Conditions: Advanced Gastric Cancer
Keywords: lenvatinib, pembrolizumab, phase II, gastric cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 29
Healthy volunteers: no

Brief summary:
The efficacy and safety of the use of pembrolizumab in combination with lenvatinib.

Detailed description:
In this study, if combination therapy with lenvatinib and pembrolizumab in patients with gastric cancer is judged to be effective, a prospective treatment regimen can be expected for a larger number of participating subjects.

The anticipated disadvantages include any adverse events associated with lenvatinib and pembrolizumab. 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.

Arms:
arm 1: Lenvatinib and Pembrolizumab will be administrated simultaneously for advanced gastric cancer patients.

Interventions: intervention 1: Lenvatinib intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Lenvatinib will be administered with water orally once a day (with or without food) in 21-day cycles at approximately the same time each day. On Day 1 of each cycle, in case concomitantly administered, it will be administered approximately within 1 hour after completion of pembrolizumab administration. intervention 2: Pembrolizumab will be administered as a dose of 200 mg as a 30-minute IV infusion, every 3 weeks (25 minutes to 40 minutes are acceptable).

Protocol document:
Prot_SAP_000.pdf: 
 
An Open label Phase 2 Study to Evaluate the Safety and 
Efficacy of Lenvatinib with Pembrolizumab in Patients with 
Advanced Gastric Cancer 
 
Investigator-initiated Study Protocol 
 
 
Protocol Number：EPOC1706 
 
Coordinating investigator (representative): Kohei Shitara 
Department of Gastroenterology and Gastrointestinal Oncology, National Cancer 
Center Hospital East 
6-5-1, Kashiwanoha, Kashiwa-shi, Chiba 277-8577 
Tel: 04-7133-1111 (extension: 91520) 
E-mail：kshitara@east.ncc.go.jp 
Coordinating investigators:  
Shota Fukuoka 
Exploratory Oncology Research & Clinical Trial Center, National Cancer Center 
Akihito Kawazoe, Akihiro Sato  
Department of Gastroenterology and Gastrointestinal Oncology,  
Clinical Research Support Office 
National Cancer Center Hospital East 
E-mail:LenvaPem_core@east.ncc.go.jp  
 
Precautions for Confidential Information 
This protocol is confidential information and provided to the coordinating committee, 
principal investigators, subinvestigators and study collaborators (including external 
contractors such as a site management organization (SMO) conducting this study, 
study sites participating in the study, institutional review board, and efficacy and safety 
evaluation committee. 
This protocol therefore shall not be disclosed to any third party or used for any other 
purpose except this study without written consent of the coordinating committee and 
investigational drug providers, except when explaining the contents of the study to 
patients 
Protocol No.: EPOC1706 
Version No.:1.2 
Date of preparation:20/05/2020


 
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Revision History： 
25/05/2018 Investigator-initiated Study Protocol ver 1.0 
23/04/2019 Investigator-initiated Study Protocol ver 1.1 
20/05/2020 Investigator-initiated Study Protocol ver 1.2 
 


 
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0. SYNOPSIS 
Study Title 
An Open label Phase 2 Study to Evaluate the Safety and Efficacy of 
Lenvatinib with Pembrolizumab in Patients with Advanced Gastric Cancer 
Phase 
Phase II 
Objectives 
To evaluate antitumor activity and safety of Lenvatinib with Pembrolizumab 
for AGC patients 
Endpoint 
Primary endpoint： 
Objective response rate (ORR) 
by Response Evaluation Criteria In Solid Tumors (RECIST) ver1.1 
 
Secondary endpoints: 
・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 4.0. 
・Efficacy 
- Objective response rate (ORR) according to immune-related (ir) RECIST 
- Progression-free survival (PFS) 
- Overall survival (OS) 
- Disease control rate (DCR) 
 
Exploratory endpoints  
(performed as accompanying research in the present trial): 
Tests of various biomarkers 
Study population 
Inclusion criteria: 
 
1. 
Patients have histologically or cytologically confirmed advanced or 
recurrent gastric cancer. 
2. 
Patients at least 20 years of age on the day of providing consent. 
3. 
Patients have measurable disease as defined by RECIST 1.1 as 
determined by investigator. 
4. 
Patients with a performance status of 0 or 1 on the Eastern Cooperative 
Oncology Group. 
5. 
Patients with adequate organ function at the time of enrollment as 
defined below: 


 
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・Neutrophil count ≥1200mm3 
・Platelet count ≥7.5 × 104/mm3  
・Hemoglobin (Hb) ≥ 8.0 g/dL, 
・Total bilirubin ≤1.5 mg/dL 
・AST (SGOT) and ALT (SGPT) ≤ 100 IU/L 
for subjects with liver metastases≤200 IU/L 
・Creatinine ≤1.5-times the upper limit of normal 
・International normalized ratio (INR) ≤ 1.5  
・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) Urine Protein Creatinine(UPC) ratio <3.5  
(iii) 24-hour urine protein was measured, urinary protein ≦ 3500 mg 
 
6. 
Patients who not received a blood transfusion within 7 days of 
registration. 
7. 
Patients have recovered adverse events associated with chemotherapy, 
radiation and surgical operation as pretreatment to Grade 1 or lower with 
CTCAE v4.0 excluding stable symptoms (eg alopecia, peripheral 
sensory neuropathy, skin hyperpigmentation, dysgeusia etc.). 
8. 
Female of childbearing potential who are negative in a pregnancy test 
within 14 days before enrollment. Both male and female patients should 
agree to use an adequate method of contraception (total abstinence, an 
intrauterine device or hormone releasing system, an contraceptive 
implant and an oral contraceptive) starting with the first dose of study 
therapy through 120 days after the last dose of study therapy. Duration 
will be determined when the subject is assigned to treatment. 
9. 
Patients capable of taking oral medication 
10. Patients who provided written informed consent to be subjects in this 
trial 
 
Exclusion criteria: 
1. 
Patients who received prior anticancer treatment within 14 days (or 5 
times the half-life time, whichever is shorter) or any investigational agent 
within 28 days prior to the first dose of study drugs. 


 
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2. 
Patients who have undergone surgical treatment and radiotherapy with 
in 2 weeks before enrollment. 
3. 
Patients with a history of prior treatment with Lenvatinib or any anti-PD-
1, anti-PD-L1, or anti-PD-L2 agent. 
4. 
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. 
5. 
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. 
6. 
Patients with symptomatic brain metastasis. 
7. 
Patients with a history of New York Heart Association congestive heart 
failure of grade II or above, unstable angina, myocardial infarction within 
the past 6 months, or serious cardiac arrhythmia associated with 
significant cardiovascular impairment within the past 6 months 
8. 
Patients have an active malignancy (except for definitively treated 
melanoma in-situ, basal or squamous cell carcinoma of the skin, or 
carcinoma in-situ of the cervix) within the past 24 months 
9. 
Patients 
have 
severe 
(hospitalization 
required) 
complications 
(intenstinal palsy, intestinal obstruction, pulmonary fibrosis, diabetes 
difficult to control, heart failure, myocardial infarction, unstable angina, 
renal failure, liver failure, mental disease, cerebrovascular disease etc). 
10. Patients with a history of a gastrointestinal perforation and /or 
gastrointestinal fistula within 6 months before enrollment.  
11. Patients with active hepatitis. 
12. Patients with a history of human immunodeficiency virus (HIV). 
13. Patients with active symptoms or signs of interstitial lung disease. 
14. Patients with concurrent autoimmune disease, or a history of chronic or 
recurrent autoimmune disease 
15. 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. 
16. Patients have a history of (non-infectious) pneumonitis that required 
steroids or have current pneumonitis 


 
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17. Patients who are administered live vaccines <30 days before the 
initiation of treatment with the investigational drug. 
18. Patients have serious non-healing wound, ulcer, or bone fracture. 
19. Females who are pregnant or breastfeeding 
20. Patients have no intention to comply with the protocol or cannot comply. 
21. Patients were judged unsuitable as subject of this trial by investigator. 
Duration of study 
participation 
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. 
Number of 
patients 
Statistical 
analysis 
First stage : 10 patients 
Second stage : 19 patients 
Total 29 patients 
Administration 
method 
Lenvatinib 20 mg /day orally 
Pembrolizumab 200 mg (every 3 weeks [Q3W], intravenous [IV]) 
One cyle will last 21 days 
Safety evaluation 
Evaluations will be performed using CTCAE version 4.0. 
Efficacy 
evaluation 
The antitumor effect will be evaluated in accordance with irRECIST and 
RECIST version 1.1 every 6 weeks. 
・Image evaluation: computed tomography (CT) or magnetic resonance 
imaging (MRI) 
In all patients, PFS and survival will be evaluated. 
Observations 
and tests 
Physical examination, vital signs, PS, laboratory tests (hematology and 
biochemistry), urinalysis, laboratory findings, tumor markers, ECG, CT/MRI 
of chest, abdomen and pelvis, etc. 
Trial Design 
This trial is an open label phase II study to evaluate the safety and efficacy 
of Lenvatinib with Pembrolizumab in patients with ACG. The Simon’s Optimal 
two-stage design will be used in this trial.   
Statistical 
matters 
Statistical procedures will be as follows: 
Primary endpoint 
The analysis set for the primary endpoint is the Full Analysis Set (FAS). The 
statistical criteria for main analysis will be based on the number of patients 


 
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with the best overall response of Complete Response (CR) or Partial 
Response (PR) according to RECIST guideline version 1.1. In the first stage, 
if two or more objective response (CR or PR) was observed among 10 
patients (no confirmation required), the study will proceed to the second 
stage. If objective response (CR or PR) was less than two, the study will not 
proceed to the second stage and we will consider discontinuation of this trial. 
on the basis of a precise method based on the binomial distribution 
In the second stage 19 patients will be enrolled. If there are ≥ 6 patients with 
objective response (CR or PR), the main objective of this trial will be 
achieved. An accurate confidence interval based on a binomial distribution 
is used for calculating the proportion of confidence intervals. 
 
Secondary endpoint 
The following analyses will be performed for ① FAS, ② ITT (Intention to 
Treat:ITT) and FAS, ③ SP (Safety Population).  
 
① ORR by irRECIST, DCR  
Confidence intervals for ORR and DCR will be created using the exact test 
according to a binomial distribution.  
② PFS, OS 
A survival function will be estimated using the Kaplan-Meier method. The 
median with the 95% CI and annual survival rate with the 95% CI will be 
estimated. 
③ Incidence of adverse events 
As incidence of adverse events, in addition to tabulation of the frequency of 
adverse events, the incidence of Grade 3 or higher adverse events and the 
incidence of Grade 4 or higher adverse events will be calculated. 
Planned period of 
the study 
Planned enrollment period: October 2018 to Jun 2019 
Planned observation period: 2 years from the date of enrollment of the last 
patient  
Entire study period (including a procedure for study completion): 3 year and 
6 months from the date of enrollment of last patient 
When the administration of all subjects would be completed during the 
observation period, the observation period of the present trial will be also 
ended at the end of the observation period of the final administration subject. 


 
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Representative 
coordinating 
investigator 
Kohei Shitara, National Cancer Center Hospital East 
Planned 
study 
sites 
National Cancer Center Hospital East 
 
Contact information: LenvaPembro_core@east.ncc.go.jp 
Those requiring clinical judgements such as inclusion/exclusion criteria and criteria for 
treatment change: Coordinating investigators (Title page) 
Enrollment procedure, electronic case report form (eCRF), etc.: Data Management Office, 
Clinical Research Support Unit, National Cancer Center Hospital East 
(Attachment 1) 
AE report, etc.: Clinical Research Support Unit, National Cancer Center Hospital East 
(Attachment 1) 
 
 


 
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TABLE OF CONTENTS 
0. SYNOPSIS ........................................................................................................................................................... 3 
1. OBJECTIVES ................................................................................................................................................... 13 
2. BACKGROUND and RATIONALE FOR THE THE SELECTION OF TE TREATMENT PLAN . 14 
2.1. Epidemiology of the Subjects ............................................................................................................... 14 
2.2. The Standard of Care of Subjects ...................................................................................................... 14 
2.3. Molecular targeted drug of the Subjects ....................................................................................... 14 
2.4.Immunotherapy for the Subjects .......................................................................................................... 15 
2.5. Rationales for the Selection of the Treatment Plan .................................................................. 16 
2.6. Lenvatinib ....................................................................................................................................................... 17 
2.7. Pembrolizumab ............................................................................................................................................ 18 
2.8The combination of Lenvatinib and Pembrolizumab ................................................................... 19 
2.9. Treatment regimen in the present trial ............................................................................................. 20 
2.10. Study Design .............................................................................................................................................. 22 
2.11. Summary of Expected Benefits and Disadvantages Associated with the Study 
Participation ............................................................................................................................................................ 24 
2.12. Rationale for the Investigator-Initiated Study ............................................................................ 24 
3. Standards and definitions used in this study ......................................................................................... 26 
3.1. Standards for disease staging ............................................................................................................. 26 
3.2. Performance Status （ECOG classification） ................................................................................ 26 
3.3. Evaluation criteria for adverse events .............................................................................................. 26 
3.4. Evaluation criteria for response rate ................................................................................................. 26 
4. Eligibility criteria/exclusion criteria .......................................................................................................... 27 
4.1. Inclusion criteria .......................................................................................................................................... 27 
4.2. Exclusion criteria ......................................................................................................................................... 28 
5. Registration/allocation ................................................................................................................................. 30 
5.1. Contact information for subject’s registration and time in ...................................................... 30 
5.2. Precautions for registration.................................................................................................................... 30 
6. TREATMENT PLAN AND CRITERIA FOR TREATMENT CHANGE ............................................... 32 
6.1. Protocol Treatment..................................................................................................................................... 32 


 
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6.1. 1 Study Treatment ...................................................................................................................................... 32 
6.2. Discontinuation Criteria for the Protocol Treatment .................................................................. 33 
6.3. Criteria for Dose Modifications for the Protocol Treatment ................................................... 34 
6.4. Special instructions for subjects .......................................................................................................... 43 
6.5. Concomitant and Supportive Therapies ......................................................................................... 43 
6.6. Subsequent Treatment ............................................................................................................................ 45 
7. INFORMATION ON THE INVESTIGATIONAL DRUGS ....................................................................... 46 
7.1. Drug Information on Lenvatinib ........................................................................................................... 46 
7.2. Drug Information on Pembrolizumab................................................................................................ 46 
7.3. Management of Study Drugs ................................................................................................................ 47 
7.4. Expected AEs ............................................................................................................................................... 47 
8. ENDOPOINTS, LABORATORY TESTS AND EVALUATION SCHEDULE .................................... 48 
8.1. Observations and tests ............................................................................................................................ 48 
8.2. Observation and schedule ..................................................................................................................... 49 
8.3. Examination findings ................................................................................................................................. 51 
8.4. Laboratory tests ........................................................................................................................................... 52 
8.5. Biomarkers ..................................................................................................................................................... 53 
8.6. Tumor evaluation ........................................................................................................................................ 53 
8.7. Follow-up......................................................................................................................................................... 55 
9. DATA COLLECTION ..................................................................................................................................... 57 
9.1. Handling and Retention of CRF Data .............................................................................................. 57 
9.2. Identification of Source Documents .................................................................................................. 57 
10. REPORTING OF ADVERSE EVENTS .................................................................................................... 58 
10.1. Evaluation of AEs ..................................................................................................................................... 58 
10.2. Reporting of Serious Adverse Events (SAEs) ........................................................................... 60 
10.3. Collection of Safety Information ....................................................................................................... 64 
10.4. Reporting of Pregnancy and Lactation ......................................................................................... 64 
11. ASSESSMENT OF RESPONSE AND DEFINITIONS OF THE ENDPOINTS .............................. 66 
11.1. Assessment of Respons ....................................................................................................................... 66 
11.2. Definitions of the Endpoints ................................................................................................................ 66 
12. STATISTICAL MATTERS .......................................................................................................................... 68 


 
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12.1. Handling of the Patients ....................................................................................................................... 68 
12.2. Definitions of Analysis Populations ................................................................................................. 68 
12.3. Data Handling ............................................................................................................................................ 68 
12.4. Positioning of Analyses and Analysis Methods ........................................................................ 69 
12.5. Efficacy Analyses ..................................................................................................................................... 69 
12.6. Safety Analyses ........................................................................................................................................ 70 
12.7. Planned Sample Size ............................................................................................................................ 70 
12.8. Interim Analysis ......................................................................................................................................... 71 
12.9. Final Analysis ............................................................................................................................................. 71 
12.10. Special Notes .......................................................................................................................................... 71 
13. ETHICAL MATTERS.................................................................................................................................... 74 
13.1. Policies, Laws and Regulations with Which the Study Complies ................................... 74 
13.2. Informed Consent .................................................................................................................................... 74 
13.3. Protection of Personal Information and Patient Identification ........................................... 75 
13.4. Approval of the Institutional Review Board (IRB) .................................................................... 77 
13.5. Changes in the Contents of the Protocol ..................................................................................... 77 
13.6. Management of Conflict of Interest (COI) ................................................................................... 78 
13.7. Compensation ............................................................................................................................................ 78 
14. MONITORING AND AUDITS ..................................................................................................................... 79 
14.1. Monitoring .................................................................................................................................................... 79 
14.2. Protocol Deviations and Violation .................................................................................................... 79 
14.3. Audit ................................................................................................................................................................ 79 
14.4. Direct Access ............................................................................................................................................. 80 
15. SPECIAL NOTES ......................................................................................................................................... 81 
15.1. Retention of Records ............................................................................................................................. 81 
15.2. Completion of the Study ....................................................................................................................... 81 
15.3. Discontinuation at the Study Site ..................................................................................................... 81 
15.4. Interruption of the Study and Discontinuation of the Entire Study .................................. 82 
15.5. Associated research ............................................................................................................................... 82 
16. STUDY ORGANIZATION ........................................................................................................................... 83 
16.1. Study Implementation Structure ....................................................................................................... 83 
16.2. Funding Source of the Study ............................................................................................................. 83 


 
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17. ATTRIBUTION OF STUDY RESULTS AND PUBLICATION OF STUDY RESULTS ............... 84 
18. REFERENCES ............................................................................................................................................... 85 


 
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1.  OBJECTIVES 
….. 
To evaluate antitumor activity and safety of Lenvatinib with Pembrolizumab for AGC patients 
 
Primary endpoint 
・Objective response rate (ORR) 
by Response Evaluation Criteria In Solid Tumors (RECIST) ver1.1 
 
Secondary endpoint 
・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 4.0. 
・Efficacy 
- Objective response rate (ORR) according to immune-related (ir) RECIST 
- Progression-free survival (PFS) 
- Overall survival (OS) 
- Disease control rate (DCR) 
 
Exploratory endpoints 
Tests of various biomarkers 


 
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2. BACKGROUND and RATIONALE FOR THE THE SELECTION OF TE 
TREATMENT PLAN 
2.1. Epidemiology of the Subjects 
The number of deaths of gastric cancer in Japan is about 50,000 per year (about 13% of 
360,000 deaths total) and is the second leading cause of death due to malignant neoplasms. 
However, the mortality rate (against 100,000 inhabitants) have tendency to decrease in 
male and female to 53.9, 33.2 (1980) and 50.5, 24.7 (2015), respectively1. On the otherhand, 
the morbidity rate (against 100,000 inhabitants) remained high, In 1980, male and female 
were 86.6 and 49.1 respectively, rising to 146.7 and 62.8 respectively in 2012, the first in 
male and the third in women most common cause of cancer-related death2.     Gastric 
cancer is the fifth most common cancer worldwide and the third most common cause of 
cancer-related death (after lung and liver cancer), with an estimate of 723,073 deaths 
annually. Currently, patients with gastric cancer can be cured only when diagnosed with 
early stage disease in which a complete resection of the tumor can be  therapy. 
Approximately 50% of patients with gastric cancer have advanced disease at the time of 
diagnosis.  
 
