Node-Sparing Short-Course Radiotherapy Plus Chemotherapy, Bevacizumab and PD-1 Inhibitor in Metastatic pMMR/MSS Colorectal Cancer (MODIFI-CRC)

NCT06958419 | Recruiting Phase 2 DMC

• 1 other identifier: 2025ZSLYEC-418
• Study Type: interventional
• Target: 286
• Locations: 1 country
• Sites: 1

Brief Summary

The current standard first-line treatment for metastatic colorectal cancer is chemotherapy combined with targeted therapy, yet the prognosis remains poor. Although combining immunotherapy, anti-angiogenic agents, and chemotherapy has shown some efficacy in MSS/pMMR metastatic patients, progression-free survival (PFS) remains suboptimal. Radiotherapy-particularly high-dose radiotherapy-can enhance tumor antigen release and potentially improve the response of MSS/pMMR colorectal cancer to PD-1 inhibitors. Tumor-draining lymph nodes (TDLNs) are key sites for PD-1-mediated anti-tumor activity, but radiation-induced damage and fibrosis may impair their immune function. Prior studies have reported a remarkable pathologic complete response (pCR) rate of 77.8% using node-sparing radiotherapy in locally advanced rectal cancer. This phase II/III study aims to evaluate whether node-sparing modified short-course radiotherapy combined with chemotherapy, bevacizumab, and PD-1 blockade can improve objective response rate (ORR) in phase II and progression-free survival (PFS) in phase III, together with treatment tolerance, and overall prognosis in patients with pMMR/MSS metastatic colorectal cancer.

Conditions

Immune Checkpoint Therapy; Radiotherapy; Metastatic Colorectal Cancer (CRC)

Outcome Measures

Primary Outcomes (2)

• Objective Response Rate(ORR)

  Phase II: To evaluate whether node-sparing modified short-course radiotherapy combined with chemotherapy, bevacizumab, and a PD-1 inhibitor can improve Objective Response Rate(ORR) in patients with metastatic pMMR/MSS colorectal cancer.

  From initiation of treatment until disease progression or death, whichever occurs first, assessed over a period of up to 36 months

• Progression-free survival (PFS)

  Phase III: To evaluate whether node-sparing modified short-course radiotherapy combined with chemotherapy, bevacizumab, and a PD-1 inhibitor can improve progression-free survival (PFS) in patients with metastatic pMMR/MSS colorectal cancer.

  From initiation of treatment until disease progression or death, whichever occurs first, assessed over a period of up to 36 months

Secondary Outcomes (5)

• Duration of response

  From the first documented occurrence of complete response (CR) or partial response (PR) to the first documented disease progression (per RECIST v1.1) or death from any cause, whichever occurs first, assessed over a period of up to 36 months

• Disease control rate

  From treatment start to the end of study at 3 years

• Overall survival (OS) rate

  From treatment start to the end of study at 3 years

• Treatment related adverse effect

  From treatment start to 30 days after the end of treatment

• Time to response (TTR)

  From randomization to the first documented occurrence of complete response (CR) or partial response (PR), assessed over a period of up to 36 months

Study Arms (2)

Node-sparing Radiotherapy Group

EXPERIMENTAL

Combination Product: Node-Sparing Radiotherapy plus first-line therapy

First-line therapy Group

ACTIVE COMPARATOR

Combination Product: First-line treatment

Interventions

Node-Sparing Radiotherapy plus first-line therapy COMBINATION_PRODUCT

Patients will receive node-sparing modified short-course radiotherapy, followed by 8 cycles of FOLFOX chemotherapy combined with bevacizumab and a PD-1 inhibitor. After induction therapy, patients will continue with maintenance therapy using bevacizumab, PD-1 inhibitor, and 5-fluorouracil (5-FU), administered every 2 weeks (Q2W).

Node-sparing Radiotherapy Group

First-line treatment COMBINATION_PRODUCT

Patients will receive 8 cycles of FOLFOX chemotherapy combined with bevacizumab, followed by maintenance therapy with bevacizumab and 5-fluorouracil (5-FU), administered every 2 weeks (Q2W).

