Node-Sparing Short-Course Radiotherapy Sequential Chemotherapy and PD-1 Inhibitor for Mid/Low pMMR/MSS Rectal Cancer (MODIFI-RC-II)

NCT06958432 | Recruiting Phase 2 DMC

• 1 other identifier: 2025ZSLYEC-417
• Study Type: interventional
• Target: 430
• Locations: 1 country
• Sites: 1

Brief Summary

Most rectal cancers are microsatellite stable (MSS) or mismatch repair-proficient (pMMR) and respond poorly to PD-1 inhibitors. Radiotherapy can enhance tumor antigen release and improve responsiveness to PD-1 blockade in MSS/pMMR rectal cancer. Tumor-draining lymph nodes (TDLNs) are critical sites for anti-tumor immune activation, but radiation-induced damage and fibrosis may impair lymphatic drainage and immune responses. Previous studies have reported a remarkable pathologic complete response (pCR) rate of 77.8% using node-sparing radiotherapy in locally advanced rectal cancer. This study aims to evaluate whether node-sparing short-course radiotherapy followed by sequential chemotherapy and PD-1 blockade can improve complete response rate in the phase II part and event-free survival in phase III part, together with sphincter preservation, treatment tolerance, and prognosis in patients with mid-low pMMR/MSS rectal cancer.

Conditions

Rectal Cancer; Neoadjuvant Therapies; Immune Checkpoint Therapy; Radiotherapy

Outcome Measures

Primary Outcomes (2)

• Complete response (CR) rate

  Phase II: Evaluate whether node-sparing modified short-course radiotherapy followed by sequential chemotherapy and PD-1 inhibitor as total neoadjuvant therapy can improve the complete response (CR) rate in mid/low MSS rectal cancer.

  From enrollment to 2 weeks after finishing TNT

• Event-Free Survival (EFS)

  Phase III: To evaluate whether node-sparing modified short-course radiotherapy combined with chemotherapy and a PD-1 inhibitor can improve Event-Free Survival (EFS) in patients with pMMR/MSS rectal cancer.

  From enrollment to 3 years after finishing Surgery

Secondary Outcomes (8)

• Sphincter preservation rate

  From date of randomization until the date of surgery or the date of watch-and-wait for CR patients，up to 24-30 weeks

• Tumor regression grade (TRG)

  From enrollment to 2 weeks after finishing TNT

• Tumor downstaging rate

  From enrollment to 2 weeks after finishing TNT

• R0 resection rate

  From date of randomization until the date of surgery，up to 24-30 weeks

• Incidence of treatment-related adverse events (toxicity)

  From enrollment to 2 weeks after finishing TNT

Study Arms (2)

Node-sparing radiotherapy Group

EXPERIMENTAL

Node-sparing short-course radiotherapy followed by sequential chemotherapy and PD-1 inhibitor as total neoadjuvant therapy

Combination Product: Node-Sparing Radiotherapy plus Chemotherapy and PD-1 inhibitor

Conventional Group

ACTIVE COMPARATOR

Conventional short-course radiotherapy followed by sequential chemotherapy as total neoadjuvant therapy

Combination Product: Conventional Radiotherapy plus Chemotherapy and PD-1 inhibitor

Interventions

Node-Sparing Radiotherapy plus Chemotherapy and PD-1 inhibitor COMBINATION_PRODUCT

Patients will receive node-sparing modified short-course radiotherapy, followed by six cycles of CAPOX chemotherapy combined with a PD-1 inhibitor. After neoadjuvant treatment, patients will either undergo total mesorectal excision (TME) surgery or enter a watch-and-wait strategy based on clinical assessment.

Node-sparing radiotherapy Group

Conventional Radiotherapy plus Chemotherapy and PD-1 inhibitor COMBINATION_PRODUCT

Patients will receive conventional-target short-course radiotherapy, followed by six cycles of CAPOX chemotherapy. After neoadjuvant treatment, patients will either undergo TME surgery or enter a watch-and-wait strategy based on clinical assessment.

