Clinical trial NCT03406871
Conditions: Advanced and Metastatic Solid Tumor
Keywords: Regorafenib Nivolumab Phase I clinical trial
Sponsor: Kohei Shitara
Start date: 2018-01-15; Completion date: 2020-12-15
Enrollment: 50 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
the efficacy and safety ofhe use of regorafenib in combination with nivolumab

Detailed description:
The present trial consists of a dose-escalation cohort to verify the tolerability of nivolumab and regorafenib when used in combination for patients with solid tumors, and to examine the clinical recommended dose(RD). The trial also consists of an expansion cohort to examine the safety and efficacy when the clinical RD is administered for several advanced solid tumors.

In the dose-escalation cohort, three patients with solid tumors will be administered 3.0 mg/kg of nivolumab once every 2 weeks and regorafenib daily for 21days, with a 1-week washout period at dose of 80 mg (level 1), 120 mg (level 2), or 160 mg (level 3). As a general rule, one cycle will last 28 days (day 1-29); however, in the event of treatment prolongation, the cycle period will be extended. The Dose Limiting Toxicity(DLT) evaluation period will be 28 days. Furthermore, for each level, three additional subjects will be added depending on the state of DLT.

In the expansion cohort, the target subject sample will consist of approximately 30 patients who will be administered 3.0 mg/kg of nivolumab once every 2 weeks, and the clinical RD of regorafenib will be determined in the dose-escalation cohort.

Arms: arm 1: Regorafenib: Oral administration at a dose of 80 mg given once per day for 21 consecutive days, with a 1-week washout period.

Nivolumab: Given once every 2 weeks at a dose of 3.0 mg/kg via an intravenous infusion.

When it is deemed that there is no problem with safety at the doses described above, tolerability will be verified at the level-2 dosages described below. arm 2: Regorafenib: Oral administration at a dose of 120 mg/day for 21 consecutive days, with a 1-week washout period.

Nivolumab: Given once every 2 weeks at a dose of 3.0 mg/kg.

When it is deemed that there is no problem with safety at the doses described above, tolerability will be verified at the level-3 dosages described below. arm 3: Regorafenib: Oral administration at a dose of 160 mg/day for 21 consecutive days, with a 1-week washout period.

Nivolumab: Given once every 2 weeks at a dose of 3.0 mg/kg.

After starting the trial, three cases are registered at level 1, and temporary case registration is suspended until safety evaluation of the first course is completed in all cases. If there are cases in which evaluation of DLT can not be performed properly, such as being canceled due to reasons other than safety during the course of the first course, the necessary number of cases is appropriately added to the administration level. arm 4: After completion of the final DLT evaluation period of the subjects in the dose escalating cohort, the decision to move the subjects into the expansion cohort will be determined once it is decided, upon deliberation between the sponsor and the principal investigator, that there are no problems associated with moving on. Furthermore, the opinion of the Data and Safety Monitoring Committee (DSMC) can be sought as required .

Regarding the review of RD in the expansion cohort, please refer to "Analysis Population Description" in Primary Outcome Measures.
Interventions: intervention 1: Regorafenib intervention 2: Nivolumab
Intervention descriptions: intervention 1: One course will last 28 days. Oral administration for 21 consecutive days, with a 1-week washout period. As for the expansion cohort, implemented using the RD estimated in the dose-escalation cohort. intervention 2: One course will last 28 days. Given once every 2 weeks at a dose of 3.0 mg/kg.

Protocol documents:
Prot_SAP_000.pdf: 
Title: Regorafenib and Nivolumab Simultaneous Combination Therapy (REGONIVO) 
NCT Number: NCT03406871 
Protocol Approve Date: 20-May-2020 
Certain information within this protocol has been redacted (ie, specific content is 
masked irreversibly from view with a black/blue bar) to protect either personally 
identifiable information or company confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

Proprietary
information, 
such 
as 
scales 
or 
coding 
systems, 
which 
are 
considered confidential information under prior agreements with license holder. 

Other information as needed to protect confidentiality of NCCHE, personal
information, or to otherwise protect the integrity of the clinical study.
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 


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Confidential information disclosure statement 
This protocol contains confidential information, which will be provided to the trial coordinating committee, 
principal investigator, subinvestigator, trial collaborators (including outsourced service providers such as Site 
Management Organization [SMO]), medical institutions participating in the trial, as well as the Institutional Review 
Boards and Data and Safety Monitoring Committees of these institutions. 
Except when explaining the trial details to the patient, this protocol will not be disclosed to any third party 
without the written consent of the trial coordinating committee and the investigational drug provider. Furthermore, 
the protocol cannot be used for any purpose other than the present trial. 
Regorafenib and Nivolumab Simultaneous Combination Therapy for 
Advanced and Metastatic Solid Tumors: Phase I Clinical Trial 
 
Investigator-initiated trial protocol 
 
 
 
Protocol Number: EPOC-1603 
 
Coordinating investigator (principal investigator): Kohei Shitara 
Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital 
East, 6-5-1, Kashiwanoha, Kashiwa, Chiba 277-8577, Japan 
TEL: 04-7133-1111 (ext. 91520) 
E-mail: kshitara@east.ncc.go.jp 
 
 
Coordinating investigators: 
Shota Fukuoka 
Exploratory Oncology Research & Clinical Trial Center, National Cancer Center 
Akihiro Sato 
Clinical Research Support Office, National Cancer Center Hospital East 
E-mail: regonivo_core@east.ncc.go.jp 
 
 
Protocol Number:EPOC1603 
Version number: Ver.1.7, Prepared: Apr, 09, 2020 


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Revision history: 
Investigator-initiated trial protocol ver. 1.0, prepared: Sept, 12, 2017 
Investigator-initiated trial protocol ver. 1.1, prepared: Jan, 22, 2018 
Investigator-initiated trial protocol ver. 1.2, prepared: Febr, 2, 2018 
Investigator-initiated trial protocol ver. 1.3, prepared: Aug, 20, 2018 
Investigator-initiated trial protocol ver. 1.4, prepared: Feb, 25, 2019 
Investigator-initiated trial protocol ver. 1.5, prepared: May, 8, 2019 
Investigator-initiated trial protocol ver. 1.6, prepared: Aug, 19, 2019 
Investigator-initiated trial protocol ver. 1.7, Prepared: Apr, 09, 2020 


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1. Summary 
 
Phase 
Phase I 
Subjects 
Patients with unresectable recurrent solid tumors who are refractory or intolerant to 
standard chemotherapy 
Objectives 
Primary objective 
To examine the safety and tolerability of repeated dosing of regorafenib and nivolumab 
in patients with unresectable recurrent solid tumors who are refractory or intolerant to 
standard chemotherapy, and to investigate the maximum tolerated dose (MTD) and 
recommended dose (RD) of the drug when used in combination therapy. 
Dose-escalation cohort 
The safety of regorafenib and nivolumab combination therapy will be evaluated in 
patients with unresectable recurrent solid tumors who are refractory or intolerant to 
standard chemotherapy in order to determine the MTD and RD of regorafenib 
according to dose-limiting toxicity (DLT) when used in combination therapy. 
Expansion cohort 
An exploratory evaluation of the efficacy and safety of the combined treatment using 
the RD found in the dose-escalation cohort will be performed. 
Secondary objective 
• Safety 
- The incidences and types of adverse events that occur during treatment will be 
evaluated according to the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03. 
• Efficacy 
- Objective response rate (ORR) according to Response Evaluation Criteria in Solid 
Tumours (RECIST) version. 1.1, and immune-related (ir) RECIST 
- Progression-free survival (PFS) 
- Overall survival (OS) 
- Disease control rate (DCR) 
Exploratory items (performed as accompanying research in the present trial): 
Tests of various biomarkers 
Trial design 
The present trial is a phase I clinical trial intended to evaluate the safety of regorafenib 


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and nivolumab combination therapy in patients with unresectable recurrent solid 
tumors who are refractory or intolerant to standard chemotherapy. 
Trial 
study 
population 
Inclusion criteria 
1. 
Patients who provided written informed consent to be subjects in this trial 
2. 
Patients at least 20 years of age on the day of providing consent 
3. 
Dose-escalation cohort: Patients with histologically or cytologically confirmed 
advanced or metastatic solid tumors. 
Expansion cohort: Patients with histologically or cytologically confirmed 
advanced or metastatic solid tumors (gastric, colorectal, or hepatocellular cancer). 
4. 
Patients with an Eastern Cooperative Oncology Group (ECOG) performance 
status (PS) of 0 or 1 
5. 
Patients capable of taking oral medication 
6. 
Patients with evaluable or measurable lesions as per RECIST version 1.1 
7. 
Patients with adequate organ function at the time of enrollment as defined below: 
[Acceptable 7 days examination before the same day of the registration date] 
• Neutrophil count ≥1500mm3 
• Platelet count ≥10.0 × 104/mm3 
• Hemoglobin (Hb) ≥ 9 g/dL, 
• aspartate transaminase (AST), alanine transaminase (ALT) ≤100 U/L (≤100 U/L in 
patients with Hepatocelular carcinoma, ≤250 U/L in patients with liver metastasis) 
• Total bilirubin ≤1.5mg /dLtimes the upper limit of normal 
• Creatinine ≤1.5mg /dL 
• Urinary protein: It satisfies one of the following (if any of the inspection criteria are 
satisfied, other examination may not be carried out) 
(i) urinary protein (test paper method) is 2+ or less 
(ii) UPC (Urine Protein Creatinine) ratio <3.5 
(iii) 24-hour urine protein was measured, urinary protein ≦ 3500 mg 
• PT-INR: ≤ 1.5 (≦ 3.0 in case of anticoagulant administration) 
* It is Child A in the case of Expansion cohort's hepatocellular carcinoma 
8. For women who are likely to become pregnant (including those without 
menstruation due to medical reasons such as chemical menopause) Note 1, we 
agreed to double contraceptive Note 2 for at least 5 months after the final 
administration of the investigational product from consent acquisition patient. 
Also, patients who agreed not to breast feeding for at least 5 months after the final 
investigational drug administration after acquiring consent. 


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For men, patients agreeing to double contraceptive for at least 7 months after the 
final investigational drug administration from the time of starting investigational 
drug administration. 
Note 1): A woman who is likely to become pregnant is a woman who has 
experienced menarche and is not undergoing sterilization surgery (such as 
hysterectomy, bilateral salpingo ligation or bilateral oophorectomy), a woman 
without menopause Everything is included. The definition after menopause shall 
be amenorrhea continuously for 12 months or more even though there is no 
noteworthy reason. Women who are using oral contraceptives or mechanical 
contraceptive methods (such as intrauterine contraceptive devices or barrier 
methods) are considered to be pregnant. 
Note 2): With regard to contraception, it is necessary to use two of the vasectomy 
or condom of a male patient or male male, the uterine tube ligation of a female 
patient or the other woman, a contraceptive pessary, an intrauterine contraceptive 
device or an oral contraceptive I need to agree to heavy contraception. 
Exclusion criteria 
1. 
Patients who have undergone systemic chemotherapy, radiotherapy, surgery, 
hormone therapy, or immunotherapy <2 weeks before enrollment. Immune 
checkpoint blockade as pretreatment is permitted. 
2. 
Patients with a history of taking regorafenib. 
3. 
Patients with hypertension that is difficult to control (systolic blood pressure ≥160 
mmHg and diastolic blood pressure ≥90 mmHg) despite treatment with several 
hypotensive agents 
4. 
Patients with acute coronary syndrome (including myocardial infarction and 
unstable angina), and with a history of coronary angioplasty or stent placement 
performed within 6 months before enrollment 
5. 
Patients with a large amount of pleural effusion or ascites requiring drainage. 
6. 
Patients with a ≥grade 3 active infection according to NCI-CTCAE version 4.03 
7. 
Patients with symptomatic brain metastasis 
8. 
Patients with partial or complete gastrointestinal obstruction 
9. 
Patients with interstitial lung disease with symptoms or signs of activity 
10. Patients who test positive for either anti-HIV-1 antibodies, anti-HIV-2 antibodies, 
hepatitis B surface antigen (HBsAg), or anti-hepatitis C virus (HCV) antibodies* 
*Patients who test positive for either anti-HBs or anti-HBc antibodies, and those 
who have HBV-DNA measurements greater than the detection sensitivity will 


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also be excluded. 
(However, patients with hepatocellular carcinoma in the expansion cohort will not 
be excluded even if they test positive for HBsAg and anti-HCV antibodies.) 
11. Patients with concurrent autoimmune disease, or a history of chronic or recurrent 
autoimmune disease 
12. Patients who require systemic corticosteroids (excluding temporary usage for 
tests, prophylactic administration for allergic reactions, or to alleviate swelling 
associated with radiotherapy) or immunosuppressants, or who have received such 
a therapy <14 days before enrollment in the present study 
13. Patients with a history or findings of ≥grade III congestive heart failure according 
to the New York Heart Association functional classification 
14. Patients with a seizure disorder who require pharmacotherapy 
15. Patients who had grade 3 or higher bleeding during 4 weeks before enrollment. 
16. Patients undergoing major surgery (thoracotomy or laparotomy, etc.), laparotomy 
biopsy, trauma within 28 days before registration. The same day of the week 
before 4 weeks can be registered 
(However, in case of an artificial anastomosis without intestinal resection, it shall 
be within 14 days before registration). 
17. Non-healing wound, non-healing ulcer, or non-healing bone fracture. 
18. Patients with a history of hypersensitivity to any of the study drugs, similar drugs, 
or excipients. 
19. Pregnant women, lactating women or possibly pregnant women 
Trial 
participation 
period 
The investigational drug will be repeatedly administered until the criteria for 
discontinuation are met. 
In the event that the treatment is discontinued for reasons other than an exacerbation of 
the underlying disease via imaging (e.g., unacceptable side effects), tumor evaluation 
follow-up will continue until either an exacerbation of the underlying disease is 
observed via imaging or a new anticancer treatment is initiated, whichever happens 
first. 
Sample size 
Dose-escalation cohort: A total of 3–6 patients per level, for a total of 9–18 patients 
Expansion cohort: Approximately 30 patients in total 
Administration 
method 
Dose-escalation cohort 
One course will last 28 days*, and tolerability will be verified for the following 
dosages. 
Level 1 
Regorafenib: Oral administration at a dose of 80 mg/day for 21 consecutive days, with 


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a 1-week washout period. 
Nivolumab: Given once every 2 weeks at a dose of 3.0 mg/kg. 
When it is deemed that there are no safety issues associated with the above dosages, 
tolerability will be verified for the following level-2 dosages. 
Level 2 
Regorafenib: Oral administration at a dose of 120 mg/day for 21 consecutive days, 
with a 1-week washout period. 
Nivolumab: Given once every 2 weeks at a dose of 3.0 mg/kg. 
Level 3 
Regorafenib: Oral administration at a dose of 160 mg/day for 21 consecutive days, 
with a 1-week washout period. 
Nivolumab: Given once every 2 weeks at a dose of 3.0 mg/kg. 
When tolerability has been confirmed for the level-3 dosages, the above dosages will 
be the recommended dosages. 
The administered dose will increase using a 3 + 3 design in accordance with the DLT. 
Three or more patients will be enrolled at each level. In the event that DLT is not 
observed during the initial course in the first three patients, these patients will move 
onto the next level. In the event that DLT is observed in one of the first three patients, 
an additional three patients will be added to the level in question. When all three 
additional patients have completed the first course without presenting with any DLT, 
these patients will move onto the next level. If DLT is observed in one of the three 
additional patients, an additional three patients will be added to the level below to 
determine the MTD. 
Expansion cohort: The trial will be conducted using the estimated RD found in the 
dose-escalation cohort. 
Safety 
evaluation: 
Evaluations will be performed using CTCAE version 4.03. 
Efficacy 
evaluation: 
The antitumor effect will be evaluated in accordance with irRECIST and RECIST 
version 1.1. The tumor evaluation will be performed as follows: 
• Image evaluation: computed tomography (CT) or magnetic resonance imaging (MRI) 
• Image evaluation schedule: evaluations will be performed at baseline as well as at 6, 
12, 18, and 24 weeks (thereafter every 9 weeks until week 42 and subsequently every 
12 weeks after week 42). 


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PFS and OS will be evaluated in all subjects. 
TR 
TR: A separate protocol will be prepared and implemented as ancillary research 
Observation 
and test items 
Physical measurements, vital signs, PS, laboratory tests (i.e., blood and biochemistry), 
urine analysis, clinical laboratory findings, tumor markers, as well as chest, abdominal 
and pelvic CT or MRI, etc. 
Trial design 
The present trial will comprise a dose-escalation cohort to simultaneously examine 
clinically RDs and tolerability of nivolumab and regorafenib combination therapy in 
patients with solid tumors, and an expansion cohort to examine the safety and efficacy 
of the clinically RDs in patients with multiple advanced solid tumors. 
In the dose-escalation cohort, three patients with solid tumors will be administered 
nivolumab at a dose of 3.0 mg/kg once every 2 weeks, and regorafenib at a dose of 80 
mg (level 1), 120 mg (level 2) or 160 mg (level 3) for 21 consecutive days, with a 
1-week washout period. As a general rule, one cycle will last 28 days (day 1–29). The 
DLT evaluation period will be 28 days. Furthermore, for each level, three additional 
subjects will be added depending on the occurrence of DLT. 
In the expansion cohort, approximately 30 patients with solid tumors will be 
administered the clinically RD of regorafenib found in the dose evaluation cohort. 
Scheduled trial 
period 
Planned enrollment period: January 2018 to October 2018 (10 months)Planned 
follow-up period: Two years from the last day of patient enrollment 
Overall trial period (including the procedures for trial completion): 2 years and 6 
months after the last day of patient enrollment 
When the administration of all subjects would be completed during the observation 
period, the observation period of this study will be also terminated at the end of the 
observation period of the last administered patient. 
Number 
of 
institutions 
One institution (an additional one or two institutions are planned for the expansion 
cohort) 
Cordinating 
investigator 
representative 
Kouhei Shitara, National Cancer Center Hospital East 
Planned 
trial 
institution 
National Cancer Center Hospital East (an additional one or two institutions are planned 
for the expansion cohort) 
 
Contact: 
Queries regarding clinical decisions, such as eligibility criteria and criteria for treatment changes: 
Principal investigator (refer to front page) 
Queries regarding enrollment procedures and eCRF, etc.: Clinical Trial Support Division, National 


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Cancer Center Hospital East 
(Attachment 1) 
Queries regarding the adverse event report, etc.: Clinical Trial Support Division, National Cancer 
Center Hospital East 
(Attachment 1) 


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Table of Contents 
1. Summary .......................................................................................................................................... 3 
Table of Contents ............................................................................................................................. 10 
1. Objectives ....................................................................................................................................... 15 
2. Background .................................................................................................................................... 17 
2.1 Patient epidemiology ............................................................................................................... 17 
2.2 Treatment of patients .............................................................................................................. 17 
2.3 Immunotherapy for patients .................................................................................................... 18 
2.4 Rationale behind treatment plan setting ................................................................................ 19 
2.4.1 Trial regimen .................................................................................................................... 19 
2.5 Nivolumab ................................................................................................................................ 20 
2.5.1 Summary of nonclinical trials of nivolumab ................................................................... 20 
2.5.2 Summaries of clinical trial data and known or potential risks and benefits to 
subjects ....................................................................................................................................... 22 
2.5.3 Japanese phase I trial of malignant melanoma .............................................................. 24 
2.5.4 Japanese phase II trial of patients with malignant melanoma ...................................... 24 
2.5.5 Clinical efficacy in lung cancer patients .......................................................................... 25 
2.5.6 The clinical efficacy in malignant melanoma patients.................................................... 25 
2.6 Regorafenib .............................................................................................................................. 26 
2.6.1 Regorafenib clinical outcomes ......................................................................................... 26 
2.6.2 Summary of adverse events associated with regorafenib .............................................. 27 
2.7 Treatment regimen in the present trial ................................................................................... 27 
2.7.1 Rationale for setting the nivolumab administration route, dose, and treatment 
schedule ...................................................................................................................................... 27 
2.7.2 Rationale for setting the regorafenib administration route, dose, and treatment 
schedule ...................................................................................................................................... 28 
2.8 Trial design .............................................................................................................................. 29 
2.8.1 Setting of endpoints .......................................................................................................... 29 
2.8.2 Planned number of enrollments ...................................................................................... 30 
2.9 Summary of the anticipated advantages and disadvantages of participation in this trial30 
2.10 The significance of performing the present study as an investigator-led trial ................... 31 
3 CRITERIA AND DEFINITIONS TO BE USED IN THE STUDY ................................... 32 
3.1 Staging Criteria ....................................................................................................................... 32 
3.2 Performance Status (Eastern Cooperative Oncology Group (ECOG) Classification) ........32 
3.3 Assessment Criteria for AEs ...................................................................................................32 


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3.4 Assessment Criteria for Response Rate.................................................................................. 32 
4 INCLUSION AND EXCLUSION CRITERIA.................................................................... 33 
4.1 Inclusion criteria...................................................................................................................... 33 
4.2 Exclusion criteria ..................................................................................................................... 34 
5 Enrollment ...................................................................................................................................... 36 
5.1 Enrollment procedure ............................................................................................................. 36 
5.2 Important notes regarding enrollment ................................................................................... 36 
6 Dosing schedule and combination therapy.................................................................................... 38 
6.1 Protocol treatment ................................................................................................................... 38 
6.1.1 Dosing and administration method ................................................................................. 38 
6.1.2 Recommended dose (RD) and transition to the expansion cohort................................. 39 
6.1.3 Definition of DLT ............................................................................................................. 41 
6.1.4 Target subjects for DLT evaluation ............................................................................... 41 
6.1.5 Determining transition to the expansion cohort ............................................................. 42 
6.2 Criteria for the commencement and termination of the treatment protocol ....................... 43 
6.2.1 Criteria for terminating the treatment protocol ................................................................ 43 
6.2.2 Data collection after treatment termination and the follow-up of subjects .................. 44 
6.3 Criteria for changing the treatment protocol ........................................................................ 44 
6.3.1 Criteria for changing the dose of regorafenib ................................................................ 44 
6.3.2 Criteria for changing the nivolumab dosage .................................................................. 47 
6.4 Specific instructions for subjects ............................................................................................ 53 
6.5 Combination therapy and supportive treatment ................................................................... 54 
6.5.1 Recommended combination and supportive therapies .................................................. 54 
6.5.2 Permitted combination and supportive therapies .......................................................... 54 
6.5.3 Unpermitted combination and supportive therapies ..................................................... 54 
6.6 Aftertreatment ......................................................................................................................... 55 
7 Investigational drug information ................................................................................................... 56 
7.1 Nivolumab drug information .................................................................................................. 56 
7.2 Regorafenib drug information ................................................................................................ 57 
7.3 Investigational drug management .......................................................................................... 57 
7.4 Anticipated adverse events...................................................................................................... 58 
8 Endpoints, laboratory tests, and evaluation schedule .................................................................. 59 
8.1 Observations, tests, and endpoints ......................................................................................... 59 
8.2 Observation and test schedule ................................................................................................ 60 
8.3 Examination findings .............................................................................................................. 63 


