Rectal CancerPhase 2/3NCT06958432
Node-Sparing Short-Course Radiotherapy Sequential Chemotherapy and PD-1 Inhibitor for Mid/Low pMMR/MSS Rectal Cancer (MODIFI-RC-II)
A Phase 2/3 study testing Node-Sparing Radiotherapy plus Chemotherapy and PD-1 inhibitor and Conventional Radiotherapy plus Chemotherapy in people with Rectal Cancer and Neoadjuvant Therapies, run by Sixth Affiliated Hospital, Sun Yat-sen University at 1 site in China.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Rectal Cancer, Neoadjuvant Therapies, Immune Checkpoint Therapy
- What is being tested?
- Node-Sparing Radiotherapy plus Chemotherapy and PD-1 inhibitor and Conventional Radiotherapy plus Chemotherapy
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 430 participants
- Where
- 1 siteChina
- Study dates
- 6 May 2025to 31 Dec 2031
- Phase
- Phase 2/3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- • 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 MLH1, MSH2, MSH6, and PMS2, or molecular testing confirms microsatellite stability (MSS).
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- 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.
- 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
- Renal:
- Calculated creatinine clearance (CrCl) ≥ 50 mL/min using the Cockcroft-Gault formula:
- CrCl (mL/min) = [(140 - age) × weight (kg) × 0.85 (if female)] / (72 × serum creatinine [mg/dL])
- Urine protein < 2+ on dipstick or < 1.0 g per 24-hour collection
- Hepatic:
- Total bilirubin ≤ 1.5 × ULN
- AST and ALT ≤ 2.5 × ULN
- Serum albumin ≥ 28 g/L
- Coagulation:
- INR and APTT ≤ 1.5 × ULN
- Cardiac:
- Left ventricular ejection fraction (LVEF) ≥ 50%
- Women of childbearing potential must have a negative urine or serum pregnancy test within 3 days prior to initiating study treatment. If the urine test is inconclusive, a serum test must confirm the negative result. Women of childbearing potential who are sexually active with non-sterilized male partners must agree to use highly effective contraception from screening through 120 days after the last dose of study drug. The need for continued contraception beyond this period should be discussed with the investigator.
- Women of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) and have not undergone menopause (defined as ≥12 months of amenorrhea without alternative medical cause, with FSH levels in the postmenopausal range).
- Highly effective contraception methods are those with <1% failure rate per year when used consistently and correctly (e.g., hormonal contraceptives). In addition to barrier methods, hormonal contraception is required. Periodic abstinence and the calendar method are not considered acceptable.
- Willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study requirements.
Who cannot join
- • 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.
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- 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.
- Arterial thromboembolism, grade ≥3 venous thromboembolism (per NCI-CTCAE v5.0), transient ischemic attack, stroke, hypertensive crisis, or hypertensive encephalopathy within 6 months prior to study treatment.
- Acute exacerbation of COPD within 1 month prior to treatment; current hypertension not controlled to <160/100 mmHg despite antihypertensive medication.
- Active or prior inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) or chronic diarrhea.
- Severe infections within 4 weeks prior to treatment, including complications requiring hospitalization, sepsis, or severe pneumonia; active infections requiring systemic anti-infective therapy within 10 days prior to treatment (excluding antiviral therapy for HBV or HCV).
- Major surgery or serious trauma within 30 days prior to treatment; minor local surgery within 3 days (excluding PICC placement).
- History of immunodeficiency or HIV antibody positivity; long-term systemic corticosteroid or immunosuppressive therapy.
- Active tuberculosis or suspected TB not ruled out via clinical assessment (e.g., sputum test, chest X-ray); known active syphilis.
- History of allogeneic organ or hematopoietic stem cell transplantation.
- Untreated active hepatitis B (HBsAg-positive with HBV DNA > 1,000 copies/mL or 200 IU/mL); active hepatitis C (HCV antibody-positive with detectable HCV RNA).
- Receipt of a live vaccine within 30 days prior to treatment or planned live vaccination during the study.
- Known hypersensitivity to any component of the investigational drugs, or history of serious hypersensitivity reactions to monoclonal antibodies.
- Known history of psychiatric disorders, substance abuse, alcoholism, or drug addiction.
- Pregnant or breastfeeding women.
- Any disease, treatment, or abnormal laboratory finding that may interfere with study results, affect full study participation, or is not in the patient's best interest.
- Systemic or local disease caused by a benign tumor, or tumor-related complications/symptoms that pose high medical risk or survival uncertainty (e.g., leukemoid reaction with WBC > 20 × 10⁹/L, cachexia with >10% weight loss in 3 months prior to screening, or BMI ≤18).
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Yikan Cheng contact
China1 site, 1 recruiting
- Recruiting
The Sixth Affiliated Hospital of Sun Yat-sen University
Guangzhou, Guangdong, 510655
Qian Wu, +86-020-38379764, zslyllb@mail.sysu.edu.cn
About this study
Official title: Node-Sparing Short-Course Radiotherapy Plus Sequential Chemotherapy and PD-1 Inhibitor for Mid/Low pMMR/MSS Rectal Cancer: An Open-Label, Randomized, Prospective Phase II/III Trial (MODIFI-RC-II)
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.
- Being tested
- Node-Sparing Radiotherapy plus Chemotherapy and PD-1 inhibitor, Conventional Radiotherapy plus Chemotherapy
- Medical subject headings
- Rectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Node-Sparing Radiotherapy plus Chemotherapy and PD-1 inhibitorCombination 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.
Conventional Radiotherapy plus ChemotherapyCombination 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.
| Study group | Role | What they receive |
|---|---|---|
| Node-sparing radiotherapy Group | Experimental | Node-sparing short-course radiotherapy followed by sequential chemotherapy and PD-1 inhibitor as total neoadjuvant therapy Receives: 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 Receives: Combination Product: Conventional Radiotherapy plus Chemotherapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: For cCR: from randomization to 2-4 weeks after finishing TNT; no more than 12 weeks after the last dose of systermic therapy. For pCR: from randomization to 2-4 weeks after finishing TME surgery
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.
Measured: From randomization to 3 years after finishing surgery or choosing watch and wait strategy
Secondary outcomes (7)
Sphincter preservation rate
Measured: From date of randomization until the date of surgery or the date of watch-and-wait for cCR patients，up to 24-30 weeks
Tumor regression grade (TRG)
Measured: From randomization to 2 weeks after finishing surgery
R0 resection rate
Measured: From date of randomization until the date of surgery，up to 24-30 weeks
Incidence of treatment-related adverse events (toxicity)
Measured: From randomization to 90 days after the last dose of neoadjuvant therapy or 30 days after surgery (whichever is longer)
3-year distant metastasis rate
Measured: From randomization to 3 years after finishing surgery or choosing watch and wait strategy
3-year local recurrence rate
Measured: From randomization to 3 years after finishing surgery or choosing watch and wait strategy
3-year overall survival (OS) rate
Measured: From randomization to 3 years after finishing surgery or choosing watch and wait strategy
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 May 2025
- Study start6 May 2025
- Primary completion31 Dec 2030 (estimated)
- Study completion31 Dec 2031 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Rectal CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 430 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Sixth Affiliated Hospital, Sun Yat-sen University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Yanxin Luo,MD, Sixth Affiliated Hospital, Sun Yat-sen University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06958432
- Sponsor's protocol ID
- 2025ZSLYEC-417
- Status last verified
- Jul 2026
- First submitted
- 24 Apr 2025
- Last updated
- 28 Sep 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No