Clinical trial NCT06076135: Intestinal Low Dose Radiotherapy Combined With Immunotherapy in Immune-resistant Metastatic Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Metastatic Malignant Solid Neoplasm
Radiotherapy
Immune Checkpoint Blockade
Resistance to Immunotherapy
Lead sponsor: Shantou University Medical College
Sponsor class: OTHER
First posted: 2023-10-10
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: 6, 12, 24 weeks after start of ILDR.
measure: Disease Control Rate（DCR）
timeFrame: 6, 12, 24 weeks after start of ILDR.
measure: Progression Free Survival while Receiving ILDR combined Therapy (PFS2)
timeFrame: 6, 12, 24 weeks after start of ILDR.
measure: Lesion-based Abscopal Response Rate
timeFrame: 6, 12, 24 weeks after start of ILDR.
Secondary outcomes:
measure: Incidence of Adverse Events
timeFrame: 12, 24, 48 weeks after start of ILDR.
measure: Overall survival (OS)
timeFrame: 24, 48 weeks after start of ILDR.
measure: Cancer-specific survival (CSS)
timeFrame: 24, 48 weeks after start of ILDR.
Other outcomes:
measure: Changes of Intestinal Flora
timeFrame: Before the first treatment, 3-7 days after start of ILDR, before each immunotherapy.
measure: Metabolites in fecal samples
timeFrame: Before the first treatment, 3-7 days after start of ILDR, before each immunotherapy.
measure: Tissue Immune Analyses
timeFrame: Before the first treatment, 3 weeks after start of ILDR.
measure: Peripheral Blood Immune Analyses
timeFrame: Before the first treatment, 3-7 days after start of ILDR, before each immunotherapy.
measure: Changes of Serum Metabolites
timeFrame: Before the first treatment, 3-7 days after start of ILDR, before each immunotherapy.
Locations:
city: Shantou
country: China
facility: Cancer Hospital, Shantou University Medical College
state: Guangdong
Study officials:
References: