Intestinal Low Dose Radiotherapy Combined With Immunotherapy in Immune-resistant Metastatic Malignant Solid Tumors

NCT ID: NCT07071103

Last Updated: 2025-11-20

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 48 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-09-26
• Study Completion Date: 2028-01-01

Brief Summary

Preclinical and clinical evidence suggests that intestinal low-dose radiotherapy (ILDR) may enhance antitumor immune responses by modulating the gut microenvironment, thereby improving the efficacy of immune checkpoint inhibitors (ICBs) in refractory solid tumors. Based on these findings, the investigators initiate a multicohort phase II clinical trial to evaluate the clinical benefit and safety of ILDR combined with PD-1/PD-L1 monoclonal antibody therapy in patients with metastatic solid tumors resistant to prior ICB treatment.

In this study, patients are stratified into three parallel cohorts by tumor type (lung cancer, esophageal cancer, and other solid tumors), with 16 patients per cohort (48 in total, including subjects enrolled from the ILDR-01 study). Eligible participants includes patients with advanced metastatic solid tumors progressing after monotherapy or combination ICB treatment, meeting criteria of ECOG performance status 0-2, life expectancy ≥3 months, and have at least one measurable lesion. Exclusion criteria encompasses prior pelvic radiotherapy, ongoing infections, major organ dysfunction, or concurrent antitumor therapies.

The primary endpoints includes objective response rate (ORR), disease control rate (DCR), progression-free survival after ILDR (PFS2), and the incidence of abscopal effects. Secondary endpoints includes overall survival (OS), treatment safety, α/β diversity changes in gut microbiota, peripheral blood immune cell subset dynamics, and tumor immune microenvironment remodeling characteristics. All patients receives a 1 Gy jejunoileal radiotherapy followed by PD-1/PD-L1 monoclonal antibody administration (in accordance to prior protocols or guidelines) within 24 hours, with maintenance therapy up to 2 years. Therapeutic efficacy is assessed via RECIST v1.1, while therapeutic toxicity is assessed according to CTCAE v5.0.

Paired pre- and post-treatment samples (including wumor tissue, stool, peripheral blood etc.) are collected for metagenomic sequencing, metabolomic analysis, and multi-omics integrative modeling to systematically elucidate the regulation mechanism of gut microbiota-metabolite-immune axis mediated by ILDR. This approach aims to provide theoretical foundations for optimizing treatment strategies in immunotherapy-resistant tumors and identify biomarkers that potentially associated with therapeutic efficacy.

Conditions

Radiotherapy; Metastatic Solid Cancers; Immune Checkpoint Blockade; Esophageal Neoplasms Malignant; Lung Neoplasm Malignant; Drug Resistance

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Lung cancer arm

This arm includes patients with metastatic non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC) who have progressed after previous immune checkpoint blockades (ICBs) administration, and the intervention involves 1Gy/1F ILDR plus PD-1/PD-L1 inhibitors.

Group Type: EXPERIMENTAL

Low-dose radiotherapy to the intestine (ILDR)

Intervention Type: RADIATION

A single total dose of 1 Gy irradiation targeting the jejunum and ileum. Primary tumor or metastatic lesions that are within the irradiation field are irradiated concurrently.

PD-1/PD-L1 monoclonal antibodies

Intervention Type: DRUG

Pre-progression immunotherapy regimen continues or switches to an alternative PD-1/PD-L1 monoclonal antibody according to clinical guidelines.PD-1/PD-L1 monoclonal antibody will be given 1 day after ILDR at a 3-week interval.

Esophageal cancer group

This arm includes patients with metastatic esophageal cancer (including squamous cell carcinoma or adenocarcinoma) who have progressed after previous ICB administration, and the intervention involves 1Gy/1F ILDR plus PD-1/PD-L1 inhibitors.

Group Type: EXPERIMENTAL

Low-dose radiotherapy to the intestine (ILDR)

Intervention Type: RADIATION

A single total dose of 1 Gy irradiation targeting the jejunum and ileum. Primary tumor or metastatic lesions that are within the irradiation field are irradiated concurrently.

PD-1/PD-L1 monoclonal antibodies

Intervention Type: DRUG

Pre-progression immunotherapy regimen continues or switches to an alternative PD-1/PD-L1 monoclonal antibody according to clinical guidelines.PD-1/PD-L1 monoclonal antibody will be given 1 day after ILDR at a 3-week interval.

Other solid tumor group

This arm includes patients with other malignant solid tumors except lung cancer and esophageal cancer who have progressed after previous ICB administration, and the intervention involves 1Gy/1F ILDR plus PD-1/PD-L1 inhibitors.

Group Type: EXPERIMENTAL

Low-dose radiotherapy to the intestine (ILDR)

Intervention Type: RADIATION

A single total dose of 1 Gy irradiation targeting the jejunum and ileum. Primary tumor or metastatic lesions that are within the irradiation field are irradiated concurrently.

PD-1/PD-L1 monoclonal antibodies

Intervention Type: DRUG

Pre-progression immunotherapy regimen continues or switches to an alternative PD-1/PD-L1 monoclonal antibody according to clinical guidelines.PD-1/PD-L1 monoclonal antibody will be given 1 day after ILDR at a 3-week interval.

Interventions

Low-dose radiotherapy to the intestine (ILDR)

A single total dose of 1 Gy irradiation targeting the jejunum and ileum. Primary tumor or metastatic lesions that are within the irradiation field are irradiated concurrently.

Intervention Type: RADIATION

PD-1/PD-L1 monoclonal antibodies

Pre-progression immunotherapy regimen continues or switches to an alternative PD-1/PD-L1 monoclonal antibody according to clinical guidelines.PD-1/PD-L1 monoclonal antibody will be given 1 day after ILDR at a 3-week interval.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Age ≥18 years, ≤80 years, regardless of gender.
• ECOG level 0-2.
• Expected life span>3 months.
• At least one accessible and measurable lesion should be selected as the target lesion for observation according to RECIST criteria.
• Patients with metastatic solid tumors (of any histology) without standard therapy options, who have previously received immunotherapy, immunotherapy combined with chemotherapy, or immunotherapy combined with anti-angiogenesis treatment and have shown disease progression.
• Patients should not be considered eligible for surgical treatment.
• Patients with brain metastases that are assessed as clinically stable after treatment through repeated CT and/or MRI scans are eligible.
• Patients have complete clinical and pathological information.
• Patients should not be borthered by any psychological, family, social or geographical conditions that may hinder compliance with the research protocol.
• Patients should be able to understand the informed consent form, voluntarily participate, and sign the informed consent form.

Exclusion Criteria

• Patients with contraindications to radiation therapy and immunotherapy.
• Previous occurrence of unacceptable immune related toxic side effects (immune myocarditis, pneumonia, etc.).
• Patients who were assessed as hyperprogressive disease (HPD).
• Patients who have received pelvic and abdominal radiation therapy within 6 months prior to enrollment.
• The adverse reactions from prior treatment have not yet recovered to a CTCAE5.0 rating of ≤ 1 (excluding toxicity that has been determined to be risk-free, such as fatigue or hair loss).
• Patients with active uncontrolled systemic bacterial, viral, or fungal infections despite optimal treatment.
• Significant liver or kidney dysfunction (i.e., laboratory values >3 times the upper limit of normal).
• Active hepatitis B, hepatitis C, HIV, or syphilis.
• Brain disorders, symptomatic central nervous system (CNS) or meningeal metastases, or impaired cognitive function.
• Hypersensitivity to any drug included in the trial.
• Drug and/or alcohol abuse.
• Pregnant or breastfeeding women.
• Concurrent participation in another therapeutic clinical trial.
• Poorly controlled pleural effusion, pericardial effusion, or ascites requiring frequent drainage (recurrence within ≤14 days after intervention).
• Major surgery within 30 days.
• Use of antibiotics, antifungals, antivirals, antiparasitics, or probiotics within 4 weeks before enrollment.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Chuangzhen Chen

OTHER

Sponsor Role: lead

Responsible Party

Chuangzhen Chen

Director

Responsibility Role: SPONSOR_INVESTIGATOR

Locations

Cancer Hospital, Shantou University Medical College

Shantou, Guangdong, China

Site Status: RECRUITING

Countries

China

Central Contacts

Chuangzhen Chen, MD

Role: CONTACT

czchen2@stu.edu.cn

+86 13923995569

Facility Contacts

Chuangzhen Chen

Role: primary

Other Identifiers

SUMC-ILDR02

Identifier Type: -

Identifier Source: org_study_id