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8.3.1 Subject background ......................................................................................................... 63 
8.3.2 Height and weight measurements and vital signs ........................................................... 63 
8.3.3 ECOG performance status (PS) ...................................................................................... 63 
8.3.4 Adverse events (subjective and objective symptoms)/combination therapy ................. 63 
8.4 Laboratory tests....................................................................................................................... 63 
8.4.1 Blood tests/biochemical tests/blood coagulation tests/urine analysis/thyroid function 
tests  ........................................................................................................................................... 64 
8.4.2 Tumor markers ................................................................................................................ 64 
8.4.3 Pregnancy tests ................................................................................................................. 64 
8.4.4 Infection tests .................................................................................................................... 64 
8.4.5 Twelve-lead ECG at rest .................................................................................................. 64 
8.5 Tumor evaluation .................................................................................................................... 64 
8.6 Biomarker Biopsy Blood sampling ......................................................................................... 67 
8.7 Follow-up .................................................................................................................................. 67 
9 DATE COLLECTION ................................................................................................................... 68 
9.1 Handling and Retention of CRF Data .................................................................................... 68 
9.2 Identification of Source Documents ....................................................................................... 68 
10 Reporting of adverse events ......................................................................................................... 69 
10.1 Adverse event evaluation ...................................................................................................... 69 
10.1.1 Definition of adverse events ........................................................................................... 69 
10.1.2 Method of recording adverse events .............................................................................. 69 
10.1.3 Adverse event report items ............................................................................................ 69 
10.1.4 Determination of a causal relationship ......................................................................... 69 
10.1.5 Follow-up observation upon the onset of an adverse event ......................................... 71 
10.1.6 Adverse event evaluation period ................................................................................... 71 
10.2 Reporting of serious adverse events ..................................................................................... 71 
10.2.1 Definition of serious adverse events .............................................................................. 71 
10.2.2 Mandatory reporting and reporting procedures for the principal investigator (or 
subinvestigator) ......................................................................................................................... 72 
10.2.3 Mandatory reporting and reporting procedures for the trial coordinating 
committee ................................................................................................................................... 73 
10.2.4 Duties of the Data and Safety Monitoring Committee ................................................. 74 
10.3 Collection of safety information ........................................................................................... 74 
10.4 Pregnancy .............................................................................................................................. 74 
10.5 Overdosing ............................................................................................................................. 74 


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11 Response evaluation and endpoints ............................................................................................. 76 
11.1 Response evaluation .............................................................................................................. 76 
11.2 Endpoint definitions .............................................................................................................. 76 
11.2.1 Incidence of adverse events ............................................................................................ 76 
11.2.2 Objective response rate (ORR)...................................................................................... 76 
11.2.3 Progression-free survival (PFS) ..................................................................................... 76 
11.2.4 Disease control rate (DCR) ............................................................................................ 77 
11.2.5 Overall survival (OS) ..................................................................................................... 77 
12 Statistical items ............................................................................................................................. 78 
12.1 Handling of subjects .............................................................................................................. 78 
12.2 All enrollments ....................................................................................................................... 78 
12.3 Definition of analysis sets ...................................................................................................... 78 
12.4 Handling of data .................................................................................................................... 78 
12.4.1 Handling of missing data and outliers........................................................................... 78 
12.4.2 Management of additional analyses .............................................................................. 79 
12.5 Analysis order and analysis method ..................................................................................... 79 
12.6 Safety analysis........................................................................................................................ 79 
12.6.1 Analysis of the incidence of adverse events ................................................................... 79 
12.7 Analysis of secondary efficacy endpoints ............................................................................. 79 
12.8 Target number of subjects .................................................................................................... 80 
12.9 Rationale for settings ............................................................................................................. 80 
12.10 Interim analysis ................................................................................................................... 80 
12.11 Final analysis ....................................................................................................................... 80 
12.12 Special considerations regarding analysis items ................................................................ 80 
12.12.1 Analysis items in the final analysis .............................................................................. 80 
12.12.2 Analysis items included in the clinical study report ................................................... 81 
13 ETHICAL MATTERS ................................................................................................................. 82 
13.1 Policies, Laws and Regulations with Which the Study Complies ....................................... 82 
13.2 Informed Consent .................................................................................................................. 82 
13.2.1 Explanation to the Patients ............................................................................................ 82 
13.2.2 Informed Consent ........................................................................................................... 83 
13.2.3 Protection of Personal Information and Patient Identification ................................... 83 
13.3 Protection of Personal Information and Patient Identification .......................................... 84 
13.3.1 Purposes of Using Personal Information, Items to Be Used and Methods of Use ...... 84 
13.3.2 Secondary Use of Data ........................................................................................................ 84 


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13.3.3 Safety Management Responsibility System .................................................................. 85 
13.3.4 Handling of Disclosure of the Patients’ Information ................................................... 85 
13.4 Approval of the Institutional Review Board (IRB) ............................................................. 85 
13.4.1 Approval at the Start of the Study ................................................................................ 85 
13.4.2 Approval of the IRB for the Appropriateness of Continuing the Study ..................... 85 
13.4.3 Changes in the Contents of the Protcol ......................................................................... 85 
13.4.4 Categories of Changes in the Contents of the Protocol ................................................ 86 
13.4.5 Approval of the IRB at the Time of Protocol Revision ................................................ 86 
13.5 Management of Conflict of Interest (COI) ........................................................................... 86 
13.6 Compensation ........................................................................................................................ 87 
14 MONITORING AND AUDITS ................................................................................................... 88 
14.1 Monitoring ............................................................................................................................. 88 
14.2 Protocol Deviations and Violation ........................................................................................ 88 
15 Special considerations ........................................................................................................................ 89 
15.1 Retention of Records ............................................................................................................ 89 
15.1.1 Sponsor-investigator ....................................................................................................... 89 
15.1.2 Study Sites ................................................................................................................................... 89 
15.2 Completion of the Study ........................................................................................................ 89 
15.3 Discontinuation at the Study Site ........................................................................................ 89 
15.4 Interruption of the Study and Discontinuation of the Entire Study .................................. 90 
15.4.1 Interruption of the Study ............................................................................................... 90 
15.4.2 Discontinuation of the Entire Study .............................................................................. 90 
15.5 Accompanying research ........................................................................................................ 90 
16 Research organization .................................................................................................................. 92 
16.1 Main research group of this trial .......................................................................................... 92 
16.2 Funding of the present trial................................................................................................... 92 
17 Ownership of the trial outcomes and announcement of the trial results................................... 93 
18 References ..................................................................................................................................... 94 


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1. Objectives 
 
To examine the safety and tolerability of repeated dosing of regorafenib and nivolumab in patients 
with unresectable recurrent solid tumors who are refractory or intolerant to standard chemotherapy, 
and to determine the MTD and RD of the drugs when used in combination therapy. 
 
Dose-escalation cohort (an additional one to two institutions are planned for the expansion cohort) 
The safety of regorafenib and nivolumab combination therapy will be evaluated in patients with 
unresectable recurrent solid tumors who are refractory or intolerant to standard chemotherapy to 
determine the RD of regorafenib when used in combination therapy. 
 
Expansion cohort 
An exploratory evaluation of the efficacy and safety of the combined treatment will be performed on 
the basis of the RD found in the dose-escalation cohort. 
 
Primary endpoint: 
The safety of combination regorafenib and nivolumab combination therapy will be evaluated in 
patients with unresectable recurrent solid tumors who are refractory or intolerant to standard 
chemotherapy to determine the MTD and RD of regorafenib on the basis of the DLT when used in 
combination therapy. 
 
Secondary endpoints: 
• Safety 
- According to the "Common Terminology Criteria for Adverse Events (CTCAE) v4.03-JCOG) 
[CTCAE v4.03 / MedDRA v12.0]" (hereinafter referred to as CTCA v4.03 ), the incidences and 
types of adverse events that occur during treatment will be evaluated. 
 
• Efficacy 
- ORR（Objective Response rate） according to "New guideline for judgment of therapeutic effect 
of solid cancer (RECIST guideline) - Revised version 1.1 - Japanese translation JCOG version ver. 
1.0 (hereinafter referred to as RECIST version 1.1) and immune - related RECIST (hereinafter, 
irRECIST). 
- PFS（Progression Free survival） 
- OS（Overall survival：OS） 
- DCR（Disease Control rate） 


16 
 
Exploratory items 
Tests of various biomarkers 
Furthermore, for this exploratory research, a separate protocol will be prepared and implemented 
as accompanying research. Moreover, the results will not be included in the clinical study report. 


17 
 
2. Background 
 
2.1 Patient epidemiology 
The term “cancer” indicates a disease in which abnormal cells (cancer cells) divide uncontrollably. 
Cancer cells arise when the genes of normal cells become damaged. In Japan, cancer has been the 
leading cause of death for over 30 years1. In a survey conducted in 2013, approximately 365,000 
people died due to cancer that year, and it was reported that 26% of all men (1 in 4 individuals), and 
16% of all women (1 in 6 individuals) died of cancer2. Furthermore, the mortality rate of cancer 
patients increases with age and it is reported that from 60 years of age onwards, the rate of 
cancer-related death increases for both men and women1. 
Cancer can arise in any part of the body. In general, cancer nomenclature is derived from the 
classification according to the organ and tissue of origin. Cancers arising from epithelial cells and 
nonepithelial cells (e.g., interstitial cells) are called solid cancers (e.g., lung cancer, gastric cancer, 
colorectal cancer, and osteosarcoma), whereas those arising from the hematopoietic system are 
called hematological cancers (e.g., leukemia). In Japan, cancers that carry a high mortality rate 
(>30,000 individuals per year) include lung cancer (approximately 73,000 individuals), gastric 
cancer (approximately 49,000 individuals), colorectal cancer (approximately 48,000 individuals), 
pancreatic cancer (approximately 31,000 individuals), and liver cancer (approximately 30,000 
individuals), with solid cancers accounting for the majority of cancer-related deaths3. Solid cancers 
can invade and spread from the primary tumor to other organs and tissue in the body. Solid cancers 
exhibiting invasion or metastasis are called advanced or metastatic solid cancer. The prognosis of 
patients with solid cancer generally varies according to the cancer stage (e.g., tumor size, invasion 
depth, and presence or absence of metastasis). In highly advanced or metastatic solid cancer, the 
prognosis is poor. 
 
2.2 Treatment of patients 
The ultimate goal of cancer treatment is to prolong the survival of the patient. There are three 
main treatments for solid cancer, which include “surgery (surgical treatment)” and “radiotherapy” for 
localized treatment, and “pharmacotherapy (anticancer chemotherapy and hormone therapy)” for 
systemic treatment. Localized treatment is used when the lesion is limited to the primary onset site, 
and if no recurrence is observed, recovery can be expected. By contrast, systemic treatment is used 
when cancers (e.g., advanced or metastatic solid cancers) invade or metastasize to other organs and 
tissues. This is because with advanced or metastatic solid cancers, it is difficult to remove all the 
lesions using localized treatment. The effect of pharmacotherapy for advanced or metastatic solid 
cancers differs depending on the cancer type. Thus, the standard treatment (treatment system) differs 
according to the type of cancer according to the results of several clinical trials. However, some 
types of advanced and metastatic solid cancers are rarely reported in clinical trials and have no 


18 
 
established standard treatment. Furthermore, with the exception of some cancers (e.g., testicular and 
ovarian cancer), it is difficult to achieve a cure for most advanced or metastatic solid cancers despite 
standard treatment. As a result, patients with advanced or metastatic solid cancer who do not recover 
with pharmacotherapy have no treatment option other than palliative care, which ultimately leads to 
death. Multiple clinical trials are therefore currently underway to test the efficacy of new anticancer 
agents for prolonging the survival of patients with advanced or metastatic solid cancer. 
 
2.3 Immunotherapy for patients 
In recent years, “immunotherapy” has been attracting attention as the fourth treatment method for 
advanced or metastatic solid cancer4. Immunotherapy is a treatment method used to remove the 
tumor via the human innate immune system. Various immunotherapies have been investigated, such 
as vaccine therapy using cancer antigen peptides and dendritic cells, and treatment using immune 
response-activating cytokines (e.g., interferon [IFN]-α, IFN-γ, and interleukin [IL]-2); however, the 
efficacy of such treatments has only been observed in some patients5. This is likely attributable to the 
tumor microenvironment inhibiting the antitumor immune response5. The tumor microenvironment 
is invaded with immune cells, including natural killer (NK) cells, dendritic cells, and T cells, which 
have a potent antitumor action and are responsible for the antitumor immune response that inhibits 
tumor growth. 
Cancer cells have a wide variety of immunosuppressive mechanisms that are employed to evade 
the antitumor immune response6. Some notable examples include suppressive mechanisms whereby 
immune cells recognize cancer cells (decreased expression of cancer antigens and major 
histocompatibility complex-class I), expression of various immunosuppressive molecules (e.g., 
indoleamine-2, 
3-dioxygenase, 
cytotoxic 
T 
lymphocyte-associated 
antigen-4 
[CTLA-4], 
programmed cell death-ligand 1 [PD-L1], IL-10, and tumor growth factor-β), and the induction of 
immunosuppressive cells (e.g., myeloid-derived suppressor cells [MDSCs] and regulatory T cells)6. 
The antitumor immune response could potentially be activated by inhibiting these molecules that 
suppress the antitumor immune response, as well as the function of immunosuppressive cells. 
Treatments targeting immunosuppressive mechanisms that have resulted in remarkable clinical 
outcomes for several types of cancer include immune checkpoint inhibitors, such as 
anti-PD-1/PD-L1 and anti-CTLA-4 antibodies. Several agents are already approved by the US Food 
and Drug Administration as treatments for several types of cancer, including malignant melanoma 
and lung cancer. Additionally, in Japan, nivolumab (an anti-PD-1 antibody) has been approved for 
malignant melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma. Moreover, 
ipilimumab (an anti-CTLA-4 antibody) has been approved for malignant melanoma. For other solid 
cancers (e.g., gastric cancer8 and hepatic cell carcinoma9), clinical developments are underway and 
efficacy has been reported. However, the immunosuppressive mechanisms of cancer cells vary 


19 
 
greatly. The effect of immunotherapeutic agents is thus limited, and it is considered unlikely that all 
patients with solid cancer will benefit from of a single therapeutic agent. A trial is proposed to 
further activate the antitumor immune response and enhance drug efficacy by combining therapeutic 
agents that inhibit immunosuppression while simultaneously eliminating several immunosuppressive 
mechanisms. Clinical studies are actively underway to this end10. 
 
2.4 Rationale behind treatment plan setting 
2.4.1 Trial regimen 
As mentioned before, although immune checkpoint inhibitors exhibit a certain antitumor effect 
against solid cancers, the response rate to a single agent is only 10%–40% and the number of 
patients who respond to treatment remains limited. One reason for this is that the number of 
regulatory T cells, MDSCs, and tumor-associated macrophages is considered to increase as cancer 
progresses. In fact, nivolumab likely increases the activity of tumor-cell-specific T cells present 
locally at the tumor site by binding to PD-1 on the surface of activated T cells and removing the 
immunosuppressive signal of PD-L1/PD-1; however, in clinical trials of malignant melanoma 
patients receiving combination vaccine therapy, the post-treatment level of peripheral blood 
regulatory T cells was found to be increased in patients with progressive disease (PD) compared with 
patients with complete response (CR), partial response (PR), or stable disease (SD)11. Furthermore, 
in a case study using gastric cancer specimens administered anti-PD1 antibodies, it was similarly 
suggested that the proportion of localized regulatory T cells tended to be higher in patients with a 
poor response to treatment (data not published). This suggests that inhibiting the function of 
immunosuppressive cells could improve the efficacy of immune checkpoint inhibitors. 
Angiogenic factors (vascular endothelial growth factor: VEGF) are considered to be involved in 
the production of regulatory T cells, MDSC, and tumor-associated macrophages. It has therefore 
been reported that the suppression of VEGF or VEGF receptors (VEGFR) inhibits the production of 
these immunosuppressive cells and increases localized T-cell invasion of the tumor12-15. Similarly, it 
has been reported that sunitinib and sorafenib, which are multikinase inhibitors that block signals 
downstream of VEGFR, suppress regulatory T cells and MDSCs16-18, and activate antigen-presenting 
cells19. In the studies conducted at our hospital, the analysis of biopsy tissue specimens before and 
after regorafenib administration has revealed that the ratio of regulatory T cells decreases from 
27.2% to 13.6%, which suggests that regorafenib decreases the production of immunosuppressive 
cells as mentioned before. On the other hand, it has also been reported that the administration of 
selective RAF and MEK inhibitors increases T-cell invasion of tumors20, 21. RAS/RAF pathway 
inhibitors are thus expected to enhance the effect of immune checkpoint inhibitors. 
According to the findings described above, the combined effect of multi-kinase inhibitors that 
exert both an antiangiogenic effect and RAF-inhibitory action together with immune checkpoint 
inhibitors is promising. 


20 
 
In renal cell carcinoma, trials are underway regarding the combined effect of immune checkpoint 
and antiangiogenic agents. In particular, a phase I trial of nivolumab in combination with 
pazopanib/sunitinib is underway. In this trial, a high response rate has been observed in the sunitinib 
combination therapy group (52%) and the pazopanib combination therapy group (45%)23. 
We therefore believe that by combining nivolumab and regorafenib, we can expect a greater 
activation of the antitumor immune response and antitumor effect compared with the therapeutic 
effect of a single agent, and we have planned the present trial accordingly. 
 
2.5 Nivolumab 
Nivolumab, manufactured by Ono Pharmaceutical Co., Ltd., and Medarex (currently 
Bristol-Myers Squibb Co. [BMS Co.]), is an anti-PD-1 human monoclonal antibody (programmed 
cell death-1 [otherwise known as CD279]). It is under clinical development by Ono Pharmaceutical 
and BMS, and has been approved for manufacture and sale in Japan, the US, and Europe for the 
treatment of malignant melanoma. PD-1 (CD279) is a 55-kDa type-1 transmembrane protein that 
belongs to the CD28 family of T-cell costimulatory receptors, including CD28, CTLA-4, ICOS, and 
BTLA of the immunoglobulin superfamily. PD-1 is highly expressed on activated T cells and B cells. 
Furthermore, PD-1 expression is also found in memory T-cell subsets, but the level of expression 
varies. Two PD-1-specific ligands have been identified: PD-L1 (B7-H1 or CD274) and PD-L2 
(B7-DC or CD273). In mice and humans, T-cell activation is found to be negatively regulated when 
PD-L1 and PD-L2 bind to PD-1. 
Nivolumab is expected to exert an antitumor action by inhibiting the binding of PD-L1 and 
PD-L2 to PD-1, thereby blocking the PD-1 signal to inhibit T-cell activation, consequently resulting 
in T-cell activation within the tumor microenvironment. Under the commercial name of “Opdivo®”, 
nivolumab was approved on July 4, 2014 as a therapeutic agent for curatively unresectable 
malignant melanoma. Furthermore, on December 22, 2014, nivolumab was approved in the US as a 
therapeutic agent for unresectable or metastatic malignant melanoma. 
 
2.5.1 Summary of nonclinical trials of nivolumab 
Nivolumab is a human monoclonal antibody against human PD-1. It is produced by recombinant 
DNA technologies using Chinese hamster ovary cells. For the bulk drug substance, nivolumab is an 
aqueous solution in the form of a clear to opalescent, colorless to pale yellow liquid that may contain 
some fine particles. The preparation is provided as an aqueous injection with 100 mg of nivolumab 
contained per vial, and is stored in a dark environment at 2°–8°C. 
Nivolumab binds specifically to PD-1, and shows a high binding affinity to human and monkey 
PD-1, which is demonstrated by KD values of 3.06 nmol/L and 3.92 nmol/L, respectively. In vitro, 
nivolumab inhibits the binding of PD-1 to PD-1 ligands (PD-L1 and PD-L2), and in a human mixed 
lymphocyte reactions, it has increased both T-cell proliferative capacity and IFN-γ production. 


