT07113275
• Lead Sponsor: Tao Zhang

Brief Summary

This study is a national multicenter, prospective randomized controlled Phase III clinical trial designed to investigate the potential therapeutic benefit of immunotherapy combined with total neoadjuvant therapy (TNT) and to compare the efficacy of different radiotherapy modalities followed by immunotherapy.

Detailed Description

This study is a national multicenter, prospective randomized controlled phase III clinical trial, with the following objectives: 1. For patients with high-risk LARC, to determine whether the efficacy of TNT combined with immunotherapy is superior to that of the treatment mode of LCRT followed by TNT; 2. To compare the differences in efficacy and toxicity between long-course radiotherapy and short-course radiotherapy under the mode of TNT combined with immunotherapy.

Study Timeline

• Status Verified: 2025-07
• Study First Submitted: 2025-08-02
• Study First Submitted QC: 2025-08-02
• Last Update Submitted: 2025-08-02
• Study First Posted: 2025-08-08
• Last Update Posted: 2025-08-08
• Study Start: 2026-01-01
• Primary Completion: 2028-01-01
• Study Completion: 2028-12-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 435

Inclusion Criteria

1. Patients or their family members agree to participate in the study and sign the informed consent form;
2. Age 18-75 years, male or female;
3. Histologically confirmed Locally Advanced rectal adenocarcinoma
4. inferior margin ≤ 10 cm from the anal verge;
5. Pelvic MRI shows high risk [meets one of the following conditions]: • Clinical tumor (cT) staging cT4a or cT4b (according to AJCC 8th Edition) • Extramural vascular infiltration • Clinical lymph node (cN) staging cN2 (according to AJCC 8th Edition) • Mesenteric fascia is involved • Lateral lymph node enlargement
6. ECOG performance status score is 0-1;
7. Untreated with anti-tumor therapy for rectal cancer, including radiotherapy, chemotherapy, surgery, etc;
8. There was no operative contraindication;
9. Laboratory tests were required to meet the following requirements: white blood cell (WBC) ≥ 4×109/L; Absolute neutrophil count (ANC) ≥ 1.5×109/L; Platelet count ≥ 100×109/L; Hemoglobin ≥90 g/L; Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN); Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN; Serum creatinine ≤1.5 times the upper limit of normal value or creatinine clearance rate ≥50 mL/min; International normalized ratio (INR) ≤ 1.5 × ULN; Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN;
10. Urinary protein < 2+ or 24-hour urinary protein excretion < 1 g at baseline.

