Checkpoint Inhibitor and Radiotherapy for Recurrent Gastric Cancer (CIRCUIT)

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

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).

Study Overview

• Status: Unknown
• Conditions: Gastric Cancer
• Intervention / Treatment: Radiation: Radiotherapy + Nivolumab

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Anticipated): 41
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Japan
  • Fukushima, Japan, 960-1295
    • Fukushima Medical University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Unresectable recurrent gastric cancer with progression (intolerance or PD) after standard treatment (primary and secondary chemotherapy).
2. 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.
3. Age: 20 =<
4. ECOG performance status (PS): 0-2
5. No contraindication for nivolumab (anti-PD-1 antibody) administration.
6. No contraindication for radiotherapy.

7. 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)]

8. Expected survival >=3 months.
9. Written informed consent obtained before entry to the study.

Exclusion Criteria:

1. No tumor lesions to be irradiated.
2. 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).
3. Past severe hypersensitive reaction to antibody (Ab) drugs.
4. Use of immunosuppressant drugs or adrenocortical hormone (predonine or prednisolone (PDN/PSL) equivalent >=15 mg/day).
5. 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.
6. History of interstitial pneumonia or pulmonary fibrosis diagnosed with imaging studies (CT is preferred) or clinical findings.
7. Presence of severe disease or pathology.
8. Pts during pregnancy or lactation.
9. Fertile female pts w/o intention to practice contraception.
10. Fertile male pts w/o intention to practice contraception during and for 7 months after the study, if the partners are fertile females.

11. 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.

12. Concurrent participation in other clinical trials/studies (excludes those w/o intervention).
13. Positivity in HIV-1 Ab test, HIV-2 Ab test, or HTLV-1 Ab test.
14. 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.
15. Pts whom the physicians in the study consider inappropriate for entry.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Radiotherapy + Nivolumab; 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; 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.; Other Names: Nivolumab

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Fukushima Medical University
• Collaborators: Kanagawa Cancer Center
• Investigators: Principal Investigator: Koji Kono, Professor, Fukushima Medical University Hospital

Publications and helpful links

General Publications

• Suzuki Y, Mimura K, Yoshimoto Y, Watanabe M, Ohkubo Y, Izawa S, Murata K, Fujii H, Nakano T, Kono K. Immunogenic tumor cell death induced by chemoradiotherapy in patients with esophageal squamous cell carcinoma. Cancer Res. 2012 Aug 15;72(16):3967-76. doi: 10.1158/0008-5472.CAN-12-0851. Epub 2012 Jun 14.
• Yoshimoto Y, Suzuki Y, Mimura K, Ando K, Oike T, Sato H, Okonogi N, Maruyama T, Izawa S, Noda SE, Fujii H, Kono K, Nakano T. Radiotherapy-induced anti-tumor immunity contributes to the therapeutic efficacy of irradiation and can be augmented by CTLA-4 blockade in a mouse model. PLoS One. 2014 Mar 31;9(3):e92572. doi: 10.1371/journal.pone.0092572. eCollection 2014.
• Sato H, Suzuki Y, Yoshimoto Y, Noda SE, Murata K, Takakusagi Y, Okazaki A, Sekihara T, Nakano T. An abscopal effect in a case of concomitant treatment of locally and peritoneally recurrent gastric cancer using adoptive T-cell immunotherapy and radiotherapy. Clin Case Rep. 2017 Feb 15;5(4):380-384. doi: 10.1002/ccr3.758. eCollection 2017 Apr.
• Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Chen LT. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Dec 2;390(10111):2461-2471. doi: 10.1016/S0140-6736(17)31827-5. Epub 2017 Oct 6.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 28, 2018
• Primary Completion (ANTICIPATED): January 14, 2021
• Study Completion (ANTICIPATED): February 28, 2021

Study Registration Dates

• First Submitted: February 21, 2018
• First Submitted That Met QC Criteria: February 26, 2018
• First Posted (ACTUAL): March 5, 2018

Study Record Updates

• Last Update Posted (ACTUAL): July 15, 2020
• Last Update Submitted That Met QC Criteria: July 14, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: Radiotherapy; anti-PD-1 antibody
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Stomach Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: RK29040

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No