21 
 
Nivolumab was shown to increase the amount of IFN-γ produced in response to antigen stimulation 
in a dose-dependent manner in an assay in which human peripheral mononuclear cells obtained from 
donors with a history of cytomegalovirus (CMV) infection were restimulated using CMV antigens. 
Furthermore, in monkeys inoculated with HBsAg, SKMel, and dinitrophenyl-Ficoll, nivolumab 
increased the specific antibody titers for the SKMel cell line. Several syngeneic tumor-bearing 
mouse models have shown that the anti-murine PD-1 antibody 4H2 delays tumor growth, which 
confirmed the antitumor effect of anti-PD-1 antibodies that inhibit PD-1 from binding to PD-1 
ligands. It is therefore thought that nivolumab exerts an antitumor effect by blocking PD-1 from 
binding to PD-1 ligands and increasing antigen-specific T-cell activity, thereby enhancing the 
anticancer immune response. 
When nivolumab was administered in a single intravenous dose to conscious monkeys, no effect on 
general symptoms, body temperature, heart rate, blood pressure, and electrocardiography was 
observed up to a dose of 50 mg/kg. Moreover, in a 13-week repeat-dose toxicity study using 
monkeys, no effect was seen in the central nervous system, cardiovascular system, or respiratory 
system in observations of general health and internal medical tests. 
When monkeys received a single intravenous injection of 1, 10, or 50 mg/kg of nivolumab, the area 
under the curve (AUC) for serum concentrations of nivolumab generally exhibited a dose-dependent 
increase. 
The steady-state volume of the distribution was comparable to that of plasma volume, which 
indicated that nivolumab is primarily distributed in the circulating blood. The serum concentrations 
of nivolumab in anti-nivolumab antibody-positive patients were lower than those in anti-nivolumab 
antibody-negative patients. In a reproductive and developmental toxicity study using pregnant 
monkeys, nivolumab was found in the serum of newborn animals, which suggested that nivolumab 
may be transferred to fetuses via the maternal placenta. 
In the study of intravenous single-dose toxicity using monkeys, no death or toxicity changes were 
seen at a maximum dose of 10 mg/kg. In the study of intravenous repeat-dose toxicity using monkeys, 
no nivolumab-associated toxicity changes were observed at the maximum dose of 50 mg/kg given 
once a week for 4 weeks or when administered twice a week for 13 weeks. The no-observed 
adverse effect level was thus deemed to be 50 mg/kg/dose. Furthermore, these studies also found no 
changes suggestive of localized irritation at the site of injection or surrounding area for a nivolumab 
concentration of up to 10 mg/mL. 
In an extended study of prenatal and postnatal development using pregnant monkeys, ≥10 mg/kg 
of nivolumab resulted in an increase in the mortality rates of embryos, fetuses, and newborns during 
the third trimester; however, no effect on the teratogenicity, neonatal growth, behavior, or immune 
function was observed. 
In a cross-reactivity study using normal tissues from monkeys and humans, the results revealed a 


22 
 
positive reaction to the cell membrane of lymphocytes in monkeys and humans reported to express 
PD-1. Furthermore, as an unintentional response, a positive reaction was observed in the cytoplasm 
of pituitary endocrine cells in monkeys and humans; however, nivolumab is an antibody preparation 
and does not traverse the cell membrane. This means that nivolumab is not considered to act directly 
on the cytoplasm of pituitary endocrine cells. Moreover, in the 4-week and 13-week repeat-dose 
toxicity study using monkeys, no abnormalities were observed in pituitary hormones, pituitary organ 
weights, or in histopathological test findings. 
In the presence of effector cells (using human peripheral blood mononuclear cells [PBMC], and 
human complement, nivolumab did not exhibit antibody-dependent-cellular cytotoxicity against 
activated human CD4+ T cells or complement-dependent cytotoxicity. Moreover, nivolumab did not 
affect the cytokine production in whole blood derived from humans. 
Ipilimumab (a human anti-CTLA-4 monoclonal antibody) and BMS-986061 (an anti-LAG-3 
monoclonal antibody) were also administered intravenously in combination with nivolumab to 
monkeys for 4 weeks. This resulted in inflammatory changes within the colon and central nervous 
system that were not observed with nivolumab monotherapy, suggesting that the combined use of 
nivolumab and agents that activate T cells could excessively increase T-cell immune responsiveness 
to regorafenib. 
 
2.5.2 Summaries of clinical trial data and known or potential risks and benefits to subjects 
Ono Pharmaceutical and BMS have conducted phase I, phase II, and phase III clinical trials in 
cancers, such as NSCLC, malignant melanoma, renal cell carcinoma, and esophageal cancer for 
examining the efficacy, safety and pharmacokinetics of nivolumab. Clinical trials are currently 
underway for nivolumab monotherapy as well as nivolumab in combination with chemotherapy, 
molecular-targeting agents, as well as other immunotherapies. 
The pharmacokinetics of nivolumab when administered as a single dose were found to be linear 
and dose-dependent in the range of 0.3–10 mg/kg. The pharmacokinetics of nivolumab when 
administered repeatedly were also linear and exposure increased in a dose-dependent manner in the 
range of 0.1–10 mg/kg. Both the elimination and distribution of nivolumab appeared similar 
irrespective of the dose. Moreover, a population pharmacokinetics (PPK) analysis (interim data) 
revealed that in the range of 0.1–10 mg/kg, nivolumab clearance was independent of the cancer. 
Approximately 12,300 subjects have received Nivolumab as a single dose of Nivolumab or in 
combination with other treatments. Frequent adverse events were fatigue, diarrhea, nausea, anemia, 
diarrhea, many of which were mild (Grade 1 to 2). Adverse events of altitude (Grade 3 to 4) that can 
not deny the causal relationship with investigational drugs are fatigue, anemia, m which is reported 
to rise in AST / ALT, and its frequency is relatively small in many studies. As described in Section 
6.3.2, adverse events due to immunologic factors are also observed, with pneumonitis, colitis, 
hepatitis, pituitaryitis, nephritis and abnormal thyroid function as the main ones. 


23 
 
In nivolumab monotherapy, no major difference was found in the safety profile of each cancer type, 
and no dose-dependence was observed in the incidence, severity, or causality of adverse events. On 
the other hand, in patients with NSCLC, a numerically higher incidence of inflammatory lung 
disease was seen as an adverse event compared with that of patients with other types of cancer. This 
is attributable to the fact that in patients with NSCLC, it can be difficult to determine changes, as 
well as the presence or absence of a relationship with nivolumab, according to lung symptoms and 
radiographic findings. 
Clinical trials currently underway involve examining the safety of nivolumab when used in 
combination with other agents, including ipilimumab, cytotoxic chemotherapy, angiogenesis 
inhibitors, and molecular-targeting agents. Among these trials, the most prioritized combination 
under development is nivolumab + ipilimumab for NSCLC, malignant melanoma, and renal cell 
carcinoma. Thus far, the combination of both agents has demonstrated a safety profile that is 
comparable to that shown by each agent when used alone; however, in some instances the incidence 
of adverse events is higher with combination therapy. 
The efficacy and safety data found in various clinical trials that have been completed or are 
ongoing in Japan and elsewhere is noted in the latest investigator’s brochure. Furthermore, it has 
been reported that some patients require long-term high-dose adrenocorticosteroid treatment or the 
administration of immunosuppressants to treat adverse events in which a causal relationship with 
nivolumab cannot be ruled out. In addition, although the incidence is rare, there have been some 
reported cases of patients who have developed opportunistic infections caused by treatment with 
immunosuppressants. In particular, one case involved a male patient with NSCLC receiving 
nivolumab combined with chemotherapy that developed corticosteroid-responsive pneumonitis. 
Immediately following the completion of treatment with corticosteroids, the recurrence of 
respiratory symptoms was observed. As the result of a subsequent lung biopsy, invasive aspergillosis 
was diagnosed and no inflammatory findings (pneumonia) were observed in the lungs. This patient 
died approximately 1 week after the diagnosis of invasive aspergillosis. In another case, a female 
patient with NSCLC developed corticosteroid-responsive pneumonitis after receiving nivolumab 
monotherapy for >24 weeks. Thereafter, the patient exhibited recurrence of respiratory symptoms, 
and as a result of a lung biopsy, aspergillus-related pneumonia was diagnosed without any findings 
of inflammation in the lungs (pneumonia). This patient recovered with antifungal treatment. The 
final case was of a male patient with renal cell carcinoma who, during treatment with nivolumab in 
combination with pazopanib, developed corticosteroid-responsive pneumonitis. The patient’s 
condition improved while receiving treatment with high-dose corticosteroids for >2 months; 
however, the symptoms subsequently recurred. Examination of a specimen obtained by 
bronchoscopy led to a diagnosis of Pneumocystis jirovecii pneumonia. The patient made a complete 
recovery with antimicrobial therapy. 


24 
 
 
2.5.3 Japanese phase I trial of malignant melanoma 
The safety and tolerability of nivolumab single-dose therapy and repeat-dose therapy administered 
intravenously in patients with malignant melanoma has been examined in a nonblinded, 
dose-escalation study. This study has been completed, and the data obtained as of July 26, 2013 has 
undergone an interim analysis for a total of 17 patients (three patients in the 1-mg/kg group, five 
patients in the 3.0-mg/kg group, six patients in the 10-mg/kg group, and three patients in the 
20-mg/kg group). With regard to severe adverse events, the cutoff data was tabulated on July 26, 
2013. With regard to safety, severe adverse events were observed in four out of 17 patients (23.5%). 
Severe adverse events that undeniably had a causal relationship with the investigational drug 
included dehydration in one patient in the 10-mg/kg group; however, this adverse event was 
alleviated with treatment. During the period of the study itself, there were no deaths because of 
nivolumab in any of the groups. In terms of efficacy, the antitumor effect was determined in 
accordance with the RECIST guidelines version 1.0, and a CR was observed in one out of 17 
patients (5.9%), a PR in two patients (11.8%), and SD in three patients (17.6%). Of these responses, 
CR was observed in one patient with malignant melanoma in the 3.0-mg/kg group, whereas PR was 
observed in one patient with colorectal cancer in the 1-mg/kg group and one patient with thyroid 
cancer in the 10-mg/kg group. 
The pharmacokinetics of an intravenous single dose of nivolumab were verified in a total of 17 
patients administered nivolumab. AUC up to day 21 after nivolumab injection (AUC21 day) 
increased in a dose-dependent manner within the investigated dose range of 1–20 mg/kg. The peak 
serum concentration (Cmax) of nivolumab generally increased dose-dependently within the dose 
range of 1–10 mg/kg; however, in the 20-mg/kg group, a major difference was observed between the 
patients. In a comparison of the Cmax and AUC21 day of the CA20901 (phase I ascending dose trial 
of nivolumab in patients with treatment-refractory and recurrent malignancy [e.g., NSCLC, 
colorectal cancer, renal cell carcinoma, malignant melanoma, and metastatic castration-resistant 
prostate cancer]) and the ONO-4538-0 (a phase I repeat-dose-escalation trial following on from 
nonblinded, single-dose administration of nivolumab in Japanese patients with advanced and 
recurrent solid cancers) trials, the pharmacokinetics of nivolumab were found to be comparable, 
indicating no ethnic differences in the pharmacokinetics of nivolumab. 
 
2.5.4 Japanese phase II trial of patients with malignant melanoma 
The safety and efficacy of intravenous repeat-dose nivolumab therapy (2 mg/kg) at 3-week 
intervals in malignant melanoma patients with a history of treatment was examined in a multicenter 
collaborative nonblinded controlled study. After obtaining approval for the manufacture and sale of 
the nivolumab as an effective treatment for “curatively unresectable malignant melanoma” on July 4, 
2014, the trial was changed to a post-marketing clinical trial (33-601). The data as of August 30, 


25 
 
2013 for all 35 patients was included in the interim analysis. In terms of safety, severe adverse events 
were observed in 17 out of the 35 patients (48.6%). Severe adverse events for which a causal 
relationship with the trial agent could not be ruled out were observed in five patients (14.3%), 
including liver damage in two patients (5.7%) as well as hypothyroidism, bacterial pneumonia, 
interstitial lung disease and psoriasis in one patient (2.9%) each. With regard to efficacy, the 
antitumor effect was determined in accordance with the RECIST guidelines version 1.0 in a total of 
the 35 patients administered nivolumab, and a response was observed in eight out of the 35 patients 
(ORR: 22.9%; 90% confidence interval [CI]: 13.4–36.2). The median PFS was 169.0 days (90% CI: 
72.0–277.0), and the median OS was 473.0 days (90% CI: 276.0–). 
 
2.5.5 Clinical efficacy in lung cancer patients 
The CA209057 and CA209017 trials are randomized phase III trials comparing nivolumab and 
docetaxel in patients with unresectable and metastatic nonsquamous NSCLC [CA209057], and 
squamous NSCLC [CA209017] who have received pretreatment with two types of chemotherapy, 
including platinum-based agents. The two trials have ended and the results have been reported. The 
endpoints for efficacy associated with the tumor response were evaluated by a clinical trial physician 
according to the criteria in the RECIST guidelines version 1.1. 
In patients with unresectable or metastatic nonsquamous NSCLC with a history of pretreatment 
(CA2090057), compared with docetaxel, nivolumab monotherapy resulted in a clinically and 
statistically significant improvement (hazard ratio [HR] = 0.73; 95.92% CI: 0.59–0.89; p = 0.0015 in 
a stratified log-rank test), and was associated with excellent OS24. In patients with unresectable or 
metastatic squamous NSCLC with a history of pretreatment (CA209017), compared with docetaxel, 
nivolumab monotherapy resulted in a clinically and statistically significant improvement (HR = 
0.59; 96.85% CI: 0.43–0.81; p = 0.0002 in a stratified log-rank test), and was also associated with 
excellent OS25. 
 
2.5.6 The clinical efficacy in malignant melanoma patients 
The CA209066 trial (phase III trial comparing nivolumab and decarbazine in patients with 
untreated B-RAF wild-type melanoma) has already ended, and the results have been reported. The 
endpoints for efficacy associated with the tumor response were evaluated by a clinical trial physician 
according to the criteria in the RECIST guidelines version 1.1. 
In patients with untreated B-RAF wild-type advanced (unresectable or metastatic) malignant 
melanoma, compared with decarbazine, nivolumab resulted in superior OS and showed a clinically 
and statistically significant improvement (HR = 0.42; 99.79% CI: 0.25–0.73; p < 0.0001). As 
secondary and exploratory endpoints, the results for the PFS, ORR, duration of response and time to 
response further supported the persistent and sustained antitumor activity of nivolumab in the same 
population26. 


26 
 
2.6 Regorafenib 
Regorafenib is a new oral diphenylurea multikinase inhibitor of angiogenic, stromal, and 
oncogenic kinases with potent antitumor activity demonstrated in preclinical trials, and a long-term 
sustained antiangiogenic effect observed on dynamic contrast-enhanced MRI. In biochemical kinase 
phosphorylation assays (50% inhibitory concentration [IC50] of 4–311 nM) and cell-based kinase 
phosphorylation assays (IC50 of 3–200 nM), regorafenib exhibits a potent inhibition of angiogenic 
kinases VEGFR 1-3, TIE2, and PDGFRβ, as well as fibroblast growth factor receptor 1. Furthermore, 
regorafenib demonstrates a potent inhibition of mutant oncogenic kinases involved in 
gastrointestinal stromal tumors (GIST) and thyroid cancer, including KIT (IC50 c-KITK642E = 22 
nM in cell-based assays) and RET (IC50 RETC634W to 10 nM in cell-based assays). Regorafenib 
also inhibits B-RAF located on RAS/RAF/MEK/ERK signal transduction pathways (IC50 of 
wild-type B-RAF = 28 nM and IC50 of B-RAFV600E = 19 nM in biochemical assays). Furthermore, 
regorafenib inhibits Raf-1 (IC50 = 2.5 nM) and p38 mitogen activated protein kinase (MAPK; IC50 
= 24 nM). In vivo, tissue sections from human colon cancer and a xenograft model of breast cancer 
showed a reduction in the microvessel area, Ki-67 staining, and pERK 1/2 staining, suggesting that 
regorafenib has antiangiogenic and proliferation-inhibitory actions. In several xenograft models (e.g., 
breast cancer, colon cancer, renal cancer, NSCLC, malignant melanoma, pancreatic cancer, thyroid 
cancer, and ovarian cancer), regorafenib inhibited tumor proliferation in a dose-dependent manner 
and also had a tumor-reducing effect in a model of renal and breast cancer27. 
 
2.6.1 Regorafenib clinical outcomes 
The clinical development of regorafenib began in July 2005. Several phase I, phase II, and phase 
III trials are underway to evaluate regorafenib for various types of advanced cancer. To date, clinical 
trials have been conducted in >1,100 patients treated with regorafenib for various types of cancer, 
including colorectal cancer (CRC), GIST, renal cell carcinoma (RCC), and hepatocellular carcinoma 
(HCC). Moreover, all these phase I and phase II trials revealed antitumor action and long-term 
stability. In the CORRECT study, a randomized, double-blinded, placebo-controlled phase III 
international trial in patients with metastatic CRC exhibiting disease progression following standard 
treatment, regorafenib in combination with best supporting care (BSC) was compared with a placebo 
in combination with BSC, and the primary endpoint was satisfied (i.e., there was a statistically 
significant improvement in the OS)28. The GRID trial was a similar international collaborative study 
involving 199 patients (PS: 0 or 1, including 17 Japanese patients) with unresectable or metastatic 
GIST who exhibited disease progression following treatment with imatinib and sinitinib; as a result, 
a significant prolongation of PFS was observed29. Furthermore, 85% of the placebo group (56 out of 
66 patients) crossed over to the regorafenib group following disease progression; however, 
regardless of this issue, the hazard ratio was 0.77, and the OS tended to be prolonged in the 
regorafenib group. The RESORCE trial evaluated the efficacy and safety of regorafenib in patients 


27 
 
with advanced liver cancer who have progressed on sorafenib treatment. Patients on regorafenib 
showed a 38% reduction in the risk of death and a 54% reduction in the risk of 
progression or death compared to placebo. PFS was 3.1 months with regorafenib and 1.5 
months with placebo, while OS was 10.6 months for regorafenib and 7.8 months with placebo. 
 
 
 
2.6.2 Summary of adverse events associated with regorafenib 
Approximately 4000 safety analysis reports that received Regorafenib are listed in the study drug 
summary. Therapeutic-related adverse events with an incidence of over 20% were hand-foot 
syndrome (45.7%), fatigue (40.9%), loss of appetite (35.7%), diarrhea (34.7%), high blood pressure 
(34.5% %), Weight loss (27.9%), fever (21.4%). Adverse events of grade 3 and above with an 
incidence of over 5% were high blood pressure (15.6%), hand and foot syndrome (14.9%), fatigue 
(10.3%), diarrhea (5.9%), asthenia, (5.8% (5.7%). Severe adverse events that occurred during 
treatment with an incidence of> 1% were severe adverse events (8.1%), fever (2.4%), abdominal 
pain (2.2%), dyspnea (1.4%), pneumonia (1.3% ), Diarrhea (1.2%), intestinal obstruction (1.1%). 
Although many of the deaths occurring within 30 days of Regorafenib administration and within 
30 days from discontinuation of treatment were disease progression, 65 cases of "adverse events not 
related to disease progression" or "toxicity related to investigational drugs" have been reported. Of 
17 of them, it is judged that the association with regorafenib cannot be denied. Among them, rectal 
and vaginal bleeding (1 case), pulmonary bleeding (1 case), pulmonary embolism (1 case), 
pulmonary sepsis (1 case), femoral hematoma (1 case), cardiac arrest (4 cases) , A cardiopulmonary 
arrest (1 case), a heart failure (1 case), a cerebral vascular attack (1 case), a cerebral hemorrhage (1 
case), a decrease in general health condition (1 case), sepsis (1 case), sudden death (1 case) It was 
acute liver failure (1 case). 
 
2.7 Treatment regimen in the present trial 
The treatment protocol in the present trial consists of nivolumab and regorafenib combination therapy. 
Nivolumab will be administered at a dose of 3.0 mg/kg given once every 2 weeks. Regorafenib will 
be administered orally as a single dose each day for 21 consecutive days with a 1-week washout 
period. One course will last 28 days, and will be repeated until the criteria for termination are 
satisfied. 
 
2.7.1 Rationale for setting the nivolumab administration route, dose, and treatment schedule 
In the phase I repeat-dose trial of nivolumab (CA209003) conducted overseas, patients with 
malignant melanoma were administered a 0.1–10 mg/kg dose intravenously, which was repeated at 
2-week intervals. The trial included 306 patients primarily with NSCLC, malignant melanoma, or 
RCC for whom nivolumab was considered to exhibit a potent antitumor effect at a dose of ≥3 mg/kg. 


28 
 
Regarding safety, in phase I trials of nivolumab monotherapy conducted in Japan and 
internationally (respective trial numbers: ONO-4538-01 and CA209003), the tolerability of an 
intravenous repeat-dose therapy administered every 2 weeks was confirmed up to a dose of 20 
mg/kg in Japan and 10 mg/kg internationally. According to these data concerning efficacy and safety, 
phase II and III trials have been conducted for nivolumab at a dose of 3 mg/kg (one dose 
administered every 2 weeks) in patients with NSCLC, malignant melanoma, and RCC. 
Thus, many clinical trials have been conducted that involve the administration of nivolumab at a 
dose per body weight (mg/kg). The results of the PPK analysis have shown that the 
pharmacokinetics of nivolumab are linear with a dose-dependent increase in the exposure level 
(range: 0.1–10 mg/kg) and no difference in pharmacokinetics was observed according to the type of 
cancer. 
The safety and tolerability of nivolumab up to a dose of 10 mg/kg has been confirmed, and the 
relationship between the exposure level and efficacy was relatively constant when administered at a 
dose of 3 mg/kg. To date, clinical trials for nivolumab monotherapy have shown that when 
administered for >60 min within a dose range of up to 10 mg/kg, the treatment can be administered 
safely and is event free over a long period. In a phase II trial in patients with advanced or metastatic 
RCC (CA209010), the dose was found to be associated with the incidence of localized reactions and 
hypersensitivity near the injection site (1.7% at 0.3 mg/kg, 3.7% at 2 mg/kg, and 18.5% at 10 
mg/kg); however, all events were grade 1 or 2 and manageable. The administration of nivolumab at 
3.0 mg/kg for 30 min corresponds to 30% of the dosage when administered at 10 mg/kg for 60 
minutes. It is therefore thought that there is no concern regarding safety compared with when 
nivolumab is administered at 10 mg/kg for 60 min. 
On the basis of the abovementioned findings, in the present trial, we chose to give nivolumab at an 
intravenous dose of 3.0 mg/kg repeated every 2 weeks, and set the administration time to at least 
25-40 min. 
 
2.7.2 Rationale for setting the regorafenib administration route, dose, and treatment schedule 
On the basis of the phase I clinical trial outcomes obtained from the results of the regorafenib 
phase I trials, regorafenib was administered at a gradually escalating dose from 10 to 220 mg, with 
an intermittent schedule (continuous administration for 3 weeks with a 1-week washout period over 
a 4-week cycle). Signs of antitumor activity were observed in the subjects administered a dose of 60–
220 mg. A reduction in the dose because of toxicity was required in eight out of 12 subjects who 
received a dose of 220 mg/day, whereas at the dose of 160 mg/day, only one out of 12 subjects 
required a dose reduction31. Therefore, according to the efficacy and toxicity data, the approved dose 
was 160 mg given once per day. However, the safety when used in combination with nivolumab was 
not confirmed. Consequently, in the present study, a dose-escalation cohort was included to 
determine the RD of regorafenib when used in combination with nivolumab. 


