Checkpoint Inhibitor and Radiotherapy for Recurrent Gastric Cancer (CIRCUIT)

• ClinicalTrials.gov Identifier: NCT03453164
• Recruitment Status: Unknown
• First Posted: March 5, 2018
• Last Update Posted: July 15, 2020
• Sponsor: Fukushima Medical University
• Collaborator: Kanagawa Cancer Center
• Information provided by (Responsible Party): Koji Kono, Fukushima Medical University

Tracking Information

• First Submitted Date: February 21, 2018
• First Posted Date: March 5, 2018
• Last Update Posted Date: July 15, 2020
• Actual Study Start Date: March 28, 2018
• Estimated Primary Completion Date: January 14, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 26, 2018)

Disease control rate [ Time Frame: 6 months ]

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".

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 26, 2018)

• Median survival time [ Time Frame: 6 months ]
  Median value of survival time in full analysis set.
• Incidence of treatment-emergent adverse events [ Time Frame: 6 months ]
  The frequency of adverse events according to the grades based on CTCAE ver. 4.0. will be evaluated.
• Local control rate [ Time Frame: 6 months ]
  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".
• Expression of PD-L1 and MHC class I on tumor cells, number of CD8 positive lymphocytes in tumor microenvironment [ Time Frame: 6 months ]
  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.
• Peak plasma cytokine concentration [ Time Frame: At the time of registration, 2 weeks, 6 weeks, 10 weeks, and 6 months. ]
  HMGB-1, IL-1β, IL-10, IFN-γ in plasma will be measured by ELISA. Measurement will be performed at different time points.
• Peak regulatory T-cell population [ Time Frame: At the time of registration, 2 weeks, 6 weeks, 10 weeks, and 6 months. ]
  The rate of regulatory T-cell population in peripheral blood will be evaluated by flow cytometry. Measurement will be performed at different time points.
• Peak antigen-specific cytotoxic T lymphocyte population [ Time Frame: At the time of registration, 2 weeks, 6 weeks, 10 weeks, and 6 months. ]
  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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

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
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Gastric Cancer

Intervention

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 Name: Nivolumab

Study Arms

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)

Intervention: Radiation: Radiotherapy + Nivolumab

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.

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: July 14, 2020): 41
• Original Estimated Enrollment (submitted: February 26, 2018): 40
• Estimated Study Completion Date: February 28, 2021
• Estimated Primary Completion Date: January 14, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 20 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Japan

Administrative Information

• NCT Number: NCT03453164
• Other Study ID Numbers: RK29040
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Koji Kono, Fukushima Medical University
• Original Responsible Party: Same as current
• Current Study Sponsor: Fukushima Medical University
• Original Study Sponsor: Same as current
• Collaborators: Kanagawa Cancer Center

Investigators

• Principal Investigator: Koji Kono, Professor; Fukushima Medical University Hospital

• PRS Account: Fukushima Medical University
• Verification Date: July 2020