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

NCT06076135 | Active Not Recruiting Phase 2

• 1 other identifier: ShantouUMC
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

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). In the treatment stage Ⅰ, sixteen subjects will be enrolled in this trial. The primary objective of this stage 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. The inclusion criteria, exclusion criteria and sample size for treatment stage Ⅱ will be modified on the basis of results from Stage Ⅰ. The objective of the stage Ⅱ is to determine effects and safety of various dosage regimen of ILDR combined with PD-1/PD-L1 inhibitors in target patients. Eligible patients will be subjected to 1-3Gy 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.

Conditions

Metastatic Malignant Solid Neoplasm; Radiotherapy; Immune Checkpoint Blockade; Resistance to Immunotherapy

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (3)

• Incidence of Adverse Events

  12, 24, 48 weeks after start of ILDR.

• Overall survival (OS)

  24, 48 weeks after start of ILDR.

• Cancer-specific survival (CSS)

  24, 48 weeks after start of ILDR.

Other Outcomes (5)

• Changes of Intestinal Flora

  Before the first treatment, 3-7 days after start of ILDR, before each immunotherapy.

• Metabolites in fecal samples

  Before the first treatment, 3-7 days after start of ILDR, before each immunotherapy.

• Tissue Immune Analyses

  Before the first treatment, 3 weeks after start of ILDR.

Study Arms (2)

Treatment Stage Ⅰ

EXPERIMENTAL

1Gy/1F ILDR + PD-1/PD-L1 inhibitors.

Radiation: Intestinal Low Dose Radiotherapy-1Gy; Drug: PD-1/PD-L1 Inhibitors

Treatment Stage Ⅱ

EXPERIMENTAL

2-3Gy/2-3F ILDR + PD-1/PD-L1 inhibitors.

Radiation: Intestinal Low Dose Radiotherapy-2-3Gy; Drug: PD-1/PD-L1 Inhibitors

Interventions

Intestinal Low Dose Radiotherapy-1Gy RADIATION

1Gy ILDR will be administered to patients in a single fraction. The radiation treatment volume composes both the jejunum and ileum.

Treatment Stage Ⅰ

Intestinal Low Dose Radiotherapy-2-3Gy RADIATION

ILDR will be administered as single fractions within 10 days. The total dose of radiotherapy will be 2-3 Gy in 2-3 fractions. ILDR design is as above.

Treatment Stage Ⅱ

PD-1/PD-L1 Inhibitors DRUG

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.

Treatment Stage Ⅰ; Treatment Stage Ⅱ

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• The patient is considered ineligible for surgical treatment.
• Patients with brain metastases assessed as clinically stable after treatment through repeated CT and/or MRI scans are eligible.
• Patients have complete clinical and pathological information.
• Any psychological, family, social or geographical conditions may hinder compliance with the research protocol.
• Patients are able to understand the informed consent form, voluntarily participate, and sign the informed consent form.

You may not qualify if:

• 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).
• Accompanied by severe infections.
• 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.
• Clinical symptoms of brain metastases or meningeal metastasis.
• The patients with known allergies or allergies to the test drug ingredients.
• Substance/alcohol abuse.
• Patients who are pregnant or planning to.
• Patients participating in other clinical studies that may affect the efficacy/safety of this clinical study.
• Patients who have undergone major surgical procedures within 30 days.
• Patients who have received antibiotics, antifungal drugs, antiviral, antiparasitic drugs, or probiotics within 4 weeks.

Sponsors & Collaborators

• Chuangzhen Chen: lead

Study Sites (1)

Cancer Hospital, Shantou University Medical College

Shantou, Guangdong, 515031, China

Location

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

Immune Checkpoint Inhibitors

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Antineoplastic Agents, Immunological; Antineoplastic Agents; Therapeutic Uses

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Dr

Study Record Dates

• First Submitted: September 28, 2023
• First Posted: October 10, 2023
• Study Start: December 26, 2023
• Primary Completion: September 30, 2025
• Study Completion (Estimated): September 30, 2026
• Last Updated: June 15, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)