29 
 
2.8 Trial design 
The present trial consists of a dose-escalation cohort to verify the tolerability of nivolumab and 
regorafenib when used in combination for patients with solid tumors, and to examine the clinical RD. 
The trial also consists of an expansion cohort to examine the safety and efficacy when the clinical 
RD is administered for several advanced solid tumors. 
In the dose-escalation cohort, three patients with solid tumors will be administered 3.0 mg/kg of 
nivolumab once every 2 weeks and regorafenib daily for 21 days, with a 1-week washout period at 
dose of 80 mg (level 1), 120 mg (level 2), or 160 mg (level 3). As a general rule, one cycle will last 
28 days (day 1–28); however, in the event of treatment prolongation, the cycle period will be 
extended. The DLT evaluation period will be 28 days. Furthermore, for each level, three additional 
subjects will be added depending on the state of DLT. 
In the expansion cohort, the target subject sample will consist of approximately 30 patients who 
will be administered 3.0 mg/kg of nivolumab once every 2 weeks, and the clinical RD of regorafenib 
will be determined in the dose-escalation cohort. 
In both parts of the study, treatment can be continued until the criteria for termination are satisfied; 
however, in the dose-escalation cohort, the subjects’ consent must be obtained again for the 
continuation of treatment after completing the DLT evaluation period. 
The trial will proceed as follows for all subjects. After providing written informed consent to 
participate in the trial, each subject will undergo preliminary examination in the preceding 2 weeks 
(day −14 to −1) before receiving the investigational drug. Subjects who are enrolled in the trial will 
be admitted to the hospital the day that the administration of the investigational drug begins (cycle 1, 
day 1), and they will receive the investigational drug at the appropriate dose for each level. After 
completing the prescribed observations and tests on cycle 1 day 4, the subjects are allowed to be 
discharged. Furthermore, the subjects will be administered the investigational drug and undergo the 
prescribed tests on cycle 1 day 8, cycle 1 day 15, cycle 1 day 22, cycle 2 day 1, and cycle 2 day 15, 
after which they will undergo the test once every 2 weeks until the criteria for termination are 
satisfied. After treatment is discontinued, the subjects will undergo follow-up tests on days 30 after 
the final day of treatment. Thereafter, the survival of each subject will be investigated every 90 days. 
 
2.8.1 Setting of endpoints 
Primary endpoints 
In patients with unresectable recurrent solid tumors who are refractory or intolerant to standard 
chemotherapy, the safety and tolerability of a repeated dose of regorafenib and nivolumab will be 
evaluated, and the MTD and RD of the two drugs when used in combination will be examined. 
 
Dose-escalation cohort 
In patients with unresectable recurrent solid tumors who are refractory or intolerant to standard 


30 
 
chemotherapy, the safety of regorafenib and nivolumab combination therapy will be evaluated to 
determine the MTD and RD of regorafenib according to DLT when used in combination. 
 
Expansion cohort 
An exploratory evaluation of the efficacy and safety of the combination therapy will be performed 
on the basis of the RD found in the dose-escalation cohort. 
 
Secondary endpoints 
• Safety 
- According to the NCI- CTCAE version 4.0, the incidence and type of adverse events that occur 
during treatment will be evaluated. 
• Efficacy 
- ORR according to RECIST ver. 1.1, and irRECIST 
- PFS 
- OS 
- DCR 
 
 
Exploratory items (performed as accompanying research in the present trial): 
Tests of various biomarkers 
 
 
2.8.2 Planned number of enrollments 
Dose-escalation cohort: Three to six patients per level, for a total of 9–18 patients. 
Expansion cohort: Approximately 30 patients in total. 
If two or more cases of CR/PR or SD ≧ 4 months were observed in specific cancer types, we will 
consider adding around 10 patients with same cancer type in expansion cohort. 
 
2.9 Summary of the anticipated advantages and disadvantages of participation in this trial 
The present trial is a phase I trial designed to determine the optimal dose of regorafenib and 
nivolumab for concomitant use. Although it is difficult to predict the advantages that may be 
obtained, if the synergistic effect of the two drugs yields an antitumor effect, it will be beneficial to 
the participants. 
The anticipated disadvantages include any adverse events associated with regorafenib and 
nivolumab. To minimize the risk and disadvantages of adverse events, the data center together with 
the Data and Safety Monitoring Committee will monitor any adverse events in the present trial to 
determine whether or not they are within the expected range. These bodies will also conduct a 
thorough examination in the event that serious or unexpected adverse events occur, and adopt an 
appropriate system to take any necessary actions. 


31 
 
 
2.10 The significance of performing the present study as an investigator-led trial 
Nivolumab is a drug currently under development by Ono Pharmaceutical, and regorafenib is a 
drug currently under development by Bayer Healthcare Pharmaceutical. Both drugs have been 
approved for the treatment of some types of cancer; however, these drugs have yet to be approved 
for the majority of cancers. Plans are currently underway internationally to move forward with 
various combination therapies, such as immune checkpoint inhibitors, cytocidal drugs, and 
molecular-targeting drugs. At present, the two drugs are unapproved drugs of different companies, 
and there are no plans in Japan or internationally for the company-led development of combination 
therapy with nivolumab and regorafenib. Furthermore, by analyzing biomarkers in accompanying 
research, we hope to pursue the significance of simultaneously inhibiting the VEGF, MEK/ERK, and 
PD1 pathways, as well as the possibility of further combined uses for the two drugs. 
In the present trial, the safety of the use of regorafenib in combination with nivolumab will be 
confirmed. When it is confirmed that a combined effect can be expected with these two drugs, this 
combination therapy will be regarded as a promising new treatment strategy for use in combination 
with immune checkpoint inhibitors. 


32 
 
3 CRITERIA AND DEFINITIONS TO BE USED IN THE STUDY 
 
3.1 Staging Criteria 
Staging will be classified in accordance with the “TNM Classification of Malignant Tumours, 
7th Edition by the Union for International Cancer Control (UICC-TNM 7th edition).” 
Classification will be made in accordance with the staging method for main histological types 
(squamous cell carcinoma in the esophagus and adenocarcinoma in other primary organs) in 
each primary organ (see Appendix 1). 
 
 
3.2 Performance Status (Eastern Cooperative Oncology Group (ECOG) Classification) 
(See Appendix 1.) 
 
 
3.3 Assessment Criteria for AEs 
For event terms and grades of AEs, the “Common Terminology Criteria for Adverse Events 
(CTCAE) v4.0 – Japanese Translation by the Japan Clinical Oncology Group (JCOG)” 
[equivalent to CTCAE v4.03/MedDRA v12.0] will be used. In this study, they will be as 
operated by the JCOG. 
 
 
3.4 Assessment Criteria for Response Rate 
For the assessment of tumor response, the “New Response Evaluation Criteria in Solid Tumors 
(RECIST guideline), Revised version 1.1 - Japanese translation by the JCOG-: Revised RECIST 
guideline (version 1.1)” and the irRECIST (immune-related response criteria), which is the 
RECIST version 1.1 with partial revisions, will be used (see Appendices 2 and 3). 


33 
 
4 INCLUSION AND EXCLUSION CRITERIA 
 
4.1 Inclusion criteria 
1. 
Patients who provided written informed consent to be subjects in this trial 
2. 
Patients at least 20 years of age on the day of providing consent 
3. 
Dose-escalation cohort: Patients with histologically or cytologically confirmed advanced or 
metastatic solid tumors. 
Expansion cohort: Patients with histologically or cytologically confirmed advanced or metastatic 
solid tumors (gastric, colorectal, or hepatocellular cancer). 
4. 
Patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 
1 
5. 
Patients capable of taking oral medication 
6. 
Patients with evaluable or measurable lesions as per RECIST version 1.1 
7. 
Patients with adequate organ function at the time of enrollment as defined below: [Acceptable 7 
days examination before the same day of the registration date] 
• Neutrophil count ≥1500/mm3 
• Platelet count ≥10.0 × 104/mm3 (transfusion >2 weeks before testing permitted) 
• aspartate transaminase (AST), alanine transaminase (ALT) ≤100 U/L2.5-times the upper limit of 
normal (200U/L I patients with hepatocellular cancer ,or ≤250U/L in patients with liver 
metastasis) 
• Total bilirubin ≤1.5-mg/dL 
• Creatinine ≤1.5-times the upper limit of normal 
• Urinary protein: It satisfies one of the following (if any of the inspection criteria are satisfied, 
other examination may not be carried out) 
• 
(i) urinary protein (test paper method) is 2+ or less 
• 
(ii) UPC (Urine Protein Creatinine) ratio <3.5 
• 
(iii) 24-hour urine protein was measured, urinary protein ≦ 3500 mg 
• 
PT-INR: ≤ 1.5 (≦ 3.0 in case of anticoagulant administration) 
* It is Child A in the case of Expansion cohort's hepatocellular carcinoma 
8. 
For women who are likely to become pregnant (including those without menstruation due to 
medical reasons such as chemical menopause) Note 1, we agreed to double contraceptive Note 
2 for at least 5 months after the final administration of the investigational product from consent 
acquisition patient. Also, patients who agreed not to breast feeding for at least 5 months after 
the final investigational drug administration after acquiring consent. 
For men, patients agreeing to double contraceptive for at least 7 months after the final 
investigational drug administration from the time of starting investigational drug administration. 


34 
 
Note 1): A woman who is likely to become pregnant is a woman who has experienced 
menarche and is not undergoing sterilization surgery (such as hysterectomy, bilateral salpingo 
ligation or bilateral oophorectomy), a woman without menopause Everything is included. The 
definition after menopause shall be amenorrhea continuously for 12 months or more even 
though there is no noteworthy reason. Women who are using oral contraceptives or 
mechanical contraceptive methods (such as intrauterine contraceptive devices or barrier 
methods) are considered to be pregnant. 
Note 2): With regard to contraception, it is necessary to use two of the vasectomy or condom 
of a male patient or male, the uterine tube ligation of a female patient or the other woman, a 
contraceptive pessary, an intrauterine contraceptive device or an oral contraceptive I need to 
agree to heavy contraception. 
 
4.2 Exclusion criteria 
1. 
Patients who have undergone systemic chemotherapy, radiotherapy, surgery, hormone therapy, 
or immunotherapy <2 weeks before enrollment. Immune checkpoint blockade as pretreatment is 
permitted. 
2. 
Patients with a history of taking regorafenib. 
3. 
Patients with hypertension that is difficult to control (systolic blood pressure ≥150 mmHg and 
diastolic blood pressure ≥90 mmHg) despite treatment with several hypotensive agents 
4. 
Patients with acute coronary syndrome (including myocardial infarction and unstable angina), 
and with a history of coronary angioplasty or stent placement performed within 6 months before 
enrollment 
5. 
Patients with a large amount of pleural effusion or ascites requiring drainage. 
6. 
Patients with a ≥grade 3 active infection according to NCI-CTCAE version 4.03 
7. 
Patients with symptomatic brain metastasis 
8. 
Patients with partial or complete gastrointestinal obstruction 
9. 
Patients with interstitial lung disease with symptoms or signs of activity 
10. Patients who test positive for either anti-HIV-1 antibodies, anti-HIV-2 antibodies, anti-HTLV-1 
antibodies, hepatitis B surface antigen (HBsAg), or anti-hepatitis C virus (HCV) antibodies* 
*Patients who test positive for either anti-HBs or anti-HBc antibodies, and those who have 
HBV-DNA measurements greater than the detection sensitivity will also be excluded. (However, 
patients with hepatocellular carcinoma in the expansion cohort will not be excluded even if they 
test positive for HBsAg and anti-HCV antibodies.) 
11. Patients with concurrent autoimmune disease, or a history of chronic or recurrent autoimmune 
disease 
12. Patients who require systemic corticosteroids (excluding temporary usage for tests, prophylactic 


35 
 
administration for allergic reactions, or to alleviate swelling associated with radiotherapy) or 
immunosuppressants, or who have received such a therapy <14 days before enrollment in the 
present study 
13. Patients with a history or findings of ≥grade III congestive heart failure according to the New 
York Heart Association functional classification 
14. Patients with a seizure disorder who require pharmacotherapy 
15. Major surgical procedure or significant traumatic injury within 28 days before start of study 
medication. 
16. Patients undergoing major surgery (thoracotomy or laparotomy, etc.), laparotomy biopsy, 
trauma within 28 days before registration. The same day of the week before 4 weeks can be 
registered 
(However, in case of an artificial anastomosis without intestinal resection, it shall be within 14 
days before registration). 
17. Non-healing wound, non-healing ulcer, or non-healing bone fracture 
18. Patients with a history of hypersensitivity to any of the study drugs, similar drugs, or excipients. 
19. Pregnant women, lactating women or possibly pregnant women. 


36 
 
5 Enrollment 
 
5.1 Enrollment procedure 
Verification that the target patients meet all the eligibility criteria and none of the exclusion criteria 
will be performed; then the Web enrollment system will be used to perform the enrollment. 
 
■ Contact and reception hours for patient enrollment 
Notification of the Web enrollment URL and other information will be given via the separate “EDC 
input manual.” 
(Enrollment can be made 24 h a day. However, in the event that the site is inaccessible [e.g., for 
maintenance], notification will be given in advance). 
 
■ Contact for queries regarding enrollment: 
Data Management Office, Clinical Trial Support Division, National Cancer Center Hospital East 
TEL: 04-7133-1111 (Ext. 5106), E-mail: regonivo_core@east.ncc.go.jp 
Weekdays: 10:00–17:00 (closed on national holidays, Saturday and Sunday) 
■ Contact for queries regarding patient selection criteria: 
Trial coordinating (principal) investigator: Dr. Kohei Shitara 
Assistant Chief at the Department of Gastroenterology and Gastrointestinal Oncology, National 
Cancer Center Hospital East 
6-5-1, Kashiwanoha, Kashiwa, Chiba 277-8577, Japan 
TEL: 04-7133-1111 (ext. 91520), E-mail: kshitara@east.ncc.go.jp 
Coordinating investigator: Dr. Shota Fukuoka 
Exploratory Oncology Research & Clinical Trial Center, National Cancer Center 
E-mail: regonivo_core@east.ncc.go.jp 
 
5.2 Important notes regarding enrollment 
 
1) Enrollments after the initiation of the treatment protocol will not be permitted without exception. 
2) When the enrollment and eligibility checklist content is unsatisfactory, the enrollment will not 
be accepted until it is all the content is satisfied. 
3) After confirmation of eligibility, a registration number will be issued. Enrollment will be 
completed once the registration number has been issued. 
4) Except in the event of withdrawal of consent, including the refusal of the use of data in the trial, 
patients will not be removed from the trial (erased from the database) once they have been 
enrolled. In the event of a double registration, the information from the first enrollment 
(registration number) will be used. 


37 
 
5) When a misregistration or double registration is discovered, the data management office should 
be contacted as soon as possible. 
6) At the time of enrollment, in the event of an ongoing medical examination at another hospital or 
department, the attending physician is to be contacted and notified that the patient concerned is 
participating in the present trial. 


38 
 
6 Dosing schedule and combination therapy 
 
If the safety of the subject is not at risk, treatment and changes to treatment will be carried out 
in accordance with the content of this chapter. If a medical emergency is identified when the 
present protocol is followed, the treatment will be changed in accordance the medical judgment 
of the principal investigator (or subinvestigator) for the trial (hereinafter “principal investigator”). 
 
6.1 Protocol treatment 
In the present trial, the protocol treatment will consist of the investigational drug, nivolumab, 
used in combination with regorafenib. However, in the event that the termination criteria are satisfied 
for one of these drugs, the trial investigator can consider continuing the treatment protocol with 
either nivolumab or regorafenib monotherapy upon deliberation with the trial coordinating committee. 
The treatment protocol will commence within 14 days of enrollment, including the day of enrollment. 
Furthermore, in the event that administration of the investigational drug cannot be initiated within 14 
days of enrollment (including the day of enrollment), the trial coordinating committee is to be 
contacted to examine how the patient should be handled. 
The following terminology is used in the present protocol: 
• 
Termination: Administration of the investigational drug is not resumed. 
• 
Washout: Omission of one or more doses of the investigational drug and moving onto the 
next dosing schedule. 
• 
Washout period: The duration of time that the investigational drug is not 
administered. 
 
6.1.1 Dosing and administration method 
In the dose-escalation cohort, the stipulated doses for each level are shown in Table 6.1.1a. At 
least 1 day will be left between the initial starting day of the trial protocol (cycle 1 day 1) for the first 
and second patient in each level. The expansion cohort will be given the clinically RD determined on 
the basis of the results of the dose-escalation cohort. The method of determining the clinical RD is 
described in section 7.1.2. 
The dose administered to each individual subject will be calculated according to body weight at 
the time of enrollment. However, in the event of a change in body weight of >10% as measured on 
day 1 of each cycle compared with that at the time of enrollment, the dose will be calculated 
according to the new body weight. Thereafter, the same action will be taken, upon observation of a 
change of over 10% in body weight compared with the most recent body weight change. The 
administered dose (mg units) will be calculated and rounded to two decimal places. 


39 
 
 
Table 6.1.1a Doses of nivolumab and regorafenib 
 
Level 
Nivolumab dose 
Regorafenib dose 
Target number of subjects 
for the DLT evaluation 
1 
3.0 mg/kg 
80 mg/day 
3–6 
2 
3.0 mg/kg 
120 mg/day 
3–6 
3 
3.0 mg/kg 
160 mg/day 
3–6 
 
Regorafenib will be administered with water once per day after eating (low-fat meal 
recommended) at a dose of 80 mg (level 1), 120 mg (level 2), or 160 mg (level 3). Regorafenib will 
be given orally for 21 consecutive days, followed by a washout period of 7 days. In the event of 
withdrawal because of adverse events, the period of withdrawal will be included in the 21-day oral 
therapy period, and will be followed by a washout period of seven days. 
Nivolumab will be administered via intravenous infusion given once every 2 weeks at a dose of 
3.0 mg/kg over a 30 min period after 1 h (up to 2 h permissible) has passed because the oral 
administration of regorafenib in the morning. The dosing period will be set to as close to 30 min as 
possible (25–40 min) by the medical institution administering the treatment. 
For precautions regarding dosing, refer to “Patient instructions regarding the handling of the 
investigational drug.” 
 
From cycle 2 onward, the treatment will commence after verifying that the dosing criteria listed in 
section 6.3 have been satisfied. The start day for nivolumab will be defined as day 1, including the 
washout period even in the event of conflict with the criteria defined in 6.3, and one cycle will last 
28 days. If nivolumab is terminated and treatment is resumed as regorafenib monotherapy, the 
subsequent day of regorafenib resumption will be defined as day 1. In such an instance one cycle 
will also last 28 days. 
Treatment will continue until the “criteria for treatment termination” are satisfied. 
 
 
6.1.2 Recommended dose (RD) and transition to the expansion cohort 
In the present trial, the starting dose of regorafenib will commence from level 1 (80 mg/day), 
and tolerability of combination therapy with nivolumab (3.0 mg/kg at 2-week intervals) will be 
verified. One cycle will last 28 days and DLT will be evaluated using a 3 + 3 design for the 
following doses to verify tolerability. 
 
Level１ 
Regorafenib: Oral administration at a dose of 80 mg given once per day for 21 consecutive days, 


40 
 
with a 1-week washout period. 
Nivolumab: Given once every 2 weeks at a dose of 3.0 mg/kg via an intravenous infusion. 
 
 
When it is deemed that there is no problem with safety at the doses described above, tolerability will 
be verified at the level-2 dosages described below. 
 
Level 2 
Regorafenib: Oral administration at a dose of 120 mg/day for 21 consecutive days, with a 1-week 
washout period. 
Nivolumab: Given once every 2 weeks at a dose of 3.0 mg/kg. 
 
 
When it is deemed that there is no problem with safety at the doses described above, tolerability will 
be verified at the level-3 dosages described below. 
 
Level 3 
Regorafenib: Oral administration at a dose of 160 mg/day for 21 consecutive days, with a 1-week 
washout period. 
Nivolumab: Given once every 2 weeks at a dose of 3.0 mg/kg. 
 
 
After starting the trial, three cases are registered at level 1, and temporary case registration is 
suspended until safety evaluation of the first course is completed in all cases. If there are cases in 
which evaluation of DLT cannot be performed properly, such as being canceled due to reasons other 
than safety during the course of the first course, the necessary number of cases is appropriately 
added to the administration level. 
1) In cases where no DLT is observed in 3 cases, registration of the case is started at the next dose 
level, and the same procedure is repeated until MTD is reached with level 3 as the upper limit. 
2) When DLT is observed in 2 cases or more in 3 cases, the administration level is judged as MTD. 
3) If DLT is observed in 1 out of 3 cases, 3 further cases are additionally registered at the 
administration level (total 6 cases). When DLT is observed in 2 out of 6 cases, the administration 
level is judged as MTD. However, if there are two cases of DLT-expressing cases before the number 
of registered cases at the administration level reaches 6, the administration level is judged as MTD at 
that time point. 
4) If it is judged that MTD is exceeded, 6 cases of DLT evaluation are already carried out at the level 
one level below and if the DLT is 1 case or less of 6 cases, the dose is taken as MTD and RD. At the 
relevant dose, if only 3 people are evaluating DLT, add 3 cases (total 6 cases). When the number of 


41 
 
DLT is 1 or less out of 6, the dose is defined as MTD and RD. If it is judged that Level 1 exceeds the 
MTD, review the dose or consider stopping the trial. 
5) MTD should be the highest dose level of DLT expression less than 1 in 6 cases. 
 
 
Expansion cohort: Implemented using the RD estimated in the dose-escalation cohort. 
 
 
6.1.3 Definition of DLT 
As a general rule, DLT includes the observation of any of the side effects listed below during the 
DLT evaluation period and will ultimately be determined upon deliberation between the sponsor and 
the principal investigator of the trial. Furthermore, the opinion of the Data and Safety Monitoring 
Committee can be sought as required (refer to attachment 1: trial protocol [supplement]). 
 
