Neoadjuvant Immunotherapy ± Radiotherapy in MSI-H/dMMR Locally Advanced Colorectal Cancer

NCT07403877 | Not Yet Recruiting Phase 2

• 1 other identifier: FDRT-2025-592-4741
• Study Type: interventional
• Target: 114
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II clinical trial evaluates the efficacy and safety of three neoadjuvant regimens in patients with locally advanced microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) colorectal cancer (CRC): 1) Regimen A: Dual immune checkpoint blockade with nivolumab plus ipilimumab. 2) Regimen B: Nivolumab plus radiotherapy. 3) Regimen C: Nivolumab monotherapy. The primary objectives are to determine whether: 1) Dual immune checkpoint blockade (Regimen A) is superior to nivolumab monotherapy (Regimen C); and 2) Immunotherapy plus radiotherapy (Regimen B) is superior to nivolumab monotherapy (Regimen C). Methods: Participants will be randomized in a 1:1:1 ratio to one of the three arms. For patients with resectable tumors, surgical resection will be performed. In patients with low rectal cancer and poor prospects for sphincter preservation, a watch-and-wait (WW) strategy is an option if a clinical complete response (CR) is achieved following neoadjuvant therapy.

Conditions

Colorectal Cancer (MSI-H)

Keywords

colorectal cancer; microsatellite instability high; mismatch repair-deficient; neoadjuvant therapy; radiotherapy; immunotherapy; locally advanced

Outcome Measures

Primary Outcomes (1)

• Complete regression (CR) rate

  Proportion of patients achieving either clinical CR (and undergoing WW) or pathological CR (confirmed by pathology) among all evaluable patients.

  1 month after surgery or the completion of neoadjuvant therapy

Secondary Outcomes (7)

• R0 resection rate

  1 month after surgery

• Objective response rate (ORR)

  6 months after the enrollment of the last subject

• Event-free survival (EFS)

  36 months after the enrollment of the last subject

• Overall survival (OS)

  36 months after the enrollment of the last subject

• Toxicities

  From the time of enrollment, assessed up to 28 days after the last dose of study therapy

Study Arms (3)

anti-PD-1 plus anti-CTLA-4

EXPERIMENTAL

Arm A: Nivolumab 240 mg every 2 weeks (6 doses) plus ipilimumab 1 mg/kg every 3 weeks (4 doses).

Drug: Nivolumab; Drug: Ipilimumab (1mg/kg); Procedure: Radical surgery; Other: Watch & wait

anti-PD-1 plus radiotherapy

EXPERIMENTAL

Arm B: Radiotherapy (5 Gy per fraction, total 4 fractions, delivered every 3 weeks) to the primary lesion plus nivolumab 240 mg every 2 weeks (6 doses).

Drug: Nivolumab; Radiation: PULSAR; Procedure: Radical surgery; Other: Watch & wait

anti-PD-1 monotherapy

ACTIVE COMPARATOR

Arm C: Nivolumab 240 mg every 2 weeks (6 doses).

Drug: Nivolumab; Procedure: Radical surgery; Other: Watch & wait

Interventions

Nivolumab DRUG

Nivolumab 240 mg every 2 weeks

anti-PD-1 monotherapy; anti-PD-1 plus anti-CTLA-4; anti-PD-1 plus radiotherapy

Ipilimumab (1mg/kg) DRUG

Ipilimumab 1 mg/kg every 3 weeks

anti-PD-1 plus anti-CTLA-4

PULSAR RADIATION

Irradiation targeted to the primary lesion (5 Gy per fraction, total 4 fractions, delivered every 3 weeks).

anti-PD-1 plus radiotherapy

Radical surgery PROCEDURE

Surgical resection will be performed in resectable cases.

anti-PD-1 monotherapy; anti-PD-1 plus anti-CTLA-4; anti-PD-1 plus radiotherapy

Watch & wait OTHER

For patients with low rectal cancer who are unable to preserve the anal sphincter, a watch-and-wait (WW) strategy can be considered if a clinical complete response (CR) is achieved.

anti-PD-1 monotherapy; anti-PD-1 plus anti-CTLA-4; anti-PD-1 plus radiotherapy

Eligibility Criteria

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

You may qualify if:

• Histopathologically confirmed primary colorectal adenocarcinoma.
• Radiographic assessment showed a stage II-III based on AJCC Stage 8th ed.
• At least 18 years old.
• MSI-H or dMMR.
• The Eastern Cooperative Oncology Group performance status (ECOG PS) score is 0 or 1.
• Physical state or organ function can tolerate the planned treatment of the study protocol.
• Agreed to sign written informed consent before recruitment.

You may not qualify if:

• Previously received any antitumor therapy for the disease under study, including surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, etc.
• Pregnancy or breastfeeding women.
• History of other malignancies within 5 years.
• Serious medical illness, such as severe mental disorders, cardiac disease, uncontrolled infection, etc.
• Immunodeficiency disease or long-term using of immunosuppressive agents.
• Allergic to any component of the therapy.
• Any other condition or disease that is not suitable to take the therapy included in the protocol.
• Concurrent participation in another clinical study, unless participating in an observational (non-interventional) clinical study or in the survival follow-up phase of an interventional study.
• Received any investigational drug or device treatment within 4 weeks prior to initial administration of the investigational drug.

Sponsors & Collaborators

• Fudan University: lead

Study Sites (1)

Fudan University Shanghai Cancer Center

Shanghai, China

Location

MeSH Terms

Conditions

Colorectal Neoplasms; Turcot syndrome

Interventions

Nivolumab; Ipilimumab; DEAE-Dextran

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Dextrans; Glucans; Polysaccharides; Carbohydrates

Central Study Contacts

Menglong Zhou, MD

CONTACT

86+18121299608; mrzhouml@163.com

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: Professor, Chief Physician, Department of Radiation Oncology, Fudan University Shanghai Cancer Center

Study Record Dates

• First Submitted: February 1, 2026
• First Posted: February 11, 2026
• Study Start: February 1, 2026
• Primary Completion (Estimated): December 31, 2031
• Study Completion (Estimated): December 31, 2034
• Last Updated: February 11, 2026

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)