2.2. The Standard of Care of Subjects 
Standard chemotherapy regimens for advanced gastric cancer include fluoropyrimidines, 
platinum derivatives, and taxanes, or irinotecan4. Based on the results of the ToGA study, 
the addition of trastuzumab to chemotherapy has become standard of care, where available, 
for first-line treatment of patients with HER2-neu-positive (HER2+) advanced or metastatic 
gastric adenocarcinoma5. As a second-line treatment, in two phase III trials, taxanes and 
irinotecan showed a significant survival extension compared with the best supportive care6,7. 
Ramucirumab, a vascular endothelial growth factor-2 (VEGFR-2) antibody, has been shown 
to increase OS when administered alone or in combination with paclitaxel in patients who 
have progressed following first-line therapy; and was recently approved in Japan for 
second-line therapy of gastric cancer8. Among patients with advanced metastatic gastric 
cancer who have received standard first-line therapies, the 5-year survival rate remains less 
than 5% and the median OS is less than 12 months, therefore, further development of 
effective treatment is urgent. 
 
2.3.  Molecular targeted drug of the Subjects 
Trastuzumab and Ramucirumab mentioned above are approved in Japan for molecular 
targeted drug for gastric cancer. Clinical trials of EGFR inhibitors such as Panitumumab and 


 
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Cetuximab and anti-VEGF antibody drugs such as Bevacizumab were carried out, but all 
were negative. Other molecularly targeted drug under development are mainly drugs having 
angiogenesis inhibiting action. Apatinib is a novel small molecule tyrosine kinase inhibitor 
that selectively inhibits VEGFR2, and Phase III trials were conducted in China targeting 
second-line treatment. As a result, the median OS was significantly longer than 6.5 months 
in the Apatinib group and 4.7 months in the placebo group (HR = 0.709, p = 0.0149). The 
international joint Phase III trial (ANGEL test) is currently being conducted. Regorafenib is 
an oral multi-kinase inhibitor that targets factors related to angiogenesis (VEGFR1-3, TIE-
2), tumor microenvironment (PDGFR, FGFR), tumor growth (RAF, RET, KIT) and is a drug 
whose efficacy has been confirmed in colon cancer and GIST. International joint Phase II 
trials were conducted for gastric cancer that became refractory to primary or secondary 
therapy. As a result, it was 2.6 months in the Regorafenib group and 0.9 months in the 
placebo group in PFS, the primary endpoint, and significantly prolonged in the Regorafenib 
group (HR = 0.40, p <0.0001). International joint Phase III trials are currently under way. 
 
2.4.Immunotherapy for the Subjects 
In recent years, “immunotherapy” has been attracting attention as the fourth treatment 
method for advanced or metastatic solid cancer. 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 patients9. This is likely attributable to the tumor microenvironment 
inhibiting the antitumor immune response9. 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 response10. 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)10. The antitumor immune 
response could potentially be activated by inhibiting these molecules that suppress the 


 
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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. On 22 September 2017, nivolumab was approved for 
the treatment of unresectable advanced or recurrent gastric cancer which has progressed 
after chemotherapy. This approval was based on the phase III study ATTRACTION-2, in 
which nivolumab significantly reduced patients’ risk of death by 37% (HR = 0.63; 95% CI = 
0.51–0.78, p < .0001) when compared to placebo11. Similary, the FDA has approved 
Pembrolizumab for the treatment of patients with PD-L1–positive recurrent or advanced 
gastric cancer who have received 2 or more lines of chemotherapy, including 
fluoropyrimidine- and platinum-containing chemotherapy, and, if appropriate, HER2/neu-
targeted therapy. The approval is based on findings from the phase II KEYNOTE-059 study. 
The overall response rate in all patients was 11.6% (95% CI, 8.2-20.0) and in PD-L1–
positive patients was 15.5%. The phase III KEYNOTE-061 trial investigating pembrolizumab 
as a second-line treatment for patients with advanced gastric cancer did not meet its primary 
endpoint of overall survival (OS) (HR = 0.82, 95% CI = 0.66–1.03; p = 0.042 ) in patients 
whose tumors expressed PD-L1. 
As mentioned above, the immunosuppressive mechanisms of cancer cells vary greatly. 
Therefore, 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 end. 
 
2.5. Rationales for the Selection of the Treatment Plan 
2.5.1. Treatment 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 (TAM) is 


 
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considered to increase as cancer progresses.  
Angiogenic factors (vascular endothelial growth factor: VEGF) are considered to be 
involved in the production of regulatory T cells, MDSC, and TAM. 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 tumor12-16. 
Similarly, stem cell factor (SCF)-mediated signaling of MDSCs was repressed by blocking 
the interaction with its receptor c-Kit. This inhibition resulted in decreased MDSC expansion 
and tumor angiogenesis17. In the studies conducted at our hospital, the analysis of biopsy 
tissue specimens before and after lenvatinib administration has revealed that the ratio of 
regulatory T cells decreases, which suggests that lenvatinib decreases the production of 
immunosuppressive cells (data not published).. 
Lenvatinib showed a superior antitumor activity in immune-competent mice compared to 
in immune-deficient mice with immune modulating effects to decrease TAMs and MDSC. 
Lenvatinib also enhanced antitumor activity of PD-1 inhibitors treatment in two syngeneic 
models. In the phase Ib part of lenvatinib and pembrolizumab, patients with solid tumors 
that had progressed after treatment with approved therapies were administered either 24mg 
or 20mg of lenvatinib daily and 200mg of pembrolizumab intravenously every three weeks. 
DLTs were reported in two of three patients in lenvatinib 24mg / pembrolizumab 200mg 
group and no DLTs were reported in lenvatinib 20mg / pembrolizumab 200mg group of ten 
patients, and the MTD was confirmed as 20mg of lenvatinib / 200mg of pembrolizumab 
every three weeks. Out of the 13 patients, the objective response rate was 69.2%. Currently, 
several phase 2 or 3 trials are ongoing for renal cell cancer. However, to our knowledge, 
there is no study using lenvatinib in combination with anti-PD1 antibody for AGC patients. 
Therefore we planned this study. 
 
2.6. Lenvatinib 
Lenvatinib mesylate was developed at Eisai Tsukuba Research Laboratories to explore 
agents that inhibit RTKs activities associated with tumor angiogenesis. It is a multikinase 
inhibitor that exhibits potent inhibitory effects not only on VEGFR1 to VEGFR 3 at the level 
of inhibition constant Ki 1 nmol/L, but also on FGFR 1 to FGFR4 and KITs. 
In nonclinical studies, lenvatinib showed inhibitory activities dose-dependently in 
VEGFR2-driven phosphorylation, tube formation and proliferation in human vascular 
endothelial cells (human umbilical vein endothelial cell – HUVEC) induced by VEGF. In vivo 
study where human cancer cells are transplanted in immune deficient mouse models, 
lenvatinib also demonstrated high anticancer effect in a wide variety of cancers. In addition, 
safety results in nonclinical studies showed lenvatinib was well tolerated within the 


 
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therapeutic range18. 
Three phase 1 studies were conducted in Japan, US, and Europe with different regimen 
to determine the safety, tolerability, and pharmacokinetics of lenvatinib. Treatment regimen 
for each study was: continuous once daily for E7080-E044-101 (Europe), continuous twice 
daily for E7080-A001-102 (US), and twice daily for 2 weeks with dosing intervals of 1 week 
for E7080-J081-103 (Japan). Based on the results from these studies, a continuous dose 
of 24 mg once daily has been selected to treat solid tumors for ongoing lenvatinib 
development.  The tolerability in 24 mg once daily continuous dose in Japanese patients 
was confirmed in another study conducted in Japan (E7080-J081-105). There was no 
significant difference in tolerability and pharmacokinetics among patients in Japan, Europe, 
and US19. 
Lenvatinib is expected to be efficacious regardless of cancer type; clinical studies are 
being conducted for various solid malignancies including thyroid carcinoma, hepatocellular 
carcinoma, renal cell carcinoma, non-small-cell lung cancer, endometrial cancer, glioma, 
malignant melanoma, and ovarian cancer. Lenvatinib is approved in the US for the treatment 
of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory 
differentiated thyroid cancer, and approved in Japan with an indication for unresectable 
thyroid cancer.   
As outlined below, data from Phase 2 clinical studies showed lenvatinib monotherapy has 
antitumor activity in multiple other tumors. In a 3 arm study of lenvatinib 24 mg once daily, 
everolimus 10 mg once daily, and the combination of lenvatinib 18 mg with everolimus 5 mg 
in patients with unresectable advanced or metastatic renal cell carcinoma (E7080-G000-
205), lenvatinib monotherapy showed plonongation of PFS compared with everolimus 
monotherapy. Although a large scale study in gastric cancer has not been conducted, 3 out 
of 6 patients with advanced gastric cancer patients during phase 1 trials achieved durable 
stable disease. 
 
