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

Phase 2

Recruiting

• Conditions: Metastatic Malignant Solid Neoplasm; Radiotherapy; Immune Checkpoint Blockade; Resistance to Immunotherapy
• Interventions: Radiation: Intestinal Low Dose Radiotherapy-1Gy; Radiation: Intestinal Low Dose Radiotherapy-2-3Gy; Drug: PD-1/PD-L1 Inhibitors

• Registration Number: NCT06076135
• Lead Sponsor: Chuangzhen Chen

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2023-09-28
• Study First Submitted QC: 2023-10-07
• Study First Posted: 2023-10-10
• Study Start: 2023-12-26
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-10
• Last Update Posted: 2024-10-14
• Primary Completion: 2025-09-30
• Study Completion: 2026-09-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

1. Age ≥18 years, ≤80 years, regardless of gender.
2. ECOG level 0-2.
3. Expected life>3 months.
4. According to RECIST criteria, at least one accessible and measurable lesion should be selected as the target lesion for observation.
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 has been assessed as unsuitable for surgical treatment.
7. Patients with brain metastases assessed as clinically stable after treatment through repeated CT and/or MRI scans are allowed to be enrolled.
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) (our previous study found that patients assessed as HPD did not benefit from ILDR and even had worse prognosis).
4. Patients who have received pelvic and abdominal radiation therapy within 6 months of 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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment Stage Ⅰ	Intestinal Low Dose Radiotherapy-1Gy	1Gy/1F ILDR + PD-1/PD-L1 inhibitors.
Treatment Stage Ⅰ	PD-1/PD-L1 Inhibitors	1Gy/1F ILDR + PD-1/PD-L1 inhibitors.
Treatment Stage Ⅱ	Intestinal Low Dose Radiotherapy-2-3Gy	2-3Gy/2-3F ILDR + PD-1/PD-L1 inhibitors.
Treatment Stage Ⅱ	PD-1/PD-L1 Inhibitors	2-3Gy/2-3F ILDR + PD-1/PD-L1 inhibitors.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	6, 12, 24 weeks after start of ILDR.	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.
Disease Control Rate（DCR）	6, 12, 24 weeks after start of ILDR.	The proportion of patients with optimal response to ILDR combined with PD-1/PD-L1 inhibitors.
Progression Free Survival while Receiving ILDR combined Therapy (PFS2)	6, 12, 24 weeks after start of ILDR.	The time from the date of ILDR initiation to the documented disease progression or death due to cancer.
Lesion-based Abscopal Response Rate	6, 12, 24 weeks after start of ILDR.	The proportion of patients with tumor objective response in one or more lesions.

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Cancer Hospital, Shantou University Medical College; 🇨🇳 Shantou, Guangdong, China