Gastric Cancer
Conditions
Keywords
Radiotherapy, anti-PD-1 antibody
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).
Interventions
RADIATIONRadiotherapy
Radiotherapy of 22.5 Gy/5 fractions/5 days was given to a symptomatic lesion or the largest asymptomatic lesion suitable for irradiation from Day 1.
DRUGNivolumab
Nivolumab was administered intravenously starting on Day 15-22 at a dose of 3 mg/kg (body weight) or 240 mg/body every 2 weeks to a total of 6 courses of administration.
Sponsors
Fukushima Medical University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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) or 240 mg/body, every 2 weeks to a total of 6 courses)
Radiotherapy of 22.5 Gy/5 fractions/5 days was given to a symptomatic lesion or the largest asymptomatic lesion suitable for irradiation from Day 1.
Nivolumab was administered intravenously starting on Day 15-22 at a dose of 3 mg/kg (body weight) or 240 mg/body every 2 weeks to a total of 6 courses of administration. | 41 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | 3 cases did not meet the criteria for nivolumab initiation. | 3 |
| Overall Study | Lack of Efficacy | 16 |
Baseline characteristics
| Characteristic | Radiotherapy + Nivolumab | — |
|---|---|---|
| Age, Continuous | 70 years | — |
| Eligible patients | 40 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Sex: Female, Male Female | 7 Participants | — |
| Sex: Female, Male Male | 34 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 28 / 41 |
| other Total, other adverse events | 19 / 41 |
| serious Total, serious adverse events | 16 / 41 |
Outcome results
Primary
Disease Control Rate
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).
Time frame: 6 months
Population: Since one patient whose target lesions did not meet the selection criteria for this study according to the RECIST guideline version 1.1 was ineligible and was excluded from the efficacy analysis, 40 patients were included in the efficacy analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radiotherapy + Nivolumab | Disease Control Rate | 9 Participants |
Secondary
Local Control Rate
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.
Time frame: 6 months
Population: Since one patient whose target lesions did not meet the selection criteria for this study according to the RECIST guideline version 1.1 was ineligible and was excluded from the efficacy analysis, 40 patients were included in the efficacy analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Radiotherapy + Nivolumab | Local Control Rate | 16 Participants |
Secondary
Median Survival Time
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.
Time frame: 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.
Population: Since one patient whose target lesions did not meet the selection criteria for this study according to the RECIST guideline version 1.1 was ineligible and was excluded from the efficacy analysis, 40 patients were included in the efficacy analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Radiotherapy + Nivolumab | Median Survival Time | 230 Days |
Secondary
Safety (Grade and Frequency of Adverse Events)
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.
Time frame: 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.
Population: The frequency and rate of grade 3 or higher adverse events.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Radiotherapy + Nivolumab | Safety (Grade and Frequency of Adverse Events) | Anemia | 8 Participants |
| Radiotherapy + Nivolumab | Safety (Grade and Frequency of Adverse Events) | Anorexia | 5 Participants |
| Radiotherapy + Nivolumab | Safety (Grade and Frequency of Adverse Events) | Tumor pain | 3 Participants |
| Radiotherapy + Nivolumab | Safety (Grade and Frequency of Adverse Events) | Dehydration | 2 Participants |
| Radiotherapy + Nivolumab | Safety (Grade and Frequency of Adverse Events) | Nausea | 2 Participants |
| Radiotherapy + Nivolumab | Safety (Grade and Frequency of Adverse Events) | Alkaline phosphatase increased | 1 Participants |
| Radiotherapy + Nivolumab | Safety (Grade and Frequency of Adverse Events) | Blood bilirubin increased | 1 Participants |
| Radiotherapy + Nivolumab | Safety (Grade and Frequency of Adverse Events) | Cholecystitis | 1 Participants |
| Radiotherapy + Nivolumab | Safety (Grade and Frequency of Adverse Events) | Dyspnea | 1 Participants |
| Radiotherapy + Nivolumab | Safety (Grade and Frequency of Adverse Events) | Febrile neutropenia | 1 Participants |
| Radiotherapy + Nivolumab | Safety (Grade and Frequency of Adverse Events) | Fever | 1 Participants |
| Radiotherapy + Nivolumab | Safety (Grade and Frequency of Adverse Events) | Gastric hemorrhage | 1 Participants |
| Radiotherapy + Nivolumab | Safety (Grade and Frequency of Adverse Events) | Hyperglycemia | 1 Participants |
| Radiotherapy + Nivolumab | Safety (Grade and Frequency of Adverse Events) | Hyperkalemia | 1 Participants |
| Radiotherapy + Nivolumab | Safety (Grade and Frequency of Adverse Events) | Hyperuricemia | 1 Participants |
| Radiotherapy + Nivolumab | Safety (Grade and Frequency of Adverse Events) | Hypoalbuminemia | 1 Participants |
| Radiotherapy + Nivolumab | Safety (Grade and Frequency of Adverse Events) | Hyponatremia | 1 Participants |
| Radiotherapy + Nivolumab | Safety (Grade and Frequency of Adverse Events) | Ileus | 1 Participants |
| Radiotherapy + Nivolumab | Safety (Grade and Frequency of Adverse Events) | Platelet count decreased | 1 Participants |
| Radiotherapy + Nivolumab | Safety (Grade and Frequency of Adverse Events) | Proteinuria | 1 Participants |
| Radiotherapy + Nivolumab | Safety (Grade and Frequency of Adverse Events) | White blood cell decreased | 1 Participants |
| Radiotherapy + Nivolumab | Safety (Grade and Frequency of Adverse Events) | Lung infection | 1 Participants |
| Radiotherapy + Nivolumab | Safety (Grade and Frequency of Adverse Events) | Supraventricular tachycardia | 1 Participants |