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

Study Overview
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Brief Summary
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Preclinical and clinical studies have shown that intestinal low dose radiotherapy (ILDR) can enhance antitumor immunity and response to immune checkpoint blockade (ICB) by regulating intestinal flora. Therefore, the investigators design a phase II trial to validate the clinical value of combining ILDR and programmed cell death-1 (PD-1) inhibitors in patients with metastatic malignant solid tumors who have failed immunotherapy. The primary endpoints of this analysis are disease control rate (DCR), progression free survival while receiving second-line therapy (PFS2), and objective response rate (ORR). The secondary endpoints are the incidence of adverse events (AEs) and the overall response rate. This study is a researcher-initiated, prospective clinical study. The target population is patients with advanced metastatic malignant solid tumors who have progressed after immunotherapy. Thirty participants will be enrolled in this study. The primary objective of the study is to evaluate the efficacy and safety of ILDR combined with PD-1 inhibitors in immune-resistant metastatic malignant solid tumors, and the effect of ILDR combined with PD-1 inhibitors on the intestinal flora. Treatment will be given to patients who meet the eligibility criteria after obtaining their written informed consent. Subjects will be allocated into 3 groups. The jejunum and ileum will be selected and performed with low dose radiation of 1Gy/F, 1F/W, 1Gy-3Gy. The immunotherapy regimen is determined by the doctor in charge based on the patient's clinical status, original immunotherapy regimen, radiological findings, and pathological results. Immunotherapy is administered in combination with radiotherapy, with a treatment frequency of once every 3 weeks until progression. Assess the occurrence rates of DCR, PFS2, ORR, and AEs in accordance with the guidelines for response criteria for use in trials testing immunotherapeutics (iRECIST) to determine the extent of benefit for patients participating in this trial. At least one accessible and measurable lesion should be selected as the target lesion for observation. Furthermore, tissue samples, stool samples, and peripheral blood samples will be collected to assess the effect of this treatment on immune status and intestinal flora.

Official Title
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Efficacy and Safety of Combining Intestinal Low Dose Radiotherapy and PD-1 Inhibitors for Metastatic Malignant Solid Tumors After Acquired Resistance to Immunotherapy

Conditions
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Metastatic Extracranial Malignant Solid Neoplasm, Radiotherapy, Immune Checkpoint Blockade, Resistance to Immunotherapy

Intervention / Treatment
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* Radiation: Intestinal Low Dose Radiotherapy-1Gy
* Radiation: Intestinal Low Dose Radiotherapy-2Gy
* Radiation: Intestinal Low Dose Radiotherapy-3Gy
* Drug: PD-1 Inhibitors


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years, ≤70 years, regardless of gender. ECOG level 0-1. Expected life>3 months. According to RECIST criteria, at least one accessible and measurable lesion should be selected as the target lesion for observation. 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 has been assessed as unsuitable for surgical treatment. Patients have complete clinical and pathological information. The site planned for radiation was not irradiated. 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. Other indicators accord with the general inclusion criteria for clinical trials. 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 have received pelvic and abdominal radiation therapy within 3 months of 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>1Gy/1F of ILDR + PD-1 inhibitors. | Radiation: Intestinal Low Dose Radiotherapy-1Gy<br>* ILDR will be administered as single fractions every 3 weeks (Q3W). The total dose of radiotherapy was 1 Gy in 1 fractions. The radiation treatment volume included the jejunum and ileum.<br>Drug: PD-1 Inhibitors<br>* The immunotherapy regimen is determined by the physician in charge. PD-1 inhibitors were given on the day after each ILDR, with a treatment frequency of once every 3 weeks（Q3W） until progression.<br>|
| Experimental: Cohort 2<br>1Gy/2F of ILDR + PD-1 inhibitors. | Radiation: Intestinal Low Dose Radiotherapy-2Gy<br>* ILDR will be administered as single fractions every 3 weeks (Q3W). The total dose of radiotherapy was 2 Gy in 2 fractions. The radiation treatment volume included the jejunum and ileum.<br>Drug: PD-1 Inhibitors<br>* The immunotherapy regimen is determined by the physician in charge. PD-1 inhibitors were given on the day after each ILDR, with a treatment frequency of once every 3 weeks（Q3W） until progression.<br>|
| Experimental: Cohort 3<br>1Gy/3F of ILDR + PD-1 inhibitors. | Radiation: Intestinal Low Dose Radiotherapy-3Gy<br>* ILDR will be administered as single fractions every 3 weeks (Q3W). The total dose of radiotherapy was 3 Gy in 3 fractions. The radiation treatment volume included the jejunum and ileum.<br>Drug: PD-1 Inhibitors<br>* The immunotherapy regimen is determined by the physician in charge. PD-1 inhibitors were given on the day after each ILDR, with a treatment frequency of once every 3 weeks（Q3W） until progression.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate（DCR） | The proportion of patients with optimal response to ILDR combined with PD-1 inhibitors to achieve complete response, partial response, or stable disease after acquired resistance to immunotherapy. | 12 months after completion of radiotherapy。 | 
| Progression Free Survival while Receiving Second-line Therapy (PFS2) | The time from the date of enrollment to the second documented disease progression or death due to any cause. | 12 months after completion of radiotherapy。 | 
| Objective Response Rate (ORR) | The objective effective rate of ILDR combined with PD-1 inhibitors in patients with metastatic malignant solid tumors after acquired resistance to immunotherapy, including complete response and partial response. | 12 months after completion of radiotherapy. | 

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. | 24 months after completion of radiotherapy. | 
| Overall Response Rate | The proportion of patients showing complete or partial response of metastatic lesions | 12 months after completion of radiotherapy. |