Conditions: Gastric Cancer
Keywords: Radiotherapy anti-PD-1 antibody
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 41
Healthy volunteers: no

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).

Arms:
arm 1: 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)

Interventions: intervention 1: Radiotherapy intervention 2: Nivolumab
Intervention descriptions: intervention 1: 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. intervention 2: 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.

Protocol document:
SAP_002.pdf: 
Identifiers: 
NCT03453164   Unique Protocol ID: RK29040 
Brief Title:  Checkpoint Inhibitor and Radiotherapy for Recurrent Gastric 
Cancer (CIRCUIT) 
Date:  
31 Jan, 2020 
 
 
 
Phase I/II Clinical Trial of Nivolumab (Anti-PD-1 Antibody)  
in Combination with Local Radiation Therapy  
for Unresectable Advanced or Recurrent Gastric Cancer 
Refractory to Standard Therapy 
 
CIRCUIT trial 
 
 
Statistical Analysis Plan 
 
 
 
Approver: Gastrointestinal Tract Surgery, Fukushima Medical University Hospital  
Principal investigator:    Koji  Kono    
 
Author:  Department of Information Science, Iwate Medical University  
Science Head of Statistical Analysis,    Fumiaki  Takahashi    
 
 


Table of contents 
1. 
Definition of Statistical Analysis Plan. ....................................................................................... 3 
2. 
General matters ........................................................................................................................... 3 
2.1 
Software used ...................................................................................................................... 3 
2.2 
Significance levels and confidence coefficients .................................................................. 3 
2.3 
Numerical display of results .................................................................................................... 3 
3. 
Case handling and analysis population ....................................................................................... 3 
3.1 
Case handling ........................................................................................................................... 3 
3.2 
Analysis population ............................................................................................................. 4 
4. 
Examination of test reliability. ........................................................................................................ 4 
5. 
Comparability considerations. .................................................................................................... 4 
5.1 
 Demographic items and baselines ..................................................................................... 4 
5.2 
Treatment status .................................................................................................................. 5 
6. 
Efficacy considerations. .............................................................................................................. 5 
6.1 
Investigation on primary endpoint ...................................................................................... 5 
6.2 
Investigation of secondary endpoints .................................................................................. 6 
6.2.1 
Median survival time ...................................................................................................... 6 
6.2.2 
Local control rate ............................................................................................................ 6 
6.3 
Interim analysis ................................................................................................................... 6 
6.4 
Adjusted analysis by patient background and baseline ....................................................... 6 
6.5 
Sensitivity analysis (handling of omissions or missing values) .......................................... 6 
6.6 
Examination of homogeneity between institutions .............................................................. 7 
6.7 
Subgroup and supplementary analyses ................................................................................... 7 
7. 
Safety considerations. ................................................................................................................. 7 
7.1 
Investigation of adverse events.................................................................................................... 7 
7.2 
Investigation of clinical laboratory values .................................................................................. 7 
8. 
List of patient data. ........................................................................................................................... 8 
8.1 
List of cases excluded from safety analysis (untreated cases) ............................................ 8 
8.2 
List of cases excluded from efficacy analysis ..................................................................... 8 
8.3 
List of early discontinuation cases ...................................................................................... 8 
8.4 
List of cases of deviation from the Study Protocol ............................................................. 9 
8.5 
Lists regarding demographic data/baselines ....................................................................... 9 
8.6 
List of treatment status ........................................................................................................ 9 
8.7 
List of effective response data............................................................................................. 9 
8.8 
List of adverse events per patient. ......................................................................................... 10 
8.9 
List of individual laboratory values and other information for each patient. .................... 10 


1. 
Definition of Statistical Analysis Plan 
The purpose of this Statistical Analysis Plan is to specify the rationale and details of the analysis 
methods to be used in the clinical trial, entitled “Phase I/II Clinical Trial of Nivolumab (Anti-PD-1 
Antibody) in Combination with Local Radiation Therapy for Unresectable Advanced or Recurrent 
Gastric Cancer Refractory to Standard Therapy”. This Statistical Analysis Plan was prepared in 
accordance with the Study Protocol of this clinical trial. 
 
 
2. 
General matters 
2.1 
Software used 
SAS for Windows ver. 9.4 or R software (version 4.0.3.). 
 
2.2 
Significance levels and confidence coefficients 
Unless otherwise noted, confidence intervals are two-tailed with a confidence coefficient of 95%. 
 
2.3 
Numerical display of results 
As a rule, the results of the analysis should be displayed in the formats shown below. Rounding of 
the displayed value is done by round off. 
 
Minimum value maximum value  
Significant digits of data  
Average value, quantile 
Significant digits of data + 1 digit 
standard deviation 
Significant digits of data + 2 digits 
% 
1 decimal place 
P-value 
3 decimal places; however, if the value is 0.001 or less, it is 
expressed as “< 0001”.    
 
 
3. 
Case handling and analysis population 
3.1 
Case handling 
The principal investigator decides on the handling of cases before the data are fixed, following a 
review of eligibility and non-compliance with the Study Protocol at the case review meeting. 
1) All enrolled cases: the population of enrolled patients excluding duplicate enrollments and incorrect 
enrollments. 
2) All eligible cases: the population excluding ineligible cases (posterior ineligibility, ineligibility at 
enrollment, offending enrollment) from all enrolled cases. 
3) Largest analyzed population (FAS): all eligible patients for whom treatment was administered. 
4) Safety analysis population: all enrolled cases, those for whom treatment was administered. 


 
3.2 
Analysis population 
Efficacy is examined in the FAS and safety is examined in the safety analysis population. 
 
 
4. 
Examination of test reliability 
1） 
Purpose 
Describe the occurrence of major registration violations, discontinuations, drop-outs, etc. in all 
enrolled cases, and specify the population to be analyzed. 
2） 
Analysis population 
All enrolled cases. 
3） 
Analysis items 
(1) Number of cases belonging to the analyzed population. 
(2) Early discontinued or not. 
(3) Any deviations from the Study Protocol. 
4） 
Method of analysis 
(1) Number of cases in the enrolled, eligible, and largest analyzed cohort are tabulated. 
(2) Cases of early discontinuation are tabulated according to reason and institution. 
(3) Cases of deviation from the Study Protocol are tabulated according to reason and institution. 
(4) A list of cases of treatment failure, early discontinuation, and deviations from the Study Protocol 
is prepared. 
 
 
5. 
Comparability considerations 
5.1 
Demographic items and baselines 
1） 
Purpose 
To get an overview of the analyzed population in terms of patient background and baseline. 
2） 
Analysis population 
FAS and safety analysis population. 
3） 
Analysis items 
Gender, age, presence or absence of allergies, presence or absence of medical history, presence 
or absence of complications, history of treatment for cancer, general condition (ECOG PS), 
cancer lesions, organs with cancer, rheumatoid factor (RA), antinuclear antibodies (ANA), SP-
D, KL-6, thyroid-stimulating hormone (TSH), free triiodothyronine (free T3), free thyroxine 
(free T4), tumor markers (CEA, CA19-9). 
4） 
Method of analysis 


For continuous quantities, summary statistics (mean, standard deviation, minimum, first quartile, 
median, third quartile, maximum) are calculated. For categorical data, frequencies and 
proportions are calculated. 
 
5.2 
Treatment status 
1） 
Purpose 
Assessing treatment status. 
2） 
Analysis population 
FAS. 
3） 
Analysis items 
(1) Number of subjects who do not complete radiotherapy or discontinue radiotherapy by Day 
14 and the reasons for those discontinuations. 
(2) During protocol treatment (from the start of radiotherapy to the sixth dose of nivolumab), 
distribution of the number of doses of nivolumab, distribution of the number of days between 
doses, and reasons for discontinuation of nivolumab. 
4） 
Analysis methods 
(1) Calculate the completion rate of radiotherapy and determine the frequency of uncompleted 
treatment by reason of incompletion. 
(2) Calculate the distribution of nivolumab dosing frequency and the proportion of protocol 
treatment completed. Calculate the basic statistics of the number of days between doses.  
(3) Prepare a list of the above treatments. 
 
 
6. 
Efficacy considerations  
6.1 
Investigation of primary endpoint 
1） 
Purpose 
To explore the efficacy of protocol treatment for unresectable advanced or recurrent gastric 
cancer, determine the disease control rate of the best overall response, which is SD or better, 
confirmed by Day 180. 
2） 
Analysis items 
Disease control rate of non-irradiated target lesions. 
3） 
Analysis methods 
(1) Construct a waterfall plot for disease control. 
(2) Summarize the responses of non-irradiated target lesions in a contingency table, and calculate 
the cumulative disease control rate and the Clopper & Pearson two-side 90% confidence interval. 
 


6.2 
Investigation of secondary endpoints 
6.2.1 
Median survival time 
1） 
Purpose 
To explore the efficacy of protocol treatment for unresectable advanced or recurrent gastric 
cancer, determine the median survival time using overall survival defined as the period from the 
start date of radiotherapy until the date of death from any cause. 
2） 
Analysis items 
Survival time from the start date of study treatment to death from any cause. 
3） 
Analysis methods 
(1) Estimate and draw the survival function using the Kaplan-Meier method with log-rank test. 
(2) Estimate of the median survival time is calculated using the Kaplan-Meier method, along with 
a two-sided 95% confidence interval using the Brookmeyer-Crowley method.  
(3) Estimate of the probability survival rate is calculated using the Kaplan-Meier method, along 
with a two-sided 95% confidence interval using the Greenwood’s formula. 
 
6.2.2 
Local control rate 
1） 
Purpose 
To explore the efficacy of protocol treatment for unresectable advanced or recurrent gastric 
cancer, determine the local control rate of the best overall response, which is SD or better, 
confirmed by Day 180. 
2） 
Analysis items 
Local control rate (disease control rate of irradiated target lesions). 
3） 
Analysis methods 
(1) Construct a waterfall plot for the local control rate. 
(2) Summarize the responses of irradiated target lesions in a contingency table, and calculate the 
cumulative disease control rate and the Clopper & Pearson two-side 90% confidence interval. 
 
6.3 
Interim analysis 
Not conducted in this study. 
 
6.4 
Adjustment analysis by patient background and baseline 
Not conducted in this study. 
 
6.5 
Sensitivity analysis (handling of omissions or missing values) 
Not conducted in this study. 
 


6.6 
Examination of homogeneity between institutions 
Not conducted in this study. 
 
6.7 
Subgroup and supplementary analyses 
The disease control rate and local control rate are analyzed in the same manner as in the main 
analysis by irradiation site and administration status, etc. 
Survival is analyzed in the same manner as the main analysis by completion of study treatment and 
by irradiation site, etc. 
 
 
7. 
Safety considerations 
7.1 
Investigation of adverse events 
1） 
Purpose 
Examine the occurrence of adverse events to examine the safety of the protocol treatment. 
2） 
Analysis items 
Name of adverse event, date of onset, worst grade, severity, outcome, and association with 
protocol treatment. 
3） 
Analysis methods 
The frequency of adverse events occurring from the start date of radiotherapy to the end of study 
is tabulated by adverse event name and worst grade (toxicity) according to CTCAE ver.4.0, and 
the Clopper & Pearson two-sided 95% confidence interval is calculated. Calculate the frequency 
and rate of adverse events, the frequency and rate of adverse events by severity, and the frequency 
and rate of grade 3 or higher adverse events. 
A serious adverse event is defined as having occurred if at least one of the following adverse 
events is observed, and the frequency and proportion of serious adverse events is calculated. 
① Death during protocol treatment or within 30 days of last protocol treatment. 
② Death with undeniable causal relationship to protocol treatment after 31 days of last 
protocol treatment. 
③ Grade 4 infection with neutropenia. 
④ Grade 4 non-hematological toxicity (excluding adverse events in the blood/bone marrow). 
Prepare a list of adverse event cases. 
 
7.2 
Investigation of clinical laboratory values 
1） 
Purpose 
Examine the clinical laboratory values to examine the safety of protocol treatment. 
5） 
Analysis population 


FAS. 
2） 
Analysis items 
Vital signs (temperature, pulse, blood pressure). 
Subjective and objective findings (PS, fever, nausea, vomiting, diarrhea, decreased appetite). 
Hematological examination (white blood cell count, neutrophil ratio, lymphocyte ratio, monocyte 
ratio, eosinophil ratio, basophil ratio, red blood cell count, hemoglobin concentration, MCV, 
MCH, MCHC, Ht, platelets). 
Blood biochemical tests (total protein, albumin, total bilirubin, direct bilirubin, AST, ALT, γ-
GTP, BUN, creatinine, LDH, uric acid, CPK, P, Ca, Na, K, Cl, CRP, blood sugar, rheumatoid 
factor (RF), anti-nuclear antibodies (ANA), SP-D, KL-6, thyroid-stimulating hormone (TSH), 
free triiodothyronine (free T3), free thyroxine (free T4), CEA, CA19-9). 
3） 
Analysis methods 
Prepare transition graphs (per individual and group) of the measured values. Calculate the basic 
statistics (median and quartiles, or frequency and rate) of the measured values. 
Prepare lists of vital signs, subjective and objective findings, hematological examination, and 
blood biochemistry tests. 
 
 
8. 
List of patient data 
8.1 
List of cases excluded from safety analysis (untreated cases) 
1） 
Purpose 
Prepare a list of untreated cases. 
2） 
Analysis object 
Untreated cases 
3） 
Analysis items 
Case number, institution name, age, gender, reason for not treated. 
 
8.2 
List of cases excluded from efficacy analysis 
1） 
Purpose 
Prepare a list of cases excluded from FAS. 
2） 
Analysis object 
Cases excluded from FAS. 
3） 
Analysis items 
Case number, institution name, age, gender, reason for exclusion from analysis. 
 