Exclusion Criteria

1. Patients with non-high-risk pMMR LARC；
2. Subjects who have previously received any form of immunotherapy, including but not limited to immune checkpoint inhibitors, immune checkpoint agonists, immune cell therapy, or any other treatment targeting tumor immunomodulatory mechanisms;
3. Presence of any concurrent disease, condition (including laboratory abnormality), history of substance abuse, or current evidence thereof, which, in the judgment of the Investigator, may compromise subject safety, interfere with the process of obtaining informed consent, affect subject compliance, or confound the safety assessment of the investigational product(s).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group B: LCRT + iTNT	TME surgery	Group B: LCRT + iTNT Radiotherapy with Concurrent Chemotherapy (LCRT): Total dose 50.4 Gy delivered in 28 fractions (1.8 Gy per fraction, once daily, 5 days per week). Concurrent Capecitabine: 825 mg/m² orally twice daily, 5 days per week (administered on radiotherapy days). Immunotherapy (Camrelizumab): 200 mg IV infusion q3w for 6 cycles, initiated 2 weeks after radiotherapy completion. Chemotherapy (CAPEOX regimen): Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1. Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14. Cycle duration: 3 weeks per cycle; initiated 2 weeks post-radiotherapy; total of 6 cycles during the neoadjuvant phase.
Group C: LCRT + TNT	Long-course radiotherapy	Group C: LCRT + TNT Radiotherapy with Concurrent Chemotherapy (LCRT): Total dose 50.4 Gy delivered in 28 fractions (1.8 Gy per fraction, once daily, 5 days per week). Concurrent Capecitabine: 825 mg/m² orally twice daily, 5 days per week (administered on radiotherapy days). TNT Chemotherapy (CAPEOX regimen, without immunotherapy): Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1. Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14. Cycle duration: 3 weeks per cycle; initiated 2 weeks post-radiotherapy; total of 6 cycles during the neoadjuvant phase.
Group C: LCRT + TNT	Capecitabine	Group C: LCRT + TNT Radiotherapy with Concurrent Chemotherapy (LCRT): Total dose 50.4 Gy delivered in 28 fractions (1.8 Gy per fraction, once daily, 5 days per week). Concurrent Capecitabine: 825 mg/m² orally twice daily, 5 days per week (administered on radiotherapy days). TNT Chemotherapy (CAPEOX regimen, without immunotherapy): Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1. Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14. Cycle duration: 3 weeks per cycle; initiated 2 weeks post-radiotherapy; total of 6 cycles during the neoadjuvant phase.
Group C: LCRT + TNT	Oxaliplatin	Group C: LCRT + TNT Radiotherapy with Concurrent Chemotherapy (LCRT): Total dose 50.4 Gy delivered in 28 fractions (1.8 Gy per fraction, once daily, 5 days per week). Concurrent Capecitabine: 825 mg/m² orally twice daily, 5 days per week (administered on radiotherapy days). TNT Chemotherapy (CAPEOX regimen, without immunotherapy): Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1. Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14. Cycle duration: 3 weeks per cycle; initiated 2 weeks post-radiotherapy; total of 6 cycles during the neoadjuvant phase.
Group C: LCRT + TNT	TME surgery	Group C: LCRT + TNT Radiotherapy with Concurrent Chemotherapy (LCRT): Total dose 50.4 Gy delivered in 28 fractions (1.8 Gy per fraction, once daily, 5 days per week). Concurrent Capecitabine: 825 mg/m² orally twice daily, 5 days per week (administered on radiotherapy days). TNT Chemotherapy (CAPEOX regimen, without immunotherapy): Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1. Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14. Cycle duration: 3 weeks per cycle; initiated 2 weeks post-radiotherapy; total of 6 cycles during the neoadjuvant phase.
Group A: SCRT + iTNT	Short-course radiotherapy	Group A: SCRT + iTNT Radiotherapy (SCRT): Total dose 25 Gy delivered in 5 fractions (5 Gy per fraction, once daily over 5 consecutive days). Immunotherapy (Camrelizumab): 200 mg via intravenous infusion every 3 weeks (q3w) for 6 cycles, initiated 1 week after radiotherapy completion. Chemotherapy (CAPEOX regimen): Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1. Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14. Cycle duration: 3 weeks per cycle; total of 6 cycles during the neoadjuvant phase.
Group A: SCRT + iTNT	Capecitabine	Group A: SCRT + iTNT Radiotherapy (SCRT): Total dose 25 Gy delivered in 5 fractions (5 Gy per fraction, once daily over 5 consecutive days). Immunotherapy (Camrelizumab): 200 mg via intravenous infusion every 3 weeks (q3w) for 6 cycles, initiated 1 week after radiotherapy completion. Chemotherapy (CAPEOX regimen): Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1. Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14. Cycle duration: 3 weeks per cycle; total of 6 cycles during the neoadjuvant phase.
