Checkpoint Inhibitor and Radiotherapy for Recurrent Gastric Cancer (CIRCUIT)

Study Overview
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Brief Summary
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This study aims to evaluate safety and efficacy of nivolumab (anti-PD-1 antibody), which is approved as tertiary therapy, and neoadjuvant short-term limited local radiotherapy in patients with unresectable recurrent gastric cancer who progressed (intolerance or PD) after standard treatment (primary and secondary chemotherapy) and have more than one lesion assessable in diagnostic imaging (one lesion must be >=2cm).

Detailed Description
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In patients with unresectable recurrent gastric cancer who progressed (intolerance or PD) after standard treatment (primary and secondary chemotherapy) and have more than one lesion assessable in diagnostic imaging (one lesion must be >=2cm), localized short-term radiotherapy of 22.5 Gy/5 fractions/5 days will be applied to a symptomatic lesion or the largest asymptomatic lesion suitable for irradiation (Day 1-5). Nivolumab will be administered starting from Day 15-22 at a dose of 3 mg/kg (body wait) every 2 weeks to a total of 6 courses (end of intervention). The patients will be observed up to Day 180±14 and evaluated on Day 180±14 (end of study).

Official Title
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Combination of Checkpoint Inhibitor and Radiotherapy for Recurrent Gastric Cancer After Initial Treatment With Standard Therapy (CIRCUIT).

Conditions
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Gastric Cancer

Intervention / Treatment
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* Radiation: Radiotherapy + Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Unresectable recurrent gastric cancer with progression (intolerance or PD) after standard treatment (primary and secondary chemotherapy). More than one measurable lesion defined by RECIST guideline version 1.1 in diagnostic imaging (whole-body contrast-enhanced CT or PET-CT) within 14 days before entry, with at least one lesion >=2 cm. Age: 20 =< ECOG performance status (PS): 0-2 No contraindication for nivolumab (anti-PD-1 antibody) administration. No contraindication for radiotherapy. The most recent laboratory results within 14 days before study entry fulfill the following. However, if the laboratory results for study entry do not fall within 7 days before the first administration of nivolumab, the blood test must be performed again within 7 days before the administration to check if the results fulfill the following. The use of G-CSF or blood transfusion within 14 days before the laboratory testing is not allowed. WBC >=3000/micro liter(ul), neutrophil >=1500/ul, hemoglobin>=9.0g/dl, platelets >=100,000/ul, total bilirubin <=2.0 times the institutional standard upper limit (ISUL), AST (GOT) and ALT (GPT) <=3.0 times ISUL (in case with liver metastasis, <=5.0 times ISUL), serum creatinine <=1.5 times ISUL or creatinine clearance >=60 ml/min calculated with cockcroft-Gault equation. Male Ccr = [(140-age)*body weight(kg)]/[72*serum creatinine(mg/dl)] Female Ccr = 0.85*[(140-age)*body weight(kg)]/[72*serum creatinine(mg/dl)] Expected survival >=3 months. Written informed consent obtained before entry to the study. Exclusion Criteria: No tumor lesions to be irradiated. History of other cancers (intraepithelial cancer of uterine cervix, fully treated basal cell carcinoma of skin, malignant tumors treated before >=5 yrs and w/o recurrence are excluded). Past severe hypersensitive reaction to antibody (Ab) drugs. Use of immunosuppressant drugs or adrenocortical hormone (predonine or prednisolone (PDN/PSL) equivalent >=15 mg/day). Active autoimmune diseases or history of recurrent autoimmune diseases. Patients (Pts) with type-1 diabetes, hypothyroid controlled with hormone replacement therapy, dermatosis without need for systemic therapy (for example, vitiligo, psoriasis, alopecia) are eligible. History of interstitial pneumonia or pulmonary fibrosis diagnosed with imaging studies (CT is preferred) or clinical findings. Presence of severe disease or pathology. Pts during pregnancy or lactation. Fertile female pts w/o intention to practice contraception. Fertile male pts w/o intention to practice contraception during and for 7 months after the study, if the partners are fertile females. Prohibited pre-treatment. Within 56 days before entry: radioactive drugs (exclude those intended for testing or diagnosis) Within 28 days before entry: systemic adrenocortical hormone (excludes temporary use or PDN/PSL equivalent of <15 mg/day), immunosuppressant drugs, anti-cancer drugs, adhesive treatment of pleura or pericardium, surgery with general anesthesia, use of unapproved drugs. Within 14 days before entry: surgery with local or superficial anesthesia. Concurrent participation in other clinical trials/studies (excludes those w/o intervention). Positivity in HIV-1 Ab test, HIV-2 Ab test, or HTLV-1 Ab test. History of treatment using ONO-4538, anti-PD-1 Ab, anti-PD-L1 Ab, anti-PD-L2 Ab, anti-CD137 Ab, anti-CTLA-4 Ab, or other Ab or drugs intended for T-cell regulation. Pts whom the physicians in the study consider inappropriate for entry.

Ages Eligible for Study
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Minimum Age: 20 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radiotherapy + Nivolumab<br>Localized short-term radiotherapy (22.5 Gy/5 fractions/5 days, Day 1-5) + nivolumab (starting on Day 15-22, a dose of 3 mg/kg (body weight), every 2 weeks to a total of 6 courses) | Radiation: Radiotherapy + Nivolumab<br>* Radiotherapy of 22.5 Gy/5 fractions/5 days will be given to a symptomatic lesion or the largest asymptomatic lesion suitable for irradiation from Day 1. Nivolumab will be administered intravenously starting on Day 15-22 at a dose of 3 mg/kg (body weight) every 2 weeks to a total of 6 courses of administration.<br>* Other names: Nivolumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control rate | Tumor growth (PD) in CT (MRI possible) or PET-CT, in comparison to the images at study entry will be non-control, and evaluation of CR/PR/SD will be control. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median survival time | Median value of survival time in full analysis set. | 6 months | 
| Incidence of treatment-emergent adverse events | The frequency of adverse events according to the grades based on CTCAE ver. 4.0. will be evaluated. | 6 months | 
| Local control rate | Tumor growth (PD) in CT (MRI possible) or PET-CT, in comparison to the images at study entry will be non-control, and evaluation of CR/PR/SD will be control. | 6 months | 
| Expression of PD-L1 and MHC class I on tumor cells, number of CD8 positive lymphocytes in tumor microenvironment | The evaluation of PD-L1 and MHC class I expression on tumor cells, and the number of CD8 positive lymphocytes in tumor microenvironment will be conducted by immunohistochemistry only for participants with available samples. | 6 months | 
| Peak plasma cytokine concentration | HMGB-1, IL-1β, IL-10, IFN-γ in plasma will be measured by ELISA. Measurement will be performed at different time points. | At the time of registration, 2 weeks, 6 weeks, 10 weeks, and 6 months. | 
| Peak regulatory T-cell population | The rate of regulatory T-cell population in peripheral blood will be evaluated by flow cytometry. Measurement will be performed at different time points. | At the time of registration, 2 weeks, 6 weeks, 10 weeks, and 6 months. | 
| Peak antigen-specific cytotoxic T lymphocyte population | The rate of antigen-specific cytotoxic T lymphocyte in peripheral blood will be evaluated by flow cytometry. Measurement will be performed at different time points. | At the time of registration, 2 weeks, 6 weeks, 10 weeks, and 6 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Radiotherapy, anti-PD-1 antibody