8.3 
List of early discontinuation cases 


1） 
Purpose 
Prepare a list of early discontinuation cases. 
4） 
Analysis object 
Safety analysis population. 
2） 
Analysis items 
Case number, institution name, age, gender, date of discontinuation, reason for discontinuation. 
 
8.4 
List of cases of deviation from the Study Protocol 
1） 
Purpose 
Prepare a list of cases of deviation from the Study Protocol. 
2） 
Analysis object 
Cases of deviation from the Study Protocol. 
3） 
Analysis items 
Case number, institution name, age, gender, reason and extent of the deviation.  
 
8.5 
Lists regarding demographic data/baselines 
1） 
Purpose 
Prepare a list of enrolled cases. 
2） 
Analysis object 
All enrolled cases. 
3） 
Analysis items 
Case number, institution name, age, gender, allergies, smoking cessation history, alcohol 
consumption history, medical history, complications, history of cancer chemotherapy, PS, RA, ANA, 
SP-D, KL-6, TSH, free T3, free T4, CEA, CA19-9. 
 
8.6 
List of treatment status 
1） 
Purpose 
Prepare a list of treatment status for cases subjected to safety analysis. 
2） 
Analysis object 
Safety analysis population. 
3） 
Analysis items 
Case number, age, gender, radiotherapy start date, radiotherapy end date, nivolumab administration 
date, concomitant medications. 
 
8.7 
List of effective response data 
1） 
Purpose 


Prepare a list of effective response data for cases subject to efficacy analysis. 
2） 
Analysis object 
FAS. 
3） 
Analysis items 
Case number, age, gender, radiotherapy start date, date of death or last verified survival, alive or 
dead status, regimen, irradiation site, best overall response on disease control, best overall response 
on local control, and changes in lesions over time (examination date, tumor diameter). 
 
8.8 
List of adverse events per patient 
1） 
Purpose 
Prepare a list of adverse events in cases in which adverse events are observed among the cases 
subjected to safety analysis. 
2） 
Analysis object 
Safety analysis population. 
3） 
Analysis items 
Case number, age, gender, name of adverse event (serious adverse events are marked with *), date 
of occurrence (day), worst grade, severity, outcome, date of outcome (day), relevance. 
 
8.9 
List of individual laboratory values and other information for each patient 
1） 
Purpose 
Prepare a list of laboratory values for cases in which vital signs, subjective and objective findings, 
and laboratory tests were performed. 
2） 
Analysis object 
Safety analysis population. 
3） 
Analysis items 
Vital signs (temperature, pulse, blood pressure). 
Subjective and objective findings (PS, fever, nausea, vomiting, diarrhea, decreased appetite). 
Hematological examination (white blood cell count, neutrophil ratio, lymphocyte ratio, monocyte 
ratio, eosinophil ratio, basophil ratio, red blood cell count, hemoglobin concentration, MCV, 
MCH, MCHC, Ht, platelets).  
Blood biochemistry tests (total protein, albumin, total bilirubin, direct bilirubin, AST, ALT, γ-
GTP, BUN, creatinine, LDH, uric acid, CPK, P, Ca, Na, K, Cl, CRP, blood glucose, rheumatoid 
factor (RF), antinuclear antibody (ANA), SP-D, KL-6, thyroid stimulating hormone (TSH), free 
triiodothyronine (free T3), free thyroxine (free T4), CEA, CA19-9. 

Prot_001.pdf: 
Identifiers: 
NCT03453164   Unique Protocol ID: RK29040 
Brief Title:  Checkpoint Inhibitor and Radiotherapy for Recurrent Gastric 
Cancer (CIRCUIT) 
Date:  
20 Sep, 2017 
 
 
Phase I/II Clinical Trial of Nivolumab (Anti-PD-1 Antibody) 
in Combination with Local Radiation Therapy  
for Unresectable Advanced or Recurrent Gastric Cancer  
Refractory to Standard Therapy 
 
CIRCUIT trial 
 
 
 
 
Principal Investigator: Koji Kono 
  
Gastrointestinal Tract Surgery, Fukushima Medical University Hospital  
1 Hikarigaoka, Fukushima-city, Fukushima 960-1295  
TEL: 024-547-1111 (extension 2342)  
E-mail: kojikono@fmu.ac.jp 
 
 


Research Plan Summary 
Purpose of Research 
Patients with unresectable advanced or recurrent gastric cancer with intolerance or progression 
for standard treatment (primary and secondary chemotherapy) will receive short-term radiation 
therapy on selected lesions prior to of nivolumab (anti-PD-1 antibody) therapy, which is approved 
as a third-line chemotherapy, to determine its safety and efficacy (enhancement of the systemic 
effect of nivolumab and sensitization of the local effect of radiation). 
Method of Research 
 
 
 
 
 
Evaluation Items 
Primary endpoint: 1) Disease control rate  
Secondary endpoints: 1) Median survival time,  
                  2) Safety (grade and frequency of adverse events),  
                  3) Local control rate 
                  4) Immunological parameters  
・Expected Number of Cases  
Observation and Evaluation of Efficacy 
Treatment = Radiotherapy + Nivolumab (anti-PD-1 mAb) 
① Radiotherapy: If the patient has symptoms such as pain or paralysis, irradiate the lesion 
thought to be the main cause of symptoms, or if asymptomatic, irradiate the largest lesion 
(or the second largest lesion if radiotherapy to the largest lesion is difficult) with 4.5 Gy 
once a day for 5 days (total 22.5 Gy/5 times/5 days). Day 1 is the start date of radiotherapy. 
② Nivolumab: Start administration between Days 15–22. Nivolumab is administered at 3 
mg/kg body weight or 240 mg every 2 weeks for a total of six doses. 
Preliminary review, confirmation of eligibility criteria, acquisition of consent to participate in 
this study, registration 
Candidates: Patients with unresectable advanced or recurrent gastric cancer who are diagnosed 
as ineffective (intolerant or progression) to standard treatment (first-line or second-line 
chemotherapy) and have two or more lesions that can be confirmed by imaging. 


40 cases 
Duration of Study 
Registration period: March 1, 2018 to August 31, 2020 (2 years and 6 months)  
Total research period: March 1, 2018 to August 31, 2021 (3 years and 6 months) 
Research Subject Selection Policy 
Patients with unresectable advanced or recurrent gastric cancer who are diagnosed as ineffective 
(intolerant or progression) to standard treatment (first-line or second-line chemotherapy) and 
have two or more lesions that can be confirmed by imaging. 
 
 
 
 


Table of Contents 
1. Purpose and significance of research .............................................................................. 6 
1.1. Background and Significance ..................................................................................... 6 
1.2. Objectives of the study .............................................................................................. 7 
2. Methods and duration of the study ................................................................................. 7 
2.1. Schema .................................................................................................................... 7 
2.2. Research design ........................................................................................................ 8 
2.3. Treatment and intervention plans ................................................................................ 8 
2.4. Combination therapy ............................................................................................... 11 
2.5. Criteria for changes in dosage/use ............................................................................. 12 
2.6. Evaluation items ..................................................................................................... 13 
2.7. Observation and examination items ........................................................................... 15 
2.8. Expected number of cases ........................................................................................ 20 
2.9. Case registration ..................................................................................................... 20 
2.10. Statistical analysis ................................................................................................. 21 
2.11. During the study .................................................................................................... 22 
3. Policy for selecting research subjects ........................................................................... 22 
3.1. Inclusion criteria ..................................................................................................... 22 
3.2. Exclusion criteria .................................................................................................... 23 
4. The scientific rationale for the research ........................................................................ 24 
5. The procedure for obtaining informed consent ............................................................... 24 
5.1. Explanation and consent of research subjects .............................................................. 24 
5.2. Procedures for obtaining informed consent from a substitute or other person .................. 25 
5.3. Procedures for obtaining informed assent ................................................................... 25 
6. Handling of Adverse Events ........................................................................................ 25 
6.1. Response to Adverse Events ..................................................................................... 25 
6.2. Response to the occurrence of serious adverse events .................................................. 25 
7. Criteria for discontinuation and completion ................................................................... 26 
8. Data management methods ......................................................................................... 27 
8.1. Prepare and filling out a Case Report Form (CRF) ...................................................... 27 
8.2. Sending and storing Case Report Form (CRF) ............................................................ 27 
8.3. Procedures for amending CRF .................................................................................. 27 
8.4. Identification of source material ................................................................................ 28 
9. Transfer of samples and information to and from other institution .................................... 28 
10. Method of storage and disposal of samples and information .......................................... 28 
10.1. Storage ................................................................................................................. 28 


10.2. Disposal ............................................................................................................... 29 
11. Handling of personal data ......................................................................................... 30 
11.1. Method of use ....................................................................................................... 30 
11.2. Security management responsibility system .............................................................. 30 
12. The burdens and foreseeable risks and benefits to the research subjects, the comprehensive 
assessment of them and measures to minimize such burdens and risks ................................. 30 
13. The status of funding sources for research and the conflicts of interest related to research of 
the research institution, individual revenues, and attending doctors, etc. ............................... 31 
14. Methods of disclosing information on research ............................................................ 32 
14.1. Registration of the research plan.............................................................................. 32 
14.2. Publication of research results ................................................................................. 33 
15. Report .................................................................................................................... 34 
16. Response to consultation from research subjects and others concerned ........................... 34 
17. Handling of research in situations where there is an immediate and obvious life-threatening 
situation for the research subject ..................................................................................... 34 
18. In cases involving financial burdens or gratuities to research subjects ............................. 34 
19. In the case of research involving invasive procedures, any compensation for damage to 
health caused by the research .......................................................................................... 35 
20. In the case of research involving medical treatment beyond normal medical treatment, 
handling of provision of medical treatment to research subjects after completion of the 
research…………………………………………………………………………………………35 
21. Handling of research results (including incidental findings) in relation to research subjects 
for cases in which the conduct of research may lead to important findings, such as the health of 
the research subjects, genetic characteristics that can be passed on to their offspring, etc. ....... 35 
22. Possibility that the sample/information will be used for future research not identified at the 
time when consent is received ......................................................................................... 35 
23. Quality control implementation system and procedures for clinical trials ........................ 35 
23.1. Monitoring ........................................................................................................... 36 
23.2. Data center ........................................................................................................... 36 
23.3. Biostatistics .......................................................................................................... 36 
23.4. Audits .................................................................................................................. 36 
24. Research implementation organization........................................................................ 36 
25. Outsourced research and assay ................................................................................... 37 
26. Citations ................................................................................................................. 38 
27. Appendix ................................................................................................................ 38 
 


1. Purpose and significance of research 
1.1. Background and Significance 
Treatment of unresectable advanced or recurrent gastric cancer 
Chemotherapy is the first line treatment option that is considered for unresectable advanced or 
recurrent gastric cancer. Currently, in Japan, the combination therapy of oral fluoropyrimidine 
antineoplastic agents (S-1, capecitabine) plus platinum (cisplatin, oxaliplatin) is recommended as first-
line treatment for HER2-negative gastric cancer, and ramucirumab plus paclitaxel as second-line 
treatment. Trastuzumab combination therapy is also recommended for HER2-positive gastric cancer 
(1). Recent advances in chemotherapy have allowed a high degree of tumor reduction in unresectable 
advanced or recurrent gastric cancer, but the median survival time is approximately 6–13 months based 
on the results of national and international clinical trials, and the prognosis is still poor. 
 
In 2017, the results of a multicenter international clinical trial of the immune checkpoint 
inhibitor, nivolumab (anti-PD-1 antibody (Ab)), in unresectable advanced or recurrent gastric cancer 
that was refractory or intolerant to standard treatment were reported, showing a significant overall 
survival (OS) benefit (hazard ratio [HR]: 0.63; 95% confidence interval. [CI]: 0.50–0.78; p < 0.0001) 
and it was approved as a tertiary chemotherapy in Japan in 2017. However, even in the aforementioned 
report, the response rate was not as high as expected at 11.2% (95% confidence interval: 7.7–15.6), 
and the development of new treatments and combination therapies is urgently needed. 
 
Radiotherapy is used for various malignant tumors throughout the body, but for advanced 
or recurrent gastric cancer that is not curatively resectable, especially in cases with multiple foci, 
treatment is only performed in symptomatic and conservative approaches based on the tolerable dose 
of the surrounding tissues and the therapeutic effect (radiosensitivity). 
 
Combination therapy with radiotherapy and immune checkpoint inhibitors 
Although there is no established consensus on the efficacy (additive or synergistic effect) of the 
combination of radiotherapy and immunotherapy, its efficacy has been reported in many basic studies, 
translational studies, case reports, and relatively small clinical studies in recent years. We have also 
reported the induction of cancer antigen-specific T lymphocytes after irradiation in patients with 
esophageal squamous cell carcinoma (2) and the drug-resistant/unresectable recurrent gastric cancer 
showing an abscopal effect in combination with immuno-cell therapy (3). The mechanism is thought 
that irradiation-induced cell death of cancer cells became new antigen and a tumor immune response 
was activated in vivo.  
 
Significance of this examination 
This clinical trial is designed to evaluate the additive effect to nivolumab and radiotherapy in patients 


with unresectable advanced or recurrent gastric cancer who have been diagnosed to have an inadequate 
response (intolerance or progression: PD) to standard (first- and second-line) chemotherapy by 
combining radiation therapy immediately before the third-line nivolumab treatment. The trial will be 
positioned as a proof of concept (POC) to explore the efficacy of this therapy by conducting 
exploratory clinical and immunological analyses as a phase I/II study. The safety of this combination 
therapy will also be investigated as a secondary study. It is positioned to provide basic data on median 
survival time (MST) and percentage of local control for future randomized controlled trials (RCTs) of 
this therapy. 
 