Group A: SCRT + iTNT	Oxaliplatin	Group A: SCRT + iTNT Radiotherapy (SCRT): Total dose 25 Gy delivered in 5 fractions (5 Gy per fraction, once daily over 5 consecutive days). Immunotherapy (Camrelizumab): 200 mg via intravenous infusion every 3 weeks (q3w) for 6 cycles, initiated 1 week after radiotherapy completion. Chemotherapy (CAPEOX regimen): Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1. Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14. Cycle duration: 3 weeks per cycle; total of 6 cycles during the neoadjuvant phase.
Group A: SCRT + iTNT	Camrelizumab	Group A: SCRT + iTNT Radiotherapy (SCRT): Total dose 25 Gy delivered in 5 fractions (5 Gy per fraction, once daily over 5 consecutive days). Immunotherapy (Camrelizumab): 200 mg via intravenous infusion every 3 weeks (q3w) for 6 cycles, initiated 1 week after radiotherapy completion. Chemotherapy (CAPEOX regimen): Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1. Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14. Cycle duration: 3 weeks per cycle; total of 6 cycles during the neoadjuvant phase.
Group A: SCRT + iTNT	TME surgery	Group A: SCRT + iTNT Radiotherapy (SCRT): Total dose 25 Gy delivered in 5 fractions (5 Gy per fraction, once daily over 5 consecutive days). Immunotherapy (Camrelizumab): 200 mg via intravenous infusion every 3 weeks (q3w) for 6 cycles, initiated 1 week after radiotherapy completion. Chemotherapy (CAPEOX regimen): Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1. Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14. Cycle duration: 3 weeks per cycle; total of 6 cycles during the neoadjuvant phase.
Group B: LCRT + iTNT	Long-course radiotherapy	Group B: LCRT + iTNT Radiotherapy with Concurrent Chemotherapy (LCRT): Total dose 50.4 Gy delivered in 28 fractions (1.8 Gy per fraction, once daily, 5 days per week). Concurrent Capecitabine: 825 mg/m² orally twice daily, 5 days per week (administered on radiotherapy days). Immunotherapy (Camrelizumab): 200 mg IV infusion q3w for 6 cycles, initiated 2 weeks after radiotherapy completion. Chemotherapy (CAPEOX regimen): Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1. Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14. Cycle duration: 3 weeks per cycle; initiated 2 weeks post-radiotherapy; total of 6 cycles during the neoadjuvant phase.
Group B: LCRT + iTNT	Capecitabine	Group B: LCRT + iTNT Radiotherapy with Concurrent Chemotherapy (LCRT): Total dose 50.4 Gy delivered in 28 fractions (1.8 Gy per fraction, once daily, 5 days per week). Concurrent Capecitabine: 825 mg/m² orally twice daily, 5 days per week (administered on radiotherapy days). Immunotherapy (Camrelizumab): 200 mg IV infusion q3w for 6 cycles, initiated 2 weeks after radiotherapy completion. Chemotherapy (CAPEOX regimen): Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1. Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14. Cycle duration: 3 weeks per cycle; initiated 2 weeks post-radiotherapy; total of 6 cycles during the neoadjuvant phase.
Group B: LCRT + iTNT	Oxaliplatin	Group B: LCRT + iTNT Radiotherapy with Concurrent Chemotherapy (LCRT): Total dose 50.4 Gy delivered in 28 fractions (1.8 Gy per fraction, once daily, 5 days per week). Concurrent Capecitabine: 825 mg/m² orally twice daily, 5 days per week (administered on radiotherapy days). Immunotherapy (Camrelizumab): 200 mg IV infusion q3w for 6 cycles, initiated 2 weeks after radiotherapy completion. Chemotherapy (CAPEOX regimen): Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1. Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14. Cycle duration: 3 weeks per cycle; initiated 2 weeks post-radiotherapy; total of 6 cycles during the neoadjuvant phase.
Group B: LCRT + iTNT	Camrelizumab	Group B: LCRT + iTNT Radiotherapy with Concurrent Chemotherapy (LCRT): Total dose 50.4 Gy delivered in 28 fractions (1.8 Gy per fraction, once daily, 5 days per week). Concurrent Capecitabine: 825 mg/m² orally twice daily, 5 days per week (administered on radiotherapy days). Immunotherapy (Camrelizumab): 200 mg IV infusion q3w for 6 cycles, initiated 2 weeks after radiotherapy completion. Chemotherapy (CAPEOX regimen): Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1. Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14. Cycle duration: 3 weeks per cycle; initiated 2 weeks post-radiotherapy; total of 6 cycles during the neoadjuvant phase.

Primary Outcome Measures

Name	Time	Method
complete response (CR) rate	an expected average of 12 months	Defined as pathological complete response (pCR) + Clinical complete response (cCR)

Secondary Outcome Measures

Name	Time	Method
Overall Survival	an expected average of 5 years	The time from the date of randomization to the death caused by any cause
3-year disease-Free Survival	an expected average of 3 years	The time from the first day of disease free (operation date) to local or distant recurrence, or the death event caused by any reason, whichever occurs first
Adverse events (AEs) were graded according to the NCI CTCAE version 5·0	an expected average of 1.5 years	Adverse events and surgical safety

Trial Locations

Locations (1)

Union Hospital, Tongji Medical College, Huazhong University of Science and Technology; 🇨🇳 Wuhan, Hubei, China