Checkpoint Inhibitor and Radiotherapy for Recurrent Gastric Cancer (CIRCUIT)

Phase 1

• Conditions: Gastric Cancer
• Interventions: Radiation: Radiotherapy; Drug: Nivolumab

• Registration Number: NCT03453164
• Lead Sponsor: Fukushima Medical University

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 Timeline

• Study First Submitted: 2018-02-21
• Study First Submitted QC: 2018-02-26
• Study First Posted: 2018-03-05
• Study Start: 2018-03-28
• Status Verified: 2020-07
• Last Update Submitted: 2020-07-14
• Last Update Posted: 2020-07-15
• Primary Completion: 2021-01-14
• Study Completion: 2021-02-28

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 41

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Radiotherapy + Nivolumab	Radiotherapy	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) or 240 mg/body, every 2 weeks to a total of 6 courses)
Radiotherapy + Nivolumab	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) or 240 mg/body, every 2 weeks to a total of 6 courses)

Primary Outcome Measures

Name	Time	Method
Disease Control Rate	6 months	Analysis item: Disease control rate of non-irradiated target lesions. The rate of patients with a best overall response of stable disease (SD) or better confirmed by 180 days, starting from the start date of radiotherapy. The RECIST Guidelines Version 1.1 was used to determine overall response such as complete response (CR), partial response (PR), SD, and progressive disease (PD) at each imaging time. If imaging is not available, the patient is considered deficient (NE).

Secondary Outcome Measures

Name	Time	Method
Median Survival Time	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.	Overall survival is defined as the period from the start date of radiotherapy until the date of death from any cause or date of last documented survival. In surviving cases, the last date of confirmation of survival is the date of termination. Untraceable cases are terminated on the last date of confirmed survival before the loss of follow-up. At the end of the study period, all enrolled cases are confirmed alive.
Safety (Grade and Frequency of Adverse Events)	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.	The frequency of adverse events from all enrolled cases is tabulated by adverse event name and worst grade according to CTCAE ver.4.0. All adverse events are summarized without regard to causal relationships to the study treatment. The frequency and rate of grade 3 or higher adverse events are calculated.
Local Control Rate	6 months	Analysis item: Disease control rate of irradiated target lesions. The rate of patients with a best overall response of SD or better confirmed by 180 days, starting from the start date of radiotherapy. The RECIST Guidelines Version 1.1 was used to determine overall response such as CR, PR, SD, and PD at each imaging time. If imaging is not available, the patient is considered NE.

Trial Locations

Locations (1)

Fukushima Medical University Hospital; 🇯🇵 Fukushima, Japan