Conventional Group

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 the time of 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 indicates proficient mismatch repair (pMMR), defined by positive immunohistochemical staining for MSH1, MSH2, MSH6, and PMS2, or molecular testing confirms microsatellite stability (MSS).
• Clinical stage T3-4N0M0 or TanyN+M0 based on the 8th edition of the AJCC TNM classification, as evaluated by high-resolution MRI ± endoscopic ultrasound/transrectal ultrasonography, with the tumor located in the mid-to-lower rectum below the peritoneal reflection.
• Prior to enrollment, a qualified surgical attending physician must assess the patient's medical history and confirm eligibility for curative R0 resection.
• No prior systemic or local anti-tumor treatment for rectal cancer, including radiotherapy, chemotherapy, immunotherapy, biologics, or small-molecule targeted therapy.
• Agrees to provide tumor tissue and peripheral blood samples during screening and throughout the study for research purposes.
• Adequate organ function, defined as follows:
• Hematologic (without use of blood components or growth factors within 7 days prior to treatment initiation):
• Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L
• Platelet count ≥ 100 × 10⁹/L
• Hemoglobin ≥ 90 g/L

You may not qualify if:

• Presence of suspected metastatic lesions or unresectable locally advanced disease, regardless of clinical stage.
• History of any other malignancy within 5 years prior to enrollment, excluding those considered cured by local therapy (e.g., basal cell carcinoma, squamous cell carcinoma of the skin, superficial bladder cancer, or ductal carcinoma in situ of the breast).
• Lesions initially staged as T1N0 eligible for local excision, or T2N0 suitable for sphincter-preserving surgery after multidisciplinary discussion.
• Evidence of acute conditions requiring emergency surgery, such as bowel obstruction, perforation, or gastrointestinal bleeding.
• Synchronous 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 therapy for locally advanced rectal cancer, including curative surgery, chemotherapy, radiotherapy, immunotherapy (e.g., immune checkpoint inhibitors, agonists, or cell-based therapies), biologics, or small-molecule targeted therapy.
• Use of nonspecific immunomodulatory treatments (e.g., interleukins, interferons, thymic peptides, tumor necrosis factor) within 2 weeks prior to study treatment (excluding IL-11 for thrombocytopenia), or use of herbal or traditional Chinese medicines with anti-tumor indications within 1 week prior to treatment.
• Active autoimmune disease requiring systemic treatment (e.g., with disease-modifying drugs, corticosteroids, or immunosuppressants) within the past 2 years. Replacement therapies (e.g., thyroid hormone, insulin, or physiological corticosteroids for adrenal or pituitary insufficiency) are not considered systemic treatments.
• History of or current interstitial lung disease or non-infectious pneumonitis requiring systemic corticosteroid treatment.
• History of bleeding disorders or coagulopathy; patients requiring long-term anticoagulation (e.g., atrial fibrillation with CHADS2 score ≥ 2).
• Uncontrolled comorbidities, including but not limited to: decompensated cirrhosis, nephrotic syndrome, uncontrolled metabolic disorders, severe peptic ulcer or gastritis, or psychiatric/social conditions affecting compliance or consent.
• History of myocarditis, cardiomyopathy, or malignant arrhythmias; unstable angina, heart failure requiring hospitalization, or vascular disease (e.g., aortic aneurysm requiring repair or deep vein thrombosis) within 12 months prior to study treatment; other cardiac conditions impacting safety (e.g., poorly controlled arrhythmia, myocardial infarction, or ischemia).
• Within 6 months prior to treatment: history of gastroesophageal varices, severe ulcers, non-healed wounds, gastrointestinal perforation, fistulas, bowel obstruction, intra-abdominal abscess, or acute GI bleeding.

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

Interventions

Drug Therapy; Immune Checkpoint Inhibitors

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

Intervention Hierarchy (Ancestors)

Therapeutics; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Antineoplastic Agents, Immunological; Antineoplastic Agents; Therapeutic Uses

Central Study Contacts

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

CONTACT

+86-20-38254221; luoyx25@mail.sysu.edu.cn

Yikan Cheng

CONTACT

15102033641

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: MD PHD

Study Record Dates

• First Submitted: April 24, 2025
• First Posted: May 6, 2025
• Study Start: May 1, 2025
• Primary Completion (Estimated): December 31, 2030
• Study Completion (Estimated): December 31, 2031
• Last Updated: August 7, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)