Hypofractionated Radiotherapy Plus Immunotherapy Versus Conventional Radiotherapy in Locally Recurrent Rectal Cancer

Multicenter, Randomized, Phase II Trial of Neoadjuvant Hypofractionated Radiotherapy Plus Immunotherapy and First-line Therapy Versus Conventional Radiotherapy Plus First-line Therapy in pMMR Locally Recurrent Rectal Cancer (TORCH-R2)

TORCH-R2 is a prospective, multicenter, randomized, phase II clinical trial. Patients aged 18 years or older with pelvic recurrence rectal cancer without synchronous distant metastases or recent chemo- and/or radiotherapy treatment, Eastern Cooperative Oncology Group performance status of 0-1will be enrolled . Patients will be randomized to receive either hypofractionated radiotherapy (25-40Gy/5Fx irradiation or 15-30Gy/5Fx reirradiation), 18 weeks sintilimab and investigator's choice of first-line chemotherapy +/- target therapy (experimental arm), or conventional radiotherapy (50Gy/25Fx irradiation or 39Gy/30Fx bid reirradiation) and chemotherapy +/- target therapy (control arm). Patiens will be restaged and followed by multidisciplinary team (MDT) for decision: radical surgery, sustained systerm+/- local treatment of non resection.

The primary endpoint was progression-free survival. Secondary endpoints were objective response rate (ORR), complete response rate, R0 resection rate, duration of response (DOR), overall survival (OS), and safety and tolerability of the treatment.

Study Overview

• Status: Recruiting
• Conditions: Locally Recurrent Rectal Cancer
• Intervention / Treatment: Drug: Capecitabine; Drug: folinic acid; Drug: Oxaliplatin; Drug: Irinotecan; Drug: Bevacizumab; Radiation: Conventional Radiotherapy; Drug: 5-fluorouracil; Drug: Cetuximab; Radiation: Hypofractionated radiotherapy; Drug: PD-1 antibody

• Study Type: Interventional
• Enrollment (Estimated): 221
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Zhen Zhang, MD, PhD; Phone Number: 86-18801735029; Email: zhen_zhang@fudan.edu.cn

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Recruiting
      • Fudan University Shanghai Cancer Center
      • Contact: Zhen Zhang, M.D, PH.D; Phone Number: 19521280960; Email: zhen_zhang@fudan.edu.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

Patient is 18-75 years. ECOG performance status 0-1. MRI/enhanced CT confirmed pelvic recurrence. Without synchronous distant metastases. No prior radiotherapy within 6 month. No prior first-line chemotherapy. Has an investigator determined life expectancy of at least 24 weeks. Demonstrate adequate organ function. Non pregnant or lactating patients. Fully informed and willing to provide written informed consent for the trial.

Exclusion Criteria:

Neutrophil< 1.5×109/L, PLT< 100×109/L (PLT< 80×109/L in patients with livermetastasis), or Hb< 90 g/L.

TBIL > 1.5 ULN, or TBIL > 2.5 ULN in patients with liver metastasis. AST or ALT > 2.5 ULN, or ALT and/or AST > 5 ULN in patients with liver metastasis.

Cr > 1.5 ULN, or creatinine clearance< 50 mL/min (calculated according to Cockcroft Gault formula).

APTT > 1.5 ULN, PT > 1.5 ULN (subject to the normal value of the clinical trial research center).

Serious electrolyte abnormalities. Urinary protein ≥ 2+, or 24-h urine protein ≥1.0 g/24 h. Uncontrolled hypertension: SBP >140 mmHg or DBP > 90 mmHg. A history of arterial thrombosis or deep vein thrombosis within 6 months; a history of bleeding or evidence of bleeding tendency within 2 months.

A history of heart disease within 6 months. Uncontrolled malignant pleural effusion, ascites, or pericardial effusion. History of checkpoint inhibitor therapy. The presence of a clinically detectable second primary malignancy, or history of other malignancies within 5 years.

A history of liver disease including, but not limited to, HBV infection or HBV DNA positive (≥1×104/mL), HCV infection or HCV DNA positive (≥1×103/mL), and liver cirrhosis.

Pregnant or lactating women or women who may be pregnant have a positive pregnancy test before the first medication, or the female participants themselves and their partners who were unwilling to implement strict contraception during the study period.

The investigator considers that the subject is not suitable to participate in this clinical study due to any clinical or laboratory abnormalities or compliance problems.

Serious mental abnormalities. The diameter of brain metastasis is greater than 3 cm or the total volume is greater than 30 cc. Clinical or radiological evidence of spinal cord compression, or tumors within 3 mm of the spinal cord on MRI.

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Conventional radiotherapy arm; Conventional radiotherapy (50Gy/25Fx irradiation or 39Gy/30Fx bid reirradiation) and investigator's choice of first-line chemotherapy +/- target therapy.	Drug: Capecitabine; 1000mg/m2 d1-14 q3w; Drug: folinic acid; 400 mg/m2 q2w; Drug: Oxaliplatin; 130 mg/m² q3w or 85 mg/m² q2w; Drug: Irinotecan; 180 mg/m² q2w and 200 mg/m² q3w; Drug: Bevacizumab; 5 mg/kg q2w or 7.5mg/kg q3w; Radiation: Conventional Radiotherapy; 50Gy/25Fx irradiation or 39Gy/30Fx bid reirradiation (previous pelvic radiation); Drug: 5-fluorouracil; 400 mg/m2 (bolus) and 2400 mg/m2 (continuous infusion for 48hr); Drug: Cetuximab; 500 mg/m² q2w
Experimental: Hypofractionated radiotherapy plus Immunotherapy arm; Hypofractionated radiotherapy (25-40Gy/5Fx irradiation or 15-30Gy/5Fx reirradiation), 18 weeks sintilimab and investigator's choice of first-line chemotherapy +/- target therapy.	Drug: Capecitabine; 1000mg/m2 d1-14 q3w; Drug: folinic acid; 400 mg/m2 q2w; Drug: Oxaliplatin; 130 mg/m² q3w or 85 mg/m² q2w; Drug: Irinotecan; 180 mg/m² q2w and 200 mg/m² q3w; Drug: Bevacizumab; 5 mg/kg q2w or 7.5mg/kg q3w; Drug: 5-fluorouracil; 400 mg/m2 (bolus) and 2400 mg/m2 (continuous infusion for 48hr); Drug: Cetuximab; 500 mg/m² q2w; Radiation: Hypofractionated radiotherapy; 25-40Gy/5Fx irradiation or 15-30Gy/5Fx reirradiation (previous pelvic radiation); Drug: PD-1 antibody; 200mg IV q3w; Other Names: Sintilimab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival	time from the date of start treatment until disease progression or censored at last follow-up or death.	up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
R0 resection rate	the proportion of patients who achieve R0 resection of pelvic recurrent tumour after therapy.	up to 1 year
Objective response rate (ORR)	the proportion of patients with the best response of confirmed complete or partial response according to RECIST 1.1, as assessed by the investigator.	up to 1 year
Complete response rate	the proportion of patients with the best response of confirmed complete response according to RECIST 1.1, as assessed by the investigator.	up to 1 year
Duration of response (DOR)	time from the first documented pelvic objective response to pelvic or extrapelvic disease progression in patients with confirmed response.	up to 3 years
Overall Survival	from the date of start treatment until the date of death from any cause or censored at last follow-up.	up to 3 years
Safety and tolerability	proportion of patients with treatment-related acute toxicities as assessed by NCI CTCAE v5.0, from treatment initiation until 90 days upon completion of immunotherapy.	up to 1 year

Collaborators and Investigators

• Sponsor: Fudan University
• Investigators: Principal Investigator: Zhen Zhang, MD PhD, PhD, Fudan University

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2025
• Primary Completion (Estimated): March 10, 2030
• Study Completion (Estimated): March 10, 2030

Study Registration Dates

• First Submitted: April 8, 2025
• First Submitted That Met QC Criteria: April 14, 2025
• First Posted (Actual): April 15, 2025

Study Record Updates

• Last Update Posted (Actual): April 15, 2025
• Last Update Submitted That Met QC Criteria: April 14, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Disease Attributes; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Rectal Diseases; Rectal Neoplasms; Recurrence; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Micronutrients; Topoisomerase I Inhibitors; Topoisomerase Inhibitors; Protective Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antidotes; Vitamin B Complex; Vitamins; Hematinics; Capecitabine; Oxaliplatin; Bevacizumab; Irinotecan; Cetuximab; Fluorouracil; Leucovorin; Levoleucovorin; Antibodies; Folic Acid
• Other Study ID Numbers: FDRT-2024-416-3970

Drug and device information, study documents

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