1.2. Objectives of the study 
Eligible patients will be those with unresectable advanced or recurrent gastric cancer who have been 
diagnosed as having an inadequate respond (intolerance or progression: PD) to standard therapy 
(primary or secondary chemotherapy) and who have at least two image-confirmable lesions (one of 
which is at least 2 cm in length). To evaluate the safety and efficacy of the combination 
immunotherapy by administering short-term radiotherapy on selected lesions prior to nivolumab (anti-
PD-1 Ab) treatment, which is approved as a third-line chemotherapy, in eligible patients, the following 
items will be assessed: 
① Primary endpoint: disease control rate 
② Secondary endpoint:  
1. 
Median survival time (MST) 
2. 
Safety (grade and frequency of adverse events) 
3. 
Local control rate 
4. 
Immunological parameters: 
Histological examination 
  ・Analysis of the tumor microenvironment by immunostaining. 
Peripheral blood test 
  ・Analysis of peripheral blood lymphocyte subset 
  ・Measurement of cytokines in plasma 
  ・Analysis of regulatory T cell function 
  ・Analysis of antigen-specific T cell function 
 
2. Methods and duration of the study 
2.1. Schema 
 


 
 
 
 
 
 
 
 
 
2.2. Research design 
Phase I/II, single-arm, open (non-randomized), prospective study 
2.3. Treatment and intervention plans 
(1) Test chemicals/test equipment 
Radiation therapy 
X-rays or electron beams generated by radiation therapy equipment installed 
in the Department of Radiation Therapy at Fukushima Medical University 
・Patients with unresectable advanced or recurrent gastric cancer. 
・Patients who are diagnosed as ineffective (intolerant or progression) to standard 
treatment (first-line or second-line chemotherapy) and have two or more lesions 
that can be confirmed by imaging. 
・40 cases 
Obtaining consent to participate in the trial, checking eligibility criteria, enrolment 
Treatment = radiotherapy ≫ Nivolumab (anti-PD-1 Ab) 
Radiotherapy: 4.5 Gy once daily for 5 days (total 22.5 Gy/5 times/5 days) to the 
lesion thought to be the main cause of symptoms if there are symptoms such as 
pain or paralysis, or to the largest lesion if asymptomatic (second largest lesion if 
radiotherapy to the largest lesion is difficult). The day that radiotherapy is started 
is Day 1. 
Nivolumab: Dosing is started between Days 15 and 22; Nivolumab is 
administered at 3 mg/kg (body weight) or 240 mg every 2 weeks for a total of six 
doses. 
Follow-up (～Day 180 ± 14) and efficacy assessment (Day 180 ± 14) 
End of trial 
End of administration 


Hospital and the Department of Radiation Oncology at Kanagawa Cancer 
Center. 
Nivolumab (Anti-PD-1 Ab)  Ono Pharmaceutical Industries Ltd/Bristol-Myers Squibb Co.  
 
 
 
Opdivo intravenous infusion 20 mg, 100mg 
 (2) Dosage/applications 
 Radiotherapy 
 Exposure  22.5 Gy/5 times/5 days 
 Irradiation range   
In accordance with the usual treatment methods used in symptomatic and palliative treatment, only 
the tumor is targeted and the irradiated area has a margin that takes into account the physical 
uncertainties assumed at each irradiated site (i.e. the clinical and prophylactic irradiation area is not 
considered). 
 
    Basis for setting 
 
  Prognosis and early initiation of nivolumab therapy are priorities, and the main target 
 
lesions were assumed to be liver metastases, lymph node metastases, local (surgical) 
 
recurrent lesions and bone metastases. Therefore, the radiotherapy period was kept short and 
 
the irradiation dose was set at 22.5 Gy/5 times/5 days, which is below the tolerable dose at 
 
each site and close to the tolerable dose in the brain and spinal cord.  
 
 Selection of irradiated tumors 
If symptoms such as pain or paralysis are present, the lesion thought to be the main cause of symptoms 
should be selected; if asymptomatic, the largest lesion (or the second largest if radiotherapy of the 
largest lesion is difficult) should be selected. Tumors larger than 2 cm should be selected, taking into 
account the possibility that tumors that are too small may not cause an adequate biological response 
(induction of anti-tumor immunity). 
 
  Irradiation day interval 
Radiotherapy is performed on consecutive Department of Radiation Therapy working days (weekdays 
and consecutive days). This does not apply during the end of the year and New Year holidays, national 
holidays and other holidays.). The day that radiotherapy is started is Day 1. If radiotherapy is not 
completed by Day 14, the patient is considered to have dropped out. 
 
  Irradiation implementation conditions 
On each irradiation day, ensure that all of the following conditions are met before the day's irradiation 
1） Body temperature: < 38.5°C (axilla) 
2） Confirmation by the attending doctor that there are no problems with radiotherapy. 


If the above criteria are not met, irradiation is postponed on a day-to-day basis until the criteria are 
met. 
 
Nivolumab (anti-PD-1 Ab) treatment 
  Dosage and administration 
In accordance with the recommended treatment for unresectable advanced or recurrent gastric cancer, 
3 mg/kg (body weight) of nivolumab once every two weeks over at least one hour, or 240 mg once 
every two weeks over at least 30 minutes, is administered via intravenous infusion. 
 
A total of six administered doses is considered the completion of protocol treatment, but 
there are no specific provisions for treatment after completion. 
 
Continuation of treatment with nivolumab is also permitted within the insurance coverage 
at the discretion of the attending doctor. 
 
However, any 'unacceptable concomitant or supportive therapy' as defined in 2.4.3) shall be 
considered a protocol deviation. 
 
Dosing conditions 
All of the following conditions should be met when starting administration of this drug.  
1)   White blood cell count ≥ 3,000/µL and neutrophil count ≥ 1,500/µL 
2)   Hemoglobin ≥ 9.0 g/dL 
3)   Platelets ≥ 100,000/μL 
4)   Total bilirubin ≤ 2.0 times the upper limit of the institutional reference value 
5)   AST (GOT) and ALT (GPT) ≤ 3.0 times the upper limit of the facility reference value. (If 
liver metastases are present, ≤ 5.0 times the upper limit of the institutional reference value.) 
6)   Serum creatinine ≤ 1.5 times the upper limit of the facility reference value or creatinine - 
clearance(Ccr) estimate ≥ 60 mL/min. 
 
Basis for setting 
It is expected that radiotherapy will enhance the efficacy of anti-tumor immunity. We speculate that 
the use of nivolumab in combination with post-irradiation therapy may induce an abscopal effect in 
some cases. We decided to start nivolumab between Days 15-22, with Day 1 as the start date of 
radiotherapy. Because IFN-γ and TNF-α in serum increased about 10-14 days after irradiation (mouse 
model) (4), and immune responses such as CTL activation were observed about 2 weeks after 
administration of peptide vaccines and activated dendritic cells (clinical observation). 
 
A possible disadvantage of this treatment strategy is that the combination of radiotherapy 
and nivolumab may increase or intensify adverse events; however, as far as we have searched, there 
have been no reports of serious adverse events occurring. 


 
2.4. Combination therapy 
1) Acceptable concomitant and supportive therapies 
The following concomitant and supportive care may be given as necessary. However, the name of 
the applicable event, the name of the drug used, its dosage, and the duration of use, etc., should be 
noted in the case report form. The drugs listed in this section are examples and do not limit the drugs 
used. 
① Symptomatic treatment of Grade 1 or less interstitial lung disease and eye disorders caused 
by nivolumab or that of Grade 2 or less bronchospasm, diarrhea, colitis, neurotoxicity, 
hypersensitivity reactions, injection reactions (fever, chills, nausea, pain, headache, cough, 
scratchiness, rash, etc.) and thrombocytopenia. The dosage and administration of each drug 
used is in accordance with the package insert (insurance indications). 
② Hepatoprotective drugs for the following liver function abnormalities caused by nivolumab. 
AST or ALT < 5–10 times the upper limit of the facility reference value for more than 2 weeks. 
AST or ALT < 10 times the upper limit of the facility reference value. Total bilirubin level < 
five times the upper limit of the facility reference value. Concomitant AST or ALT < three 
times the upper limit of the facility reference value and total bilirubin < two times the upper 
limit of the facility reference value. The dosage and administration of the respective drug 
should be in accordance with the accompanying documentation (insurance coverage). 
③ 
Nausea, vomiting and anorexia (hostility) caused by radiotherapy. Metoclopramide 
(primperan) is tolerated to prevent symptom exacerbation. The standard of care for use is 
nausea, vomiting or anorexia of Grade 2 or above. The dosage and administration of 
metoclopramide (primperan) to be used should be in accordance with the package insert 
(insurance indication).  
④ Radiotherapy-induced dermatitis. 
The use of skin protectants such as hydride for Grade 1 dermatitis and topical corticosteroids 
for Grade 2 or higher skin rashes is acceptable. The dosage and administration of each drug 
should be in accordance with the package insert (insurance coverage). 
  ⑤ Radiotherapy to other metastatic lesions. 
   During the course of nivolumab treatment, if palliative radiotherapy becomes necessary due to 
symptoms such as pain and bleeding worsen caused by an increase in lesions other than those 
treated with radiotherapy, radiotherapy should be allowed and observation continued if there 
are other evaluable lesions with no history of radiotherapy. 
 
2) Unacceptable concomitant and supportive therapies 


During protocol treatment (from the start of radiotherapy until after the sixth dose of nivolumab), 
none of the following treatments should be administered. Any of the following treatments are 
considered a protocol deviation. 
① 
Treatment for cancers other than this protocol (chemotherapy, surgery, radiotherapy, 
endocrine therapy, immunotherapy, etc.). However, radiotherapy is permitted if the provisions 
of 2.4.1.⑤ are met. 
② Other treatments presumed to influence the assessment of efficacy and safety in the study. 
③ 
Immunosuppressive therapy. However, corticosteroids are only allowed in doses of 
hydrocortisone ≤ 200 mg/day for transfusion allergy and small-dose steroids (< 15 mg/day of 
prednisone) for the prevention of cerebral hypertension symptoms and adrenal insufficiency. 
④ Administration of other study medicines, including development products. 
 
2.5. Criteria for changes in dosage/use 
1) Radiation dose escalation and dose reductions will not be performed. Nivolumab dosage and 
administration should be in accordance with the recommendations for the treatment of unresectable 
advanced or recurrent gastric cancer (Appendix). 
2) Criteria for discontinuation of treatment 
 ① Nivolumab (anti-PD-1 Ab) discontinuation criteria: 
1) Failure to meet the criteria for initiation of nivolumab (anti-PD-1 Ab) in '2.3.(2) Nivolumab 
(anti-PD-1 Ab) treatment' and failure to resume treatment within 14 days of the planned 
treatment date. 
2) If a patient requests discontinuation of nivolumab treatment, irrespective of whether or not it 
is associated with an adverse event. 
3) Death during protocol treatment. 
4) Ineligibility due to a known protocol violation, change of pathology diagnosis after enrolment, 
etc. 
5) It is deemed inappropriate to continue treatment due to apparent worsening of clinical 
symptoms caused by disease progression. 
6) Occurrence of Grade 2 or higher interstitial lung disease. 
7) Occurrence of Grade 2 or higher eye disorders. 
8) Occurrence of Grade 3 or higher bronchospasm, diarrhea, colitis, neurotoxicity, 
hypersensitivity reactions and injection reactions. 
9) Occurrence of Grade 3 or higher thrombocytopenia. 
10) Abnormalities in liver function that fulfill one of the following criteria have emerged. AST 
or ALT > 5–10 times the upper limit of the facility reference value for more than 2 weeks. 


AST or ALT > 10 times the upper limit of the facility reference value. Total bilirubin levels > 
5 times the upper limit of the institutional reference value. Concurrent AST or ALT > 3 times 
the upper limit of the facility reference value and total bilirubin > 2 times the upper limit of the 
facility reference value. 
11) The principal investigator or a member of research team decides that continued treatment 
with nivolumab is not appropriate. 
 
② Criteria for discontinuation of radiotherapy 
Discontinue radiotherapy if any of the following occur: 
1) Failure to meet the treatment criteria for radiotherapy in ‘2.3(2) – Radiotherapy’. 
2) When the attending doctor decides that discontinuation is necessary due to an adverse event. 
3) If the patient requests discontinuation of radiotherapy, irrespective of whether or not it is 
associated with an adverse event. 
4) Patient deaths. 
5) Ineligibility due to a known protocol violation, change of pathology diagnosis after enrolment, 
etc. 
6) The principal investigator or a member of research team decides that continuation of treatment 
is not appropriate, taking into account efficacy or safety. 
 
If this protocol treatment is discontinued, follow the decision of the attending doctor with regard to 
subsequent treatment. The reasons for discontinuation should be documented in the medical record 
and the case report form. If consent is withdrawn after treatment has started, it should be made as clear 
as possible whether the withdrawal of consent was due to ineffectiveness of the treatment or to an 
adverse or incidental event, and this should be record in order to assist in the selection of the case for 
safety evaluation. If circumstances permit, a discontinuation inspection should be carried out within 
14 days of the decision to discontinue (see 2.7.). 
 
2.6. Evaluation items 
 The primary endpoint of this clinical trial is the disease control rate of non-irradiated target lesions, 
in order to explore the efficacy (additive effect) of radiotherapy to immunotherapy with nivolumab, 
which is already established as third-line chemotherapy in unresectable advanced or recurrent gastric 
cancer. Secondary endpoints will also include 1) median survival time (MST) and 2) safety (grade and 
frequency of adverse events), 3) local control rate (disease control rate of irradiated target lesions), 
and 4) immunological parameters. 
 


(1) Primary endpoint 
   Disease control rate 
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 (Day 1). CT (MRI is also acceptable) and whole-
body PET-CT will be used to determine overall response such as complete response (CR), partial 
response (PR), SD, progressive disease (PD) at each imaging time according to the RECIST 
Guidelines Version 1.1. If imaging is not available, the patient is considered deficient (NE). CR 
or PR as the best overall response is defined as two or more consecutive CRs or PRs. If the best 
overall response does not meet the criteria for CR or PR, and the patient has no PD on the 6th 
dose of nivolumab and Day 120, the best overall response is considered to be SD. For evaluation, 
target lesions other than those treated with local radiotherapy are considered as target lesions. If 
the lesions cannot be evaluated based on the above criteria, they will not be included in the 
analysis for best overall response. 
 
