Preclinical and clinical evidence suggests that intestinal low-dose radiotherapy (ILDR) may enhance antitumor immune responses by modulating the gut microenvironment, thereby improving the efficacy of immune checkpoint inhibitors (ICBs) in refractory solid tumors. Based on these findings, the investigators initiate a multicohort phase II clinical trial to evaluate the clinical benefit and safety of ILDR combined with PD-1/PD-L1 monoclonal antibody therapy in patients with metastatic solid tumors resistant to prior ICB treatment. In this study, patients are stratified into three parallel cohorts by tumor type (lung cancer, esophageal cancer, and other solid tumors), with 16 patients per cohort (48 in total, including subjects enrolled from the ILDR-01 study). Eligible participants includes patients with advanced metastatic solid tumors progressing after monotherapy or combination ICB treatment, meeting criteria of ECOG performance status 0-2, life expectancy ≥3 months, and have at least one measurable lesion. Exclusion criteria encompasses prior pelvic radiotherapy, ongoing infections, major organ dysfunction, or concurrent antitumor therapies. The primary endpoints includes objective response rate (ORR), disease control rate (DCR), progression-free survival after ILDR (PFS2), and the incidence of abscopal effects. Secondary endpoints includes overall survival (OS), treatment safety, α/β diversity changes in gut microbiota, peripheral blood immune cell subset dynamics, and tumor immune microenvironment remodeling characteristics. All patients receives a 1 Gy jejunoileal radiotherapy followed by PD-1/PD-L1 monoclonal antibody administration (in accordance to prior protocols or guidelines) within 24 hours, with maintenance therapy up to 2 years. Therapeutic efficacy is assessed via RECIST v1.1, while therapeutic toxicity is assessed according to CTCAE v5.0. Paired pre- and post-treatment samples (including wumor tissue, stool, peripheral blood etc.) are collected for metagenomic sequencing, metabolomic analysis, and multi-omics integrative modeling to systematically elucidate the regulation mechanism of gut microbiota-metabolite-immune axis mediated by ILDR. This approach aims to provide theoretical foundations for optimizing treatment strategies in immunotherapy-resistant tumors and identify biomarkers that potentially associated with therapeutic efficacy.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
48
A single total dose of 1 Gy irradiation targeting the jejunum and ileum. Primary tumor or metastatic lesions that are within the irradiation field are irradiated concurrently.
Pre-progression immunotherapy regimen continues or switches to an alternative PD-1/PD-L1 monoclonal antibody according to clinical guidelines.PD-1/PD-L1 monoclonal antibody will be given 1 day after ILDR at a 3-week interval.
Cancer Hospital, Shantou University Medical College
Shantou, Guangdong, China
RECRUITINGObjective Response Rate (ORR)
Proportion of patients achieving complete response (CR) or partial response (PR) (sustained ≥4 weeks) per RECIST v1.1.
Time frame: 6, 12, 24 weeks after ILDR initiation.
Disease Control Rate(DCR)
Proportion of patients with CR, PR, or stable disease (SD) per RECIST v1.1.
Time frame: 6, 12, 24 weeks after ILDR initiation.
Progression Free Survival while Receiving ILDR combined Therapy (PFS2)
Time from ILDR treatment to second documented disease progression (assessed by investigator via PSA, imaging, symptom, or the combinations) or death from any cause.
Time frame: 6, 12, 24 weeks after ILDR initiation.
Incidence of Abscopal Effect
Proportion of patients demonstrating tumor response in one or more non-irradiated lesions.
Time frame: 6, 12, 24 weeks after ILDR initiation.
Overall Survival (OS)
Time from ILDR treatment initiation to death from any cause.
Time frame: 24, 48 weeks after radiotherapy initiation.
Cancer-Specific Survival (CSS)
Time from ILDR treatment initiation to death due to cancer.
Time frame: 24, 48 weeks after radiotherapy initiation.
Adverse Events
Proportion of patients with treatment-related adverse events as assessed by CTCAE v5.0.
Time frame: 12, 24, 48 weeks after radiotherapy initiation
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