Intestinal Low Dose Radiotherapy Combined With Immunotherapy in Immune-resistant Metastatic Solid Tumors (ILDR-01)

Efficacy and Safety of Combining Intestinal Low Dose Radiotherapy and PD-1/PD-L1 Inhibitors for Metastatic Malignant Solid Tumors After Acquired Resistance to Anti-PD1/PD-L1 Treatment

Preclinical and clinical studies have shown that intestinal low dose radiotherapy (ILDR) can enhance antitumor immunity and response to immune checkpoint blockade (ICB). Therefore, the investigators launch a phase Ⅱ trial to evaluate the clinical value of combining ILDR and programmed cell death-1/ -ligand 1 (PD-1/PD-L1) inhibitors in patients with ICB refractory metastatic solid tumor.

This study is designed as a researcher-initiated, two-stage and prospective clinical trial. The target population is patients with advanced metastatic malignant solid tumors who have progressed after immunotherapy. The primary endpoints include objective response rate (ORR), disease control rate (DCR), progression free survival while receiving ILDR combined therapy (PFS2), and lesion-based abscopal response rate. The secondary endpoints include incidence of adverse events (AEs), cancer-specific survival (CSS), and overall response rate (OS).

Sixteen subjects will be enrolled in this trial. The primary objective is to evaluate the safety and efficacy of 1Gy ILDR combined with PD-1/PD-L1 inhibitors in immune-resistant metastatic malignant solid tumors, and biomarker exploration for response prediction.

Eligible patients will be subjected to 1Gy ILDR. Tumor response will be assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as well as Immune related RECIST (iRECSIST). The extent or severity of adverse reactions will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) (version 5.0). Furthermore, tissue samples, stool samples, and peripheral blood samples will be collected for biomarker exploration.

Study Overview

• Status: Completed
• Conditions: Metastatic Malignant Solid Neoplasm; Radiotherapy; Immune Checkpoint Blockade; Resistance to Immunotherapy
• Intervention / Treatment: Radiation: Intestinal Low Dose Radiotherapy-1Gy; Drug: PD-1/PD-L1 Inhibitors

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Shantou, Guangdong, China, 515031
      • Cancer Hospital, Shantou University Medical College

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18 years, ≤80 years, regardless of gender.
2. ECOG level 0-2.
3. Expected life span>3 months.
4. At least one accessible and measurable lesion should be selected as the target lesion for observation according to RECIST criteria.
5. 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.
6. The patient is considered ineligible for surgical treatment.
7. Patients with brain metastases assessed as clinically stable after treatment through repeated CT and/or MRI scans are eligible.
8. Patients have complete clinical and pathological information.
9. Any psychological, family, social or geographical conditions may hinder compliance with the research protocol.
10. Patients are able to understand the informed consent form, voluntarily participate, and sign the informed consent form.
11. Other indicators accord with the general inclusion criteria for clinical trials.

Exclusion Criteria:

1. Patients with contraindications to radiation therapy and immunotherapy.
2. Previous occurrence of unacceptable immune related toxic side effects (immune myocarditis, pneumonia, etc.).
3. Patients who were assessed as hyperprogressive disease (HPD).
4. Patients who have received pelvic and abdominal radiation therapy within 6 months prior to enrollment.
5. 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).
6. Accompanied by severe infections.
7. Serious liver disease (such as cirrhosis), kidney disease, respiratory disease, or chronic system diseases such as uncontrollable diabetes and hypertension; Patients who cannot tolerate radiation therapy.
8. Clinical symptoms of brain metastases or meningeal metastasis.
9. The patients with known allergies or allergies to the test drug ingredients.
10. Substance/alcohol abuse.
11. Patients who are pregnant or planning to.
12. Patients participating in other clinical studies that may affect the efficacy/safety of this clinical study.
13. Patients who have undergone major surgical procedures within 30 days.
14. Patients who have received antibiotics, antifungal drugs, antiviral, antiparasitic drugs, or probiotics within 4 weeks.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ILDR; 1Gy/1F ILDR + PD-1/PD-L1 inhibitors.	Radiation: Intestinal Low Dose Radiotherapy-1Gy; 1Gy ILDR will be administered to patients in a single fraction. The radiation treatment volume composes both the jejunum and ileum.; Drug: PD-1/PD-L1 Inhibitors; The immunotherapy regimen is the previous ICB therapy regimen or modified by the physician in charge. PD-1/PD-L1 inhibitors will be given 1 day after ILDR at a 3-week interval.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	The objective effective rate of ILDR combined with PD-1/PD-L1 inhibitors in patients with metastatic malignant solid tumors after acquired resistance to immunotherapy, including complete response and partial response.	6, 12, 24 weeks after start of ILDR.
Disease Control Rate（DCR）	The proportion of patients with optimal response to ILDR combined with PD-1/PD-L1 inhibitors.	6, 12, 24 weeks after start of ILDR.
Progression Free Survival while Receiving ILDR combined Therapy (PFS2)	The time from the date of ILDR initiation to the documented disease progression or death due to cancer.	6, 12, 24 weeks after start of ILDR.
Lesion-based Abscopal Response Rate	The proportion of patients with tumor objective response in one or more lesions.	6, 12, 24 weeks after start of ILDR.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse Events	The proportion of patients with treatment-related adverse events as assessed by CTCAE v5.0.	12, 24, 48 weeks after start of ILDR.
Overall survival (OS)	The time from the date of ILDR initiation to death from any cause.	24, 48 weeks after start of ILDR.
Cancer-specific survival (CSS)	The time from the date of ILDR initiation to death due to cancer.	24, 48 weeks after start of ILDR.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes of Intestinal Flora	Fecal samples are analyzed by metagenomics sequencing. The differential intestinal flora is obtained through differential analysis, and the correlation between the differential microbial communities and other indicators is analyzed.	Before the first treatment, 3-7 days after start of ILDR, before each immunotherapy.
Metabolites in fecal samples	The wide arrays of metabolites in fecal samples are analyzed qualitatively and quantitatively.	Before the first treatment, 3-7 days after start of ILDR, before each immunotherapy.
Tissue Immune Analyses	Tumor tissue is obtained for histopathological staining and transcriptome sequencing.	Before the first treatment, 3 weeks after start of ILDR.
Peripheral Blood Immune Analyses	Flow cytometry analysis is performed on peripheral blood samples.	Before the first treatment, 3-7 days after start of ILDR, before each immunotherapy.
Changes of Serum Metabolites	The wide arrays of metabolites in serum are analyzed qualitatively and quantitatively.	Before the first treatment, 3-7 days after start of ILDR, before each immunotherapy.

Collaborators and Investigators

• Sponsor: Chuangzhen Chen

Study record dates

Study Major Dates

• Study Start (Actual): December 26, 2023
• Primary Completion (Actual): May 10, 2026
• Study Completion (Actual): May 10, 2026

Study Registration Dates

• First Submitted: September 28, 2023
• First Submitted That Met QC Criteria: October 7, 2023
• First Posted (Actual): October 10, 2023

Study Record Updates

• Last Update Posted (Actual): June 18, 2026
• Last Update Submitted That Met QC Criteria: June 17, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplastic Processes; Pathological Conditions, Signs and Symptoms; Neoplasm Metastasis; Antineoplastic Agents, Immunological; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Therapeutic Uses; Immune Checkpoint Inhibitors
• Other Study ID Numbers: SUMC-ILDR01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No