Modified Long-Course Radiotherapy Followed by Chemotherapy and PD-1 Inhibitor for MSS/pMMR High-risk Mid/Low LARC (MODIFI-RC-I)

NCT06923345 | Recruiting Phase 2 DMC

• 1 other identifier: 2025ZSLYEC-147
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to evaluate whether a total neoadjuvant therapy (TNT) regimen combining long-course chemoradiotherapy, sequential chemotherapy, and PD-1 inhibitor can improve response rates, enhance tolerability, and improve prognosis in patients with locally advanced, microsatellite-stable (MSS) rectal cancer. The main questions it aims to answer are: Does this TNT approach improve complete response (CR) rates? How does selective reduction of clinical target volume (CTV) to S2/S3 level compare with conventional CTV irradiation in terms of efficacy and safety? Researchers will compare a selective CTV reduction group and a conventional CTV irradiation group to assess differences in treatment outcomes, including complete response, tumor regression grading (TRG), organ preservation, R0 resection rates, and long-term survival. Participants will: Receive long-course chemoradiotherapy with either conventional or reduced CTV irradiation. Undergo sequential chemotherapy. Receive PD-1 inhibitor treatment. Be monitored for safety, tumor regression, and long-term survival outcomes.

Conditions

Rectal Cancer; Neoadjuvant Therapies; Immune Checkpoint Therapy; Radiotherapy

Outcome Measures

Primary Outcomes (1)

• Complete response (CR) rate

  Evaluate whether total neoadjuvant therapy (TNT) with long-course chemoradiotherapy (selective vs. conventional CTV), sequential CAPOX chemotherapy, and PD-1 inhibitor improves the complete response (CR) rate in locally advanced MSS rectal cancer.

  From enrollment to 2 weeks after finishing TNT

Secondary Outcomes (9)

• Tumor regression grade (TRG)

  From enrollment to 2 weeks after finishing TNT

• Tumor downstaging rate

  From enrollment to 2 weeks after finishing TNT

• Watch-and-wait rate

  From enrollment to 2 weeks after finishing TNT

• Sphincter preservation rate

  From date of randomization until the date of surgery or the date of watch-and-wait for CR patients

• R0 resection rate

  From date of randomization until the date of surgery or the date of watch-and-wait for CR patients

Study Arms (2)

Reduced CTV

EXPERIMENTAL

Patients will receive long-course radiotherapy with selective reduced CTV irradiation, concurrently with 3 cycles of CAPOX chemotherapy and PD-1 inhibitor. After radiotherapy, they will receive an additional 3 cycles of CAPOX chemotherapy and PD-1 inhibitor, followed by either total mesorectal excision (TME) surgery or watch-and-wait observation.

Combination Product: Reduced CTV

Conventional CTV

EXPERIMENTAL

Patients will receive long-course radiotherapy with conventional CTV irradiation, concurrently with 3 cycles of CAPOX chemotherapy and PD-1 inhibitor. After radiotherapy, they will receive an additional 3 cycles of CAPOX chemotherapy and PD-1 inhibitor, followed by either total mesorectal excision (TME) surgery or watch-and-wait observation.

Combination Product: Conventional CTV

Interventions

Reduced CTV COMBINATION_PRODUCT

Long-course radiotherapy with selective CTV reduction (lower to S2/S3 level) + CAPOX + PD-1 inhibitor. After treatment, patients will undergo TME surgery or a watch-and-wait approach, depending on response.

Reduced CTV

Conventional CTV COMBINATION_PRODUCT

Long-course radiotherapy with conventional CTV irradiation + CAPOX + PD-1 inhibitor. After treatment, patients will undergo TME surgery or a watch-and-wait approach, depending on response.