• Hematotoxicity: 
–Persistent grade 4 neutropenia lasting ≥7 days; 
–When a neutrophil count of <1000/mm3 and fever of ≥38.0°C is observed for >2 days; 
–Grader 4 thrombopenia or thrombopenia associated with a hemorrhage requiring platelet 
transfusion. 
- Grade 3 thrombocytopenia with bleeding. 
 
• Non-hematotoxicity: 
–≥Grade 3 non-hematotoxicities. However, any of the following non-hematotoxicities will be 
deemed DLT when it is judged by the principal investigator or subinvestigator that treatment cannot 
be continued even with supportive therapy. 
 
≥Grade 3 diarrhea, nausea, vomiting, and loss of appetite for ≥5 consecutive days; 
 
≥Grade 3 electrolyte imbalance for ≥7 consecutive days; 
 
≥Grade 3 dermal toxicity for ≥7 consecutive days; 
 
≥Grade 3 T-Bil, AST (GOT) and/or ALT (GPT) elevations: In subjects with liver metastasis 
or liver cancer, elevated AST (GOT) and/or ALT (GPT) of >10 times the upper limit of the 
institutional reference value; 
 
Grade 3 or more immune related adverse event that lasts more than 8 days even after steroid 
therapy is applied. 
• General: 
When 70% of the planned regorafenib dose cannot be administered, and/or when one dose of 
nivolumab cannot be administered because of toxicity during the DLT evaluation period 
 
6.1.4 Target subjects for DLT evaluation 
For each level, at least three subjects will be enrolled, and the presence or absence of DLT will be 
evaluated during the DLT evaluation period. 
When it is determined that there is a subject who will not change levels, an additional subject will 


42 
 
be enrolled to evaluate the DLT determined in 6.1.3. 
Furthermore, among the enrolled subjects, those who meet the following conditions will be 
excluded from DLT evaluation: 
1) Subjects who are unable to receive regorafenib for ≥14 days in the first course for reasons 
other than toxicity. 
2) Subjects for whom sufficient data cannot be obtained to determine the DLT evaluation because 
of missing mandatory tests, etc. 
3) Cases in which adequate data for DLT evaluation judgment could not be obtained due to 
essential test defects 
 
Furthermore, among the participants who withdraw from regorafenib and nivolumab during the 
first course for reasons other than adverse events or who withdraw from treatment for a long period 
because of toxicities other than DLT, the decision to subject such patients to a DLT evaluation will 
be determined upon deliberation between the trial coordinating committee and the participating 
institution. 
 
6.1.5 Determining transition to the expansion cohort 
After completion of the final DLT evaluation period of the subjects in the dose escalating cohort, the 
decision to move the subjects into the expansion cohort will be determined once it is decided, upon 
deliberation between the sponsor and the principal investigator, that there are no problems associated 
with moving on. Furthermore, the opinion of the Data and Safety Monitoring Committee can be 
sought as required (refer to attachment 1: trial protocol [supplement]). 


43 
 
 
6.2 Criteria for the commencement and termination of the treatment protocol 
6.2.1 Criteria for terminating the treatment protocol 
The treatment protocol will be terminated when the participating subjects meet any of the following 
criteria: 
1) When an exacerbation of the underlying disease is observed (including marked exacerbation 
on diagnostic imaging, and clinically marked exacerbation). 
2) When the subject requests to terminate the treatment protocol. 
3) When treatment protocol-related grade 4 non-hematotoxicity is observed. 
(However temporary abnormalities in test values shall not apply). 
4) When nivolumab and regorafenib cannot be resumed for >28 days. 
5) When the conditions for the termination of the treatment protocol apply as stipulated in “7.3 
Criteria for changing the treatment protocol.” 
6) If the subject becomes pregnant. 
7) When follow-up is not possible. 
8) Death during the treatment protocol. 
9) When 54 doses of nivolumab have been completed. 
10) Termination following a CR. 
Following at least eight cycles of nivolumab (approximately 6 months), when a subject is 
deemed to exhibit CR on the basis of diagnostic imaging, and receives at least two cycles of 
nivolumab after the initial determination of CR, termination of nivolumab can be considered 
upon consultation with the trial coordinating committee. The decision to terminate or 
continue regorafenib administration after CR can be considered by the attending physician 
upon consultation with the trial coordinating committee, regardless of whether nivolumab is 
terminated or continued. 
11) Other instances when the attending physician judges it necessary to terminate the trial 
(including when treatment with other anticancer drugs, surgery, or radiotherapy not 
stipulated in the protocol is needed for lesions that are subject to evaluation). 
When, despite meeting the criteria for termination of the treatment protocol, there are clinical 
grounds that strongly suggest the efficacy of the treatment and there are reasons that justify the 
continuation of the protocol treatment, the decision shall be reconsidered with the trial coordinating 
committee on an individual basis according to the situation. 


44 
 
6.2.2 Data collection after treatment termination and the follow-up of subjects 
When the criteria for termination are satisfied, the treatment protocol will be terminated. The time, 
reason, and progress associated with termination will be recorded on a case report form (CRF), and 
the prescribed tests will be conducted during the following observation period. However, when the 
attending physician judges that various tests cannot be performed or are not required for ethical 
reasons or for the safety or benefit of the subject, such tests shall not apply. 
 
6.3 Criteria for changing the treatment protocol 
6.3.1 Criteria for changing the dose of regorafenib 
The safety profile of regorafenib has been established in the clinical trials noted above. The dose 
adjustments for regorafenib are according to the clinical trials conducted to date. Dose modifications 
are to be applied in 40 mg (one tablet) steps. When treatment with regorafenib is terminated because 
of any reason, the continuation of nivolumab monotherapy as the treatment protocol is permitted. 
The maximum daily dose is 160 mg. 
Table 6.3.1 Day dose of Regorafenib 
Level 
The dose of Regorafenib 
0 
40 mg/day(40 mg 1Tab) 
1 
80 mg/day(40 mg 2Tab) 
2 
120 mg/day(40 mg 3Tab) 
3 
160 mg/day(40 mg 4Tab) 
 
6.3.1.1 Dose adjustments for skin reactions of the hands and feet 
When skin reactions of the hands and feet occur during regorafenib treatment, dose adjustments 
will be made at the discretion of the principal investigator(or subinvestigator) with reference to 
“Table 3: Dose adjustments for skins reactions of the hands and feet.” Furthermore, in subjects who 
receive a dose reduction, when no ≥grade 2 rash or skin reaction of the hands and feet is observed at 
the decreased dose level throughout the subsequent cycle, the dose of the investigational drug can be 
increased to the starting dose at the discretion of the principal investigator (or subinvestigator). 
 
Table 3: Dose adjustments for skins reactions of the hands and feet 
Table Dose modifcation of hand-foot skin reaction 
 
NCI CTC Grade 
Dose adjustment 
Grade 2 
Painful erythema and swelling or discomfort of 
hands and feet that interfere with daily living 
Support supportive therapy as necessary. 
Take asleep until toxicity relieves to 
Grade 0 to 1. When dosing is resumed, 
the same dose or dose is administered at 
a level reduced by 1 dose. 
Grade 3 
Wet scaling of limbs, work ulcers, blistering, 
severe pain, or severe discomfort 
Wet scaling of limbs, work ulcers, 
blistering, severe pain, or severe 


45 
 
 
discomfort. 
 
 
 
6.3.1.2 Dose adjustment for hypertension 
When hypertension develops during regorafenib treatment, dose adjustments will be made at the 
discretion of the principal investigator (or subinvestigator) with reference to “Table 4: Dose 
adjustments for hypertension.” Hypertensive subjects require careful observation and it is strongly 
recommended to administer suitable hypotensive treatment during regorafenib treatment. The 
selection of hypotensive drug will be determined by the principal investigator (or subinvestigator) 
upon consideration of the treatment guidelines for each institution participating in the trial. 
Furthermore, in subjects who receive a dose reduction, when hypertension is controlled for at least 
one cycle, the dose of the investigational drug can be increased to the starting dose at the discretion 
of the principal investigator (or subinvestigator). 
 
Table 4: Dose adjustment for hypertension 
 
NCI-CTCAE grade 
Dose adjustment 
Grade 2 
Systolic blood pressure of 140–159 mmHg 
and/or diastolic blood pressure of 90–99 mmHg, 
or when the former is normal but diastolic blood 
pressure is increased > 20 mmHg and 
accompanied by symptoms. 
Continue the dosing. If poorly controlled, 
consider a dose reduction. 
When accompanied by symptoms, withdraw 
treatment until the subject recovers from the 
symptoms, and diastolic blood pressure is 
restored to <90 mmHg. When resuming 
treatment, continue at the same dose level. 
Grade 3 
Elevated systolic blood pressure of ≥160 mmHg 
and/or diastolic blood pressure of ≥100 mmHg, 
or pharmacotherapy of two or more types, and 
greater intensive therapy than before is needed. 
Withdraw treatment until the diastolic blood 
pressure is decreased below 90 mmHg and if 
there are accompanying symptoms, until the 
subject recovers from the symptoms. When 
resuming treatment, consider decreasing the 
dose. 
When hypertension cannot be controlled with the 
addition of new hypotensive drugs or with more 
intensive therapy, decrease the dose by one level. 
When grade 3 hypertension recurs despite 
decreasing the dose and hypotensive treatment, 


46 
 
 
decrease the dose further by one level. 
Grade 4 
Life-threatening (e.g., malignant hypertension, 
temporary or constant neuropathy, and 
hypertensive crises). 
Terminate the administration of the 
investigational drug. 
 
 
 
6.3.1.3 Dose adjustment for elevated AST, ALT, and T-Bil levels 
When an increase in AST, ALT, and/or T-Bil levels is observed during regorafenib treatment for 
which a causal relationship cannot be ruled out, the dose will be adjusted with reference to “Table 5: 
Dose adjustments for elevated AST, ALT, and T-Bil levels.” 
It is recommended to conduct liver function tests at least once a week until the liver function test 
results return to within the normal range or return to the grade at the time of enrollment. 
 
Table 5: Dose adjustment for elevated AST, ALT, and T-Bil levels 
 
NCI CTCAE Grade 
Expression 
times 
Dose adjustment 
Grade 2 
T-Bil exceeds 1.5 
times 
the 
normal 
value upper limit and 
3 times or less 
If 
AST 
or 
ALT 
exceeds 3 times the 
normal value upper 
limit and is 5 times 
or less 
Regardless of 
the number 
Continue administration and continue at 
least once a week for at least 4 weeks 
until T-Bil is less than 1.5 times the 
upper limit of normal value, AST or ALT 
is less than 3 times upper limit of normal 
value or recovered to Grade before 
administration, AST, ALT And T - Bil 
measurement should be carried out. 
Grade 3 
T-Bil 
exceeds 
3 
times 
the 
normal 
value upper limit and 
is 10 times or less 
If AST or ALT 
exceeds 5 times the 
normal value upper 
limit and is 20 times 
or less 
First time 
Regorafenib is withdrawn until T-Bil is 
less than 1.5 times the upper limit of 
normal value and AST or ALT is 
recovered to less than 3 times normal 
value upper limit or below registered 
Grade. 
When dosing is resumed, it is 
recommended to reduce the same 
amount or 1 level and measure AST, 
ALT and T-Bil once a week for a 
minimum of 4 weeks. 
Second time 
Discontinue administration. 
Grade 4 
T-Bil exceeds the 
normal value upper 
limit by 10 times 
AST or ALT is over 
20 times the normal 
value upper limit 
Regardless of 
the number 
Discontinue administration. 


47 
 
 
6.3.1.4 Resumption of regorafenib dosing 
When regorafenib is administered, if you develop diarrhea, fatigue, loss of appetite, nausea, 
vomiting, and other adverse events judged by your doctor as Regorafenib (excluding asymptomatic 
test values) that cannot deny the causal relationship with Regorafenib, “Table 6.3.1.4 Dose 
Adjustment for Other Adverse Events ", the investigational physician judges and adjusts the dose. 
 
Table 6.3.1.4 Dose Adjustment for Other Adverse Events 
NCI CTCAE Grade 
Possibility to continue 
administration 
Dose adjustment 
Grade 2 
Continue administration 
No change 
Grade 3 
Weigh out until recovering to 
Grade 2 or lower 
Reduce one level 
Grade 4 
Discontinue administration 
― 
 
 
 
6.3.2 Criteria for changing the nivolumab dosage 
Adverse events (irrespective of severity) associated with nivolumab exposure might be of 
immunological etiology. Such adverse events can occur immediately following the commencement 
of treatment with the investigational drug or several months after completion of treatment. For 
toxicities and severe or life-threatening adverse events with a causal relationship with nivolumab, the 
withdrawal and termination of nivolumab will be carried out in accordance with Table 6.3.2. For the 
guidelines regarding supportive therapy, including the use of corticosteroids, refer to section 6.3.2.1, 
and the investigator brochure (appendix 3 Management Algorithms). 
In accordance with the instructions given in this section, administration is withdrawn and 
administration resumed. Subjects whose resumption of Nivolumab and Regorafenib need to be delayed 
for more than 28 days from the scheduled start date will cease protocol treatment. However, 
administration of Regorafenib was discontinued, but when Nivolumab resumption is possible according 
to 6.3.2, protocol treatment can be restarted with Nivolumab alone. 
 
Table 6: Criteria for nivolumab withdrawal and termination 
 
Toxicity 
Grade 
requiring 
withdrawal 
Timing 
of 
treatment 
resumption 
after 
withdrawal 
Instance 
requiring 
nivolumab 
termination 
Diarrhea/colitis 
2–3 
Toxicity is returned to 
below grade 1 
Terminate nivolumab when the subject 
does not recover from toxicity within 12 
weeks of the last dose, or when 
corticosteroids cannot be decreased to 
below 10 mg/day of prednisolone 


48 
 
 
within 12 weeks. 
4 
Nivolumab termination 
Nivolumab termination 
Elevated 
AST, 
ALT, 
and/or 
bilirubin 
2 
Toxicity is returned to 
below grade 1 
Terminate nivolumab when the subject 
does not recover from toxicity within 12 
weeks of the last dose. 
3–4 
Nivolumab termination 
(see exceptions below)a 
Nivolumab termination. 
Type I diabetes 
(T1DM: 
when 
newly 
developed) or 
hyperglycemia 
T1DM 
or 3–4 
When 
clinically 
and 
metabolically stable 
Terminate nivolumab when the subject 
is not clinically and metabolically stable 
within 12 weeks of the last dose. 
Hypophystitis 
2–4 
Toxicity is returned to 
below grade 1. 
When 
endocrine 
hormone 
replacement 
therapy   has   been 
initiated. 
Terminate nivolumab when the subject 
does not recover from toxicity within 12 
weeks of the last dose, or when 
corticosteroids cannot be decreased to 
below 10 mg/day of prednisolone 
within 12 weeks. 
Hyperthyroidism 
3 
Toxicity is returned to 
below grade 1 
Terminate nivolumab when the subject 
does not recover from toxicity within 12 
weeks of the last dose, or when 
corticosteroids cannot be decreased to 
<10 mg/day of prednisolone within 12 
weeks. 
4 
Nivolumab termination 
Nivolumab termination 
Hypothyroidism 
Not 
stipulated 
When thyroid hormone 
replacement therapy 
has been initiated 
Infusion reaction 
2b 
Toxicity is returned to 
below grade 1 
Terminate nivolumab when toxicity 
develops 
despite 
appropriate 
pretreatment. 
3–4 
Nivolumab termination 
Nivolumab termination 
Pneumonitis 
2 
Toxicity is returned to 
below grade 1 
Terminate nivolumab when the subject 
does not recover from toxicity within 12 
weeks  of  the  last  dose,  or  when 


49 
 
 
corticosteroids cannot be decreased to 
<10 mg/day of prednisolone within 12 
weeks. 
3–4 
Nivolumab termination 
Nivolumab termination 
Renal 
impairment 
or 
nephritis 
2 
Toxicity is returned to 
below grade 1 
Terminate nivolumab when the subject 
does not recover from toxicity within 12 
weeks of the last dose, or when 
corticosteroids cannot be decreased to 
<10 mg/day of prednisolone within 12 
weeks. 
3–4 
Nivolumab termination 
Nivolumab termination 
All 
other 
toxicities with a 
causal 
relationship 
Intolerance 
or persistent 
2 
The decision to 
withdraw and resume 
nivolumab can be made 
at the discretion of the 
attending physician 
Terminate nivolumab when the toxicity 
persists after drug withdrawal and is not 
returned <grade 1 within 12 weeks from 
the last dose. 
3 or severe 
Toxicity is returned to 
below grade 1 
Terminate nivolumab when the subject 
does not recover from toxicity within 12 
weeks of the last dose, or when 
corticosteroids cannot be decreased to 
<10 mg/day of prednisolone within 12 
weeks. 
4 
Nivolumab termination 
Nivolumab termination 
Note: In the event that severe or ≥grade 3 side effects recur or when life-threatening toxicity 
develops, administration of the investigational drug will be terminated. 
a. In patients with liver metastasis and HCC, any treatment for grade 2 AST and/or and ALT elevation 
will be resumed, and nivolumab treatment will be terminated when AST and/or ALT levels continue 
to be 50% higher than at baseline for ≥1 week. 
b. If the subject recovers from symptoms within 1 h of dose suspension, the dose will be resumed at 
an infusion rate of 50% of the initial rate (e.g., 50 mL/h from 100 mL/h). If the subject does not 
recover from symptoms within 1 h of dose suspension, the dose will be withdrawn until the 
symptoms recover and pretreatment will be administered at the time of the next dose. Refer to 6.3.2.1 
for details. 


50 
 
6.3.2.1 Supportive therapy for adverse events suspected of being associated with nivolumab 
A list is provided below of examples of supportive therapy to manage adverse events with 
possible immunological etiology suspected of being associated with nivolumab. For details, refer to 
the guidance document regarding such events. A dose reduction in steroids can exacerbate symptoms, 
and, therefore, due care should be paid to the fact that the steroid dose should be gradually decreased 
over a number of courses. Additional supportive therapy may be required, and, therefore, efforts 
should be made to exclude other causes of each symptom (e.g., metastatic lesions and bacterial and 
viral infections). 
 
Pneumonitis: 
• In the event of grade 2 pneumonitis, systemic corticosteroids will be administered. When 
symptoms are returned to below grade 1, the dose of steroids will gradually be decreased over 
≥4 weeks. 
• In the event of grade 3–4 pneumonitis, steroid therapy will be administered immediately via an 
intravenous infusion. In addition, anti-inflammatory drugs will be administered as required. 
• When steroid therapy is prolonged, antibiotics will be additionally administered to prevent 
opportunistic infections. 
Diarrhea/colitis: 
• The presence or absence of signs and symptoms of enteritis (e.g., diarrhea, abdominal pain, 
blood or mucus in the stool, presence or absence of accompanying fever), as well as signs and 
symptoms of intestinal perforation (signs of peritonitis and/or intestinal obstruction) will be 
verified. 
• All patients who develop diarrhea/colitis will be instructed to drink sufficient water. If it is 
difficult for patients to drink adequate water, an intravenous infusion of fluid containing 
electrolytes will be administered. In the event of ≥grade 2 diarrhea, to confirm or rule out colitis, 
consultation of a gastroenterologist and endoscopic examination will be recommended. 
• In the event of persistent grade 2 diarrhea/colitis lasting ≥3 days, oral corticosteroids will be 
administered. 
• In the event of persistent grade 3–4 diarrhea/colitis lasting ≥1 week, a steroid intravenous 
infusion, followed by high-dose oral steroids will be given. 
• When symptoms are returned to below grade 1, the steroid dose will be gradually decreased 
over a period of ≥4 weeks. 
≥Grade 3 hyperglycemia accompanied by type-1 diabetes (including diabetic ketoacidosis in the 
event of newly developed type-1 diabetes), ketosis (ketonuria), and/or metabolic acidosis: 
 
For grade 3–4 hyperglycemia accompanied by type-1 diabetes, metabolic acidosis, and/or 
ketonuria, insulin replacement therapy will be considered. 


51 
 
 
The serum glucose level and metabolism test values (e.g., urinary ketones, glycohemoglobin, 
and C-peptides) will be evaluated. 
Hypophystitis: 
• For grade 2 hypophystitis, corticosteroids will be administered. When symptoms are returned to 
below grade 1, the steroid dose will be gradually decreased over a period of ≥4 weeks. Because 
the steroid dose is gradually decreased, appropriate hormone replacement therapy may be 
needed. 
• For grade 3–4 hypophystitis, an intravenous infusion of corticosteroids, followed by oral 
corticosteroids will be given. When the symptoms return to below grade 1, the steroid dose will 
be gradually decreased over a period of ≥4 weeks. Because the steroid dose is decreased 
gradually, appropriate hormone replacement therapy may be required. 
Hyperthyroidism and hypothyroidism: 
Thyroid dysfunction can occur at any time during the dose administration. Changes in thyroid 
function test values (conducted at the start of investigational drug dosing, then as subsequently 
required according to routine and clinical evaluations), as well as the presence or absence of 
signs/symptoms of thyroid dysfunction should be monitored. 
• Grade 2 hyperthyroidism (and grade 3–4 hypothyroidism): 
 
In hyperthyroidism, nonselective beta-blockers (e.g., propranolol) are recommended as the 
first line of treatment. 
 
In hypothyroidism, thyroid hormone replacement therapy (e.g., levothyroxine or 
liothyronine) are recommended as standard treatment. 
• Grade 3–4 hyperthyroidism: 
Following the intravenous infusion of corticosteroids, oral corticosteroids will be 
administered. When symptoms return to below grade 1, the steroid dose will be gradually 
decreased over a period of ≥4 weeks. Because the steroid dose is decreased gradually, 
appropriate hormone replacement therapy may be required. 
Liver impairment: 
• For grade 2 liver impairment, liver function tests will be performed frequently until the baseline 
values are restored (performance of weekly tests will be considered). 
1)  Corticosteroids will be administered via an intravenous infusion or orally. 
• For grade 3–4 liver impairment, corticosteroid therapy will be administered for 24–48 h via an 
intravenous infusion. 
• When symptoms are returned to below grade 1, the steroid dose will be gradually decreased 
over a period of ≥4 weeks. 
Renal impairment and nephritis: 
• For grade 2 impairment, corticosteroid therapy will be administered. 


