Clinical trial NCT03453164: 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).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Gastric Cancer
Keywords: Radiotherapy
anti-PD-1 antibody
Lead sponsor: Fukushima Medical University
Sponsor class: OTHER
First posted: 2018-03-05
Enrollment: 41
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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 is applied to a symptomatic lesion or the largest asymptomatic lesion suitable for irradiation (Day 1-5). Nivolumab is administered starting from Day 15-22 at a dose of 3 mg/kg (body wait) or 240 mg/body every 2 weeks to a total of 6 courses (end of intervention).

The patients are observed up to Day 180±14 and evaluated on Day 180±14 (end of study).

Eligibility criteria: Inclusion Criteria:

1. Unresectable advance or recurrent GC with intolerance or progression 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: WBC ≥3000/μl, neutrophil ≥1500/μl, hemoglobin ≥9.0g/dl, platelets ≥100,000/μl, 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.
8. Expected survival \>=3 months.
9. Written informed consent is obtained from the patient prior to study enrollment.

Exclusion Criteria:

1. No tumor lesions that can be irradiated.
2. Metachronous and simultaneous overlapping cancers (excluding intraepithelial cancer of the uterine cervix, fully treated basal cell carcinoma of the skin, and malignant tumors that were treated more than 5 years ago and have not recurred).
3. A history of severe hypersensitivity reactions to other Ab products.
4. Taking immunosuppressive drugs or corticosteroids (prednisone or prednisolone equivalent ≥ 15 mg/day).
5. Active autoimmune diseases or a history of recurrent autoimmune diseases (patients with type-1 diabetes, hypothyroid controllable by hormone replacement therapy, and dermatosis without the need for systemic therapy are eligible).
6. Complications or history of interstitial pneumonia or pulmonary fibrosis diagnosed by imaging studies or clinical findings.
7. Presence of severe disease or medical conditions: severe nutritional deficiencies, transient ischemic attack within 180 days prior to enrollment, cerebral vascular attack within 180 days prior to enrollment, thrombus or thromboembolism within 180 days prior to enrollment, congestive heart failure (NYHA class III or IV), unstable angina, myocardial infarction within 12 months, severe arrhythmias requiring medication, conduction abnormalities such as AV block beyond the second degree, uncontrollable hypertension, liver cirrhosis (Child Class B or higher), mental disorders that may interfere with compliance with this study protocol, unstable diabetes, uncontrolled pericardial fluid, uncontrolled ascites, uncontrolled pleural effusions, diseases requiring anticoagulation therapy (excluding antiplatelet therapy including low-dose aspirin), and systemic infection with treatment.
8. Pregnant or lactating female.
9. Fertile female who are unwilling to use contraception.
10. Fertile male who are not willing to use contraception during study drug administration and for 7 months after study completion (if the partners are fertile females).
11. Prohibited previous treatment: within 56 days of registration; radioactive drugs (except radiopharmaceuticals for examination or diagnostic purposes), within 28 days of registration; corticosteroids (excluding temporary use and predonine or prednisolone equivalent ≤15 mg/day), immunosuppressant drugs, anti-cancer drugs, adhesive treatment of pleura or pericardium, surgery with general anesthesia, and unapproved drugs, within 14 days of registration; surgery with local or superficial anesthesia.
12. Participating in other clinical trials or clinical studies (excludes those without intervention).
13. A positive HIV antigen/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 drug therapies for T-cell regulation.
15. Determined by the investigator to be ineligible for participation in this study.

Primary outcomes:
measure: Disease Control Rate
timeFrame: 6 months
Secondary outcomes:
measure: Median Survival Time
timeFrame: From the start date of radiotherapy until the date of death from any cause or date of last documented survival, assessed up to approximately 31 months.
measure: Safety (Grade and Frequency of Adverse Events)
timeFrame: Adverse events were monitored from the start date of radiotherapy until the end of study protocol or death from any cause, and were assessed up to approximately 6 months. All-Cause Mortality was assessed up to approximately 31 months.
measure: Local Control Rate
timeFrame: 6 months
Other outcomes:
Locations:
city: Fukushima
country: Japan
facility: Fukushima Medical University Hospital
Study officials:
affiliation: Fukushima Medical University Hospital
name: Koji Kono, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.