(2) Secondary endpoint 
   1) Median survival time（MST) 
Overall survival is defined as the period from the start date of radiotherapy until the date of death 
from any cause. In surviving cases, the last date of confirmation of survival is the date of 
termination (survival confirmed by telephone contact is acceptable, but confirmation of survival 
should be recorded in the medical record). 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 
will be confirmed alive. 
 
   2) Safety (grade and frequency of adverse events) 
The frequency of adverse events occurring from the start date of radiotherapy to the end of study 
will be 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. A 
serious adverse event is defined as having occurred if at least one of the following adverse events 
is observed, and the frequency and proportion of serious adverse events is calculated. 
① Death during protocol treatment or within 30 days of last protocol treatment. 
② Death with undeniable causal relationship to protocol treatment after 31 days of last 
protocol treatment. 
③ Grade 4 infection with neutropenia. 
④ Grade 4 non-hematological toxicity (excluding adverse events in the blood/bone marrow). 
 
   3) Local control rate 


  The rate of patients with a best overall response of SD or better confirmed by 180 days, starting 
from the start date of radiotherapy (Day 1). CT (MRI is also acceptable) and whole-body PET-
CT will be used to determine overall response such as complete response (CR), partial response 
(PR), SD, progressive disease (PD) at each imaging time according to the RECIST Guidelines 
Version 1.1. If imaging is not available, the patient is considered deficient (NE). CR or PR as the 
best overall response is defined as two or more consecutive CRs or PRs. If the best overall 
response does not meet the criteria for CR or PR, and the patient has no PD on the 6th dose of 
nivolumab and Day 120, the best overall response is considered to be SD. For evaluation, target 
lesions are tumors that are treated with local radiotherapy. If the lesions cannot be evaluated based 
on the above criteria, they will not be included in the analysis for best overall response. 
 
4) Immunological parameters 
Histological examination 
・Analysis of the tumor microenvironment by immunohistochemistry. 
* Immunohistochemistry will be performed in cases with available biopsy and/or resected 
surgical specimens. 
Peripheral blood test 
・Analysis of peripheral blood lymphocyte subset 
・Measurement of cytokines in plasma 
・Analysis of regulatory T cell and antigen-specific T cell function 
* According to advance of immunological technique, the contents of immunological 
parameter analyses, such as antigen-specific T cell function analysis, highly multiplexed 
flow cytometric analysis, T cell receptor repertoire analysis, and assessment of tumor 
mutation burden using plasma derived ctDNA, will also be evaluated. 
* These analysis will be performed relating to clinical outcomes, such as two groups 
divided with MST. 
 
2.7. Observation and examination items 
Pre-registration evaluation items (assess following items once within 14 days prior to date of 
registration) 
1) Patient background (subject identification number, date of obtaining written consent, gender, age, 
date of birth, height, weight, presence of allergies, medical history, presence of complications, 
concomitant medications, drinking history, smoking history, history of treatment for cancer). 
2) General findings (temperature, blood pressure, pulse). 
3) General condition: PS (ECOG). 


4) Subjective and objective symptoms: fever, nausea, vomiting, diarrhea, decreased appetite, etc. (to 
be confirmed according to CTCAE v4.0 Japanese translation). 
5) Contrast-enhanced CT (or PET-CT) of chest, abdomen and pelvis, and plus contrast-enhanced MRI 
if necessary. 
6) Blood count (peripheral blood): white blood cell count and fractions, red blood cell count, 
hemoglobin, MCV, MCH, MCHC, Ht, platelets. 
7) Blood biochemistry: total protein, albumin, total bilirubin, direct bilirubin, AST, ALT, ALP, γ-GTP, 
BUN, creatinine, LDH, uric acid, CPK, P, Ca, Na, K, Cl, CRP, blood sugar, rheumatoid factor (RA), 
antinuclear antibodies (ANA), SP-D, KL-6, thyroid stimulating hormone (TSH), free 
triiodothyronine (free T3), free thyroxine (free T4), tumor markers (CEA, CA19-9). 
8) Blood coagulation (PT, FDP, D-dimer). 
9) Infectious diseases: HIV antigens and antibodies, HTLV-1 antibodies (if testing was performed 
within 3 months prior to enrollment, the data may be used with the subject's consent). 
10) Urinalysis: specific gravity, protein, sugar, occult blood, sedimentation (white blood cells, red 
blood cells). 
11) Pregnancy test (only for women of childbearing potential). 
12) Immunological parameters. 
13) ECG. 
 
Test items and assessment during and after treatment 
After completion of radiotherapy 
(Assess the following items once within 14 days of the end date. If the test is performed on the day of 
the first dose of nivolumab, the same test will be used to evaluate them.) 
1) General findings (temperature, blood pressure, pulse). 
2) General condition: PS (ECOG).  
3) Subjective and objective symptoms: fever, nausea, vomiting, diarrhea, decreased appetite, etc. (to 
be confirmed according to CTCAE v4.0 Japanese translation). 
4) Blood count (peripheral blood): white blood cell count and fractions, red blood cell count, 
hemoglobin, MCV, MCH, MCHC, Ht, platelets. 
5) Blood biochemistry: total protein, albumin, total bilirubin, direct bilirubin, AST, ALT, ALP, γ-GTP, 
BUN, creatinine, LDH, uric acid, CPK, P, Ca, Na, K, Cl, CRP, blood glucose. 
6) Presence of adverse events (CTCAE v4.0 Japanese translation). 
7) Immunological parameters. 
 
During nivolumab administration 


(After the second dose, assess the following items on the day of administration or the day before 
administration. Assess following items once from 7 days before to 7 days after the imaging 
examination date.)  
1) General findings (temperature, blood pressure, pulse). 
2) General condition: PS (ECOG). 
3) Subjective and objective symptoms: fever, nausea, vomiting, diarrhea, decreased appetite, etc. (to 
be confirmed according to CTCAE v4.0 Japanese translation). 
4) Blood count (peripheral blood): white blood cell count and fractions, red blood cell count, 
hemoglobin, MCV, MCH, MCHC, Ht, platelets. 
5) Blood biochemistry: total protein, albumin, total bilirubin, direct bilirubin, AST, ALT, ALP, γ-GTP, 
BUN, creatinine, LDH, uric acid, CPK, P, Ca, Na, K, Cl, CRP, blood sugar. 
  (The following items are only available at the third and sixth doses) RA, ANA, SP-D, KL-6, TSH, 
free T3, free T4, tumor markers (CEA, CA19-9). 
6) Contrast-enhanced CT of the chest, abdomen and pelvis (at third and sixth doses). PET-CT is also 
acceptable. Add MRI if necessary. 
7) Presence or absence of PD (diagnosed comprehensively based on imaging and clinical findings). 
8) Presence or absence of adverse events (CTCAE v4.0 Japanese translation). 
9) Immunological parameters. 
 
During observation 
(Assess following items once from 14 days before to 14 days after the 3rd and 6th dose of Nivolumab 
and Day120.) 
1) Contrast-enhanced CT of chest, abdomen and pelvis. PET-CT is also acceptable. Add MRI if 
necessary. 
 
After completion of the protocol 
(Assess following items once from 14 days before to 14 days after the Day180.) 
1) General findings (temperature, blood pressure, pulse). 
2) General condition: PS (ECOG). 
3) Subjective and objective symptoms: fever, nausea, vomiting, diarrhea, decreased appetite, etc. (to 
be confirmed according to CTCAE v4.0 Japanese translation). 
4) Blood count (peripheral blood): white blood cell count and fractions, red blood cell count, 
hemoglobin, MCV, MCH, MCHC, Ht, platelets. 
5) Blood biochemistry: total protein, albumin, total bilirubin, direct bilirubin, AST, ALT, ALP, γ-GTP, 
BUN, creatinine, LDH, uric acid, CPK, P, Ca, Na, K, Cl, CRP, blood sugar, RA, ANA, SP-D, KL-
6, TSH, free T3, free T4, tumor markers (CEA, CA19-9). 


6) Contrast-enhanced CT of chest, abdomen and pelvis. PET-CT is also acceptable. Add MRI if 
necessary. 
7) Presence or absence of PD (diagnosed comprehensively based on imaging and clinical findings). 
8) Presence or absence of adverse events (CTCAE v4.0 Japanese translation). 
9) Immunological parameters. 
 
At the time of cessation of treatment 
(Assess following items once within 14 days after the decision to discontinue. Assessment of following 
items within 14 days prior to the date of cessation of treatment is valid. If the subject is dead, 
hospitalized in another hospital, or otherwise unable to come to the hospital, these situations should 
be noted). 
1) General findings (temperature, blood pressure, pulse). 
2) General condition: PS (ECOG). 
3) Subjective and objective symptoms: fever, nausea, vomiting, diarrhea, decreased appetite, etc. (to 
be confirmed according to CTCAE v4.0 Japanese translation). 
4) Blood count (peripheral blood): white blood cell count and fractions, red blood cell count, 
hemoglobin, MCV, MCH, MCHC, Ht, platelets. 
5) Blood biochemistry: total protein, albumin, total bilirubin, direct bilirubin, AST, ALT, ALP, γ-GTP, 
BUN, creatinine, LDH, uric acid, CPK, P, Ca, Na, K, Cl, CRP, blood sugar, RA, ANA, SP-D, KL-
6, TSH, free T3, free T4, tumor markers (CEA, CA19-9). 
6) Contrast-enhanced CT of chest, abdomen and pelvis. PET-CT is also acceptable. Add MRI if 
necessary. 
7) Presence or absence of PD (judged comprehensively based on imaging and clinical findings). 
8) Presence or absence of adverse events (CTCAE v4.0 Japanese translation). 
9) Immunological parameters. 
 


Inspection schedule 
Period 
At registration 
At the end of radiotherapy 
First dose of nivolumab 
Second dose of nivolumab 
Third dose of nivolumab 
Fourth dose of nivolumab 
Fifth dose of nivolumab 
Sixth dose of nivolumab 
Day120 
Day180 
At the time of treatment cessation  
Patient background 
〇 
 
 
 
 
 
 
 
 
 
 
General findings 
〇 
〇 
〇 
〇 
〇 
〇 
〇 
〇 
 
〇 
〇 
General condition 
〇 
〇 
〇 
〇 
〇 
〇 
〇 
〇 
 
〇 
〇 
Subjective and objective 
symptoms 
〇 
〇 
〇 
〇 
〇 
〇 
〇 
〇 
 
〇 
〇 
Imaging 
〇 
 
 
 
〇 
 
 
〇 
〇 
〇 
〇 
ECG 
〇 
 
 
 
 
 
 
 
 
 
 
Blood count 
〇 
 
〇 
〇 
〇 
〇 
〇 
〇 
 
〇 
〇 
Coagulation 
〇 
 
 
 
 
 
 
 
 
 
 
Blood biochemistry 
〇 
 
〇 
〇 
〇 
〇 
〇 
〇 
 
〇 
〇 
Urinalysis 
〇 
 
 
 
 
 
 
 
 
 
 
Infection 
〇 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
test 
(if 
required)） 
〇 
 
 
 
 
 
 
 
 
 
 
Immunological 
parameters①#1 
〇 
 
 
 
 
 
 
 
 
 
 
Immunological 
parameters②#2 
〇 
 
〇 
 
〇 
 
〇 
 
 
〇 
〇 
#1 Histological examination 
#2 Peripheral blood test 
The volume of blood required for immunological parameters is 30 mL each time. 


2.8. Expected number of cases 
40 cases. 
 
Basis for setting 
Based on a previous study (ONO-4538-12 study) (5), the disease control rate is set at 40%. At a one-
side significance level of 5% and a power of 80%, a sample size of 39 cases are required to detect an 
additional 20% improvement expected from the study treatment. 
 
2.9. Case registration 
(1) Case registration 
Case enrollment should take place within 14 days prior to the start of radiotherapy (Day 1). 
The attending doctors must obtain written consent based on the subject's own free will from 
those who meet the eligible criteria based on the inclusion/exclusion criteria. The attending doctors 
then prepare a case registration form that includes the subject identification number, the date of consent 
obtained, pre-registration assessment items, and the results of the confirmation of the inclusion and 
exclusion criteria. 
 
A case registration form is prepared for each registered case and faxed to the research office. 
Research office: Department of Gastrointestinal Tract Surgery, Fukushima Medical University 
Hospital. FAX number: 024-547-1980 (The case registration forms in Fukushima Medical 
University Hospital can use an alternative method to fax.) 
 
The case registration form received by the research office is forwarded to the Data Center, 
which issues a receipt to the chief investigators at each institution, informing them of the registration 
number. The receipt form is sent to the principal investigator by fax. 
 
In carrying out the above, the chief investigators at each institution prepare a list of subjects 
and maintain a list of subject identification numbers and registration numbers. 
 
(2) Diagnostic imaging at registration 
After case registration, the chief investigators send the imaging data to the research office as soon as 
possible. Before the start of radiotherapy, prior consultation is held with the Department of Radiation 
therapy, Fukushima Medical University Hospital regarding radiotherapy and diagnostic imaging at 
registration. 
 
(3) Notification upon discontinuation of the study 
If a subject enrolled in this study meets any of the following items, a discontinuation contact form is 
prepared and faxed to the research office.  


 
Withdrawal of consent. 
 
Termination of the study due to death. 
 
Withdrawal from the study. 
 
2.10. Statistical analysis 
(1) Statistical analysis of the evaluation 
The composition of the population to be analyzed shall be as follows: 
1) All enrolled cases: the population of enrolled patients, excluding duplicate enrollments and 
incorrect enrollments. 
2) All eligible cases: the population excluding ineligible cases (posterior ineligibility, ineligibility 
at enrollment, offending enrollment) from all enrolled cases. 
3) Largest analyzed population (FAS): all eligible cases for whom treatment was administered. 
 