52 
 
• For grade 3–4 impairment, corticosteroid therapy will be administered. 
• When the symptoms return to below grade 1, the steroid dose will be gradually decreased over 
a period of ≥4 weeks. 
Infusion reaction management: The signs and symptoms of an infusion reaction normally appear 
during administration of the drug or immediately after administration, and most patients completely 
recover within 24 h of administration. 
Table 8 lists the countermeasures to take in the event that an infusion reaction associated with 
nivolumab occurs. 
 
For grade 2 or grade 3-4 immunity-related toxicities (other than those listed above), systemic 
corticosteroid therapy will be administered as required upon deliberation with the trial coordinating 
committee. When symptoms are returned to below grade 1, the steroid dose will be gradually 
decreased over a period of ≥4 weeks. 
 
Table 7: Countermeasures in the event of an infusion reaction associated with nivolumab 
 
NCI-CTCAE grade 
Countermeasures 
Pretreatment upon the 
administration of the 
next and subsequent 
doses 
Grade 1 
Mild reaction; does not 
require infusion suspension 
or treatment. 
Increase the frequency of monitoring of 
vital signs until the symptoms of the 
patient concerned are deemed stable by 
the attending physician. 
None 
Grade 2 
Infusion 
suspension 
is 
needed; 
however, 
the 
subject responds instantly 
to symptomatic treatment 
(e.g., 
anti-histamines, 
nonsteroidal 
anti-inflammatory 
drugs 
(NSAIDs), 
opioid 
analgesics, and intravenous 
transfusion); 
prophylactic 
treatment is required within 
24 h. 
Suspend nivolumab dosing and monitor 
symptoms. 
Administer appropriate treatment (e.g., 
intravenous transfusion, anti-histamines, 
NSAIDs, 
acetaminophen, 
and 
opioid 
analgesics). 
Increase the frequency of monitoring of 
vital signs until the symptoms of the 
patient concerned are deemed stable by 
the attending physician. 
If the subject recovers from symptoms 
within 1 h of dose suspension, dosing is 
resumed at an infusion rate of 50% of the 
1.5 h (±30 min) before 
nivolumab 
dosing. 
administer 
pretreatment with the 
drugs below. 
Oral diphenhydramine 
at a dose of 50 mg (or 
similar 
antihistamine). 
Oral acetaminophen at 
a dose of 500–1000 


53 
 
 
initial rate (e.g., 50 mL/h from 100 mL/h). 
mg 
(or 
a 
similar 
If the subject does not recover from 
antifebrile agent). 
symptoms 
within 
1 
h 
of 
dosing 
suspension, the dose will be withdrawn 
until 
the 
symptoms 
recover, 
and 
pretreatment will be administered at the 
time of the next dose. 
In 
patients 
who 
develop 
≥grade 
2 
toxicities despite appropriate pretreatment, 
nivolumab treatment will be terminated 
(no resumption of dosing permitted). 
Grade 3 
Prolongation (the subject 
does not respond quickly to 
symptomatic treatment and 
short-term 
 
infusion 
suspension); 
recurrence 
despite improving once; 
hospital 
admission 
is 
required for sequelae (e.g., 
renal 
impairment, 
pulmonary infiltration). 
Grade 4 
Life-threatening; 
administration  
 of 
hypertensive 
drugs 
and 
artificial 
respiration   is 
needed. 
Suspend nivolumab dosing and monitor 
symptoms. 
Administer appropriate treatment (e.g., 
intravenous transfusion, anti-histamines, 
NSAIDs, 
acetaminophen, 
opioid 
analgesics, 
oxygen 
inhalation, 
hypertensive drugs, corticosteroids, and 
epinephrine). 
Increase the frequency of monitoring of 
vital signs until the symptoms of the 
patient concerned are deemed stable by 
the attending physician. The patient is 
hospitalized as required. 
Nivolumab treatment is terminated (no 
resumption of dosing permitted). 
Nivolumab dosing is 
not resumed. 
During nivolumab dosing, appropriate resuscitation equipment is placed in the room so that the 
physician can respond quickly. 
 
 
 
6.4 Specific instructions for subjects 
The attending physician and trial collaborators will instruct the subjects on the methods of 
regorafenib and nivolumab administration and on observing the following matters. When 


54 
 
administered on an outpatient basis, a thorough interview and investigation will be carried out 
regarding the state of regorafenib administration (e.g., the collection of untaken regorafenib [i.e., the 
investigational drug]), and the results will be recorded on a CRF. 
 
6.5 Combination therapy and supportive treatment 
All concomitant drugs and combination therapies used from the beginning of the treatment protocol 
until 30 days after the final dose (when aftertreatment is administered and up to the day before 
administration of aftertreatment) will be recorded on a CRF. Drugs used for various tests and 
diagnoses do not need to be recorded on the CRF, except when required to determine a causal 
relationship with adverse events or for another reason. 
 
6.5.1 Recommended combination and supportive therapies 
The combination and supportive therapies listed below are recommended. Nonadministration of 
the therapies will not be considered a deviation from the protocol. 
1) G-CSF will be administered in accordance with the approved usage and dosage. 
2) Antiemetic agents/fluid replacement: For severe nausea and vomiting that impedes the 
continuation of oral therapy, the appropriate treatment will be administered using antiemetic 
agents or fluid replacement. 
3) Antidiarrheal drugs. 
4) Antifebrile agent, analgesics, and steroids will be administered for immune-related events. 
 
 
6.5.2 Permitted combination and supportive therapies 
When zoledronic acid and denosumab are administered for bone metastasis before enrollment, 
such medications can be continued. 
 
6.5.3 Unpermitted combination and supportive therapies 
During the study, strong CYP3A4 inhibitors (eg, clarithromycin, grapefruit juice, indinavir, 
itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, 
voriconazole) or strong CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifampin, 
St. John’s Wort) are not permitted (See appendix 3). 
Except when required for the treatment of adverse events, safety, and ethical reasons, the 
concurrent use of the agents listed below shall not be permitted. 
1) Other anticancer drugs 
2) Other investigational drugs 
3) Live vaccines administered <30 days before the initiation of treatment with the investigational 
drug and during the trial period. Examples of live vaccines are as follows (however, the list is not 
exhaustive): measles, mumps, rubella, chicken pox/herpes zoster, yellow fever, rabies*, BCG for 


55 
 
tuberculosis, and typhoid vaccines*. Inoculation with inactive vaccines (e.g., seasonal influenza 
vaccines) is permitted; however, the intranasal administration of attenuated influenza vaccines 
(e.g., Flu-Mist®) is prohibited. (*In Japan, live vaccines are not approved). 
4) Systemic glucocorticoids for purposes other than treating symptoms caused by notable events 
with a suspected immunological etiology. Upon deliberation with the trial coordinating 
committee, the use of corticosteroids may be permitted according to the physiological dose 
required to alleviate symptoms (e.g., to control symptoms of acute asthma). 
 
Except when required for the treatment of adverse events, safety, and ethical reasons, the 
concurrent use of the drugs listed below is not permitted. However, use of these drugs to treat 
adverse events will not be considered a deviation from the protocol. 
5)  Other treatments that affect the evaluation of safety and efficacy (e.g., surgical treatment, 
radiotherapy, thermotherapy, immunotherapy, hormone therapy, and antibody therapy). 
 
6.6 Aftertreatment 
There will be no aftertreatment for subjects following the termination of the stipulated treatment 
protocol. 


56 
 
7 Investigational drug information 
7.1 Nivolumab drug information 
Investigational drug 
Nivolumab 
Formulation: 
Injection solution 
Manufacturer: 
Ono Pharmaceutical Co., Ltd. 
Content: 
Nivolumab injection solution: 100 mg/10 mL (10 mg/mL) 
Usage: 
Nivolumab injection solution is injected undiluted (10mg/mL) or 
diluted with physiological saline or 5% glucose injection solution 
to the total injection volume of 160mL or less, and through the 
in-line filter with a pore size of 0.2 to 1.2μm. The whole amount is 
administered intravenously over 30 minutes (25-40minutes). 
However, for subjects weighing less than 40kg, the total injection 
volume 
should 
not 
exceed 
4mL/kg. 
After 
intravenous 
administration, flush with a sufficient amount of physiological 
saline or 5% glucose solution. After preparation, if not used 
immediately, it is possible to save up to 24 h dosing liquid at 
refrigeration (2 ~ 8 ° C.), to store them at room temperature for up 
to 8 hours (up to 25 ° C.) and under room light It is possible. 
When storing at room temperature and in room light, use within 8 
hours after preparation, including administration time. 
*When administering nivolumab from the CV port or PICC, it is 
recommended that the dosage of nivolumab be adjusted so that the 
final concentration after dilution is 1.9 mg / mL or more. 
* It is recommended that Nivolumab could be dipped in the CV 
port or PICC catheterization, and flushing be performed before 
administration of the drug through the CV port or PICC. 
* When administering nivolumab through the CV port or PICC, 
carefully  observe  the  subject's  condition  during  or  after 
administration. 
Administration route: 
Intravenous infusion 
Expiration date 
Refer 
to 
the 
procedures 
regarding 
investigational 
drug 
management 
Labeling 
The outside of the box lists the content, lot number, expiration 
date, number of doses, and storage method along with the name, 
job title and address of the coordinating physician. The box will 
also note that the drug is for use in the trial. 


57 
 
 
Furthermore, the job title of the coordinating physician noted on 
the box will be the title at the start of the trial. If the title changes 
during the trial, there will be no modification made to the labeling 
on the box. 
Nivolumab will be provided free of charge by Ono Pharmaceutical who are the investigational drug 
sponsor. Records of the drug manufacturing and quality testing will also be provided by the sponsor. 
 
7.2 Regorafenib drug information 
Investigational drug 
Regorafenib 
Formulation: 
Light red elliptical film coated tablet 
Manufacturer: 
Bayer Yakuhin, Ltd 
Content: 
Hard capsule containing 40 mg of regorafenib 
Usage: 
Given once daily for the first 21 days of each 28 day cycle. 
Administration route: 
Oral 
Expiration date 
Refer to the procedures regarding investigational drug management 
Labeling 
The outside of the box lists the investigational drug code name, 
content, lot number, expiration date, number of doses, and storage 
method along with the name, job title and address of the 
coordinating physician. The box will also note that the drug is for 
use in the trial. 
Furthermore, the job title of the coordinating physician noted on the 
box will be the title at the start of the trial, and if the title changes 
during the trial, there will be no modification made to the labeling 
on the box. 
Storage method 
Store at 2°C–8°C in an airtight container away from light. 
Regorafenib will be provided free of charge by Bayer Yakuhin, Ltd who are the investigational drug 
sponsor. Records of the drug manufacturing and quality testing will also be provided by the sponsor. 
7.3 Investigational drug management 
After the investigational drugs (i.e., regorafenib and nivolumab) have been transported to the 
pharmacy at the National Cancer Center Hospital East from Bayer and Ono Pharmaceuticals, the 
drugs will be stored by the said pharmacy. 
The investigational drug manager at each participating medical institution will receive, handle, 
manage, store, and dispense the investigational drugs in accordance with the procedures regarding 
investigational drug management provided by the principal investigator. The investigational drug 
manager will also return or dispose of nondispensed drugs and unused drugs that have been collected 
from subjects in an appropriate manner. Records of such procedures are to be created and maintained 


58 
 
on file. 
Furthermore, the attending physician will prescribe the number of doses of the investigational drug 
considered valid according to this trial protocol, and collect any unused investigational drugs 
recovered from the subjects. The collected unused drugs will then be returned to the investigational 
drug manager. 
Moreover, the investigational drugs are not to be administered by any method other than that 
stipulated in this trial protocol. 
Throughout the study, all unused study medication will be accounted for. The information will be 
recorded in the drug dispensing log. 
 
7.4 Anticipated adverse events 
Regarding any anticipated adverse events caused by regorafenib and nivolumab, with reference to 
the latest investigator’s brochure, adverse events for which the onset tendency (including the onset or 
the number of occurrences, incidence, and onset conditions) of the adverse event concerned cannot 
be foreseen according to the investigator’s brochure of the investigational drug concerned shall be 
referred to as “unknown,” whereas those that can be foreseen shall be “known.” 


59 
 
8 Endpoints, laboratory tests, and evaluation schedule 
8.1 Observations, tests, and endpoints 
Table 8.1: Observations, tests, and endpoints 
 
Item 
Details 
Dosing situation 
The regorafenib and nivolumab dose, treatment start date, treatment 
completion date or treatment termination date (dose withholding date), 
presence or absence of dose changes and associated reasons, presence or 
absence of dose withholding, number of times doses are withheld and 
associated reasons. 
Subject background 
Medical record number or identification number (number with which the 
patient can be identified). 
Sex, age, main medical history/complications/drug allergies, type of cancer, 
histology (e.g., pap, tub1, tub2, por1, por2, sig, muc, or other), HER2 
(negative, positive, or unknown), EBV (negative, positive, or unknown), 
presence or absence of RAS mutation (when known), MSI status (when 
known), lesion site (primary site, target lesion, or nontarget lesion) and 
history of prior treatment (chemotherapy, radiotherapy). 
Physical 
measurements 
Height and weight 
Vital signs 
Body temperature, heart rate, and systolic/diastolic blood pressure 
General condition 
PS (ECOG) 
Adverse events 
≥Grade 1 subjective and objective symptoms 
Concomitant 
drugs/combination 
therapy 
Drug name, administration route, administration start date, administration 
completion date, reason for combination therapy 
Blood testing 
White blood cell count, neutrophil count, red blood cell count, hemoglobin, 
hematocrit, and platelets 
Biochemistry 
AST (GOT), ALT (GPT), ALP, LDH, albumin, total bilirubin, direct 
bilirubin, BUN, creatinine, CK, lipase, electrolytes (Na, K, Cl, Ca, IP and 
Mg), UA, and blood glucose (fasting and intermittent) 
Blood 
coagulation 
test 
PT, INR, and APTT 
Urine analysis 
Urinary protein, urinary sugar, and occult blood in urine 
Thyroid function 
Thyroid stimulating hormone,  free triiodothyronine (fT3), and free 
thyroxine (fT4) 


60 
 
 
Pregnancy test 
When pregnancy is suspected on the basis of urine analysis, blood testing 
shall be performed. 
Tests shall be performed in premenopausal women and women who 
experienced their last menstruation <1 year ago. 
Tumor markers 
Stomach cancer/colorectal cancer: CEA, CA19-9, Hepatocellular 
carcinoma : PIVKA-II, and alfa-fetoprotein (AFP) 
Electrocardiography 
12-lead electrocardiography (ECG) at rest 
Infection 
HIV antibody, HBs antigen, HBs antibody, HBc antibody, HCV antibody 
and HBV-DNA assay 
Tumor evaluation 
Chest/pelvic contrast-enhanced CT*, or abdominal/pelvic contrast-enhanced 
MRI*, as well as chest X-ray, brain CT, and brain MRI as required 
*In subjects with allergies/hypersensitivities to the contrast medium used 
for CT and MRI, the tests can be performed without a contrast medium. 
When treatment is terminated for reasons other than an exacerbation of the 
underlying disease on imaging, evaluations shall be performed until an 
exacerbation is confirmed. 
Outcome 
investigation 
The presence or absence of aftertreatment shall be investigated, and in the 
event that aftertreatment is administered, the treatment method and the start 
date shall be recorded. 
The date of death, or last day of confirmed survival, and in the event of 
death, the cause of death shall be investigated. 
*Even if a subject cannot be directly followed up for reasons such as 
hospital transfer, survival is to be confirmed as far as possible by contacting 
the hospital where the subject was transferred, and the result of such contact 
is to be noted in the medical records. 
 
8.2 Observation and test schedule 
The observation and testing schedule is presented in Table 9. When the principal investigator 
(or subinvestigator) deems it necessary to perform additional tests or observations, they will be 
performed in addition to the schedule presented in Table 9. 
 
Table 8.2 Schedule 
 
Cycle 
Screening 
Investigational drug administration period 
Terminat 30 days 
Follo 


61 
 
 
period 
(−14 days 
to day 0) 
Cycle 1 
Cycle 2 
onwards 
ion 
dated) 
after last 
dosee) 
w-up 
perio 
d 
Day 
Permissible range 
1 
8 
15 
22 
1 
15 
Day 0 
to +7 
Day 
−3 
to +7 
Visit 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Treatment 
Regorafenib 
treatment 
→ 
→ 
→ 
→ 
→ 
Compliance 
○ 
○ 
Nivolumab 
treatment 
○ 
○ 
○ 
○ 
Background, etc. 
Consent 
acquisition 
○ 
Verification of 
inclusion criteria 
and exclusion 
criteria 
○ 
Subject 
background 
○ 
Body 
meas 
urem 
ents 
Height 
○ 
Weight 
○ 
○ c) 
○ 
○ 
○ 
vital signs/PS 
Weekly BP monitoring 
for the first 6 weeks 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Combination 
drugs/therapies 
with adverse 
events 
○ 
○ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
Laboratory tests 
Blood tests (blood 
count, 
biochemistryg)) 
. 
○ 
○ c) 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Urine analysis 
○ 
○ c) 
○ 
○ 
○ 
○ 
○ 
○ 
○ 


62 
 
 
Thyroid function 
○ 
○ c) 
○ 
○ 
Coagulation test 
○ 
○ c) 
○ 
○ 
Pregnancy testa) 
○ 
Tumor markers 
○ 
○ c) 
○ 
○ 
12-lead ECG 
○ 
○ c) 
○ 
○ 
Infection test 
○ b) 
Tumor evaluation 
Chest/abdominal/ 
pelvic CT (MRI) 
and other 
evaluations 
○ 
Conducted at 6 (±1 week), 12 (±1 week), 18 (±1 week), 
and 24 weeks (±1 week) after the start of treatment, 
followed by every 9 weeks until week 42, then every 12 
weeks thereafter. 
△f) 
Exploratory biomarker tests 
Tumor specimens, 
blood sampling 
Refer to the TR protocol 
Follow-up 
Outcome 
investigation 
○ 
 
a) Limited to women capable of childbearing. Refer to section 9.3.8 
b) Tests conducted within 6 months of enrollment can be alternatively used. 
c) Pre-enrollment tests (7 days before drug administration) can be used as tests conducted on day 
1 (pretreatment).For lipase, the value measured 14 days before registration can be used. 
d) The day of termination is defined as the day when the principal investigator (or 
subinvestigator) decides to terminate the subject’s administration of the investigational drug. 
When observations and tests cannot be conducted because of the subject’s condition, they 
should be conducted as soon as possible. 
e) Follow-up tests for safety are conducted 30 days after the last dose of the investigational drug. 
When a new anticancer drug is initiated within 30 days of the last dose of the investigational 
drug, the follow-up tests for safety are to be conducted before initiating the new anticancer 
treatment. If the subject cannot come to hospital before the start of the new anticancer treatment, 
information will be collected by telephone regarding any new safety issues arising after tests 
upon completion of the last dose and before initiation of treatment with the new anticancer 
treatment. 
Furthermore, when the follow-up tests of safety are conducted <2 weeks after the tests 
conducted at the time of the last dose of the investigational drug, the tests conducted at the time 


63 
 
of the last dose of the investigational drug and the follow-up tests of safety can be conducted 
simultaneously. 
In addition, when observations and tests cannot be conducted because of the subject’s condition, 
they should be conducted as soon as possible. 
f) Refer to section 8.5. 
g) Only subjects who received explanation from the doctor agree to perform before and after 
protocol treatment start 4-6 weeks, at the time of discontinuation. Refer to 8.6 
 
8.3 Examination findings 
8.3.1 Subject background 
• Clinical diagnosis 
Primary and metastatic lesion sites, etc. 
• The following details will be collected regarding the time of the initial histological diagnosis 
(month and year), histological diagnosis, and the presence or absence of pretreatment. 
• surgery 
• chemotherapy(Number 
of enforcement 
regimens, 
pretreatment 
anti-PD1 / PD-L1 
administration) 
• radiation 
• other treatments 
 
 
8.3.2 Height and weight measurements and vital signs 
The subject’s vital signs (i.e., blood pressure, heart rate, and body temperature) as well as body 
height/weight will be measured. Vital signs are to be measured at each examination with the 
subject in the same position each time. 
 
8.3.3 ECOG performance status (PS) 
The ECOG PS will be measured (refer to appendix 1). 
 
 
8.3.4 Adverse events (subjective and objective symptoms)/combination therapy 
During the period from the start of treatment until 30 days after completion of the treatment 
protocol, adverse events (subjective and objective symptoms) are to be monitored and recorded. 
Refer to section 11 on the reporting of adverse events for details regarding the handling of adverse 
events. 
 
8.4 Laboratory tests 
The test items listed in Table 8.1 are to be measured in accordance with the time indicated in the 
schedule presented in Table 8.2. 


64 
 
 
8.4.1 Blood tests/biochemical tests/blood coagulation tests/urine analysis/hormone analysis 
/thyroid function tests 
The items listed in Table 8.1 will be tested in accordance with the time indicated in the schedule 
presented in Table 8.2, and when deemed clinically necessary. If needed, the evaluation of 
clinically significant laboratory tests will be repeated until the test values return to baseline values, 
until clinically stable, or until a different treatment is initiated. And appropriate test items for 
adrenocorticotropic hormones (such as ACTH) will be added as needed. 
 
8.4.2 Tumor markers 
The items listed in Table 8.1 are to be measured in accordance with the time indicated in the 
schedule presented in Table 8.2. 
 
8.4.3 Pregnancy tests 
In the case of a female subject capable of childbearing, confirmation that the subject is not 
pregnant will be obtained by urine test <7 days before enrollment in the trial. If pregnancy is 
suspected in the urine test, the pregnancy will be determined by a blood test. Female subjects 
deemed incapable of childbearing include those who have experienced menopause (the absence of 
menstrual periods for >1 year), and those who have undergone tube ligation or hysterectomy, the 
details of which are to be noted in the source document of the subject. 
 
8.4.4 Infection tests 
HIV antibody, HBs antigen, HBs antibody, HBc antibody, HCV antibody and HBV-DNA assay are 
to be measured before enrollment. Furthermore, in the event that results are available for tests 
conducted <12 months before enrollment, these results may be used instead. 
(HBV-DNA assay are measured only when either HBs antibody or HBc antibody are positive.  
 