First-line therapy 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 3 months.
• Histologically or cytologically confirmed colorectal adenocarcinoma.
• Patients must be considered unsuitable for curative surgical resection or local treatment and must not have received prior systemic anti-tumor therapy for recurrent or metastatic disease. Patients with prior neoadjuvant or adjuvant therapy may be enrolled if recurrence or metastasis occurs ≥12 months after the last dose of such treatment.
• At least one measurable lesion per RECIST v1.1 that can be accurately measured repeatedly. Note: Brain metastases cannot be used as target lesions.
• Able to provide 10-20 unstained tumor tissue FFPE slides from recent biopsy or archival material stored within 3 years. Ten slides will be used for immunohistochemistry and ten for genomic testing (recent biopsy preferred). If samples are of insufficient quality (as determined by the central lab), additional slides may be required. If adequate slides cannot be provided, partial or full waiver may be granted upon approval by the medical monitor.
• Agrees to provide tumor tissue and peripheral blood samples during screening and throughout the study for research purposes.
• Adequate organ function as defined below:
• Hematologic (no use of blood products or growth factors within 7 days prior to treatment):
• Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L
• Platelet count ≥ 100 × 10⁹/L
• Hemoglobin ≥ 90 g/L
• Renal:

You may not qualify if:

• Known MSI-H or dMMR status.
• History of other malignancies within the past 3 years, except for those cured by local treatment, such as basal cell carcinoma, squamous cell carcinoma of the skin, superficial bladder cancer, or ductal carcinoma in situ of the breast.
• Prior immunotherapy, including immune checkpoint inhibitors (e.g., anti-PD-1, anti-PD-L1, anti-CTLA-4 antibodies), immune agonists (e.g., ICOS, CD40, CD137, GITR, OX40), or immune cell-based therapies targeting tumor immunity.
• Prior adjuvant or neoadjuvant therapy targeting EGFR or VEGF/VEGFR pathways (e.g., bevacizumab, cetuximab, panitumumab, aflibercept, regorafenib, or biosimilars).
• Active CNS metastases. Patients with previously treated brain metastases may be eligible if clinically stable for at least 2 weeks (from the first dose of study drug) and off corticosteroids for at least 3 days prior to treatment. Patients with untreated, asymptomatic brain metastases (no neurologic symptoms, no corticosteroids, and all lesions ≤ 1.5 cm in longest diameter) may enroll but require regular CNS monitoring.
• Known brainstem, meningeal, or spinal cord metastases or compression.
• Symptomatic or recurrently drained pleural effusion, pericardial effusion, or ascites.
• Prior systemic or local anti-tumor therapy for locally advanced rectal cancer, including curative surgery, chemotherapy, radiotherapy, immunotherapy, biologics, or small-molecule targeted therapy.
• Receipt of nonspecific immunomodulators (e.g., interleukins, interferons, thymic peptides, TNF) within 2 weeks prior to study treatment (except IL-11 for thrombocytopenia), or anti-tumor traditional Chinese medicine within 1 week prior to study treatment.
• Active autoimmune disease requiring systemic treatment within the past 2 years (e.g., with corticosteroids, immunosuppressants, or DMARDs). Replacement therapy (e.g., thyroid hormone, insulin, or physiologic corticosteroids for adrenal/pituitary insufficiency) is allowed.
• History of non-infectious pneumonitis requiring systemic corticosteroids, or current interstitial lung disease.
• History of bleeding disorders or coagulopathy; 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 active peptic ulcer disease or gastritis, or psychiatric/social conditions impairing protocol compliance or informed consent.
• History of myocarditis, cardiomyopathy, or malignant arrhythmias; unstable angina, congestive heart failure, or vascular disease (e.g., aortic aneurysm requiring repair or DVT) requiring hospitalization within 12 months. Other cardiovascular conditions affecting drug safety (e.g., poorly controlled arrhythmias, myocardial infarction, or ischemia) are excluded.
• Within 6 months prior to study treatment: gastroesophageal varices, severe ulcers, unhealed wounds, GI perforation, fistulas, 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

Colorectal Neoplasms

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

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: principle investigator

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)