(2) Method of analysis 
 Primary endpoints 
1) Disease control rate 
For FAS cases, summarize the responses of non-irradiated target lesions in a contingency table, 
and calculate the cumulative disease control rate and the Clopper & Pearson two-side 90% 
confidence interval. The disease control rate was defined as the total number of patients with 
CR/PR/SD divided by the number of eligible patients. 
 
Secondary endpoint 
1) MST 
For FAS cases, estimate the MST using the Kaplan-Meier method, along with a two-sided 95% 
confidence interval using the Brookmeyer-Crowley method. 
2) Safety 
For all enrolled cases, data regarding AEs and toxicities were tabulated, and the Clopper & 
Pearson two-sided 95% CI was calculated. 
3) Local control rate 
For FAS cases, summarize the responses of irradiated target lesions in a contingency table, and 
calculate the cumulative disease control rate and the Clopper & Pearson two-side 90% confidence 
interval. The disease control rate was defined as the total number of patients with CR/PR/SD 
divided by the number of eligible patients. 
4) Immunological parameters 
Analyzes are performed at Fukushima Medical University Hospital, Kanagawa Cancer Centre, 


and by outsourced testing, as appropriate. 
 
2.11. During the study 
Registration period: March 1, 2018 to August 31, 2020 
Total study period: March 1, 2018 to August 31. 2021 
 
3. Policy for selecting research subjects 
3.1. Inclusion criteria 
Subjects who meet all of the following criteria are eligible in this study. 
1) Patients with unresectable advanced or recurrent gastric cancer with intolerance or progression after 
standard treatment (primary and secondary chemotherapy). 
2) Patients with more than one measurable lesion and with at least one lesion ≥2 cm as defined by the 
RECIST guidelines edition 1.1 on diagnostic imaging (whole-body contrast-enhanced CT or PET-
CT) within 14 days before entry. 
3) Age ≥ 20 years. 
4) ECOG performance status (PS): 0–2. 
5) No contraindication for nivolumab (anti-PD-1 Ab) administration. 
6) No contraindication for radiotherapy. 
7) The patient's most recent laboratory tests within 14 days prior to enrollment must meet the following 
criteria. However, if the clinical examination at the time of enrollment is not included within 7 days 
prior to the first dose of nivolumab, a repeat examination should be performed within 7 days prior 
to the first dose of the study drug to reconfirm that the most recent clinical examination prior to the 
first dose of nivolumab meets the criteria below. In all cases, the laboratory values must not have 
received a G-CSF product or blood transfusion within 14 days prior to the date of testing. 
 
White blood cell count ≥ 3,000/µL and neutrophil count ≥ 1,500/µL 
 
Hemoglobin ≥ 9.0 g/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 (Ccr) estimate ≥ 60 mL/min. 
Ccr is calculated by the Cockroft-Gault formula: 
Male Ccr = {(140 - age) x weight (kg)}/{72 x serum creatinine level (mg/dL)} 
Female Ccr = 0.85x {(140 - age) x weight (kg)}/{72 x serum creatinine level (mg/dL)} 
8) Patients expected survival ≥ 3 months. 


9) Written informed consent is obtained from the patient prior to study enrollment. 
 
3.2. Exclusion criteria 
Subjects who meet the following criteria are not eligible to enroll in this study: 
1) Patients with no tumor lesions that can be irradiated. 
2) Patients with 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) Patients with a history of severe hypersensitivity reactions to other Ab products. 
4) Patients taking immunosuppressive drugs or corticosteroids (prednisone or prednisolone equivalent 
≥ 15 mg/day). 
5) Patients with 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) Patients with complications or history of interstitial pneumonia or pulmonary fibrosis diagnosed by 
imaging studies or clinical findings. 
7) Patients with presence of severe disease or medical condition such as 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) Patients with a positive HIV antigen/Ab test or HTLV-1 Ab test. 
14) Patients who have 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) Patients determined by the investigator to be ineligible for participation in this study. 
 
4. The scientific rationale for the research 
This clinical trial is designed to investigate the additive effect of nivolumab and radiotherapy in 
patients with unresectable advanced or recurrent gastric cancer with intolerance or progression after 
standard treatment (primary and secondary chemotherapy), by administering the insured radiotherapy 
immediately before nivolumab treatment, a third-line treatment indicated by insurance. The results of 
basic and preclinical studies, as well as those of case reports, suggest that the combination of 
radiotherapy and anti-cancer immunotherapy may have a synergistic anti-tumor effect. However, no 
clinical trials similar to this study have been reported to date in patients with gastric cancer, and this 
study is a phase I/II clinical study exploring safety, clinical efficacy, and immunological changes of 
the combination therapy using radiotherapy and nivolumab in patients with unresectable advanced or 
recurrent gastric cancer. The number of planned cases is considered to be the minimum required for 
statistical purposes. 
 
5. The procedure for obtaining informed consent 
5.1. Explanation and consent of research subjects 
The attending doctors explain the research to the potential research subjects using a consent document 
approved by a Certificated Clinical Research Review Committee. At that time, it is also necessary to 
explain that even after consent to participate in research has been provided, consent can be withdrawn 
at any time without suffering any particular disadvantages, and that any results presented at 
conferences, papers, etc. prior to the withdrawal of consent cannot be retracted. After receiving 
explanations, the research subject is given sufficient time to consider about it and is asked to participate 
in the trial after confirming that they fully understand the content of the trial. If the research subject 
agrees to participate in the trial, the research subjects sign the consent document of their own free will. 
The principal investigator will keep the original consent form, and a copy will be handed to the 
research subject. 
 
If new information is obtained that may affect the research subject's willingness to continue 


participation in the research, the principal investigator will promptly revise the consent document 
based on the information concerned and obtain the approval of the Certificated Clinical Research 
Review Committee and permission from the head of the implementing medical institution. In addition, 
the principal investigator and the attending doctors will explain again using the revised consent 
document, and obtain written consent from the research subjects to continue their participation in the 
research. 
 
5.2. Procedures for obtaining informed consent from a substitute or other person 
Not applicable 
 
5.3. Procedures for obtaining informed assent 
Not applicable 
 
6. Handling of Adverse Events 
6.1. Response to Adverse Events 
If Grade 3 or higher adverse events and other clinically significant adverse events occur in the period 
from the start date of radiotherapy to the Day180, regardless of whether they are related to the study 
or not, the attending doctor will immediately take appropriate action against the research subject, 
including explanation and treatment for it, and record its progress in the medical record and the case 
report form. 
 
Determination of known/unknown events: Based on the content of the most recent 
nivolumab drug information, events that can be classified as equivalent in name and severity are 
considered as known events. Other events are handled as unknown events. 
  
6.2. Response to the occurrence of serious adverse events 
If an adverse event as defined in the preceding paragraph is deemed to be serious, it meets one of the 
following criteria: 
 ① Resulting in Death, 
 ② Life-threatening, 
 ③ Requiring inpatient hospitalization or prolongation of existing hospitalization for treatment, 
 ④ Resulting in permanent or conspicuous disability or dysfunction, 
 ⑤ Causing congenital anomalies in offspring. 


 
However, hospital admissions stipulated in the research protocol, hospital admissions solely for the 
purpose of carrying out a therapy or examination planned before the research (before consent was 
obtained) and during the study (e.g. planned surgery or examinations), and hospital admissions other 
than for the purpose of therapy or examinations associated with an adverse event (e.g. medical 
examination) are not treated as serious. In addition, evaluations related to progression of the primary 
disease or efficacy of treatment are not handled with adverse events. 
 
Attending doctor manage serious adverse events in accordance with the ‘Procedures for 
handling illnesses, etc.’. In addition, attending doctor report serious adverse events to the Adverse 
Event Information Desk of Ono Pharmaceutical Industries, Ltd. within 72 hours of receiving the 
information. 
 
7. Criteria for discontinuation and completion 
1) In this study, completion of protocol treatment is defined as completion of six doses of nivolumab 
(anti-PD-1 Ab) followed by 22.5 Gy/5 doses/5 days of radiotherapy. Study completion is also 
defined as the end of observation at 6 months (Day180) after the start of treatment. Survival will, 
however, be confirmed at the end of the study period. 
2) Discontinuation of treatment in individual cases is in accordance with '2.5. Criteria for changes of 
dosage/use'. 
3) Discontinuation of the trial is decided by the chief investigator at each institution. 
4) The principal investigator will monitor opinions and information from the nivolumab manufacturer 
and distributor, academic information such as papers, and regulatory information from PMDA and 
other sources, and will always manage the appropriateness of continuing this study. 
 
The criteria for discontinuation of this clinical trial is defined as follows. If any of the following 
situations occur and the principal investigator, chief investigators, or administrators of each institution 
decide that this clinical trial should be terminated, the entire study may be discontinued. 
1) Unforeseen serious adverse events occur. 
2) The intervention is not effective. 
3) Serious violation/noncompliance with the Clinical Research Act or study protocol, etc. is 
identified. 
4) Serious risks to research subjects are identified. 
 
If the principal investigator decides to discontinue the research, he will notify it to the chief 
investigators, the Certificated Clinical Research Review Committees, the administrators of each 


institution, and the Minister of Health, Labour and Welfare within 10 days of the decision. 
Furthermore, attending doctor will contact the research subjects and inform them of the change in the 
research schedule. However, even after the notification of discontinuation is submitted, attending 
doctors make disease reports and periodic reports, etc. until this clinical trial is terminated. The time 
of termination of this clinical trial after discontinuation is when the procedure for the research subjects 
is completed. 
 
8. Data management methods 
8.1. Prepare and filling out a Case Report Form (CRF) 
The CRF is prepared by the Data Center in accordance with the procedures, etc., provided by the 
principal investigator. If the CRF needs to be revised, the Data Center performs the revision in 
accordance with the stipulated procedures and inform the chief investigators at each institution. 
 
In principle, completion and correction of the CRF is conducted by the attending doctors. If 
the attending doctors fill out or revise the CRF, they should obtain confirmation from the chief 
investigators before submitting the CRF. The attending doctors should complete the CRF as soon as 
possible after the completion of each observation and examination of each subject. 
8.2. Sending and storing Case Report Form (CRF) 
The chief investigator sends the CRF to the research office by letter-pack, etc., and the research office 
submits the received CRF to the Data Center. The CRFs submitted to the Data Center are stored at the 
Data Center in accordance with the procedures. 
 
8.3. Procedures for amending CRF 
Amendments should in principle be made by the attending doctors or others in accordance with the 
procedure manual. Any amendments should be made using double lines, the reason for the amendment, 
the date and time of amendment, and the person making the amendment should write them outside the 
column. 
 
When a correction is required in a CRF that has already been submitted to the Data Center, 
or when the Data Center makes a questionable data enquiry, the correction should be carried out using 
a separate enquiry form without adding the correction to the original submitted, and a method should 
be used to ensure that the history of the correction can be obtained. The attending doctors or others 
submit the enquiry form to the Data Center. 
 


8.4. Identification of source material 
The monitor in charge checks that the case data in CRF are accurate, complete, and consistent with 
the source documents. 
 
Source documents are the original documents, data, records (e.g. admission records, medical 
records, examination notes, notes, patient diaries and assessment checklists, administration records, 
ECG record data, imaging data such as echocardiograms and X-rays, and records kept in the medical 
technology departments involved in the study such as the pharmacy and laboratory departments). 
 
The following items should be directly recorded in the CRF and should be considered as the 
source documents. 
(1) Reasons for previous and concomitant treatment (medicines and non-pharmacological therapies). 
(2) Presence/absence of adverse events, names of adverse events, serious/non-serious of adverse 
events, treatment, causal relationship with the study drug. 
(3) Reasons for discontinuation/termination of the trial and observation. 
 
9. Transfer of samples and information to and from other institution 
Transfer of documents and information on registered cases with the Kanagawa Cancer Centre. 
Transfer is conducted in compliance with ‘11. Handling of personal data’. 
 
When sending samples and information overseas (including cases of outsourcing), the 
principal investigator prepares a contract, confirmation, memorandum, and a "Record of Provision of 
Samples and Information" with the overseas recipient, which clearly declares that appropriate 
procedures equivalent to those of Japanese providers handling personal information.  
 
10. Method of storage and disposal of samples and information 
10.1. Storage 
 Research samples and information are stored as follows: 
Objectives for 
storage 
Samples obtained from the humans (serum, DNA samples, etc.). 
Information obtained from humans (copies of case reports, signed consent 
forms, test results, CT images, etc.). 
Materials relating to information used for research*. 
The person 
responsible 
for storage 
Chief investigator at each institution. 
Method of 
Signed consent forms, case registration forms, copies of CRFs, enquiry forms, 


storage 
etc., should be kept in accordance with the preservation rules of each 
institution, and the principal investigator is responsible with them. 
The principal investigator stored samples and information collected at the 
research office in a lockable locker in the Department of Gastrointestinal Tract 
Surgery, Fukushima Medical University School of Medicine. Databases and 
data sets output from the data management system of the Data Center and 
electronic data analyzed by computer software, etc., are recorded in two copies 
on CD-ROM and stored in a lockable locker in the research office. 
Retention 
period 
Samples 
5 years from the date of completion of the 
study or publication of the results. 
(whichever is later) 
Information 
Material relating to information 
used for research 
5 years from the date of completion of the 
study or publication of the results. 
(whichever is later) 
*Materials supporting the information used in the research, such as data modification histories, 
laboratory notebooks, etc. 
 
Immunological parameter samples obtained from blood collection will be frozen and stored in plasma 
(-80°C) and PBMC (liquid nitrogen) at each institution. All stored samples will be collected at the 
research office during the study period and analyzed together at a later date within the study period. 
The chief investigator will transport all specimens in frozen form to the research office. Samples 
collected at the research office will be stored in freezer (-80°C) and liquid nitrogen tanks in the 
Department of Radiation Oncology, Fukushima Medical University School of Medicine. 
 