8.4.5 Twelve-lead ECG at rest 
For the 12-lead ECG, data recording will be initiated after confirming that the subject is resting 
in the dorsal position. A physician suited to the ECG evaluation will evaluate the QT interval, as 
well as qualitative abnormalities in the ST segment form, the T-wave form, and the presence or 
absence of a U-wave. 
 
8.5 Tumor evaluation 
For all subjects, tumor evaluations will be conducted using the irRECIST and RECIST 
guidelines version 1.1. Tumor evaluations of the chest, abdomen, and pelvis (when deemed 
clinically necessary) will be conducted at each time point listed below until an exacerbation is 


65 
 
confirmed. Thoracoabdominal and pelvic contrast-enhanced CT or MRI will be performed (if the 
subject is allergic to the contrast medium, plain scans are permitted). 
• Less than 21 days before enrollment in this trial 
Evaluations will be performed in weeks 6, 12, 18, and 24 after the beginning of treatment 
(followed by every 9 weeks until week 42, then every 12 weeks thereafter). 
• When treatment is terminated for reasons other than an exacerbation of the underlying 
disease on imaging, an evaluation will be performed within 2 weeks of dosing completion. 
Furthermore, tumor evaluations are to be conducted in accordance with the schedule until an 
exacerbation of the underlying disease is confirmed, or until commencement of a new 
anticancer treatment. 
The principal investigator and radiologist will conduct tumor evaluations in accordance with the 
irRECIST and RECIST guidelines version 1.1 (refer to appendices 2 and 3). The decision to 
continue the investigational drugs will be determined on the basis of these evaluations, including 
the effects on target and nontarget lesions and the appearance of new lesions. When disease 
progression is first observed on imaging in clinically stable patients, participating medical 
institutions will conduct repeat scans 4 weeks after the initial identification of disease progression 
via an image evaluation to determine disease progression. Administration of the investigational 
drug can continue until the repeat scan is conducted (refer to Table 10). The criteria for clinical 
stability are listed below. 
• Absence of clinical signs and symptoms indicating disease progression. 
• No worsening of ECOG PS. 
• No sudden disease progression observed 
• Absence of tumor enlargement in the main anatomical site requiring new emergency medical 
intervention (e.g., spinal cord compression). 
 
Furthermore, in the present trial, a maximum of 10 lesions can be included as target lesions, with a 
maximum of five lesions per organ. 
 
Table 8.5: Imaging and investigational drug dosing after disease progression is first observed 
on imaging 
Clinically stable 
Clinically unstable 
Imaging 
Investigational 
drug dosing 
Imaging 
Investigational 
drug dosing 
Disease 
progression is first 
To 
confirm 
disease 
Investigational 
drug dosing can be 
If 
possible, 
repeat 
the 
test 
Interruption of 
dosing 


66 
 
 
determined 
by 
imaging 
progression, 
repeat 
the 
test 
after 4 weeks 
continued at the 
discretion of the 
attending 
physician 
until 
disease 
progression 
is 
confirmed  
 by 
retesting 
at 
the 
participating 
medical institution 
after 4 weeks to 
confirm 
disease 
progression 
Disease 
progression 
is 
determined 
by 
repeat imaging 
Additional 
imaging is not 
necessary 
Terminate 
dosing 
of 
 
the 
investigational 
drug 
 (exceptions 
can be permitted 
upon 
deliberation 
with 
  the 
trial 
coordinating 
committee) 
Additional 
imaging is not 
necessary 
Not applicable 
SD, PR, or SD is 
determined 
by 
repeat imaging 
Continue  
the 
prescribed 
routine imaging 
every 6 weeks 
Continue  
the 
investigational 
drug 
at 
the 
discretion of the 
attending 
physician 
Continue  
the 
prescribed 
routine imaging 
every 6 weeks 
When 
the 
subject’s 
condition 
improves, 
 or 
when 
the 
subject  
 is 
clinically 
stable, 
dosing 
of 
 
the 
investigational 
drug 
can 
resume at the 
discretion 
of 
the 
attending 
physician 


67 
 
In the event of clear clinical progression according to symptom exacerbation as judged by the 
attending physician, treatment should be terminated even if there is no confirmed progression 
according to an image diagnosis. Symptoms indicating clinical progression must be recorded in the 
subject’s medical records. Efforts shall be made to confirm progression objectively by imaging as 
much as possible, even after termination of treatment. 
 
8.6 Biomarker Biopsy Blood sampling 
Before and after the start of the investigational medicine, serum (or plasma), immunocompetent 
cells such as mononuclear cells, residual diseased tissue are obtained from peripheral blood and 
lesion tissue (biopsy specimen) around 4-6 weeks after start. For subjects who had a therapeutic 
effect, blood specimens and tissue specimens may be obtained after disease progression only when 
consent is obtained from subjects (for details see the accompanying research implementation plan). 
 
8.7 Follow-up 
Outcome investigations will be performed after termination of the treatment protocol until the 
subject dies, or up to 2 years after the day that the last subject enrolled in the present trial. Even 
when direct follow-up is not possible (e.g., because of hospital transfer), the hospital where the 
subject was transferred will be contacted to verify the outcomes as far as possible. The results of 
such contact are to be noted in the subject’s source documents. 


68 
 
9 DATE COLLECTION 
9.1 Handling and Retention of CRF Data 
Data will be managed, and CRF data will be managed and retained by the Data Management Office, 
Clinical Research Support Unit, National Cancer Center Hospital East. A data management plan will 
be prepared. In the plan, access restriction such as inputting in and browsing the database will be set, 
and records will be properly controlled and kept. 
 
9.2 Identification of Source Documents 
Source documents in this study will be as follows: 
Medical records 
Informed consent form 
Investigational drug management table 
Laboratory test data 
Diagnostic imaging films, etc. 


69 
 
10 Reporting of adverse events 
10.1 Adverse event evaluation 
10.1.1 Definition of adverse events 
Adverse events include all undesirable or unintentional signs, symptoms, and conditions 
(including abnormal changes in laboratory test values) that arise in subjects administered the 
investigational drugs, regardless of the presence or absence of a causal relationship with the 
investigational drug concerned. 
When ≥grade 1 subjective or objective symptoms are observed before the start of treatment (at the 
time of the baseline evaluation), only those for which the grade of the adverse event concerned 
deteriorates compared with the pretreatment level will be treated as adverse events. 
 
10.1.2 Method of recording adverse events 
When signs (including abnormal laboratory test values) and symptoms are included in the 
diagnosis, the name of the diagnosis according to the CTCAE will be recorded on the CRF as far as 
possible, rather than each individual sign and symptom. 
Abnormalities in laboratory test values will be reported as adverse events only when the attending 
physician deems that any of the following conditions are satisfied: 
1) 
When clinical signs or symptoms are induced 
2) 
When deemed clinically important 
3) 
When treatment is required 
4) 
When additional tests are required (only repeat tests are exempt) 
5) 
When termination or dose reduction of the investigational drug is required 
 
 
10.1.3 Adverse event report items 
For adverse events that develop, the following information will be reported on a CRF: 
1) 
Name of adverse event 
2) 
Severity (CTCAE grade 0–5 and serious/nonserious) 
3) 
Causal relationship with the treatment protocol 
4) 
Onset date, date of outcome confirmation, and outcome 
5) 
Presence or absence of treatment 
＊Investigator will assess if the AE is related to study procedure, regorafenib, or nivolumab, if 
possible 
 
10.1.4 Determination of a causal relationship 
A causal relationship with the treatment protocol is determined according to the following 
step: 
 
Causal relationship 
The assessment of the causal relationship between an AE and the administration of treatment 
is a clinical decision based on all available information at the time of the completion of the 


70 
 
CRF. 
The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question. 
Possible answers are “yes” or “no” 
An assessment of “no” would include: 
1. The existence of a clear alternative explanation, e.g. mechanical bleeding at surgical site. 
or 
2. Non-plausibility, e.g., the subject is struck by an automobile when there is no indication that the 
drug caused disorientation that may have caused the event; cancer developing a few days after the 
first drug administration. 
An assessment of “yes” indicates that there is a reasonable suspicion that the AE is associated with 
the use of the study treatment. 
 
 
 
Table 11: Classification of causal relationships 
 
Classification 
Definition 
Definite 
(certain) 
Definite 
A causal relationship with the treatment protocol is plausible, 
and symptoms cannot be explained by an exacerbation of the 
underlying disease, complications, or other drugs/treatments 
Probable 
(likely) 
Probable, likely 
A causal relationship with the treatment protocol is 
reasonable, and symptoms are unlikely attributable to the 
exacerbation of the underlying disease, complications, or other 
drugs/treatments 
Possible 
Possible 
A causal relationship with the treatment protocol is 
reasonable, and symptoms can be explained even with an 
exacerbation of the underlying disease, complications, or other 
drugs/treatments 
Unlikely 
Unlikely 
A causal relationship with the treatment protocol is 
improbable, and symptoms can be explained by exacerbation 
of  the  underlying  disease,  complications,  or  other 
drugs/treatments 
Not related 
(unrelated) 
Unrelated 
There is no causal relationship with the treatment protocol, 
and symptoms can be clearly explained by an exacerbation of 
the  underlying  disease,  complications,  or  other 
drugs/treatments 
Unassessable 
(conditional) 
Unassessable 
There is insufficient data to determine a causal relationship, 
and more detailed data is required (conditional), or evaluation 


71 
 
 
is difficult 
 
10.1.5 Follow-up observation upon the onset of an adverse event 
 
When adverse events develop, the attending physician will immediately take appropriate 
measures. 
Follow-up observation will be performed even after completion of the adverse event evaluation 
period (refer to section 11.1.6) until recovery from or alleviation of the symptoms is confirmed 
(test values). However, when one or more of the following conditions apply, follow-up observation 
of adverse events can be concluded. 
*Follow-up of adverse events shall be concluded when: 
• It is deemed that the adverse event is not serious, a causal relationship can be ruled out, and 
at least 30 days have passed since the day of the last dose 
• The principal investigator has judged that symptoms are stable and that there is no major 
medical problem 
• Aftertreatment has been administered and a causal relationship with the investigational drug 
cannot be evaluated 
• Follow-up observation is difficult because the subject has been transferred to another 
hospital or for another reason 
• The subject refuses follow-up observation 
• Death 
 
 
10.1.6 Adverse event evaluation period 
In the present trial, the adverse event evaluation period will last from “the treatment start date” 
until “30 days after the day of the final investigational drug doses, or before the start of 
aftertreatment if that occurs beforehand, whichever is earliest.” Data pertaining to any adverse events 
that occur during this period will be collected. 
Data will also be collected regarding adverse events from 31 days after the day of the final 
investigational drug doses when it is deemed that there is a causal relationship with the treatment 
protocol. 
After PD is confirmed, new adverse events that occur as a result of disease progression will not be 
included. 
 
10.2 Reporting of serious adverse events 
10.2.1 Definition of serious adverse events 
Of the adverse events described in section “11.1 Adverse event evaluation,” those that meet any of 
the following will be defined as “serious adverse events.” 


72 
 
1) 
Adverse events that cause death or are life-threatening 
2) 
Adverse events that cause permanent or marked impairment/dysfunction 
3) 
Adverse events that cause congenital abnormalities/birth defects 
4) 
Adverse events that require hospitalization or prolongation of the hospital stay 
 
 
However, the following will be exempt: 
－Hospitalization or death due to the underlying disease after PD is confirmed 
－Hospitalization or prolongation of the hospital stay that was planned beforehand 
－Hospitalization or prolongation of the hospital stay unrelated to adverse events 
－Hospitalization or prolongation of the hospital stay of <24 h for follow-up observation only 
5) 
Medically important events are defined as events that endanger the subject or events that 
require internal medicine or surgical treatment to prevent the abovementioned outcomes. 
 
10.2.2 Mandatory reporting and reporting procedures for the principal investigator (or 
subinvestigator) 
1) Reporting to the director of medical institution implementing the trial and the trial 
coordinating committee 
① Initial report 
In the event of a serious adverse event (refer to section “11.2.1 Serious adverse events”), the 
trial principal investigator (or subinvestigator) is to immediately take appropriate action. The 
subinvestigator will report promptly to the principal investigator. 
The principal investigator (or subinvestigator) will report the occurrence of serious adverse 
events to the directors of the medical institutions implementing the trial and trial coordinating 
committee in writing (by e-mail or fax) or verbally (by telephone) within 24 h of discovery of the 
adverse event concerned. When the initial report is made without using the “Report form for 
serious adverse events,” a written report is to be submitted in a promptly (by e-mail or fax). 
Furthermore, the details of serious adverse events will be reported to the directors of the medical 
institutions implementing the trial and the trial coordinating committee within 5 working days of 
discovering the adverse event. 
*Reporting by e-mail is recommended. 
② Additional reports 
The principal investigator (or subinvestigator) will follow-up serious adverse events (refer to 
section “11.1.5 Follow-up upon adverse event onset”). Additional information will be recorded on 
the “Report form for severe adverse events” (additional report), and sent to the directors of the 
medical institutions implementing the trial and the trial coordinating committee. 
Trial coordinating committee contact details: Office of the trial coordinating 


73 
 
committee 
E-mail: xxxx@east.ncc.go.jp 
TEL: 04-7133-1111 (Ext. 5200), FAX: 04-7134-6860 
 
 
When the trial coordinating committee, directors of the medical institutions implementing the 
trial, institutional review board, or trial sponsor request further information, the principal 
investigator (or subinvestigator) will comply with additional reports. 
 
 
 
10.2.3 Mandatory reporting and reporting procedures for the trial coordinating committee 
With regard to serious adverse events reported in the initial and additional reports, the trial 
coordinating committee will judge the necessity of reporting (in accordance with “Article 80-2, 
paragraph 6 of the Pharmaceutical Affairs Law” and “Article 273 of the Pharmaceutical Affairs 
Law Enforcement Regulations”) the severity, causal relationship, and predictability to the 
regulatory authority concerned (Pharmaceuticals and Medical Devices Agency: PMDA). 
The detailed reporting procedure will be performed in accordance with the “Procedures regarding 
the handling of safety information.” 
1) Reporting to the principal investigator 
According to the decision noted above, reported serious adverse events will be reported by the 
trial coordinating committee to each principal investigator without delay. Each principal 
investigator will report to the director of the medical institution concerned as quickly as 
possible in accordance with the regulations of each medical institution. 
2) Reporting to the PMDA 
When reporting to the PMDA is deemed necessary, the trial coordinating committee will 
comply in accordance with article 273 of the Pharmaceutical Affairs Law Enforcement 
Regulations and other related notifications. 
3) Reporting to the Data and Safety Monitoring Committee 
When the review of serious adverse events by the Data and Safety Monitoring Committee is 
deemed necessary, the trial coordinating committee will submit a written report requesting the 
opinion of the committee with regard to the assessment of the principal investigator and trial 
coordinating committee regarding the adverse event concerned, as well as the validity of the 
response to the adverse event concerned (judgments of the severity of the adverse event, causal 
relationship, and predictability). 
4) Reporting to the investigational drug supplier/concomitant drug supplier 
As a general rule, serious adverse events reported by the principal investigator(or 
subinvestigator) will be reported by the trial coordinating committee to the investigational drug 


74 
 
supplier (i.e., Ono Pharmaceutical) within 24 h. 
 
 
10.2.4 Duties of the Data and Safety Monitoring Committee 
The Data and Safety Monitoring Committee will examine the details of adverse event reports, 
and submit written advice to the trial coordinating committee with regard to countermeasures such 
as continuation of the trial and the need for protocol revision. Procedures will follow the 
prescribed “Procedures for the Data and Safety Monitoring Committee” attached separately. 
 
10.3 Collection of safety information 
When information regarding the investigational drugs is obtained from the investigational drug 
supplier, the trial coordinating committee will respond in accordance with article 273 of the 
Pharmaceutical Affairs Law Enforcement Regulations and other related notifications. The trial 
coordinating committee will report the safety information concerned to each principal investigator 
and each principal investigator will report to the director of their medical institution as promptly 
as possible in accordance with the regulations of each medical institution. 
The detailed reporting procedures will follow the “Procedures for handling safety information.” 
In addition, the need for revision of the protocol and informed consent form, as well as the need 
to provide an explanation to subjects will be judged, and if deemed necessary, such needs will be 
addressed. 
 
 
10.4 Pregnancy 
During individual trial participation periods and during periods of contraception, when 
information regarding pregnancy is obtained from a subject, administration of the investigational 
drug will be terminated, and the information will be reported using the designated form without 
delay to the trial coordinating committee (as a general rule, within 24 h of obtaining the information). 
As a rule, the trial coordinating committee will submit the form obtained to the investigational drug 
suppler (Ono Pharmaceutical) within 24 h. The principal investigator (or subinvestigator) will 
conduct a follow-up survey regarding the pregnancy of the subject concerned, and report this in 
writing. The reporting procedures will follow the prescribed “Procedures for handling safety 
information” attached separately. 
 
10.5 Overdosing 
In the dose escalation cohort, overdosing is given when the dose exceeded the dose prescribed at 
each level shown in Table 6.1.1a, and Expansion cohort exceeds the RD determined based on the 
result of dose escalation cohort. 
In the event of an overdose of the investigational drug, the principal investigator (or 
subinvestigator) will take the appropriate countermeasures, and report these using the designated 


75 
 
form without delay to the trial coordinating committee (as a general rule, within 24 h of obtaining 
the information). As a rule, the trial coordinating committee will submit the form obtained to the 
investigational drug suppler (Ono Pharmaceutical) within 24 h. The reporting procedures will follow 
the prescribed “Procedures for handling safety information” attached separately 


76 
 
11 Response evaluation and endpoints 
11.1 Response evaluation 
The tumor response evaluation will be conducted in accordance with the RECIST guideline 
version 1.1 and irRECIST (Appendices 2 and 3). Thoracoabdominal and pelvic contrast-enhanced 
CT or MRI will be performed (if the patient is allergic to the contrast medium, plain scans are 
permitted), and the tumor response will be according to image measurements. In the event of PD of 
the primary disease, refer to section “8.5 Tumor assessment.” 
Furthermore, the period of 4 weeks (28 days) to determine the best overall response of CR or PR 
is not required in this study. 
 
11.2 Definition of endpoints 
11.2.1 Incidence of adverse events 
Regarding AEs occurring during the protocol treatment, the incidence of each AE of the worst 
grade according to the CTCAE v4.03 throughout the entire cycles will be calculated. 
 
11.2.2 Objective response rate (ORR) 
ORR is defined as the proportion of patients whose best overall response, as per the RECIST 
guideline version 1.1 and irRECIST, is either CR or PR. 
 
11.2.3 Progression-free survival (PFS) 
PFS is defined as the time from the enrollment date to either the date when disease progression is 
determined or the date of death from any cause, whichever came earlier. 
• "Progression" is defined as PD in the assessment of overall response by diagnostic imaging 
based on the RECIST guideline version 1.1, and the imaging examination date is set as the 
date of progression. For clinical PD, the date when clinical PD is documented is defined as 
the date of progression. 
• Surviving patients who are not assessed as having progression will be censored on the last 
date on which an absence of clinical progression is confirmed (hereinafter referred to as the 
"last date of progression-free survival confirmed). (If information on progression or 
progression-free is obtained from a medical institution to which the patient was transferred or 
referred, a patient referral document indicating the basis for the diagnosis should be received 
and retained. Obtaining the information by telephone only is not permitted.) 
• Patients who died without being assessed as progression are handled as having "an event 
occurring on the date of death" in principle, unless the period from the last confirmation date 
of progression-free survival to the date of death is long. 
Whether to handle the patient as being "censored on the last confirmation date of 
progression-free survival" should be determined in the case review meeting to be held as 
required, before the data are finalized. 


77 
 
• Patients with treatment discontinuation for reasons such as AEs and their refusal to continue 
participation, who are given another treatment as subsequent treatment, should be handled as 
being "censored on the start date of the subsequent treatment." 
• The occurrence of a secondary malignancy (metachronous multiple cancers) will not be 
considered either an event or censoring, but will be considered PFS until another event is 
observed. 
 
11.2.4 Disease control rate (DCR) 
DCR is defined as the proportion of patients whose best overall response assessed based on the 
RECIST guideline version 1.1 and irRECIST is any of CR, PR, or SD. 
 
11.2.5 Overall survival (OS) 
OS is defined as the period from the date of enrollment to the date of death from any cause. 
Surviving patients will be censored on the last confirmation date of survival (confirmation of 
survival by telephone is permitted; however, the fact that survival is confirmed should be recorded in 
the medical record, etc.). 
Patients lost to follow-up will be censored on the last date on which their survival has been 
confirmed before being lost to follow-up. 


78 
 
12 Statistical Matters 
This protocol stipulates the statistical analysis plan. If any change arises in the statistical analysis 
plan, it should be described in the clinical study report, including its background. A summary of the 
statistical analysis plan is described below. 
 
12.1 Handling of patients 
The handling of patients will be determined by the representative coordinating investigator after 
discussing with the data center. 
 
12.2 All enrolled patients 
"All enrolled patients" are defined as patients enrolled in this study in accordance with Section "5. 
Enrollment," excluding those who have been enrolled multiple times or mistakenly enrolled. 
 
 
12.3 Definition of analysis populations 
Each analysis population is defined below. 
 
Abbreviation 
Analysis population 
Definition 
None 
DLT analysis set 
See Section “6. Treatment Regimen and 
Treatment Modification Criteria.” 
SP 
Safety population 
The population of patients who received 
the investigational product at least once 
among all enrolled patients. 
FAS 
Full analysis set 
The population of patients that excludes 
those to whom the following applies 
from all enrolled patients: 
• Patients who should have been judged 
as clearly ineligible based on the 
information before enrollment 
(ineligible patients). 
 
12.4 Data handling 
The handling of data (e.g., inclusion or exclusion criteria for the analysis population) will be 
determined by the coordinating committee after discussing with the data center. 
 
12.4.1 Handling of missing values and outliers 
In principle, imputation of missing values and analyses dealing with outliers will not be 
performed. However, when the presence of missing values or outliers that may have a significant 
impact on analysis results is identified before data lock, the handling of such data will be 
determined at a case review meeting and the measures to be taken will be described in the case 


79 
 
review meeting minutes. 
 
