Node-Sparing Short-Course Radiotherapy Plus First-Line Therapy and PD-1 Inhibitor in Unresectable/Metastastic pMMR/MSS Gastric Cancer (MODIFI-GC)

NCT06980389 | Not Yet Recruiting Phase 2 DMC

• 1 other identifier: 2025ZSLYEC-226
• Study Type: interventional
• Target: 176
• Locations: 1 country
• Sites: 1

Brief Summary

For patients with unresectable locally advanced or metastatic gastric cancer, systemic anti-tumor therapy remains the mainstay of treatment. Combining chemotherapy with immune checkpoint inhibitors has gradually become the standard first-line treatment for advanced gastric cancer. Radiotherapy can enhance the release of tumor-associated antigens, thereby improving the responsiveness of MSS/pMMR tumors to PD-1 inhibitors. Tumor-draining lymph nodes (TDLNs) are key sites for the anti-tumor activity of PD-1 blockade; however, radiation-induced damage and fibrosis may impair lymphatic drainage and local immune responses. Previous studies have suggested that irradiation of the primary tumor combined with immune checkpoint blockade can produce an abscopal effect, mediating regression of distant metastases. This study aims to evaluate whether node-sparing modified short-course radiotherapy followed by chemotherapy and PD-1 blockade can improve 2-year progression-free survival (PFS) in patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma.

Conditions

Immune Checkpoint Therapy; Radiotherapy; Metastatic Gastric Carcinoma

Outcome Measures

Primary Outcomes (1)

• Progression-free survival (PFS)

  From initiation of treatment until disease progression or death, whichever occurs first, assessed over a period of up to 24 months

Secondary Outcomes (8)

• Objective response rate

  From the start of treatment until disease progression, assessed over a period of up to 24 months

• 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 24 months

• Disease control rate

  From treatment start to the end of study at 2 years

• Overall survival (OS) rate

  From treatment start to the end of study at 2 years

• Treatment related adverse effect

  From treatment start to 30 days after the end of treatment

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 standard first-line chemotherapy combined with a PD-1 inhibitor starting 2-5 days after radiotherapy. Treatment will continue until disease progression or the occurrence of unacceptable toxicity.

Node-sparing Radiotherapy Group

First-line treatment COMBINATION_PRODUCT

Patients will receive standard first-line chemotherapy combined with a PD-1 inhibitor. Treatment will continue until disease progression or the occurrence of unacceptable toxicity.

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.
• At least one measurable lesion as defined by RECIST 1.1.
• Histologically confirmed unresectable locally advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction.
• Tumor biopsy indicates proficient mismatch repair (pMMR) based on positive immunohistochemical staining for MSH1, MSH2, MSH6, and PMS2, or microsatellite stability (MSS) by genetic testing.
• No prior systemic anti-tumor therapy before study treatment, 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 as defined below:
• Hematologic (without blood transfusion or hematopoietic growth factor support 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:

• Radiotherapy within 4 weeks prior to enrollment or radionuclide therapy within 8 weeks, except for palliative radiotherapy to bone metastases.
• History of other malignancies within 5 years prior to enrollment, except for those considered cured by local therapy, such as basal cell carcinoma, squamous cell carcinoma of the skin, superficial bladder cancer, or ductal carcinoma in situ of the breast.
• Gastrointestinal perforation and/or fistula within 6 months prior to enrollment.
• Clinically significant bowel obstruction.
• Symptomatic central nervous system (CNS) metastases.
• Diagnosis of HER2-positive gastric or gastroesophageal junction adenocarcinoma.
• Inability to swallow oral medications, malabsorption syndrome, or any other condition affecting gastrointestinal absorption.
• Prior systemic or local anti-tumor therapy for gastric cancer, including curative surgery, chemotherapy, radiotherapy, immunotherapy (e.g., immune checkpoint inhibitors, agonists, or cell therapy), biologics, or small-molecule targeted agents.
• Receipt of nonspecific immunomodulatory agents (e.g., interleukins, interferons, thymic peptides, tumor necrosis factor) within 2 weeks prior to study treatment (excluding IL-11 for thrombocytopenia); use of anti-tumor traditional Chinese medicine within 1 week prior to study treatment.
• Active autoimmune disease requiring systemic therapy within the past 2 years (e.g., corticosteroids, immunosuppressants, DMARDs). Replacement therapy (e.g., thyroid hormone, insulin, or physiologic corticosteroids for adrenal/pituitary insufficiency) is permitted.
• History of or current interstitial lung disease or non-infectious pneumonitis requiring systemic corticosteroids.
• History of significant bleeding disorders or coagulopathy; current or prior 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 or gastritis, or psychiatric/social conditions interfering with protocol compliance or informed consent.
• History of myocarditis, cardiomyopathy, or malignant arrhythmia; unstable angina, heart failure requiring hospitalization, or vascular disease (e.g., aortic aneurysm requiring repair or DVT) within 12 months before treatment; other cardiac conditions that may interfere with safety evaluation, such as poorly controlled arrhythmias, myocardial infarction, or ischemia.
• Within 6 months prior to treatment: gastroesophageal varices, severe ulcers, unhealed wounds, GI perforation, fistula, intestinal 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

Location

MeSH Terms

Conditions

Stomach Neoplasms

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases

Central Study Contacts

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

CONTACT

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

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 20, 2025
• Study Start: May 31, 2025
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2028
• Last Updated: May 20, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)