The retention period shall be until the later of the new research plan or the retention period specified 
in this clinical trial, if new research is conducted as indicated in ‘22’. 
 
 
10.2. Disposal 
The attending doctors or others shall use the following methods when disposing of samples, 
information, etc. obtained from the humans. 
1） Autoclave samples obtained from the humans. 
2） Printed materials should be shredded to a state where they cannot be reproduced, such as by 
cross cutting with a small cutting size, or by a dissolution process, etc., and then discarded. 
Electronic data should be physically destroyed to an unreadable level, and then properly 
discarded. 


3） Other materials should also be properly discarded after making their contents unreadable. 
 
11. Handling of personal data 
11.1. Method of use 
All subjects enrolled in this clinical trial is coded by assigning a unique enrollment number, and high 
standards of confidentiality will be maintained. A table of codes linked to personal information, such 
as medical record numbers, and corresponding registration numbers are maintained at the participating 
institutions only. 
 
The names of subjects, which were collected at the research office, are not recorded on data 
and samples etc. 
 
11.2. Security management responsibility system 
The principal investigator minimizes the risk of information leakage by taking the following safety 
control measures in the use of personal data. 
Physical security control measures 
Technical security management measures 
The collected subject data are stored on a PC 
physically separated from the network in the 
room accessible only to the principal 
investigator and those authorized by the 
principal investigator at each institution. 
For PCs that store subject data, passwords 
should be determined so that only the principal 
investigator at each institution and those 
authorized by the principal investigator can 
access the PCs. 
 
In the Data Center in the Clinical Research Center at Fukushima Medical University Hospital, a data 
security management system is maintained in accordance with the criteria based on the procedure 
manuals, etc. 
 
12. The burdens and foreseeable risks and benefits to the research subjects, the comprehensive 
assessment of them and measures to minimize such burdens and risks 
Nivolumab treatment is applicable to patients with unresectable advanced or recurrent gastric cancer 
who have failed to standard therapy (primary and secondary chemotherapy) (intolerance or 
progression: PD), but response rates and prognosis have not been satisfactory. However, at present, 
there are no reported outcomes superior to nivolumab therapy for such patients. Radiotherapy is 
commonly used in patients with unresectable advanced or recurrent gastric cancer, for symptomatic 
treatment such as pain relief from bone metastases and hemostasis of bleeding from tumors, and for 


palliative treatment of liver, lung and brain metastases. Radiotherapy is a local treatment and its 
efficacy in improving prognosis is poor when multiple lesions are present. Although dozens of clinical 
trials have been conducted on the use of nivolumab in combination with radiotherapy, there are 
currently no reliable clinical trial reports showing clear efficacy. However, based on basic and 
translational research reports and case reports, this combination may be expected to activate systemic 
anti-tumor immunity and enhance the effect of nivolumab and an abscopal effect may be expected to 
occur in some cases. A possible disadvantage is that the combination of radiotherapy and nivolumab 
may increase or enhance adverse events. Although serious adverse events, including deaths, have been 
reported with nivolumab in combination with other therapies, to the best of our knowledge, there are 
no reports of serious adverse events occurring in combination with radiotherapy. Of course, at present 
there are no reliable clinical trial reports on the combination of radiotherapy with nivolumab or 
immune checkpoint inhibitors other than nivolumab, and we need to proceed with this clinical trial 
carefully. 
 
All treatments used in this clinical trial are covered by health insurance and are carried out 
as normal insurance treatment, and treatment costs are covered by the health insurance of the research 
subject and by the research subjects' co-payment. Therefore, the research subjects will not receive any 
special medical or financial benefits for participating in this clinical trial. 
 
The combination of radiotherapy and nivolumab may increase the respective adverse events 
or induce unknown adverse events. To minimize the risk or disadvantage of these adverse events, the 
selection criteria for study subjects, treatment modification criteria, and concomitant therapy are 
carefully considered. In addition, the attending doctors also medically monitor the adverse events to 
assess whether they are within the expected range, and take necessary measures in the event of serious 
or unanticipated adverse events. Furthermore, efforts should be taken to detect these adverse events at 
an early stage by conducting the tests, etc. defined in '2.7. Observation and examination items'. 
 
13. The status of funding sources for research and the conflicts of interest related to research of 
the research institution, individual revenues, and attending doctors, etc. 
This clinical trial is funded by an academia-initiated contract research agreement between Ono 
Pharmaceutical Industries, Ltd./Bristol-Myers Squibb K.K. and Fukushima Medical University. 
Kanagawa Cancer Centre participates in this clinical trial as a collaborating institution. Prof. Kono, 
the principal investigator of this clinical trial, has received a speaker's fee from Ono Pharmaceutical 
Co. The funders, Ono Pharmaceutical Industries, Ltd. and Bristol-Myers Squibb K.K., provide 
information on the study drug, but not be involved in the planning of this clinical trial, progress of this 
clinical trial, data collection, analysis, interpretation of results, and reporting. For the purpose of 
obtaining transparency of financial interests to ensure the fairness and reliability of this clinical trial, 


its financial interests is reviewed and approved in advance by the Conflict of Interest Committee of 
each of Fukushima Medical University and Kanagawa Cancer Center. 
 
The analysis of immunological parameters in this clinical trial will be funded by the research 
grants obtained by the researchers at Fukushima Medical University. 
 
The principal investigator should decide the planning and release of this clinical trial. Each 
attending doctor shall manage conflicts of interest in accordance with the conflict of interest policies 
of the respective academic societies, Fukushima Medical University and Kanagawa Cancer Centre, 
and disclose them appropriately upon request of the academic societies or medical journals in which 
they plan to present the results of this clinical trial. Conflicts of interest are also strictly managed at 
Ono Pharmaceutical Industries, Ltd. and Bristol-Myers Squibb Co. 
 
Furthermore, upon the enforcement of the Clinical Research Act, the following procedures 
are taken for the management of conflicts of interest in this research. Regarding Article 21 of the 
Enforcement Regulations of the Act and the Management of Conflicts of Interest in Clinical Research 
under the Clinical Research Act, the principal investigator prepare the Conflict of Interest 
Management Criteria based on the "Notification of the Director, Research Development Promotion 
Division, Medical Affairs Bureau, Ministry of Health, Labour and Welfare, March 2, 2008, Medical 
Affairs Bureau No. 0302-1" and request each research institution to confirm the conflicts of interest 
of the declarant (each chief investigator, attending doctors, and persons who clearly benefit from 
conducting this clinical trial) according to the Conflict of Interest Management Criteria. The Conflict 
of Interest Management Plan based on these information is reviewed by the Certificated Clinical 
Research Review Committee. 
 
In the event of new involvement of a person who has reported a conflict of interest, the 
opinions of the Certificated Clinical Research Review Committee shall be promptly obtained if any 
changes are necessary to the Conflict of Interest Management Plan after the confirmation by the 
affiliated institution. Even if there is no change in the Conflict of Interest Management Plan, the 
principal investigator shall confirm the status of conflicts of interest once a year and report it in the 
periodic report to maintain transparency and fairness of the research. 
 
14. Methods of disclosing information on research 
14.1. Registration of the research plan 
The principal investigator registers the research plan in public databases (University Hospital Medical 
Information Network Clinical Trials Registry (UMIN): http://www.umin.ac.jp/ctr/index-j.htm, and 
ClinicalTrials.gov: https://clinicaltrials.gov /) to register a summary of the study and update the study 
information as appropriate. 
 
In addition to the above, the principal investigator also submit and release study information 


to Japan Registry of Clinical Trials (jRCT) in accordance with the provisions of the Clinical Research 
Act that came into effect on April 1, 2018. 
 
14.2. Publication of research results 
The principal investigator will register the results of the study in a public database immediately after 
the study is completed. After taking measures to protect the personal information of the research 
subjects, the researcher will publish the results of the study in medical journals, etc. 
 
In addition to the above, the principal investigator will also prepare and release the primary 
endpoint report, comprehensive report, and summary report within the timeframe specified in Article 
24 of the Clinical Research Act, which came into effect on April 1, 2018. 
 
Primary endpoint report 
The principal investigator will prepare the primary endpoint report in principle within one year after 
the end of the period for collecting data on the primary endpoint, and promptly report it to the 
administrator of the implementing medical institution as well as the Certificated Clinical Research 
Review Committee, and submit it to the Ministry of Health, Labour and Welfare. 
 
Comprehensive report and summary report 
The principal investigator will prepare the comprehensive report and summary report in principle 
within one year after the end of the period for collecting data on all evaluation items, and promptly 
report them to the administrator of the implementing medical institution as well as the Certificated 
Clinical Research Review Committee, and submit them to the Ministry of Health, Labour and Welfare. 
The comprehensive report should include the following items: 
1) Background information on the subjects of this clinical trial (age and gender, etc.) 
2) Information on the progress according to the design of this clinical trial (number of subjects, etc.) 
3) Summary of the occurrence of diseases, etc. 
4) Data analysis and results for the primary and secondary endpoints 
The Appendix Form 1 should be used to prepare the summary report. The summary report of this 
clinical trial registered in jRCT will be accepted as the summary report. The following documents 
should be submitted with the summary report:  
1) Study protocol (last revised version) 
2) Informed consent form (last revised version) 
3) Statistical analysis plan (if any) 
The parts of the study protocol that need to be withheld from release for the protection of personal 
information and intellectual property rights may be published in filled-out form so that their contents 


cannot be identified. Since the date when the summary report is recorded in the jRCT is the date of 
termination, the principal investigator will submit a Notification of Termination to the Minister of 
Health, Labour and Welfare (Appendix Form 1: Notification of Termination). 
 
15. Report 
Periodic report 
Once a year, the principal investigator submits a periodic report (Uniform Form 5) to the Certificated 
Clinical Research Review Committee on the status of implementation of the research. Thereafter, a 
periodic report (Appendix Form 3) is submitted to the Minister of Health, Labour and Welfare within 
one month from the date on which the Certificated Clinical Research Review Committee has expressed 
its opinion. 
 
Non-conformity reporting 
If the principal investigator becomes aware of a condition that does not conform to the study protocol 
(hereinafter referred to as 'non-conformity'), the principal investigator must immediately report it to 
the administrator of the implementing medical institution. If a particularly serious one is found, the 
opinion of the Certificated Clinical Research Review Committee must be promptly obtained (Uniform 
Form 7). 
 
16. Response to consultation from research subjects and others concerned 
Questions concerning this clinical trial is handled by the following person. 
Contact address: Kosaku Mimura, Gastrointestinal Tract Surgery, Fukushima Medical University  
Hospital, 1 Hikarigaoka, Fukushima-city, Fukushima 969-1295, Japan 
TEL: 024-547-1220 
 
17. Handling of research in situations where there is an immediate and obvious life-threatening 
situation for the research subject 
Not applicable. 
 
18. In cases involving financial burdens or gratuities to research subjects 
Not applicable. 
 


19. In the case of research involving invasive procedures, any compensation for damage to health 
caused by the research 
If any health damage occurs to research subjects as a result of the implementation of this clinical trial, 
the principal investigator will provide appropriate treatment and other necessary measures to the 
research subjects. In principle, the research subjects will be responsible for paying his/her own medical 
expenses in such cases. No special compensation, such as medical expenses, medical allowance, or 
compensation payments, will be provided in the event of health damage resulting from this clinical 
trial. 
 
20. In the case of research involving medical treatment beyond normal medical treatment, 
handling of provision of medical treatment to research subjects after completion of the research 
The treatment administered in this clinical trial is within the normal range of insurance coverage. There 
are no special provisions for treatment after completion of observation, but concomitant treatment 
with unapproved medications, including investigational medications, will not be administered. 
 
21. Handling of research results (including incidental findings) in relation to research subjects 
for cases in which the conduct of research may lead to important findings, such as the health of 
the research subjects, genetic characteristics that can be passed on to their offspring, etc. 
Not applicable 
 
22. Possibility that the sample/information will be used for future research not identified at 
the time when consent is received 
If new research using stored samples is to be carried out, a new study protocol must be prepared, and 
the prescribed research ethics committee review and procedures as required by the research content 
must be performed. Furthermore, the implementation of such new research will be disclosed on the 
website, and the opportunity for participants in this clinical trial to refuse participation will be 
guaranteed. 
 
23. Quality control implementation system and procedures for clinical trials 
This clinical trial is carried out in compliance with the requirements of this protocol and the ethical 
principles of the "Ethical Guidelines for Medical Research Involving Human Subjects" (partially 
revised on February 28, 2017) and the World Medical Association "Declaration of Helsinki" (Fortaleza 


revised October 2013). In addition, we manage and conduct this clinical trial in compliance with the 
Clinical Research Act and related regulations and notifications that were enforced on April 1, 2018. 
 
23.1. Monitoring 
Responsible person for implementation: Tomoko Takahashi 
Contact: Clinical Research Center, Fukushima Medical University Hospital 
TEL: 024-547-1773 
 
The principal investigator prepares the monitoring protocol. The monitoring responsible person 
conducts monitoring in accordance with the monitoring protocol. When monitoring is conducted, the 
monitoring responsible person submits a monitoring report to the principal investigator and chief 
investigators.  
 
23.2. Data center 
Responsible person for data management: Takayuki Idaka 
Contact: Clinical Research Center, Fukushima Medical University Hospital  
TEL: 024-547-1772 
 
The principal investigator prepares the data management protocol. Responsible person for data 
management operates the Data Center in accordance with the data management protocol. 
 
23.3. Biostatistics 
Biostatistician: Shiro Takahashi, Department of Information Science, Iwate Medical University 
 
The biostatistician provides advice on case design and analysis methods. 
 
23.4. Audits 
No audits will be carried out. 
 
24. Research implementation organization 
Principal investigator: Koji Kono, Gastrointestinal Tract Surgery, Fukushima Medical University  


Hospital. 
Chief investigators: Koji Kono, Gastrointestinal Tract Surgery, Fukushima Medical University  
Hospital. 
Takashi Oshima, Gastro-esophageal Division, Gastrointestinal Surgery,  
Kanagawa Cancer Centre. 
Research Office: Kosaku Mimura, Gastrointestinal Tract Surgery, Fukushima Medical University 
           Hospital     TEL: 024-547-1220 
Akihiro Inano, Clinical Research Centre, Fukushima Medical University Hospital 
TEL: 024-547-1774. 
 
The duties include managing research budget, all research documents, and serving as a contact for 
research. 
 
Diagnostic imaging at registration: Yoshiyuki Suzuki, Radiation therapy, Fukushima Medical  
University Hospital     TEL: 024-547-1590. 
 
Analysis of immunological parameters 
1) Histological examination: Department of Gastrointestinal Tract Surgery, Fukushima Medical  
 
 
       University Hospital. 
・Analysis of the tumor microenvironment by immunostaining. 
2) Peripheral blood tests: Collected samples are sent to contractors by staff in Department of  
 
 
    Gastrointestinal Tract Surgery, Fukushima Medical University Hospital. 
・Analysis of peripheral blood lymphocyte subset. 
・Measurement of cytokines in plasma. 
 
 
Yohei Miyagi, Director, Clinical Research Institute, Kanagawa Cancer Centre. 
・Analysis of regulatory T cell function. 
・Analysis of antigen-specific T cell function. 
 
25. Outsourced research and assay 
Contractor: ImmunoSCAPE Pte Ltd.  
Office address: 1 Scotts Road #24-10, Singapore, 228208 
Laboratory address: 8A Biomedical Grove #04-00 Immunos, Singapore, 138648 
Contract: Analysis of immunological parameters using peripheral blood 
 


26. Citations 
(1) Gastric Cancer Treatment Guidelines, revised May 2014, 4th edition. 
(2) 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, 72:3967-3976. 
(3) 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, 15;5(4):380-384. 
(4) 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, 31;9(3):e92572. 
(5) 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, 390(10111):2461-2471. 
 
27. Appendix 
 
Consent Explanatory Document and Consent Form 
 
Medication package inserts 
 
PS Scale (ECOG) 

ICF_003.pdf: 
Identifiers: 
NCT03453164 
Unique Protocol ID: RK29040 
Brief Title: 
 Checkpoint Inhibitor and Radiotherapy for Recurrent Gastric Cancer  
(CIRCUIT) 
Date: 
 
13 Nov, 2017 
 
 
Informed Consent Form 
 
Clinical Trial 
 
Explanation for  
Phase I/II Clinical Trial of Nivolumab (Anti-PD-1 Antibody) 
in Combination with Local Radiation Therapy  
for Unresectable Advanced or Recurrent Gastric Cancer  
Refractory to Standard Therapy 
 
Principal Investigator 
Gastrointestinal Tract Surgery, Fukushima Medical University Hospital, 
Koji Kono 
1 Hikarigaoka, Fukushima-city, Fukushima 960-1295, Japan 
TEL: 024-547-1111 
 
This study is a “clinical trial” planned and conducted by the principal investigator. Clinical trial 
is research in which patients participate and cooperate to investigate in detail how well a new 
treatment or diagnostic method works against a disease (efficacy) and what types of side effects 
or complications occur and at what rate (safety).  
We explain this study in an easy-to-understand manner. Please make your own decision whether 
or not to participate in this study after fully understanding the contents. If you have any questions, 
please do not hesitate to ask. 
 


Table of contents 
1. 
Purpose and significance……………………………………………………………………..3 
2. 
Methods and duration ............................................................................................................................... 4 
3. 
About the patients who will be included in this study .......................................................................... 7 
4. 
Anticipated benefits and disadvantages/burdens of participation ....................................................... 8 
5. 
Other treatment options if you do not participate in this study ............................................................ 9 
6. 
Freedom to participate in this study and freedom to withdraw the consent ..................................... 10 
7. 
Protection of personal data and handling of the study results ............................................................ 10 
8. 
Methods of storage and disposal of samples and information .......................................................... 11 
9. 
Treatment and compensation in the event of health problems related to this study ....................... 11 
10. 
Treatment after completion of this study ............................................................................................. 12 
11. 
The possibility of using the data and samples for future research ..................................................... 12 
12. 
Conflicts of interest (interests with companies, etc.) .......................................................................... 12 
13. 
Participant’s cost sharing ....................................................................................................................... 13 
14. 
Methods of disclosing information ....................................................................................................... 13 
15. 
The review of the suitability of this study to be carried out ............................................................... 14 
16. 
Name of the research organizations, principal investigator, and chief investigators ...................... 14 
17. 
Matters to be observed ........................................................................................................................... 14 
18. 
Consultation service ............................................................................................................................... 15 
 
 
 


1. 
Purpose and significance 
Multi-drug anticancer therapy combining several anticancer agents is currently recommended in Japan 
for the treatment of unresectable advanced or recurrent gastric cancer. Recent advances in 
chemotherapy have allowed a relatively high rate of tumor shrinkage, but the prognosis is still poor. 
The immune checkpoint inhibitor of nivolumab (anti-PD-1 antibody)1 was shown to be effective in the 
treatment of unresectable advanced or recurrent gastric cancer that is refractory or intolerant to standard 
treatment. In September 2017, nivolumab was approved as a third-line chemotherapy for patients who 
have failed to standard primary/secondary chemotherapy.2 However, the response rate of 11.2% was 
not as high as expected, and there is an urgent need to develop new treatments and combination 
therapies. 
Radiotherapy has long been widely used as a symptomatic treatment for patients with 
unresectable advanced or recurrent gastric cancer, including cancer pain associated with bone 
metastases, etc. In recently, it has been reported that cancer antigen-specific immunity (reacting only 
to cancer cells) is activated after radiotherapy. Furthermore, case reports and clinical trials have 
reported synergistic effects when radiotherapy is combined with immunotherapy with immune 
checkpoint inhibitors such as anti-PD-1 antibody and anti-CTLA-4 antibody, etc. However, there are 
no reports of this combination therapy for patients with advanced or recurrent gastric cancer. Therefore, 
we plan to conduct the study to investigate the efficacy and safety of the combination of radiotherapy 
and nivolumab. 
If this study proves that the combination therapy using radiotherapy and nivolumab is more 
effective and safer than conventional treatments, it may be new treatment for many patients with the 
same disease as yours. 
 
1 Nivolumab is an antibody that binds specifically to PD-1, a protein on the surface of lymphocytes 
responsible for immunity. By binding to PD-1, nivolumab prevents PD-1 from binding to PD-L1 on the 


surface of cancer cells. Thus, nivolumab prevents lymphocytes from decreasing their function, which is 
thought to allow them to attack cancer cells and reduce the size of the tumor. 
2 The first anticancer drug treatment is called ‘primary chemotherapy’, and when this treatment becomes 
ineffective and the patient moves on to the next type of chemotherapy, it is called ‘secondary chemotherapy’. 
 
2. Methods and duration 
1) Description of procedures 
Enrolled patients receive radiotherapy for five consecutive days, followed by nivolumab (an anti-PD-
1 antibody) intravenously once every two weeks for a total of six doses of 3 mg/kg (body weight) or 
240 mg per dose (dosage and administration of nivolumab follow the recommended treatment for 
unresectable advanced or recurrent gastric cancer). 
 
2) Observation and inspection schedules 
This study period is divided into a pre-observation period, a treatment (radiotherapy + nivolumab) 
period, and a post-observation period. Please see the table below for the medical examinations and 
tests you will undergo during each period. For the clinical examination, a blood sample of 10–50 ml is 
collected. If the attending doctor decides that it is necessary, the number of tests may be increased, or 
other tests may be required. 
 
If you are currently attending another hospital, please inform us of that the name of hospital, 
the disease for which you are receiving treatment, and what medication you are using. Please also let 
us know if you are taking any medications that you buy and use from pharmacies or other sources. 
Informing us of such medications is important to ensure the safety of the study. Please also note that if 
you are attending another hospital, we may inform that hospital that you are taking part in the study. 
① Pre-observation period 
After you have agreed to participate in this study, and before treatment begins, attending doctor 


investigate your health status and previous illnesses and treatments to ensure that you meet the 
conditions for participation. In addition, attending doctor examine you and take standard 
measurements (e.g., height, weight, blood pressure, pulse) and general condition, as well as 
perform imaging tests such as chest-abdominal-pelvic enhanced CT, blood tests, urine tests, 
electrocardiogram (12-lead ECG), and others. Please do not eat or drink anything for eight hours 
prior to each examination. 
② Treatment (Radiotherapy + Nivolumab) duration 
If you can participate this study, your health and other conditions is re-examined before each 
treatment. If no problems are found, radiotherapy is given first. Then, nivolumab treatment start 
within two weeks of the end of radiotherapy and is given every two weeks, for a total of six doses. 
You also be asked to visit the hospital at regular intervals to monitor the efficacy and safety of the 
treatment; during these visits, attending doctor check your condition and perform examinations. 
If the scheduled visit date is not convenient, you can consult attending doctor and come back 
within 14 days of the scheduled treatment date. On the day of the clinical examination, please do 
not eat or drink anything for eight hours prior to each examination.  
③ Post-observation period 
Approximately 1 month and 3 months after your last nivolumab treatment (120 and 180 days after 
the start of radiotherapy, respectively), a health status check is performed. Depending on the 
results of each examination, you may be required to undergo additional tests. Please do not eat or 
drink anything for at least eight hours before you come to the hospital until you have had the 
examination. 
④ At the time of cessation of treatment 
All medical examinations and tests should be done within 14 days after the decision to stop 
treatment has been made. There is no need to do them if you are unable to come to the hospital, 
e.g., because you are admitted to another hospital. In such cases, please inform us that you cannot 


come to the hospital. 
 
Schedule 
Period 
Registration 
At the end 
of 
radiotherapy 
Nivolumab administration 
Day 
120 
Day 
180 
At the 
time of 
cessation 
of 
treatment 
1st 
2nd 
3rd 
4th 
5th 
6th 
Patient 
background 
〇 
 
 
 
 
 
 
 
 
 
 
General 
findings 
〇 
〇 
〇 
〇 
〇 
〇 
〇 
〇 
 
〇 
〇 
General 
condition 
〇 
〇 
〇 
〇 
〇 
〇 
〇 
〇 
 
〇 
〇 
Subjective 
and objective 
findings 
〇 
〇 
〇 
〇 
〇 
〇 
〇 
〇 
 
〇 
〇 
Imaging 
〇 
 
 
 
〇 
 
 
〇 
〇 
〇 
〇 
ECG 
〇 
 
 
 
 
 
 
 
 
 
 
Blood count 
〇 
 
〇 
〇 
〇 
〇 
〇 
〇 
 
〇 
〇 
Coagulation 
〇 
 
 
 
 
 
 
 
 
 
 
Blood 
biochemistry 
〇 
 
〇 
〇 
〇 
〇 
〇 
〇 
 
〇 
〇 
Urinalysis 
〇 
 
 
 
 
 
 
 
 
 
 
Infection 
〇 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
test (if 
necessary) 
〇 
 
 
 
 
 
 
 
 
 
 
Immunological 
1parameters ①1 
〇 
 
 
 
 
 
 
 
 
 
 
Immunological 
parameters ②2 
〇 
 
〇 
 
〇 
 
〇 
 
 
〇 
〇 
1 Histology (analysis of tumor microenvironment by Immunohistochemical staining) 
 ＊No new burden, because the tumor tissue samples from the previous diagnosis are used. 
2 Peripheral blood testing (peripheral blood lymphocyte subset analysis, plasma cytokine assays, 


regulatory T cell function analysis, and antigen-specific T cell function analysis, etc.). 
 
3) Expected duration of participation in this study and number of expected participants 
This study take place between March 2018 and January 2021. 
Your participation in this study last for approximately six months (of which approximately 13 weeks 
is spent receiving treatment). 
A total of 40 patients are expected to participate. 
 
3. 
About the patients who will be included in this study 
The conditions under which you can or cannot participate in this study are listed below. However, 
please note that even after you have given your consent, you may not be able to participate depending 
on the results of the tests. 
 
Inclusion criteria 
1) Patients with unresectable advanced or recurrent gastric cancer that was intolerance or had 
progression after standard treatment (primary or secondary chemotherapy). 
2) Those aged 20 years and over. 
 
Exclusion criteria 
1) Patients with no tumor lesions that can be irradiated. 
2) Patients with metachronous or simultaneous overlapping cancers. 
3) Patients with a history of severe hypersensitivity reactions to other antibody products. 
4) Patients taking immunosuppressive drugs or corticosteroids (prednisone or prednisolone 
equivalent 15 mg or more/day). 
5) Patients with autoimmune diseases or a history of recurrent autoimmune diseases. However, 


patients with type I diabetes mellitus, hypothyroidism that can be controlled by hormone 
replacement therapy and skin diseases that do not require systemic management are eligible to 
participate. 
6) Patients with complications or history of interstitial pneumonia or pulmonary fibrosis. 
 
 
There are many other criteria for participation in this study, which is determined by the 
attending doctor after a detailed examination and consultation. In some cases, even if you meet all of 
the above criteria, you may not be able to participate in this study. In addition, even if the study has 
already started, we may stop the study if it becomes clear that you do not meet the criteria for 
participation, or if the attending doctor decides that it would be better for you not to continue with this 
study. 
 
4. 
Anticipated benefits and disadvantages/burdens of participation 
Anticipated benefits 
There is a possibility that the disease may improve more than when radiotherapy and nivolumab 
treatment are administered separately. The information obtained from this study may also be useful for 
patients suffering from the same disease. 
 