Conventional CTV

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Voluntarily signs a written informed consent form.
• Aged between 18 and 75 years at enrollment.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Expected survival of more than 2 years.
• Histologically confirmed rectal adenocarcinoma.
• Tumor biopsy immunohistochemistry indicating pMMR (MSH1, MSH2, MSH6, and PMS2 all positive) or genetic testing confirming MSS.
• According to the 8th edition of the AJCC TNM classification, high-resolution MRI ± endorectal ultrasound confirms clinical staging as cT3-4NanyM0 or cTxN+M0 (stage II-III rectal cancer). MRI confirms the tumor is located below the peritoneal reflection without lateral lymph node metastasis.
• Before study enrollment, a responsible surgical attending physician must evaluate the patient's medical history to confirm eligibility for R0 resection with curative intent.
• No prior systemic or local anti-tumor treatment for rectal cancer, including radiotherapy, chemotherapy, immunotherapy, biologics, or small-molecule targeted therapy.
• Willing to provide tumor tissue and peripheral blood samples for research purposes during screening and throughout the study.
• Adequate organ function:
• Hematology (without recent blood transfusions or growth factor support within 7 days before treatment):
• Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L (1,500/mm³)
• Platelet count ≥ 100 × 10⁹/L (100,000/mm³)
• Hemoglobin ≥ 90 g/L

You may not qualify if:

• Presence of suspected metastatic lesions or locally advanced unresectable disease, regardless of disease stage.
• Diagnosis of other malignancies within the past five years, except for patients with malignancies cured through local treatment (e.g., basal or squamous cell skin cancer, superficial bladder cancer, ductal carcinoma in situ of the breast).
• Concurrent enrollment in another clinical study, unless it is an observational, non-interventional study or a follow-up phase of an interventional study.
• Presence of intestinal obstruction, perforation, or bleeding requiring emergency surgery.
• Multiple primary rectal cancers.
• History of pelvic or abdominal radiotherapy.
• Inability to swallow tablets, malabsorption syndrome, or any condition affecting gastrointestinal absorption.
• Prior systemic or local anti-tumor treatment for locally advanced rectal cancer, including radical surgery, chemotherapy, radiotherapy, immunotherapy (e.g., immune checkpoint inhibitors, immune cell therapy), biological agents, or targeted therapy.
• Use of nonspecific immunomodulatory treatment (e.g., interleukins, interferons, thymosin, TNF) within two weeks before study treatment (excluding IL-11 for thrombocytopenia); use of traditional Chinese medicine with anti-tumor indications within one week before study treatment.
• Active autoimmune disease requiring systemic treatment in the past two years, except for replacement therapy (e.g., thyroid hormone, insulin, corticosteroids for adrenal/pituitary insufficiency).
• History of non-infectious pneumonitis requiring systemic glucocorticoid therapy or interstitial lung disease.
• History of severe bleeding tendency, coagulopathy, or long-term anticoagulation therapy (e.g., atrial fibrillation with CHADS2 score ≥2).
• Uncontrolled comorbidities, including but not limited to decompensated liver cirrhosis, nephrotic syndrome, uncontrolled metabolic disorders, severe active peptic ulcer disease, or psychiatric/social conditions limiting compliance.
• History of myocarditis, cardiomyopathy, malignant arrhythmias; hospitalization for unstable angina, congestive heart failure, or vascular diseases (e.g., aortic aneurysm requiring surgery) within 12 months before study treatment.
• History of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, chronic diarrhea).

Sponsors & Collaborators

• Sixth Affiliated Hospital, Sun Yat-sen University: lead

Study Sites (1)

The Sixth Affiliated Hospital of Sun Yat-sen University

Guangzhou, Guangdong, 510655, China

RECRUITING

MeSH Terms

Conditions

Rectal Neoplasms

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Central Study Contacts

Yanxin Luo, M.D., Ph.D.

CONTACT

+86-13826190263; luoyx25@mail.sysu.edu.cn

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant President of the Sixth Affiliated Hospital of Sun Yat-sen University; Chief Physician of Department of Colorectal Surgery

Model Details: Select-a-winner design

Study Record Dates

• First Submitted: April 1, 2025
• First Posted: April 11, 2025
• Study Start: March 31, 2025
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2028
• Last Updated: April 18, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)