2.7. Pembrolizumab 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 
inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell 
death ligand 2 (PD-L2). 
Treatment studies using mouse models revealed that administration of an antibody, 
inhibiting interactions with PD-1/PD-L1, promoted the infiltration of tumor-specific CD8-
positive T cells when administered alone or in combination with other treatments, and 
ultimately led to tumor rejection. It has been shown that anti-mouse PD-1 or PD-L1 antibody 


 
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alone has an antitumor effect in squamous cell carcinoma, pancreatic cancer, malignant 
melanomas and CRC models. The inhibition of the PD-1 pathway effectively promotes CD8-
positive T cell infiltration into tumors and IFN-γ, granzyme B and perforin production. In a 
mechanism of action, in vivo local infiltration and activation of effector T cell function have 
been suggested to be involved. In vivo studies using syngeneic mouse models of tumors 
revealed that the inhibition of the PD-1 pathway by pembrolizumab alone and in combination 
with chemotherapy was effective. Pembrolizumab has an acceptable preclinical safety 
profile and is in clinical development as an intravenous (IV) immunotherapy for advanced 
malignancies. Pembrolizumab is indicated for the treatment of patients across a number of 
indications.  
In the advanced adenocarcinoma of the gastric or gastroesophageal junction cohort in a 
Phase Ib study (KEYNOTE-012) of pembrolizumab in patients with PD-L1-positive solid 
tumors, pembrolizumab 10 mg/kg was administered every 2 weeks to 39 patients20. At 8.8 
months of follow-up, the ORR was 22.2% and 6-month survival rate was 69%. In an 
additional analysis, the median duration of response was 40 weeks and very long. The 
median OS was 11.4 months and very good while 66.7% of patients had received 2 or more 
regimens. Treatment-related AEs occurred in 24 patients (61.5%). Grade 3/4 AEs occurred 
in 4 patients (decreased appetite, malaise, hypoxia, peripheral nerve disorder and 
pneumonitis). None of the treatment-related AEs led to treatment discontinuation.  
In KEYNOTE-059 study cohort 2, the efficacy of pembrolizumab + 5-FU + cisplatin was 
investigated. Twenty-five patients were enrolled, ORR was 60% (95% CI, 38.7-78.9) , 
median PFS was 6.6 months and median OS was 20.8 months. This study suggested that 
the combination of standard therapy and pembrolizumab encourage antitumor activity.  
The ongoing phase III KEYNOTE-062 trial is evaluating pembrolizumab alone and in 
combination with chemotherapy in the frontline setting for PD-L1–positive advanced 
gastric cancer. In phase I study of the combination of pembrolizumab and ramucirumab for 
28 patients, response rate was 14% and median PFS was 5.6 months. 
The development of combination therapy of pembrolizumab and standard therapy or 
molecular targeted drug is underway in both front and secondary line. 
 
2.8The combination of Lenvatinib and Pembrolizumab 
2.8.1. Preclinical study 
It is reported that VEGF/VEGFR signal exhibits proangiogenic properties but also has a 
key role in the induction of an immunosuppressive microenvironment16. Therefore, it is 
expected that lenvatinib which inhibit VEGFR can also have immune modulating activity. 
The effect of combining lenvatinib with PD-1/L1 monoclonal antibodies (mAbs) has been 


 
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investigated in the CT26 murine colorectal cancer syngeneic model (PD-L1 mAb) as well 
as the LL/2 murine lung cancer syngeneic model (PD-1 mAb). Combination treatment with 
lenvatinib and PD 1/L1 mAb showed significant and superior antitumor effects compared 
with either compound alone. TAM cells express PD-L1 at a higher level than cancer cells in 
the CT26 syngeneic model, and lenvatinib significantly decreased the TAM population21. 
Because TAM cells produced interleukin 10 (IL-10) and transforming growth factor, beta 1 
(TGFβ)22, lenvatinib might increase antitumor immunity in the CT26 model and up-regulate 
the effect of the PD-1 signal inhibitors. Thus, immune-modulating effect of lenvatinib may 
result in potent combination effect with PD-1 signal inhibitors. 
 
2.8.2. Clinical trial 
E7080-A001-111 (Study 111) is an open-label Phase 1b/2 study in subjects with selected 
solid tumors (NSCLC, predominantly clear cell renal cell carcinoma, endometrial carcinoma, 
urothelial carcinoma, squamous cell carcinoma of the head and neck, or melanoma 
[excluding uveal melanoma]), which is conducted in US.  
In Phase 1b, subjects were to enroll in 1-3 dose levels to determine and confirm the 
maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of lenvatinib in 
combination with pembrolizumab. The dose of pembrolizumab did not change during the 
MTD phase, while lenvatinib started at 24 mg and then be reduced, if necessary, to either 
20 mg or 14 mg. In the lenvatinib 24 mg cohort, 2 DLTs were observed in the first 3 subjects 
(2 renal cell carcinoma and 1 NSCLC): Grade 3 fatigue and Grade 3 arthralgia. The dose 
was de-escalated to 20 mg/day lenvatinib and 10 additional subjects (total of 6 renal cell 
carcinoma, 1 NSCLC, 1 Melanoma and 2 Endometrial) started the treatment. There were 
no DLTs in the lenvatinib 20 mg cohort, and the MTD and RP2D are confirmed at 20 mg 
lenvatinib once daily (QD) in combination with 200 mg Q3W of pembrolizumab.   
In Phase II, subjects are assigned by tumor type to up to 6 cohorts to receive the MTD to 
assess the safety and efficacy of the combination in the selected tumor-types. This phase 
is ongoing. 
 
2.9. Treatment regimen in the present trial 
The protocol treatment of this trial is combination of lenvatinib and pembrolizumab. This 
study will begin with lenvatinib 20 mg/day orally and pembrolizumab 200 mg (every 3 weeks 
with each cycle of 21 days. The administration will be repeated until each subject falls under 
the criteria for discontinuation.  
 
2.9.1. Rationale for setting Lenvatinib administration route, dose, and treatment 


 
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schedule 
As described in Section 2.7.2, investigation in combination with Pembrolizumab was 
conducted in 111 trial. In this trial, once-daily Lenvatinib 20 mg confirmed as MTD and 
RP2D in 111 trial is considered to be appropriate as the starting dose. 
 
2.9.2. Rationale for setting Pembrolizumab administration route, dose, and treatment 
schedule 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  
Based on the totality of data generated in the Keytruda development program, 200 mg Q3W 
is the appropriate dose of pembrolizumab for adults across all indications and regardless of 
tumor type. As outlined below, this dose is justified by: 
• 
Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),  
• 
Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and 
• 
Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically-
based PK [PBPK] analysis) at 200 mg Q3W 
 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were 
enrolled with melanoma and non-small cell lung cancer (NSCLC), covering different disease 
settings (treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different 
treatment settings (monotherapy and in combination with chemotherapy). Five studies 
compared 2 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, 
KN002, KN010, and KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg 
Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006). All of these studies demonstrated 
flat dose- and exposure-response relationships across the doses studied representing an 
approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 200 mg fixed-dose) Q3W 
provided similar responses to the highest doses studied. Subsequently, flat dose-exposure-
response relationships were also observed in other tumor types including head and neck 
cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 200 
mg Q3W as the appropriate dose independent of the tumor type. These findings are 
consistent with the mechanism of action of pembrolizumab, which acts by interaction with 
immune cells, and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 


 
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demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Second, a PBPK analysis was conducted to predict tumor PD-1 saturation over a 
wide range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.  
Supported by these PK characteristics, and given that fixed-dose has advantages of 
reduced dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-
dose was selected for evaluation across all pembrolizumab protocols. 
 
2.10. Study Design 
This trial is an open label phase II study to evaluate the safety and efficacy of lenvatinib 
with pembrolizumab in patients with ACG. The Simon’s Optimal two-stage design will be 
used in this trial23.   
 
The analysis set for the primary endpoint is the Full Analysis Set (FAS). 
 
1) First stage  
In the first stage, ten patients will be enrolled in the FAS prescribed in Section 12.3. If two 
or more objective response (CR or PR) were observed among 10 patients (no confirmation 
required) in the first stage, the study will proceed to the second stage. If objective response 
(CR or PR) was less than two, the study will not proceed to the second stage and we will 
consider discontinuation of this trial. 
 
2) Second stage 
In the second stage 19 patients will be enrolled. If there are ≥ 6 patients with objective 
response (CR or PR), the main objective of this trial will be achieved. 
 
2,10.1. Rationales for the Endpoint 
 
Primary endpoint 
・Objective response rate (ORR) 
 
Secondary endpoint 


 
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- Objective response rate (ORR) according to immune-related (ir) RECIST 
- Progression-free survival (PFS) 
- Overall survival (OS) 
- Disease control rate (DCR) 
- Incidence of adverse events 
 
Rationale for primary endopoint 
In this trial, ORR was set as Primary endpoint. In the 111 test described above, ORR was 
9 69.2%. It is suggested that lenvatinib may activate antitumor immunity also in gastric 
cancer and it is considered that there is a possibility that the combination of lenvatinib and 
pembrolizumab may be the object to obtain the tumor shrinking effect. If high ORR will be 
confirmed by this protocol treatment, it is considered that there is a sufficient possibility that 
life-prolonging effect will be confirmed when comparing with standard treatment in phase III 
following this trial, therefore, ORR will be set to Primary endpoint. 
 
2.10.2. Clinical Hypothesis Planned Number of Enrollments 
1) Clinical hypothesis 
The clinical hypothesis is that the combination of lenvatinib and pertuzumab has a superior 
antitumor effect to that of pembrolizumab monotherapy. 
2) Rationales for the determination of threshold and expectation of ORR  
Based on the above clinical hypothesis, Simon's Optimal two-stage design is used with the 
threshold / expectation value. In the clinical study, the response rate of lenvatinib in gastric 
cancer was 0% (0/6)19, the response rate to gastric cancer in the phase III trial of Apatinib, 
receptor type tyrosine kinase inhibitor including angiogenesis inhibitory effect, was 1.7%24. 
The response rate of receptor type tyrosine kinase inhibitor monotherapy to gastric cancer 
is estimated to be 1 to 2%. The response rate of anti-PD-1 antibody drug for gastric cancer 
in Phase III study was 11% in all patients, but this trial including PD-L1 negative patients, it 
could be lower than 11% depending on the proportion of negative patients. Therefore, the 
threshold level was set at 10%. Considering that it will show efficacy commensurate with 
the side effects of lenvatinib or pembrolizumab, we thought that at least 20% extra in ORR 
was necessary. Based on the above, the threshold ORR was set to 10% and the expected 
ORR was set to 30%. 
 
3) Rationale for the determination of the sample size  
 
The clinical hypotheses set up in this trial according to the above are as follows (OR of FAS 


 
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is p). 
· Null hypothesis: p = 0.10 (threshold ORR) 
· Alternative hypothesis: p = 0.30 (expected ORR) 
Based on Simon's Optimal two-stage design calculation (one-side significance level 5%, 
power 80%), the number of patients is as follows. 
In the first stage, ten patients will be evaluated, and if the number of patients of CR or PR 
according to RECIST 1.1 will be 2 or more, 19 patients as FAS will be added in the second 
stage. The result will be considered statistically significant when at least 6 of the total 29 
patients as FAS have an object response. 
 
2.10.3. Anticipated Enrollment of Patients, Enrollment Period and Follow-up Period 
For a period of enrolling 29 patients in the FAS, 9 months were estimated. Since this is a 
study conducted at cancer hospitals, the abovementioned enrollment period is judged to be 
fully feasible to accumulate patients. The planned duration of follow-up will be 1 years from 
the date of enrollment of the last patient. 
 
2.11. Summary of Expected Benefits and Disadvantages Associated with the Study 
Participation 
In this study, if combination therapy with lenvatinib and pembrolizumab in patients with 
gastric cancer is judged to be effective, a prospective treatment regimen can be expected 
for a larger number of participarting subjects. 
The anticipated disadvantages include any adverse events associated with lenvatinib and 
pembrolizumab. 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. 
 
2.12. Rationale for the Investigator-Initiated Study 
Lenvatinib is a drug currently under development by Eisai, and pembrolizumab is a drug 
currently under development by MSD. 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 


 
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development of combination therapy with lenvatinib and pembrolizumab. Furthermore, by 
analyzing biomarkers in accompanying research, we hope to pursue the significance of 
simultaneously inhibiting the VEGF, KIT, 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 lenvatinib in combination with pembrolizumab 
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. 
  


 
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3. Standards and definitions used in this study 
3.1. Standards for disease staging 
Staging will be classified in accordance with the “UICC-TNM 7th edition.”  
 
3.2. Performance Status （ECOG classification）  
(Refer to Appendix 1) 
 
3.3. Evaluation criteria for adverse events 
As for the term and grade of adverse events, “Common Terminology Criteria for Adverse 
Events (CTCAE) v4.0-JCOG) [CTCAE v4.03/MedDRA v12.0]” is to be used. In this study, 
adverse events are assessed in accordance with JCOG. 
 
3.4. Evaluation criteria for response rate 
The “New Guideline for Judging Therapeutic Effects on Solid Cancer (RECIST Guideline), 
revised version 1.1 JCOG version: Revised RECIST guideline (version 1.1)” is used for 
judging tumor-reducing effects (Refer to Appendix 3). 
 


 
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4. Eligibility criteria/exclusion criteria 
Patients who satisfy the all the following eligibility criteria, and who do not fall any one of 
the exclusion criteria are to be judged as those eligible for registration. 
 
4.1. Inclusion criteria 
  
1. 
Patients have histologically or cytologically confirmed advanced or recurrent gastric 
cancer. 
2. 
Patients at least 20 years of age on the day of providing consent. 
3. 
Patients have measurable disease as defined by RECIST 1.1 as determined by 
investigator. 
4. 
Patients with a performance status of 0 or 1 on the Eastern Cooperative Oncology 
Group. 
5. 
Patients with adequate organ function at the time of enrollment as defined below: 
・Neutrophil count ≥1200mm3 
・Platelet count ≥7.5 × 104/mm3  
・Hemoglobin (Hb) ≥ 8.0 g/dL, 
・Total bilirubin ≤1.5 mg/dL 
・AST (SGOT) and ALT (SGPT) ≤ 100 IU/L 
for subjects with liver metastases≤200 IU/L 
・Creatinine ≤1.5-times the upper limit of normal 
・International normalized ratio (INR) ≤ 1.5  
・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) Urine Protein Creatinine (UPC) ratio <3.5  
(iii) 24-hour urine protein was measured, urinary protein ≦ 3500 mg 
6. 
Patients who not received a blood transfusion within 7 days of registration. 
7. 
Patients have recovered adverse events associated with chemotherapy, radiation and 
surgical operation as pretreatment to Grade 1 or lower with CTCAE v4.0 excluding 
stable symptoms (eg alopecia, peripheral sensory neuropathy, skin hyperpigmentation, 
dysgeusia etc.). 
8. 
Female of childbearing potential who are negative in a pregnancy test within 14 days 
before enrollment. Both male and female patients should agree to use an adequate 
method of contraception (total abstinence, an intrauterine device or hormone releasing 


 
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system, an contraceptive implant and an oral contraceptive) starting with the first dose 
of study therapy through 120 days after the last dose of study therapy. Duration will be 
determined when the subject is assigned to treatment. 
9. 
Patients capable of taking oral medication 
10. Patients who provided written informed consent to be subjects in this trial 
 
4.2. Exclusion criteria 
1. 
Patients who received prior anticancer treatment within 14 days (or 5 times the half-life 
time, whichever is shorter) or any investigational agent within 28 days prior to the first 
dose of study drugs. 
2. 
Patients who have undergone surgical treatment and radiotherapy with in 2 weeks 
before enrollment. 
3. 
Patients with a history of prior treatment with Lenvatinib or any anti-PD-1, anti-PD-L1, 
or anti-PD-L2 agent. 
4. 
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. 
5. 
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. 
6. 
Patients with symptomatic brain metastasis. 
7. 
Patients with a history of New York Heart Association congestive heart failure of grade 
II or above, unstable angina, myocardial infarction within the past 6 months, or serious 
cardiac arrhythmia associated with significant cardiovascular impairment within the 
past 6 months 
8. 
Patients have an active malignancy (except for definitively treated melanoma in-situ, 
basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within 
the past 24 months 
9. 
Patients have severe (hospitalization required) complications (intenstinal palsy, 
intestinal obstruction, pulmonary fibrosis, diabetes difficult to control, heart failure, 
myocardial infarction, unstable angina, renal failure, liver failure, mental disease, 
cerebrovascular disease etc). 
10. Patients with a history of a gastrointestinal perforation and /or gastrointestinal fistula 
within 6 months before enrollment.  
11. Patients with active hepatitis. 
12. Patients with a history of human immunodeficiency virus (HIV). 


 
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13. Patients with active symptoms or signs of interstitial lung disease. 
14. Patients with concurrent autoimmune disease, or a history of chronic or recurrent 
autoimmune disease 
15. 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. 
16. Patients have a history of (non-infectious) pneumonitis that required steroids or have 
current pneumonitis 
17. Patients who are administered live vaccines <30 days before the initiation of treatment 
with the investigational drug.  
18. Patients have serious non-healing wound, ulcer, or bone fracture. 
19. Females who are pregnant or breastfeeding 
20. Patients have no intention to comply with the protocol or cannot comply. 
21. Patients were judged unsuitable as subject of this trial by investigator. 


 
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5. Registration/allocation 
After confirming that target subjects satisfy all the eligibility criteria, and they are not 
corresponding to any one of the exclusion criteria, register them by the Web registration 
system. 
 
5.1. Contact information for subject’s registration and time in 
The Web registration URL, etc. are to be notified separately with “EDC Input Manual”. 
(24-hour registration is possible; however, when access is impossible due to maintenance, 
etc., this is to be notified beforehand) 
 
 
Inquiry on registration 
Research Support Center at National Cancer Center 
TEL: +81-44-7133-1111 (Extension: 5106) E-mail:LenvaPembro_core@east.ncc.go.jp 
Weekday: from 10:00 to 17:00 (not in operation on festival day, Saturday and 
Sunday) 
 
Inquiries on patients’ registration 
Representative coordinating investigator: Kohei Shitara  
Department Head,  
Department of Gastroenterology and Gastrointestinal Oncology, 
National Cancer Center Hospital East 
6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577 
TEL: +81-4-7133-1111 (Extension: 91520) E-mail: kshitara@east.ncc.go.jp 
Coordinating investigator: Shota Fukuoka 
Exploratory Oncology Research & Clinical Trial Center, National Cancer Center 
Coordinating investigator: Akihito Kawazoe 
Department of Gastroenterology and Gastrointestinal Oncology,  
National Cancer Center Hospital East 
E-mail: LenvaPem_core@east.ncc.go.jp 
 
5.2. Precautions for registration 
1) 
Registration after start of the protocol treatment is not allowed without exception. 
2) 
When confirmation of the contents of registration/eligibility confirmation sheet is 
inadequate, registration is not accepted until all the requirements are satisfied. 
3) 
After confirmation of eligibility, a registration number is issued.  Registration is 
completed upon issuance of the registration number. 


 
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4) 
When registered once, subject’s registration is not cancelled (deletion from the 
database) except for cases of retraction of consent inclusive of rejection of the use of 
data for research.  The initial registration information (registration number) is 
adopted in any cases of overlapped registration. 
5) 
When erroneous registration/overlapped registration have been proved, this should 
be promptly informed. 
6) 
When subjects are visiting other hospitals or departments continuously at the time of 
registration, inform the relevant investigator to the effect that the said subjects 
participate in this clinical trial. 


 
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6. TREATMENT PLAN AND CRITERIA FOR TREATMENT CHANGE 
Treatment and treatment changes should be implemented as specified in this section 
unless otherwise threatening the patients’ safety. When it is judged that compliance with the 
protocol may cause medical hazards, the principal investigator/subinvestigator (hereinafter 
referred to as the investigator) should change the treatment in accordance with the medical 
judgment. 
 
6.1. Protocol Treatment 
In the present trial, the protocol treatment will consist of the investigational drug, Lenvatinib, 
used in combination with Pembrolizumab. 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 Lenvatinib or Pembrolizumab monotherapy upon deliberation 
with the trial coordinating committee. Each patients will undergo study treatment on an 
inpatient or outpatient basis. 
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 terms are used in this protocol: 
 Discontinuation: Investigational drug administration is not resumed. 
 Treatment interruption: The protocol treatment is moved on to the next dosing 
schedule without administration of one or more doses of the investigational drug. 
 Washout period: A period during which no investigational drug is give 
 
6.1. 1 Study Treatment 
1) 
Lenvatinib will be administered with water orally once a day (with or without food) in 
21-day cycles at approximately the same time each day.  On Day 1 of each cycle, in 
case concomitantly administered, it will be administered approximately within 1 hour 
after completion of pembrolizumab administration. Pembrolizumab will be 
administered as a dose of 200 mg as a 30-minute IV infusion, Q3W (25 minutes to 40 
minutes are acceptable).   
2) 
The initial dose of Lenvatinib will be 20 mg per day. 
3) 
Continue administration until it will fall into "6.2.1. Discontinuation Criteria for the 
Protocol Treatment". 
 


 
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6.2. Discontinuation Criteria for the Protocol Treatment 
6.2.1. Discontinuation Criteria for the Protocol Treatment 
When the participating patients met any of the following criteria, the protocol treatment 
should be discontinued: 
1) Progression of the primary disease (including evident progression based on diagnostic 
imaging and clinically clear progression) 
2) Request for discontinuing the protocol treatment by the patient 
3) Onset of protocol treatment-related Grade 4 non-hematotoxicity 
(This is not applicable to transient abnormal laboratory values.) 
4) Both lenvatinib and pembrolizumab are not administered for greater than 28 days.  
5) Meeting the discontinuation criteria for the protocol treatment set forth in the Section “6.3. 
Criteria for Changes in the Protocol Treatment” 
6) Recurrent Grade 2 pneumonitis 
7) Pregnancy in the patients 
8) Lost to follow-up 
9) Death during the protocol treatment 
10) Completed 35 treatments with Pembrolizumab 
11) Treatment discontinuation after CR 
Following at least eight cycles of pembrolizumab (approximately 6 months), when a subject 
is deemed to exhibit CR on the basis of diagnostic imaging, and receives at least two cycles 
of pembrolizumab after the initial determination of CR, termination of pembrolizumab can 
be considered upon consultation with the trial coordinating committee.  
12) 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. 
 
6.2.2. Data Collection and Follow-up of Patients after Discontinuation of the Protocol 
Treatment 
When meeting the discontinuation criteria, the protocol treatment should be discontinued, 
its date, reason and clinical course should be recorded in the case report form (CRF), and 


 
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tests specified during the follow-up period should be performed. However, this is not 
applicable to the case where the investigator judges that the tests cannot be performed or 
are unnecessary in the light of ethics and the patients’ safety and benefits. 
 
6.3. Criteria for Dose Modifications for the Protocol Treatment 
The treatment should be interrupted and resumed as instructed in this section. For patients 
who need to resume lenvatinib and pembrolizumab more than 28 days after the planned 
start day, the protocol treatment should be discontinued. However, even if lenvatinib or 
pembrolizumab therapy is discontinued, if another monotherapy can be resumed in 
accordance with this section, the protocol treatment may be resumed only monotherapy. 
 
6.3.1. Criteria for Changes in Lenvatinib therapy 
The safety profile of regorafenib has been established in the clinical trials. The dose 
adjustments for lenvatinib are according to the clinical trials conducted to date in table 6.3.1. 
Table 6.3.1: Doses of Lenvatinib 
Dose Level 
Lenvatinib (mg,QD) 
Initial dose 
20 mg  
Reduction 1 
14 mg  
Reduction 2 
10 mg  
Reduction 3 
8 mg  
Reduction 4 
 4 mg＊ 
＊Consult the coordinating committee for further dose reduction recommendations. 
 
6.3.1.1 Dose modification of Lenvatinib 
Lenvatinib dose reduction and interruption for subjects who experience lenvatinib and 
pembrolizumab combination therapy-related toxicity will be in accordance with the dose 
reduction instructions shown in the tables below for this study, respectively. Even if the 
following conditions are not met, it is possible to withdraw administration and reduce the 
dose at the discretion of the investigator. For management of hypertension, refer to the 
section 6.3.1.2. Once the dose has been reduced, it cannot be increased at a later date.   
 
Table 6.3.1: Dose Modification of Lenvatinib 
Lenvatinib 
Treatment-
related Toxicitya, 
During Therapy 
Adjusted Dosed 


 
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Grade 1, Tolerable Grade 2 
 
Continue treatment 
No change 
Intolerable Grade 2b and Grade 3c 
First occurrence 
Interrupt lenvatinib until resolved to 
tolerable Grade 2, or Grade 0-1 
No change or  
Reduce lenvatinib by 1 dose 
level 
Second 
occurrence  
(same toxicity or 
new toxicity) 
Interrupt lenvatinib until resolved to 
tolerable Grade 2, or Grade 0-1 
Reduce lenvatinib by 1 more 
dose level 
Third occurrence 
(same toxicity or 
new toxicity) 
Interrupt lenvatinib until resolved to 
tolerable Grade 2, or Grade 0-1 
Reduce lenvatinib by 1 more 
dose level 
Fourth 
occurrence 
(same toxicity or 
new toxicity) 
Interrupt lenvatinib until resolved to 
tolerable Grade 2, or Grade 0-1 
Reduce lenvatinib by 1 more 
dose level  
Grade 4c:  Discontinue lenvatinib 
BMI = body mass index.   
a: Excluding alopecia and asymptomatic laboratory abnormalities. Initiate optimal 
medical management for nausea, vomiting, hypothyroidism and/or diarrhea prior to 
any lenvatinib interruption or dose reduction. 
b: Applicable only to Grade 2 toxicities judged by subject and/or physician to be 
intolerable. 
c: Excluding laboratory abnormalities judged to be non-life-threatening, in which case 
manage as Grade 3. Asymptomatic laboratory value abnormalities will not be 
included. 
d: Refer to the table 6.3.1.  
 
6.3.1.2 Dose modification for hypertension 
When hypertension develops during lenvatinib treatment, dose modification will be made 
at the discretion of the principal investigator (or subinvestigator) with reference to “Table 
6.3.1.2: Dose modification for hypertension.” Hypertensive subjects require careful 
observation and it is strongly recommended to administer suitable hypotensive treatment 
during lenvatinib treatment. The selection of hypotensive drug will be determined by the 
principal investigator (or subinvestigator) upon consideration of the treatment guidelines for 


 
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each institution participating in the trial. 
 
 
Table 6.3.1.2 Dose modification for hypertension 
NCI-CTCAE grade 
Dose modification 
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, 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. 
 
6.3.2. Criteria for Changes in Pembrolizumab therapy 
6.3.2.1 Dose modification of Pembrolizumab 
For AEs (whether serious or non-serious) related to pembrolizumab exposure, 
immunological factors may be involved. Such AEs may occur immediately after the start of 
investigational drug administration or several months after the last dose. For toxicity and 


 
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severe or life-threatening AEs related to pembrolizumab, pembrolizumab therapy should be 
interrupted or discontinued in accordance with Table 6.3.2.1. 
 
Table 6.3.2.1. Dose modification of Pembrolizumab 
 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over 
at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be 
permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot 
be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• 
Monitor participants for signs and 
symptoms of pneumonitis 
• 
Evaluate participants with suspected 
pneumonitis with radiographic imaging 
and initiate corticosteroid treatment 
• 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent grade 
2 
Permanently 
discontinue 
Diarrhea / colitis  
Grade 2 or 3 
Withhold 
• 
Monitor participants for signs and 
symptoms of enterocolitis (i.e. 
diarrhea, abdominal pain, blood or 
mucus in stool with or without 
fever) and of bowel perforation (i.e. 
peritoneal signs and ileus). 
• 
Participants with ≥ Grade 2 
diarrhea suspecting colitis should 
consider GI consultation and 
performing endoscopy to rule out 
colitis.  
Grade 4 
Permanently 
discontinue 


 
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• 
Participants with diarrhea/colitis 
should be advised to drink liberal 
quantities of clear fluids.  If 
sufficient oral fluid intake is not 
feasible, fluid and electrolytes 
should be substituted via IV 
infusion. 
AST / ALT elevation or 
Increased Bilirubin 
Grade 2 
Withhold 
• 
Monitor with liver function 
tests (consider weekly or 
more frequently until liver 
enzyme value returned to 
baseline or is stable 
Grade 3 or 4  
Permanently 
discontinue 
Type 1 diabetes mellitus 
(T1DM) or Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-
cell failure 
Withhold 
• 
Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• 
Monitor for signs and 
symptoms of 
hypophysitis (including 
hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
• 
Monitor for signs and 
symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
Permanently 
discontinue1 
Hypothyroidism 
No provision 
 
• 
Monitor for signs and 
symptoms of thyroid 
disorders.  
 
Nephritis and renal 
dysfunction 
Grade 2 
Withhold  
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 


 
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Myocarditis 
Grade 1 or 2 
Withhold 
• 
Ensure adequate 
evaluation to confirm 
etiology or exclude other 
causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All Other immune-related 
AEs 
intolerable/ 
persistent Grade 
2 
Withhold 
• 
Ensure adequate 
evaluation to confirm 
etiology or exclude other 
causes 
 
Grade 3  
Withhold or 
discontinue 
based on the 
type of event.  
Events that 
require 
discontinuation 
include and not 
limited to:  
Guillain-Barre 
Syndrome, 
encephalitis  
Grade 4 or 
recurrent Grade 
3 
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is 
required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal 
replacement therapy or achieved metabolic control (in case of T1DM).   
 
 
6.3.2.2 Supportive therapies for AEs Suspected to Be Related to Pembrolizumab 
 
Example supportive therapies for managing AEs, which may be immunological etiology 
suspected to be related to pembrolizumab, are presented below. For the details, see the 
guidance document on events of special interest. A reduction in the corticosteroid dose may 


 
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exacerbate symptoms; thus, attention should be paid that administration of corticosteroid 
as tapering the dose for a few cycles will be required. An additional supportive therapy may 
be needed so that an effort shall be made to eliminate other causes of disease such as 
metastatic lesions and bacterial or viral infections for each symptom. 
 
Pneumonitis: 
In case of Grade 2, systemic corticosteroid should be administered. If the symptom 
recovered to Grade 1 or lower, the corticosteroid dose should be tapered over 4 or more 
weeks. 
In case of Grade 3 to 4, treatment with intravenous corticosteroid should be immediately 
administered. As necessary, an anti-inflammatory agent should be additionally administered. 
If the duration of corticosteroid treatment is extended, an antibiotic should be additionally 
administered to prevent opportunistic infection. 
 
Diarrhoea/Colitis: 
Whether or not there is any sign or symptom of enterocolitis (e.g., whether or not being 
accompanied by diarrhoea, abdominal pain, bloody or mucous stools, or pyrexia) and sign 
or symptom of bowel perforation (signs of peritonitis or intestinal obstruction) should be 
checked. 
All patients who developed diarrhoea/colitis should be instructed to take a sufficient amount 
of water. If it is difficult to take a sufficient amount of water, water containing electrolytes 
should be intravenously administered. In case of ≥ Grade 2 diarrhoea, consultation with a 
gastroenterologist and endoscopy are recommended for confirming or denying colitis. 
In case of Grade 2 diarrhoea/colitis persisting for more than 3 days, oral corticosteroid 
should be administered. 
In case of Grade 3 to 4 diarrhoea/colitis persisting for more than one week, intravenous 
corticosteroid followed by high-dose oral corticosteroid should be administered. 
If the symptom recovered to Grade 1 or lower, the corticosteroid dose should be tapered 
over 4 or more weeks. 
 
Type 1 diabetes mellitus [if newly occurred, including diabetic ketoacidosis (DKA)], and ≥ 
Grade 3 hyperglycaemia with ketosis (ketonuria) or metabolic acidosis (DKA): 
For type 1 diabetes mellitus, and Grade 3 to 4 hyperglycaemia with metabolic acidosis or 
ketonuria, insulin replacement therapy should be considered. 
Serum glucose levels and metabolic laboratory values (urine ketone, glycohemoglobin and 
C-peptide) should be assessed. 


 
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Hypophysitis: 
In case of Grade 2, corticosteroid should be administered. If the symptom recovered to 
Grade 1 or lower, the corticosteroid dose should be tapered over 4 or more weeks. Since 
corticosteroid is administered as tapering the dose, appropriate hormone replacement 
therapy may be required. 
In case of Grade 3 to 4, intravenous corticosteroid followed by oral corticosteroid should be 
administered. If the symptom recovered to Grade 1 or lower, the corticosteroid dose should 
be tapered over 4 or more weeks. Since corticosteroid is administered as tapering the dose, 
appropriate hormone replacement therapy may be required. 
 
Hyperthyroidism and hypothyroidism: 
Thyroid dysfunction may occur at any time during dosing. Whether or not there is any 
change in thyroid function test values (Conduct at the start of the administration of the 
investigational drug, thereafter periodically and as necessary based on clinical evaluation.) 
and sign or symptom of thyroid dysfunction should be observed. 
Grade 2 hyperthyroidism (and Grade 3 to 4 hypothyroidism):  
For hyperthyroidism, non-selective β blockers (e.g., propranolol) are recommended as first-
line drugs. 
For hypothyroidism, thyroid-hormone replacement therapy with levothyroxine or liothyronine 
is recommended as standard therapy. 
Grade 3 to 4 hyperthyroidism: 
Intravenous corticosteroid followed by oral corticosteroid should be administered. If the 
symptom recovered to Grade 1 or lower, the corticosteroid dose should be tapered over 4 
or more weeks. Since corticosteroid is administered as tapering the dose, appropriate 
hormone replacement therapy may be required. 
 
Liver: 
In case of Grade 2, liver function tests should be performed frequently until values returned 
to baseline levels (Consider implementing the test every week.)． 
Intravenous or oral corticosteroid should be administered. 
In case of Grade 3 to 4, intravenous corticosteroid should be administered over 24 to 48 
hours. 
If the symptom recovered to Grade 1 or lower, the corticosteroid dose should be tapered 
over 4 or more weeks. 
 


 
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Renal failure or nephritis: 
In case of Grade 2, corticosteroid should be administered. 
In case of Grade 3 to 4, corticosteroid treatment should be given. 
If the symptom recovered to Grade 1 or lower, the corticosteroid dose should be tapered 
over 4 or more weeks. 
 
Management of infusion reactions: Signs or symptoms of infusion reactions usually appear 
during or immediately after drug administration and often completely resolve within 24 hours 
postdose. 
Actions to be taken if infusion reactions to pembrolizumab occurred are presented in Table 
6.3.2.2 
 
In the case where systemic corticosteroid treatment is judged to be necessary for immune-
related Grade 2 or ≥ 3 toxicities other than those mentioned above upon discussion with the 
coordinating committee, the treatment should be administered. If the symptom recovered to 
Grade 1 or lower, the corticosteroid dose should be tapered over 4 or more weeks. 
 
Table 6.3.2.2. Actions to be taken if infusion reactions to pembrolizumab occurred 
NCI CTCAE Grade 
Action 
Pretreatment from 
the next dosing 
Grade 1 
Mild reaction; not requiring 
infusion interruption or 
treatment. 
Vital signs should be more frequently 
monitored until the patient’s symptom 
become stable at the discretion of the 
investigator. 
None 
Grade 2 
Requiring infusion 
interruption, but 
immediately responding to 
symptomatic treatment 
(e.g., antihistamines, 
nonsteroidal anti-
inflammatory drugs 
(NSAIDs), narcotic 
analgesics, and 
intravenous infusion); 
requiring prophylactic 
treatment within 24 hours. 
Pembrolizumab infusion should be 
interrupted, and the symptom should be 
monitored. 
An appropriate therapeutic action (e.g., 
administration of intravenous infusion, 
antihistamines, NSAIDs, acetaminophen 
and narcotic analgesics) should be 
taken. 
Vital signs should be more frequently 
monitored until the patient’s symptom 
become stable at the discretion of the 
investigator. 
If the symptom resolved within one hour 
after treatment interruption, the 
treatment should be resumed at an 
infusion rate 50% slower than the 
original rate (e.g., from 100 mL/hr to 50 
mL/hr). 
If the symptom does not resolve within 
one hour after treatment interruption, the 
treatment should be discontinued until 
Pretreatment with 
the following drugs 
should be given 
1.5 hours (± 30 
minutes) before 
pembrolizumab 
infusion: 
 
Oral administration 
of 
diphenhydramine 
50 mg (or 
equivalent 
antihistamine) 
 
Oral administration 
of acetaminophen 
500 to 1000 mg (or 
equivalent 
antipyretic) 


 
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the symptom resolves. Pretreatment 
should be given at the next dosing. 
Pembrolizumab therapy should be 
discontinued in patients who developed 
Grade 2 toxicity despite appropriate 
pretreatment (reintroduction prohibited). 
Grade 3 
Prolongation (not quickly 
respond to symptomatic 
treatment or infusion 
interruption for a short 
period of time); recurring 
after improvement; and 
sequelae (e.g., renal 
disorder and lung 
infiltration) requiring 
hospitalization. 
 
Grade 4 
Life-threatening; and 
requiring treatment with a 
hypertensive drug or 
artificial respiration 
Pembrolizumab infusion should be 
interrupted. 
An appropriate therapeutic action (e.g., 
administration of intravenous infusion, 
antihistamines, NSAIDs, acetaminophen, 
narcotic analgesics, oxygen inhalation, 
hypertensive drugs, corticosteroids and 
epinephrine) should be taken. 
Vital signs should be more frequently 
monitored until the patient’s symptom 
become stable at the discretion of the 
investigator. 
The patient should be admitted to the 
hospital as necessary. 
Pembrolizumab therapy should be 
discontinued (reintroduction prohibited). 
Pembrolizumab 
should not be 
resumed. 
During pembrolizumab infusion, an appropriate resuscitation device should be placed in the 
room so that the physician can promptly take an action. 
 
6.4. Special instructions for subjects 
The attending physician and trial collaborators will instruct the subjects on the methods of 
lenvatinib and pembrolizmab administration and on observing the following matters. When 
administered on an outpatient basis, a thorough interview and investigation will be carried 
out regarding the state of lenvatinib administration (e.g., the collection of untaken lenvatinib 
[i.e., the investigational drug]), and the results will be recorded on a CRF. 
 
6.5. Concomitant and Supportive Therapies 
When subjects are undergoing post treatments, describe all the combination drugs and 
treatments that have been used during the period from start of administration until 
termination of the follow-up observation period (30 days after the final administration; in 
cases of undergoing of post treatments, until the day before the post treatments) in the 
CRFs.  It is unnecessary to describe the agents that have been used for the purpose of 
various examinations/diagnoses in the CRFs, except for cases where the use of such 
agents is necessary for judging the causality of adverse events. 
 
6.5.1. Recommended combination therapy/supportive therapy 
The 
combination 
and 
supportive 
therapies 
listed 
below 
are 
recommended. 


 
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Nonadministration of the therapies will not be considered a deviation from the protocol. 
1) 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. 
2) Antidiarrheal drugs. 
3) Antifebrile agent, analgesics, and steroids will be administered for immune-related 
events. 
 
6.5.2. Allowable combination therapy/supportive therapy 
When zoledronic acid and denosumab are administered for bone metastasis before 
enrollment, such medications can be continued. 
 
6.5.3. Unallowable combination therapy/supportive therapy 
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 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). 
 


 
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6.6. Subsequent Treatment 
There will be no subsequent treatment for patients following the termination of the stipulated 
treatment protocol. 


 
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7. INFORMATION ON THE INVESTIGATIONAL DRUGS 
7.1. Drug Information on Lenvatinib 
Study drug 
Lenvatinib 
Dosage form 
Capsule 
Manufacturer 
Eisai 
Content 
Capsule 4mg:This prodct contains 4.90 mg of lenvatinib 
mesilate in one capsule (4 mg as lenvatinib) 
Capsule 10mg:This prodct contains 12.25 mg of lenvatinib 
mesilate in one capsule (10 mg as lenvatinib) 
Administration method Oral 
Expiration date 
See the Procedures for Study Drug Management 
Labelling 
The outer box shows the content, storage method, and name, 
job title and address of the coordinating investigator, and 
indicates “For clinical study.” 
The job title of the coordinating investigator shown on the 
outer box should be that at the start of the study, and 
changes to the job tile, if any, should not be reflected on the 
label of the outer box. 
 
Lenvatinib will be supplied by Eisai, the investigational drug supplier, free of charge. 
The manufacturing records and records of quality tests of the study drug will be also 
provided by the investigational drug supplier. 
 