Disadvantages/burdens  
The side effects that may occur with the treatment administered in this study may be more severe than 
those that occur with radiotherapy and nivolumab, respectively. However, these potential side effects 
are unknown at this time. Serious side effects of nivolumab treatment that have been reported at this 
time are summarized below. 
 
Types of serious side effects 
Frequency of appearance (%) 
Interstitial pneumonia 
3.0 


Myasthenia gravis, myocarditis, myositis, rhabdomyolysis 
Frequency unknown, 
frequency unknown, 0.1, 
frequency unknown 
Colitis, severe diarrhea 
1.3, 1.0 
Type 1 diabetes mellitus 
0.4 
Immune thrombocytopenic maculopathy 
Frequency unknown 
Liver dysfunction, hepatitis, sclerosing cholangitis 
0.7, 0.3, frequency unknown 
Thyroid dysfunction (hypothyroidism, hyperthyroidism, 
thyroiditis) 
7.1, 3.1, 1.2 
Neuropathies (peripheral neuropathy, polyneuropathy, 
autoimmune neuropathy) 
1.2, 0.1, frequency unknown 
Renal impairment (renal failure, tubulointerstitial nephritis) 
0.5, 0.1 
Adrenal disorders (adrenal insufficiency) 
1.0 
Encephalitis 
Frequency unknown 
Severe skin disorders (toxic epidermal necrolysis, cutaneous 
mucous membrane eye syndrome, erythema multiforme) 
Frequency unknown, 
frequency unknown, 0.2 
Venous thromboembolism (deep vein thrombosis, pulmonary 
thrombosis) 
0.1, 0.1 
Infusion reaction 
2.5 
Additional side effects can be found in the nivolumab package insert. 
 
The side effects of radiotherapy depend on the irradiated area. The attending doctor of 
radiotherapy provide an explanation tailored to the irradiated site. 
 
In this study, the attending doctor carefully administer treatment, and if any side effects occur, 
the attending doctor treat them promptly and appropriately. 
 
5. Other treatment options if you do not participate in this study 
If you do not wish to participate in this study, we discuss and decide which of the other treatment 
options may be best for you. Other treatment options include: 
1) 
Nivolumab alone 
2) 
Radiotherapy alone 


3) 
Other anticancer drugs (fourth-line treatment or later) 
If you prefer any other treatment, please do not hesitate to talk to us. 
 
6. Freedom to participate in this study and freedom to withdraw the consent 
Your participation in this study is your own choice. Please read this document carefully and make your 
own decision whether or not to participate in this study after careful consideration, including 
consultation with your family. If you have any questions, please do not hesitate to ask. If you agree to 
participate, please sign (or write your name and seal) the consent document. 
 
You can withdraw from the participation of this study at any time, even during the course of 
the study, so please do not hesitate to inform your attending doctor. 
 
If you decline to participate in this study or withdraw from participation during the course of 
the study, you will not be disadvantaged in any way with regard to your subsequent treatment. We 
provide you with the treatment that we determine to be best for you at that point in time. 
 
In addition, if new information (e.g., changes of the study protocol or the occurrence of 
serious adverse events in other subjects for which a direct causal link to this study cannot be ruled out 
and which cannot be foreseen) becomes available after the initiation of the study, you may be asked 
again about participating in this study. 
 
7. Protection of personal data and handling of the study results 
1) 
If you participate in this study, in order to confirm that the study is being conducted properly, 
people involved in this study (e.g., staff of Fukushima Medical University Hospital and Kanagawa 
Cancer Center, monitoring personnel, audit personnel, committee officials responsible for clinical 
research review, and officials of the Ministry of Health, Labor and Welfare) will have access to 
your medical records and research records. Even in such cases, these persons are obliged to 
maintain confidentiality (not to divulge the contents of the records to outside parties), and your 


personal information is strictly protected and never revealed to any third party. 
2) 
Upon your request, materials related to the Study Protocol may be disclosed to the extent that it 
does not affect the protection of the personal information of other subjects or the originality of 
this study. 
3) 
When the results of this study are presented at conferences or in scientific journals, they will be 
anonymized so that individuals cannot be identified before publication. 
 
 
By signature (or name and seal) on the consent document, you agree that the above 1), 2), 3) 
and the attending doctor obtain your personal information related to this study, which deemed 
necessary by the attending doctor. In addition, the samples and data (test data, etc.) provided by you in 
this study will be used only for this study and will not be used for any other purpose (see also items 8 
and 11 below). 
 
8. 
Methods of storage and disposal of samples and information 
During your participation in this study, your personal data, including your health condition and 
treatment details and samples such as blood, will be stored strictly at Fukushima Medical University 
Hospital as anonymized data (coded data) that do not contain your personal information. The samples 
will be stored for five years from the date of completion of this study or five years from the date of 
publication of the results (whichever is later). The data will be stored for five years from the date of 
completion of this study or five years from the date of publication of the results (whichever is later). 
They are then processed appropriately, such as by shredding, and discarded. 
 
9. Treatment and compensation in the event of health problems related to this study 
If you have any symptoms during or after this study, please do not hesitate to contact us. We will treat 
you appropriately in the same manner as a regular medical treatment. Your health insurance will be 


used to cover your medical expenses, and you will pay a part of the cost of your medical care. 
 
In addition, there is no special compensation, such as medical expenses, medical benefits, or 
compensation payments, for any health problems that occur in this study. Please make sure that you 
fully understand this point before making a decision to participate in this study. 
 
10. Treatment after completion of this study 
After the Study Protocol is completed, treatment will continue under normal insurance coverage. 
 
11. The possibility of using the data and samples for future research 
Data and samples collected for this study may be used for other researches. This is a case where 
something is not yet planned or anticipated now but will require very significant investigation in the 
future. If we plan to use your data in the future beyond the scope of the purposes and items explained 
to you when you participated in this study, we will separately proceed with the prescribed screening 
procedures at Fukushima Medical University as new research. We will also publicize this information 
on our website, etc., and ensure that you have the opportunity to express your refusal to participate in 
new research. 
 
12. Conflicts of interest (interests with companies, etc.)  
When a research group receives funding from pharmaceutical companies or other sources other than 
public funds, questions can arise as to whether the study is being conducted for the benefit of the 
company and/or whether the results of the study will not be fairly published (i.e., there can be concerns 
that only results that are favorable to the company will be published). This is called a conflict of interest 
(a conflict between the interests of the patients and of the research group or pharmaceutical company). 
In order to ensure the transparency of economic interest relationships to ensure the fairness and 
reliability of the study, economic interest relationships in this study are managed in accordance with 


the Conflict of Interest Management Standards and Conflict of Interest Management Plan approved by 
the Certificated Clinical Research Review Committee. 
 
This study is funded by an academia-initiated contract research agreement from Ono 
Pharmaceutical Industries, Ltd. and Bristol-Myers Squibb K.K., which manufacture the drug being 
used in this study, nivolumab. The principal investigator of this study, Prof. Kono, has received a 
speaker fee from Ono Pharmaceutical Industries, Ltd. The funders of Ono Pharmaceutical Industries, 
Ltd. and Bristol-Myers Squibb K.K. are only involved in providing information on the study drug, and 
are not involved in the planning of this study, and progress, data collection, analysis, interpretation of 
results, reporting, etc. after the start of this study. Conflicts of interest between the principal investigator 
and Ono Pharmaceutical Industries, Ltd. and Bristol-Myers Squibb K.K. are appropriately managed. 
 
In addition, some analyses of immunological parameters will be carried out by scientific 
research funds (national research funds) obtained by researchers from Fukushima Medical University 
Hospital and other sources. 
 
13. Participant’s cost sharing 
The treatment provided in this study is covered by your health insurance and your.co-payment. There 
is no honorarium. 
 
14. Methods of disclosing information 
 
An overview of this study is registered with the University Hospital Medical Information 
Network 
Research 
Centre 
Clinical 
Trials 
Registry 
System 
(UMIN-CTR, 
https://www.umin.ac.jp/ctr/index-j.htm) and the US clinical trials registry system (ClinicalTrials.gov, 
https://clinicaltrials.gov) before starting the study. The content of registration will be updated according 
to changes in the Study Protocol and the progress of the study. When this study is completed, the results 
will be registered and may also be published at conferences and in scientific journals. 


 
15. The review of the suitability of this study to be carried out 
After the Certificated Clinical Research Review Committee thoroughly examined not only the medical 
aspects but also the human rights, safety, and welfare of the patients, and concluded that there are no 
problems with the implementation of this study, and following approval by the head of each institution, 
this study is conducted. In addition, a summary of the Study Protocol is submitted to the Minister of 
Health, Labor and Welfare. The review committee for this study is as follows. 
Name of the Certificated Clinical Research Review Committee: The Certificated Clinical Research 
Review Committee of Fukushima Medical University School of Medicine 
Authorization number: CRB2180002 
Location: 1 Hikarigaoka, Fukushima-City, Fukushima, Japan 
 
16. Name of the research organizations, principal investigator, and chief investigators 
Principal Investigator: Koji Kono, Chief Professor, Gastrointestinal Tract Surgery, Fukushima Medical  
University Hospital 
Chief Investigators: Koji Kono, Chief Professor, Gastrointestinal Tract Surgery, Fukushima Medical  
University Hospital 
 
 
Takashi Oshima, Chief of Gastro-esophageal Division, Gastrointestinal Surgery,  
Kanagawa Cancer Center 
 
17. Matters to be observed 
If you agree to participate in this study, please observe the following: 
1) Follow the precautions set in this study until the study is completed.  
2) Contact us immediately if your condition is unusual or you have any unusual symptoms.  
3) During the study period, there are certain medications that cannot be used because they may affect 
the evaluation of the study treatment. If you decide to use a new medication, please inform your 


attending doctor before using the medication. Even if you purchase the medication at a pharmacy, 
etc., do not take it at your own discretion, but consult your attending doctor in advance. 
4) If you consult or will consult another department in our hospital or another hospital, please notify 
your attending doctor of your consultation. To ensure your safety and to evaluate the potential 
influence on this study, we may, with your approval, inform your doctor that you are participating 
in this study and inquire about your treatment (e.g., medications used, etc.). 
5) Contact your attending doctor if you are unable to come to the hospital on the appointed date for 
any reason. 
6) Do not disclose any information related to this study to any third party. 
7) Consult your attending doctor if you have any other concerns. 
 
18. Consultation service 
If you have any questions about this study, please contact us at the following address. 
Weekdays: 9:00 a.m. to 5:00 p.m. (We can not respond on National Holidays, Saturdays, Sundays, and 
during the year-end and New Year’s holidays). 
Contact 
Kosaku Mimura 
Gastrointestinal Tract Surgery, Fukushima Medical University Hospital, 1 Hikarigaoka, Fukushima-
city, Fukushima 969-1295, Japan   TEL: 024-547-1220 
Yoshiyuki Suzuki 
Radiation therapy, Fukushima Medical University Hospital, 1 Hikarigaoka, Fukushima-city, 
Fukushima 969-1295, Japan   TEL: 024-547-1590 
 
 
The following consultation service is available for complaints, consultations, or inquiries 
regarding the research conducted at Fukushima Medical University Hospital, including this study. 


Please use this service if you have any questions that you would like to discuss with someone other 
than the attending doctors in this study. 
Contact 
Consultation Service for Clinical Research Participants 
Fukushima Medical University Hospital, 1 Hikarigaoka, Fukushima-city, Fukushima 969-1295, Japan 
TEL:090-1938-7374 (Reception hours: 9:00–17:00)   E-mail: c-kiban@fmu.ac.jp 
 
 
Please note that we may not be able to provide a response from the standpoint of protecting 
the personal information of other subjects or the intellectual property rights of the researcher. 


Consent Form 
 
To Principal investigator   Koji Kono  
 
I agree to be a subject for the following research project. 
I add that I have given my consent based on the written explanation and that I understand the following 
conditions. 
 
Title of clinical trial:  
Phase I/II Clinical Trial of Nivolumab (Anti-PD-1 Antibody) in Combination with Local Radiation 
Therapy for Unresectable Advanced or Recurrent Gastric Cancer Refractory to Standard Therapy 
 
Chief investigator 
Name:                        
Belonging to:                   
Official title:                    
 
Conditions of consent 
1. I can withdraw this consent at any time for my own reasons. 
2. I will not suffer any disadvantage in treatment etc. as a result of the withdrawal of my consent. 
3. On my request, I can obtain information regarding the results of this study on me at any time. 
4. The principal investigator and those involved in this study do their best to treat my illness or maintain 
my health in relation to this study. 
5. During the course of study protocol, the principal investigator and those involved in this study take 
appropriate measures to manage any unexpected incidents that occur to me in relation to this study. 
6. The confidentiality of any personal information regarding me obtained by anyone involved in this 
study in relation to this study will be strictly protected. 
 
[Patient’s signature] 
Date of consent: __ ___________________________________________  
Name (Signature): ______________________________________________ 
 
[Signature of the attending doctor who explained the consent form] 
Date of explanation: _____________________________________________ 
Belonging to: ___________________________________________________ 
Name (Signature): _______________________________________________ 


Consent Withdrawal Form 
 
To Principal investigator   Koji Kono  
 
I withdraw my consent to participate as a subject in the following research project. 
 
 
Title of clinical trial:  
Phase I/II Clinical Trial of Nivolumab (Anti-PD-1 Antibody) in Combination with Local Radiation 
Therapy for Unresectable Advanced or Recurrent Gastric Cancer Refractory to Standard Therapy 
 
Chief investigator 
Name:                        
Belonging to:                   
Official title:                    
 
 
With regard to this withdrawal of consent: 
 
 
□ The information can be used until the withdrawal of consent form is submitted. 
 
 
□ I withdraw my consent to the use of all information. 
 
 
 
[Patient’s signature] 
Date of withdrawal of consent: ____________________________________ 
 
 
Name (Signature): ______________________________________________