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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
16
1Gy ILDR will be administered to patients in a single fraction. The radiation treatment volume composes both the jejunum and ileum.
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.
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.
Cancer Hospital, Shantou University Medical College
Shantou, Guangdong, China
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 6, 12, 24 weeks after start of ILDR.
Incidence of Adverse Events
The proportion of patients with treatment-related adverse events as assessed by CTCAE v5.0.
Time frame: 12, 24, 48 weeks after start of ILDR.
Overall survival (OS)
The time from the date of ILDR initiation to death from any cause.
Time frame: 24, 48 weeks after start of ILDR.
Cancer-specific survival (CSS)
The time from the date of ILDR initiation to death due to cancer.
Time frame: 24, 48 weeks after start of ILDR.
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