Node-Sparing Hypofractionated Radiotherapy Plus Chemotherapy and PD-1 Inhibitor in pMMR/MSS High-Risk Locally Advanced Colon Cancer: A Prospective, Randomized, Phase II Trial

NCT07230639 | Recruiting Phase 2 DMC

• 1 other identifier: 2025ZSLYEC502
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 1

Brief Summary

Most colorectal cancers are microsatellite stable (MSS) or mismatch repair-proficient (pMMR) subtypes, which show limited efficacy to PD-1 inhibitors. Radiotherapy can enhance the release of tumor-associated antigens, thereby improving the responsiveness of pMMR/MSS colorectal cancers to PD-1 blockade. Tumor-draining lymph nodes (TDLNs) are critical sites where PD-1 inhibitors exert their antitumor effects; however, previous studies have reported that direct radiation-induced damage and fibrosis may impair lymphatic drainage and antitumor immunity. Early reports have demonstrated a remarkable pathological complete response (pCR) rate of 77.8% with lymph node-sparing short-course radiotherapy (25 Gy in 5 fractions) in locally advanced rectal cancer. In metastatic colorectal cancer, single-fraction high-dose irradiation (6-8 Gy) has been shown to induce robust abscopal effects. Based on these findings, our study aims to evaluate whether lymph node-sparing hypofractionated radiotherapy (25 Gy/5F or 24 Gy/4F) followed sequentially by chemotherapy and PD-1 blockade can increase the pCR rate, improve tolerability, and ultimately enhance outcomes in patients with pMMR/MSS high-risk locally advanced colon cancer.

Conditions

Neoadjuvant Therapies; Immune Checkpoint Therapy; Radiotherapy

Outcome Measures

Primary Outcomes (1)

• Pathological Complete Response(pCR) Rate

  Evaluate 25Gy/5F or 24Gy/4F node-sparing modified short-course radiotherapy followed by sequential chemotherapy and PD-1 inhibitor as total neoadjuvant therapy can better improve the pathological complete response(pCR) rate in colon cancer.

  From enrollment to 2-4 weeks after surgery

Secondary Outcomes (7)

• Tumor regression grade (TRG)

  From enrollment to 2-4 weeks after surgery

• Tumor downstaging rate

  From enrollment to 2-4 weeks after finishing preoperative treatment

• R0 resection rate

  From enrollment to 2-4 weeks of surgery

• 3-year overall survival (OS) rate

  From enrollment to 3 years after finishing Surgery

• Event-Free Survival (EFS)

  From enrollment to 3 years after finishing Surgery

Study Arms (2)

25Gy/5F Radiotherapy Group

EXPERIMENTAL

Node-Sparing Short-Course RT (25Gy/5F) followed by sequential Chemotherapy and PD-1 inhibitor as total neoadjuvant therapy.

Combination Product: Node-Sparing Radiotherapy(25Gy/5F) plus Chemotherapy and PD-1 inhibitor

24Gy/4F Radiotherapy Group

EXPERIMENTAL

Node-Sparing Short-Course RT (24Gy/4F) followed by sequential Chemotherapy and PD-1 inhibitor as total neoadjuvant therapy.

Combination Product: Node-Sparing Radiotherapy(24Gy/4F) plus Chemotherapy and PD-1 inhibitor

Interventions

Node-Sparing Radiotherapy(25Gy/5F) plus Chemotherapy and PD-1 inhibitor COMBINATION_PRODUCT

Patients will receive node-sparing modified short-course radiotherapy(25Gy/5F), followed by 4 cycles of CAPOX chemotherapy combined with a PD-1 inhibitor. After neoadjuvant treatment, patients will undergo surgery.

25Gy/5F Radiotherapy Group

Node-Sparing Radiotherapy(24Gy/4F) plus Chemotherapy and PD-1 inhibitor COMBINATION_PRODUCT

Patients will receive node-sparing modified short-course radiotherapy(24Gy/4F), followed by 4 cycles of CAPOX chemotherapy combined with a PD-1 inhibitor. After neoadjuvant treatment, patients will undergo surgery.

24Gy/4F Radiotherapy 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.
• Age ≥ 18 and ≤ 75 years at enrollment.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Life expectancy \> 2 years.
• Histologically confirmed colon adenocarcinoma (without squamous or sarcomatoid components).
• Tumor biopsy by immunohistochemistry indicating pMMR, i.e., MLH1, MSH2, MSH6, and PMS2 all positive, or genomic testing indicating MSS.
• Per AJCC 8th edition, imaging (contrast-enhanced CT or contrast-enhanced MRI) shows T4 and/or N+ disease (stage IIB-III).
• Prior to enrollment, the subject must be evaluated by a surgery attending physician responsible for the operation, based on medical history, to confirm eligibility for R0 resection with curative intent.
• No prior systemic or local antitumor therapy for rectal cancer before study treatment, including radiotherapy, chemotherapy, immunotherapy, biologics, or small-molecule targeted therapy.
• Subject agrees to collection and study use of required tumor tissue and peripheral blood specimens during screening and throughout the study.
• Adequate organ function:
• a) Hematologic (no blood components or hematopoietic growth factors within 7 days before starting study treatment): i. Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L (1,500/mm³); ii. Platelets ≥ 100 × 10⁹/L (100,000/mm³); iii. Hemoglobin ≥ 90 g/L. b) Renal: i. Calculated creatinine clearance (CrCl) ≥ 50 mL/min using the Cockcroft-Gault formula: CrCl (mL/min) = {(140 - age) × weight (kg) × 0.85} / \[72 × serum creatinine (mg/dL)\] ii. Urine protein \< 2+ or 24-hour urine protein \< 1.0 g. c) Hepatic: i. Total bilirubin (TBil) ≤ 1.5 × ULN; ii. AST and ALT ≤ 2.5 × ULN; iii. Serum albumin (ALB) ≥ 28 g/L. d) Coagulation: i. INR and aPTT ≤ 1.5 × ULN. e) Cardiac: i. Left ventricular ejection fraction (LVEF) ≥ 50%.
• Women of childbearing potential (WOCBP) must have a urine or serum pregnancy test within 3 days prior to starting study treatment (if the urine test cannot be definitively interpreted as negative, a serum test is required; the serum result prevails) and the result must be negative. If a WOCBP has sexual intercourse with a non-sterilized male partner, she must begin using an acceptable contraceptive method from screening and agree to continue contraception for 120 days after the last dose of study drug; whether contraception can be discontinued thereafter should be discussed with the investigator. Periodic abstinence and calendar/rhythm methods are unacceptable.
• WOCBP are defined as females who have not undergone surgical sterilization (i.e., bilateral tubal ligation, bilateral oophorectomy, or total hysterectomy) and have not been postmenopausal (amenorrhea for ≥12 consecutive months without an alternative medical cause, with serum FSH in the postmenopausal range).
• A highly effective method of contraception is one with a low failure rate when used consistently and correctly (e.g., \<1% per year). Not all methods are highly effective. Barrier methods alone are not acceptable; WOCBP must at minimum use a hormonal contraceptive (e.g., oral contraceptives) to ensure no pregnancy occurs.

You may not qualify if:

• Suspicious metastatic lesions or the presence of unresectable locally advanced disease, regardless of stage.
• Malignancy other than colorectal cancer within 5 years prior to enrollment. Subjects cured by local therapy for other malignancies (e.g., basal or squamous cell skin cancer, superficial bladder cancer, ductal carcinoma in situ) are not excluded.
• Receipt of any investigational drug or device within 4 weeks prior to the first dose of study drug.
• Intestinal obstruction, perforation, gastrointestinal bleeding, or other conditions requiring emergency surgery.
• Multiple primary colorectal cancers.
• Prior radiotherapy to the pelvis or abdomen.
• Inability to swallow tablets, malabsorption syndrome, or any condition that affects gastrointestinal absorption.
• Any prior systemic or local antitumor therapy for locally advanced colon cancer, including curative surgery, chemotherapy, radiotherapy, immunotherapy (including immune checkpoint inhibitors/agonists or cellular immunotherapy), biologics, or small-molecule targeted therapy.
• Nonspecific immunomodulatory therapy within 2 weeks before study treatment (e.g., interleukins, interferons, thymosin, tumor necrosis factor; excluding IL-11 used for thrombocytopenia); antitumor-indicated traditional Chinese herbal medicines or patent medicines within 1 week before study treatment.
• Active autoimmune disease requiring systemic therapy within the past 2 years (e.g., with disease-modifying agents, corticosteroids, or immunosuppressants). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroids for adrenal or pituitary insufficiency) is not considered systemic therapy.
• History of or current non-infectious pneumonitis requiring systemic corticosteroids, or a history of interstitial lung disease.
• History of significant bleeding tendency or coagulopathy; prior or current long-term anticoagulation (e.g., atrial fibrillation with CHADS₂ score ≥ 2).
• Uncontrolled comorbid conditions, including but not limited to decompensated cirrhosis, nephrotic syndrome, uncontrolled metabolic disorders, severe active peptic ulcer disease or gastritis, or psychiatric/social conditions that would limit compliance with study requirements or ability to provide written informed consent.
• History of myocarditis, cardiomyopathy, or malignant arrhythmias. Within 12 months prior to study treatment: unstable angina requiring hospitalization, congestive heart failure, or vascular disease (e.g., aortic aneurysm requiring surgical repair or peripheral venous thrombosis), or other cardiac damage that may affect evaluation of study-drug safety (e.g., poorly controlled arrhythmias, myocardial infarction or ischemia); within 6 months prior: esophagogastric varices, severe ulcers, unhealed wounds, gastrointestinal perforation, enteric fistula, intestinal obstruction, intra-abdominal abscess, or acute gastrointestinal bleeding; within 6 months prior: any arterial thromboembolic event, NCI CTCAE v5.0 grade ≥3 venous thromboembolism, transient ischemic attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy; within 1 month prior: acute exacerbation of COPD; current hypertension with SBP ≥160 mmHg or DBP ≥100 mmHg despite oral antihypertensive therapy.
• Active or past history of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) or 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

Interventions

Immune Checkpoint Inhibitors

Intervention Hierarchy (Ancestors)

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, M.D., Ph.D.

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: September 16, 2025
• First Posted: November 17, 2025
• Study Start: August 30, 2025
• Primary Completion (Estimated): August 29, 2030
• Study Completion (Estimated): December 31, 2031
• Last Updated: December 26, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)