 
12.4.2 Dealing with additional analyses 
All analyses planned in this study are specified in Section "12.5 Positioning of analyses and 
analysis methods." Analyses other than the final analysis are regarded as additional analyses. The 
results from additional analyses will be reported with a note clarifying that the analyses were not 
planned in advance, or will be reported in a separately prepared additional analysis report. 
 
12.5 Positioning of analyses and analysis methods 
As the purpose of this study is exploratory examination, future decision-making rules will not be 
specified. However, if this study allows the dose finding for the investigational products, 
demonstrates a certain level of safety, and confirms the efficacy and safety of the protocol 
treatment in other secondary endpoints, the future development of the protocol treatment of this 
study will be regarded as promising. In this study, the following one-time analysis (final analysis) 
will be performed. The advisability of the dose-level transition will be decided by the coordinating 
committee. However, since the decision on transition is made only based on the evaluation of the 
incidence of DLTs, analyses related to dose-level transition are positioned as part of monitoring. 
 
12.6 Safety analysis 
12.6.1 Analysis of the incidence of AEs 
The occurrences of AEs in the SP will be summarized. Confidence intervals will not be constructed, 
and subgroup analysis will not be performed. 
 
12.7 Analysis of secondary efficacy endpoints 
The following analyses will be performed as required (only listings may be presented depending on 
the study results). 
12.7.1 ORR, DCR 
The confidence intervals of ORR and DCR will be constructed using an exact method based on a 
binominal distribution. When subgroup analysis is performed, proportions or odds ratios will be 
compared among subgroups using appropriate analytical procedures, such as Fisher's exact test and 
logistic regression. 
 
12.7.2 PFS, OS 
By estimating survival functions using the Kaplan-Meier method, median survival times and their 
confidence intervals will be constructed, as well as annual survival rates and their confidence 
intervals. The confidence intervals for median survival times will be estimated by the Brookmeyer 
and Crowley method. The confidence intervals for annual survival rates will be estimated using 
Greenwood's formula. When subgroup analysis is performed, treatment responses compared among 


80 
 
the subgroups will be summarized using appropriate analytical procedures, such as the log-rank test 
and Cox proportional hazards model. 
The survival time will be calculated by defining 1 year as 365.25 days and 1 month as 365.25/12 
days. The calculation formula is [("Event date" or "Censoring date") − "Study enrollment date" + "1 
day"]. 
 
12.8 Target sample size 
[Dose escalation cohort] 3 to 6 patients at each level; 12 to 18 patients in total 
[Expansion cohort] About 30 patients in total 
 
12.9 Rationale for the sample size 
See Section "6. Treatment Regimen and Treatment Modification Criteria." 
 
 
12.10 Interim analysis 
No interim analysis will be performed in this study. 
 
 
12.11 Final analysis 
All endpoints will be analyzed in the final analysis. The final analysis will be performed according 
to the protocol and the analysis results will be reported in the clinical study report. 
 
12.12 Special notes on analysis items 
12.12.1 Items summarized and analyzed in the final analysis 
In the final analysis, the following items will be analyzed. 
<Items to be summarized> 
• 
Demographic data 
• 
Concomitant therapies 
• 
Changes in laboratory values 
To summarize a continuous variable, general descriptive statistics (mean, median, minimum, 
maximum, etc.) will be calculated. 
 
<Items to be analyzed> 
• 
Incidence of AEs 
• 
Objective response rate (ORR) 
• 
Disease control rate (DCR) 
• 
Progression-free survival (PFS) 
• 
Overall survival (OS) 
<Subgroup analysis to be performed> 
Subgroup analyses will be performed in an exploratory manner for the following factors. In these 


81 
 
analyses, adequate statistical power is not guaranteed and adjustment for multiplicity is not 
performed. Therefore, the results of each subgroup analysis will be interpreted as exploratory 
results. 
• 
Cancer type 
• 
Presence or absence of anti-PD-1 antibody use in the prior treatment 
Since data on the following factors will be collected in an additional study to this study, the 
following subgroup analysis results will not be included in the clinical study report of this study. 
• 
PD-L1 (Negative / Positive) 
• 
MMR (Proficient / Deficient) 
• 
TMB (High / Low) 
etc. 
12.12.2 Analysis items included in the clinical study report 
The following analysis items will be included in the clinical study report. 
<Efficacy evaluation (Analysis population: all enrolled patients)> 
• 
Demographic data 
• 
Objective response rate (ORR) 
• 
Disease control rate (DCR) 
• 
Progression-free survival (PFS) 
• 
Overall survival (OS) 
<Safety evaluation (Analysis population: SP)> 
• 
Incidences of DLTs/AEs (number of patients with DLTs/AEs and the incidence, by 
the worst grade) 
• 
Summary statistics of laboratory values and their changes 
<Tables, figures and graphs referred to but not included in the text of the clinical study report> 
• 
Listings of deaths, other serious and significant adverse events 
• 
Laboratory value listing by patient 
<Appendix> 
• 
List of discontinued patients 
• 
List of patients with serious protocol deviations 
• 
List of patients excluded from FAS 
• 
History of prior treatment 
• 
List of concomitant medications and therapies 
• 
Compliance 
• 
List of efficacy response data by patient (tumor assessment, OS, PFS, subsequent 
treatment, and tumor markers) 
• 
Adverse event listing by patient 


82 
 
13 ETHICAL MATTERS 
13.1 Policies, Laws and Regulations with Which the Study Complies 
This clinical study will be conducted in compliance with the protocol, Declaration of Helsinki 
(http://www.med.or.jp/wma/), Article 80-2 of the PAL, “Ministerial Ordinance on Good Clinical 
Practice (GCP)” (Ordinance No. 28 of the Ministry of Health and Welfare dated March 27, 1997) 
and its revisions, and related notifications. 
 
 
13.2 Informed Consent 
13.2.1 Explanation to the Patients 
 
1) 
That the study involves research 
 
2) 
The purpose of the study 
 
3) 
The name, title and contact address of the principal investigator or subinvestigators 
 
4) 
The method of the study (including the experimental aspect of the study and 
inclusion/exclusion criteria for the patients) 
5) 
Expected clinical benefits and foreseeable risks or inconveniences 
 
6) 
The availability of alternative therapies and their important potential benefits and risks 
 
7) 
The expected duration of the patient’s participation in the study. 
 
8) 
That the patient’s participation in the study is voluntary and that the patient may refuse to 
participate or withdraw from the study, at any time, without penalty or loss of benefits to which 
the patient is otherwise entitled. 
9) 
That the monitor(s), the auditor(s), and the regulatory authority(ies) will be granted direct 
access to the patient’s source documents without violating the confidentiality of the patient, and 
that, by signing the informed consent form, the patient is authorizing such access. 
10) If the results of the study are published, the patient’s identity will remain confidential. 
 
11) The person(s) to contact for further information regarding the study and the rights of patients, 
and whom to contact in the event of study-related injury. 
12) The compensation and/or treatment available to the patient in the event of study-related injury 
 
13) The approximate number of patients involved in the study 
 
14) That the patient will be informed in a timely manner if information becomes available that may 
be relevant to the patient’s willingness to continue participation in the study 


83 
 
15) The foreseeable circumstances and/or reasons under which the patient’s participation in the 
study may be terminated. 
16) The anticipated expenses, if any, to the patient for participating in the study. 
 
17) The anticipated payment, if any, to the patient for participating in the study. 
 
18) The patient’s responsibilities 
 
19) Type of the IRB investigating and reviewing the appropriateness of the study, matters to be 
investigated and reviewed by each IRB, and other study-related matters concerning the IRB. 
20) That the patient may check the written procedures for the IRB set forth in the preceding item 
and should request if he or she wants to do so. In addition, if the written procedures for the IRB, 
etc. are disclosed on a website, the fact that the address of the website is provided. If not 
disclosed, the fact that they are publicly available for review. 
21) That data may be secondarily used. 
 
 
13.2.2 Informed Consent 
The investigator should request the patients to participate in the study after giving an explanation on 
the study and sufficient amount of time to think to the patients, and confirming that they have 
understood well about the contents of the study. If the patients personally consent to take part in the 
study, each of the investigator who gave the explanation, the study collaborator who provided a 
supplementary explanation, and the patient who received the explanations and consented should 
record the dates of the explanations or consent and sign the informed consent form approved by the 
IRB. The investigator should retain the signed informed consent form in the medical records and 
hand a copy of the signed informed consent form to the patient. 
In the case where information, which may affect the patients’ willingness to continue participating in 
the study, is obtained, the investigator should promptly notify it to the patients who are in the study, 
verify his or her willingness to continue his or her participation in the study, and record such a fact in 
a document. In addition, when the principal investigator judges that a revision of the written 
information to patients is necessary based on the information or because of other reasons, it should 
be promptly revised, and approval of the IRB should be obtained. After approval of the IRB, an 
explanation should be provided again using the revised written information to patients, and written 
informed consent should be obtained again. 
 
13.2.3 Protection of Personal Information and Patient Identification 
 
Personal information and information concerning privacy such as medical data should be recognized 
as those requiring strict protection and careful handling under the spirit of respecting individuals’ 


84 
 
personality, and full management measures should be taken to protect privacy. The Act on the 
Protection of Personal Information (Law No. 57 dated May 30, 2003; last revision, Law No. 49 
dated June 5, 2009) should be followed. 
 
13.3 Protection of Personal Information and Patient Identification 
Personal information and information concerning privacy such as medical data should be recognized 
as those requiring strict protection and careful handling under the spirit of respecting individuals’ 
personality, and full management measures should be taken to protect privacy. The Act on the 
Protection of Personal Information (Law No. 57 dated May 30, 2003; last revision, Law No. 49 
dated June 5, 2009) should be followed. 
 
 
13.3.1 Purposes of Using Personal Information, Items to Be Used and Methods of Use 
1) 
Purposes of use 
 
In this study, the patients’ personal information will be used for the purpose of properly 
implementing monitoring, etc. 
2) 
Items to be used 
 
In consideration of the minimum necessity for identifying the patients and inquiries, items to be 
used will be as follows: 
Enrollment No., patient identification (ID) No. 
 
In other words, personal information other than the above items such as the patient’s name will 
not be disclosed from the study sites to external parties. When study results are provided to 
parties other than the study sites, all information enabling to identify individuals will be 
anonymized and then provided. 
3) 
Handling methods 
 
The personal information and medical data of the patients should be collected through reporting 
to the data center by the investigator or study collaborators. In addition, personal information 
should not be exchanged by e-mail. 
 
13.3.2 Secondary Use of Data 
Data obtained from this study may be secondarily used (e.g., metaanalysis) in a manner that they are 
not link to information identifying individuals only if the coordinating committee and investigational 
drug suppliers approved. 


85 
 
13.3.3 Safety Management Responsibility System 
When using personal information, safety management measures should be taken in accordance with 
rules at each study site to minimize the risk of information leakage. The data center should properly 
manage personal information in accordance with the guidelines for personal information handled by 
the National Cancer Center. 
 
13.3.4 Handling of Disclosure of the Patients’ Information 
The person who handles a request for the disclosure of privacy information possessed by the study 
by the patients if any, will be in principle, the investigator at the study site where the patient is 
enrolled. 
 
13.4 Approval of the Institutional Review Board (IRB) 
13.4.1 Approval at the Start of the Study 
When implementing this study, the principal investigator shall submit the protocol and documents 
specified by the GCP Ordinance such as the written information to patients to the head of the study 
site and receive approval of the IRB. As soon as approval of the IRB is granted, the principal 
investigator should send a copy of the written approval of the IRB and written information to 
patients (study site version) to the Clinical Study Coordinating Secretariat, and retain the original of 
the written approval of the IRB. 
 
 
The contents of the protocol shall not be modified by the individual study sites. The protocol in 
common among all the study sites shall be used. When the IRB requested to modify the main text of 
the protocol, the principal investigator should discuss with the coordinating committee to consider its 
handling. 
 
13.4.2 Approval of the IRB for the Appropriateness of Continuing the Study 
The appropriateness of continuing the study shall be reviewed by the IRB once a year. If the IRB 
approved the continuation of the study, the principal investigator should send a copy of the written 
approval of the IRB to the Clinical Study Coordinating Secretariat, and retain the original of the 
written approval of the IRB. 
 
13.4.3 Changes in the Contents of the Protcol 
When revising the protocol, written information to patients and other relevant documents, it should 
be made in accordance with procedures for preparation of each document. 


86 
 
13.4.4 Categories of Changes in the Contents of the Protocol 
In this study, changes in the contents of the protocol should be handles as amendments 
or revisions, and a supplementary explanation on the protocol should be handled as a 
memorandum or Q&A. 
1) 
Amendment 
 
An amendment refers to a partial change in the protocol that may increase risk to patients 
enrolled in the study or substantially affect the primary endpoint of the study. Approval of the 
efficacy and safety evaluation committee and each study site will be required. 
2) 
Revision 
 
A revision refers to a change in the protocol that may not increase risk to patients enrolled in 
the study nor substantially affect the primary endpoint of the study. Approval of each study site 
will be required. In addition, when the coordinating investigator determines that approval of the 
efficacy and safety evaluation committee is needed, a review should be requested. 
3) 
Memorandum or Q&A 
 
A memorandum or Q&A refers to not a change in the contents of the protocol but a 
supplementary explanation on the protocol to be distributed from the coordinating committee to 
study related persons for the purposes of reducing variances in interpretation of the document 
and particularly calling for attention. No review by or approval of the efficacy and safety 
evaluation committee is required. 
 
13.4.5 Approval of the IRB at the Time of Protocol Revision 
When the protocol is revised during the study, the revised documents shall be approved by the IRB. 
 
 
 
13.5 Management of Conflict of Interest (COI) 
The conflict of interest (COI) for persons involved in this study such as the principal investigator, 
subinvestigators and coordinating investigators will be properly managed in accordance with the 
rules at the study sites. In addition, the COI for the companies has been managed in accordance with 
the companies’ office regulations and compliance programs. 
The investigational drug suppliers (Sumitomo Dainippon Pharma Co., Ltd. and MSD K.K.) will not 
involve in any essential part of the study such as the operation of the study and the interpretation of 
results. However, contracts will be exchanged for the PK evaluation and the evaluation of the 
biomarkers (additional study) as joint studies. 


87 
 
13.6 Compensation 
In the event of injuries attributable to the study in the patients, the study site should provide 
compensation in accordance with the “Procedures for compensation for injuries” even if the study 
site is not legally responsible. 
The details of compensation in this study will be the provision of medical care, and no medical 
expense, medical benefit or compensation money will be paid. In principle, compensation will not 
prevent the execution of the patients’ right to seek damages. 


88 
 
14 MONITORING AND AUDITS 
14.1 Monitoring 
Monitoring will be performed in accordance with the monitoring procedures, and central monitoring 
and monitoring by visiting the sites will be conducted. 
The central monitoring will verify that the clinical study is properly implemented and the reliability 
of data is adequately kept based on documents such as the CRF collected or through other means 
(e.g., telephone, e-mail, fax and post). 
Monitoring by visiting the sites will check that the clinical study is properly implemented and the 
reliability of data is adequately kept through direct access to source documents. 
After the monitoring is performed, a monitoring report should be prepared and submitted to the 
coordinating committee, sponsor-investigator and the head of the study site. 
 
14.2 Protocol Deviations and Violation 
The investigator should record all acts of protocol deviations regardless of reasons. Of 
acts of deviations, for incompliance with the protocol for avoiding immediate hazards to 
the patients or other medically inevitable reasons, the principal investigator should 
report it in writing to the head of the study site and submit a copy of the written report 
sent to the head of the study site to the coordinating committee in accordance with the 
procedures specified at each study site. 
Deviations will be classified into any of the following items after review by the 
coordinating committee: 
 
 
1) 
Major deviation 
“Major deviations” are defined as deviations from the provisions of the protocol that are 
clinically inappropriate and meet two or more of the following items: 
(1) Affecting the evaluations of the endpoints in the study; 
(2) Intentional or systematic 
(3) Hazardous or markedly high degree of deviation 
 
 
2) 
Deviation 
Deviations excluding the item 1) 


89 
 
15 Special considerations 
15.1 Retention of Records 
15.1.1 Sponsor-investigator 
Records shall be retained from the day of marketing approval to the day 5 years after the day of 
approval (when learning that records are not attached to the application form, the day three years 
after the day of notification of such). For the details, the “Procedures for retention of records” should 
be followed. 
 
 
15.1.2 Study Sites 
The head of the study site and the founder of the IRB should retain essential documents, 
records and other relevant materials to be kept in accordance with the GCP Ordinance until the 
belowmentioned days whichever comes later. However, when it is necessary to archive the said 
documents for a longer period of time than this, the archiving period and method should be 
discussed with the coordinating committee. When retaining the records, the head of the study site 
should designate a record archiving manager: 
(1) 
Day of marketing approval for the investigational drug (When development 
discontinuation or the fact of not attaching study results to the approval application is notified, the 
day three years after the day when development discontinuation is decided or the fact of not 
attaching the study results to the application is notified) 
(2) 
Day three years after the discontinuation or termination of the study 
 
 
15.2 Completion of the Study 
When the study is completed, the principal investigator should inform in writing such a fact to the 
head of the study site and report a summary of study results in writing. 
 
 
15.3 Discontinuation at the Study Site 
When finding that major or continuous incompliance with the GCP Ordinance or protocol by the 
study site interferes with the proper conduct of the study, the sponsor-investigator may prematurely 
terminate the study at the study site. In such a case, the sponsor-investigator should report the fact of 
terminating the study at the study site to the head of the study site. Also, the sponsor-investigator 
should report the regulatory authority in writing that the study has been discontinued. 
The investigator should promptly notify such a fact to the patients, provide appropriate medical care 
and take other necessary measures. 


90 
 
15.4 Interruption of the Study and Discontinuation of the Entire Study 
15.4.1 Interruption of the Study 
When the onset of AEs is found to be beyond the acceptable range while the study is ongoing or 
when the principal investigator and coordinating committee judge that the study has to be interrupted 
because serious ADRs or new information on the investigational drugs markedly damage the patients’ 
safety, the principal investigator should promptly notify in writing such a fact and the details of the 
reason for interruption to the head of the study site. The coordinating committee should inform the 
regulatory authority in writing that the study has been interrupted. 
 
 
15.4.2 Discontinuation of the Entire Study 
When the principal investigator and coordinating committee judge that the entire study has to be 
discontinued because serious ADRs or new information on the investigational drugs markedly 
damage the patients’ safety, the principal investigator should promptly notify in writing such a fact 
and the reason for discontinuation to the head of the study site. The principal investigator should 
inform the regulatory authority in writing that the study has been discontinued. 
The investigator should promptly notify the patients, provide appropriate medical care and take other 
necessary measures. 
 
 
15.5 Accompanying research 
In the present trial, accompanying research will be conducted to analyze biomarkers. A separate 
protocol will be created for accompanying research and implemented as clinical research. The results 
of the accompanying research will not be included in the general report. 
1) Purpose 
To analyze how administration of regorafenib and nivolumab in cancer patients affects 
immune cells, as well as the local effects on the tumor site and systemic effects. 
2) Endpoints 
i. 
Microsatellite instability 
ii. 
HLA haplotype 
iii. 
Analysis of the phenotype of immunologically competent cells 
• T-cell fractionation (CD3/CD4/CD8/FoxP3/CD25/CD45RA, etc.) 
• Effector T cells/memory T cells (CCR7/CD45RO/CD127, etc.) 
• Exhausted T cells (CTLA-4/PD-1/Tim-3/LAG-3/TIGIT/GITR/ICOS, etc.) 
• Effector regulatory T cells (CCR4, etc.) 
• NK cells and NKT cells (CD16/CD161/CD56/CD117, etc.) 


91 
 
• Antigen-presenting cells, tumor-associated macrophages, and MDSCs 
(CD33/CD14/CD68/CD11b/CD11c, etc.) 
iv. 
Serum protein analysis (cytokines, chemokines, and autoantibodies) 
v. 
For the histopathological analyses (iii. above), the analysis will focus on immune 
checkpoint molecules such as PD-L1. 
 
3) Handling of samples 
In the present investigator-led trial, samples will be collected. The details regarding sample 
collection are noted in the accompanying research protocol. 
4) Data analysis 
Analysis of this accompanying research is described in the accompanying research protocol. 


92 
 
16 Research organization 
The present trial is a multicenter collaborative investigator-led trial, supported by a trial 
coordinating committee. 
 
16.1 Main research group of this trial 
Refer to attachment 1 
 
 
16.2 Funding of the present trial 
The present trial is conducted in part using funds obtained from Bayer Healthcare and Ono 
Pharmaceuticals, with the investigational drugs supplied free of charge. Furthermore, the Clinical 
Research Support Division, National Cancer Center Hospital East is responsible for data 
management, monitoring, auditing, and the office for the trial coordinating committee, and will carry 
out system maintenance through the support project to ensure clinical research safety for unapproved 
drugs (the ‘Project to develop core clinical research hospitals, National Cancer Center Hospital 
East”; chair: Atsushi Otsu, National Cancer Center Hospital East). 


93 
 
17 Ownership of the trial outcomes and announcement of the trial results 
The research results belong to the National Cancer Center. The presentation of the research results 
at conferences and in papers will be determined at the time of announcement by the trial 
coordinating committee upon deliberation with the principal investigators and other parties 
concerned. 


94 
 
18 References 
 
1. 
"Cancer statistics in Japan” Editorial Board. Cancer statistics 2013. Tokyo. Public Interest 
Incorporated Foundation, Foundation for the promotion of cancer research. 2013. p. 109. 
2. 
Cancer information service. [Internet]. Tokyo: National Cancer Research Center; (c) 2010 [cited 
2015 Mar 9]. Available from: http://ganjoho. jp/public/statistics/pub/statistics01.html. 
3. 
Cancer mortality data according to vital statistics (1958 to 2013). Statistics and Informatin 
Department, Minister's Secretariat, Ministry of Health, Labour and Welfare. Vital statistics. 
4. 
Oldham RK. Biologicals and biological response modifiers: fourth modality of cancer treatment. 
Cancer treatment reports. 1984;68:221-232. 
5. 
Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. 
Nature medicine. 2004;10:909-915. 
6. 
Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights into cancer immunoediting and its 
three component phases--elimination, equilibrium and escape. Current opinion in immunology. 
2014;27:16-25. 
7. 
Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced 
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