7.2. Drug Information on Pembrolizumab 
 
Name of investigational 
drug: 
Pembrolizumab 
Dosage form: 
Solution 
Drug code: 
MK-3475 
Manufacturer: 
MSD K.K. 
Content: 
100 mg/vial 
Dosage: 
Pembrolizumab should be diluted with normal saline or 5% 
glucose solution in a concentration range of 1 to 10 mg/mL, 
and 200 mg/body should be intravenously administered over 
30 minutes. 
Route of administration: 
Intravenous infusion 


 
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Expiration date: 
See the Procedures for Investigational Drug Management. 
Labeling: 
On the outer box, the investigational drug code, content, lot 
number, expiration date, quantity, storage method, and the 
names, job titles and addresses of the coordinating 
investigators, as well as the fact of being clinical study use 
only are mentioned. 
The job titles of the coordinating investigators to be indicated 
on the outer box should be those at the time of the start of 
the study and should not be changed even if they are 
changed during the study. 
Storage method for the 
drug: 
Store in a tight, light-resistant container at 2 to 8°C. 
Pembrolizumab will be provided free of charge by, a supplier of the investigational drug, 
MSD K.K. The supplier of the investigational drug will also provide manufacturing and quality 
study records of the investigational drug, and pembrolizumab solution. 
 
7.3. Management of Study Drugs 
Lenvatinib will be supplied by Eisai to National Cancer Center Hospital East. 
Pembrolizuamb will be supplied by MSD to National Cancer Center Hospital East. 
The Study Drug Manager of each study site will appropriately control the study drugs in 
accordance with the procedures for study drug management provided by the coordinating 
committee. 
The investigator (subinvestigator) will prescribe the study drugs at doses specified in the 
protocol, and intravenously or orally administer to subjects. The study drugs must not be 
administered by other methods than those specified in the protocol. 
 
7.4. Expected AEs 
Expected AEs associated with lenvatinib and pembrolizumab are defined as follows: 
Events, of which the onset or onset trend such as the number of cases, frequency and 
onset conditions are not expected from the investigator’s brochure of the investigational 
drug using the latest investigator’s brochure as a reference, are defined as “unknown,” 
and those which are expected are defined as “known.” However, new events reported to 
the study sites can be handled as “known” even if they are not listed on the investigator’s 
brochure. 


 
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8. ENDOPOINTS, LABORATORY TESTS AND EVALUATION SCHEDULE 
8.1. Observations and tests 
Each endpoint in this study is presented below. All data required by the protocol should be 
recorded. 
Table 8.1 Observations and tests 
Treatment compliance 
Doses of lenvatinib and pembrolizumab, date of fist dose, date of 
last dose or date of discontinuation (treatment interruption), 
presence/absence of dose change and its reason, and 
presence/absence of treatment interruption, its frequency and its 
reason 
Patient 
background 
characteristics 
Sex, age, past history, complications, histology (pap, tub1, tub2, 
por1, por2, sig, muc or other), HER2, EBV, PD-L1, presence or 
absence of the primary lesion, lesion site (primary site, target 
lesion, nontarget lesion) and presence or absence of previous 
treatment and its details 
Physical examination 
Body height and weight 
Vital signs 
Body temperature, pulse rate, systolic and diastolic blood pressure 
General condition 
PS(ECOG) 
AEs 
Presence/absence and severity of AEs will be evaluated in 
accordance with the CTCAE v 4.0. 
Concomitant 
medications/therapies 
Name of drug, route of administration, start date of treatment, end 
date of treatment and reason for concomitant use 
Hematology 
Red blood cell count, Hb, hematocrit, White blood cell count , 
neutrophil count, and platelet count 
Biochemistry 
AST(GOT), ALT(GPT), ALP, LDH, albumin, total bilirubin, BUN, 
creatinine, CK, electrolytes (Na ，K ，Cl ，Ca), Amy, UA, blood 
glucose, CRP 
Blood coagulation test 
PT, INR, APTT 
Thyroid function 
Thyroid stimulating hormone, free triiodothyronine (fT3), and free 
thyroxine (fT4) 
Tumor markers 
CEA, CA19-9 
Urinalysis 
Urine protein, urinary sugar and urinary occult blood 
Pregnancy test 
If pregnancy is suspected by urinalysis, a serum test 
It will be performed in premenopausal women or women who had 
the last menstruation no more than one year 
ECG 
12-lead resting ECG 
Infection 
HIV antibody, HBs antigen, HBc antibody, HBs antibody ,HCV 
antibody, HBV-DNA 


 
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Tumor assessment 
Chest and abdomen/pelvic contrast CT* or abdomen/pelvic 
contrast MRI*, as necessary, chest radiography, brain CT and brain 
MRI 
* For patients who are allergic or have hypersensitivity to contrast 
media to be used for CT and MRI, the tests may be performed 
without using the contrast media. 
When the treatment is discontinued because of reasons other than 
the progression of the primary disease based on imaging, the 
assessment should be made until progression is confirmed. 
Investigation of outcome 
Presence or absence of subsequent treatment, if subsequent 
treatment is given, a treatment method and start date 
Date of death or the last day of survival confirmed, and if died, the 
cause of death 
8.2. Observation and schedule 
The observation and testing schedule is presented in Table 8.2. 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 8.2. 
 
Table 8.2. Schedule 
 
At 
enrollm
ent 
 
During protocol treatment 
Day of 
discotin
uatione) 
days after 
the last 
dose f) 
After 
the 
follow
-up 
period 
Cycle1 
Cycle2 onwards 
Day 
Permissible range 
-14～ 
1 
8 
15 
1 
15d) 
0～＋7 
-3～±7 
 
Visit 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Informed Consent 
○ 
 
 
 
 
 
 
 
 
Treatment 
Lenvatinib 
Treatment 
 
○ 
→ 
→ 
○ 
→ 
 
 
 
Pembrolizumab 
treatment 
 
○ 
 
 
○ 
 
 
 
 
Patient 
background 
characteristics 
○ 
 
 
 
 
 
 
 
 


 
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Body 
measu
remen
ts 
Height 
○ 
 
 
 
 
 
 
 
 
Weight 
○ 
○c) 
 
 
○ 
 
○ 
○ 
 
Vital signs 
ECOG PS 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
 
Clinical findings 
(including AEs) 
Concomitant 
medications/con
comitant 
therapie 
○ 
○ 
→ 
→ 
→ 
→ 
→ 
→ 
 
Laboratory tests 
Blood tests 
(blood count, 
biochemistry) 
 
○ 
○c) 
○ 
○ 
○ 
○ 
○ 
○ 
 
Urine analysis 
○ 
○c) 
○ 
○ 
○ 
○ 
○ 
○ 
 
Thyroid function 
○ 
○c) 
 
 
○ 
 
 
 
 
Blood 
Coagulation test 
○ 
○c) 
 
 
○ 
 
 
 
 
Pregnancy testa) 
○ 
 
 
 
 
 
 
 
 
Tumor markers 
○ 
○c) 
 
 
○ 
 
○ 
 
 
12-lead ECG 
○ 
 
 
 
 
 
○ 
○ 
 
Infection test 
○b) 
 
 
 
 
 
 
 
 
Tumor evalustion 
Chest/abdomina
l/pelvic CT (MRI) 
and other 
evaluations g) 
○ 
Conducted at every 6 weeks after the start of treatment 
△ 
Follow-up 
Outcome 
investigation 
 
○ 


 
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○: Essential item, △:Performed as needed 
a) Limited to women capable of childbearing. Refer to section 8.4.3 
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). 
d) From 3 cycle onwards, the implementation of day 15 is unnecessary unless the 
investigator condiers clinically necessary. 
e) 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. 
f) Follow-up tests for safety are conducted 30 days after the last dose 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. 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 of the last dose of the investigational drug and the follow-up tests of safety can be 
conducted simultaneously. 
g) Refer to section 8.6. 
 
In screening, the results within 21 days before the trial registration are allowed to be used. 
 
8.3. Examination findings 
8.3.1. Patients Background 
・Clinical diagnosis 
 Primary and metastatic lesion sites, etc. 
・Clinical staging 
Staging is determined in accordance with “UICC-TNM 7th Edition,” and tumors will be 
classified according to the main histological type in each primary onset organ. 
・The following details will be collected regarding the time of the initial histological diagnosis 


 
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(month and year), histological diagnosis, and the presence or absence of pretreatment. 
・ Presence or absence of surgery, indicated site, surgical procedure, date of surgery and 
results (e.g., R0) 
・ Presence or absence of adjuvant chemotherapy, treatment details, implementation period, 
and reason for termination 
・Presence or absence of chemotherapy, treatment details, implementation period, and 
reason for termination 
・Presence or absence of chemotherapy, site, implementation period, and radiation dose 
・Presence or absence of other treatments, treatment details, and the implementation period 
 
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 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 
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 
8.4.1. Blood tests/biochemical tests/blood coagulation tests/urine analysis/thyroid 
function tests 
Blood tests/biochemical tests/blood coagulation tests/urine analysis/thyroid function tests 
The items listed in Table 9 will be tested in accordance with the time indicated in the 
schedule presented in Table 10, 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. 
 
8.4.2. Tumor markers 
The test items listed in Table 8.1 are to be measured in accordance with the time indicated 


 
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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 <14 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 
Anti-HIV antibodies, HBsAg, anti-HCV, HBs and HBc antibodies 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 quantification is measured only when either HBs or HBc antibody is possible. 
 
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. Biomarkers 
Biomarkers of tumor tissues of biopsies or past surgical specimens of patinets agreed with 
“elucidation of immune status and clinical significance in patients with solid tumor including 
gastrointestinal cancer (Research Project Number: 2015-048)” consider. Details are 
described in the plan of the accompanying research. 
 
8.6. Tumor evaluation 
For all patients, 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 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). 


 
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• 
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 according to irRECIST, 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 8.6). 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 5 lesions can be included as target lesions, 
with a maximum of two lesions per organ. 
 
Table 8.6: 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 determined 
To confirm disease 
progression, repeat 
the test after 4 
Investigational 
drug 
dosing 
can 
be 
continued 
at 
the 
If possible, repeat 
the test after 4 
weeks to confirm 
Interruption 
of 
dosing 


 
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by imaging  
weeks 
discretion 
of 
the 
attending 
physician 
until 
disease 
progression 
is 
confirmed 
by 
retesting 
at 
the 
participating medical 
institution 
 
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 
 
8.7. Follow-up 
Outcome investigations will be performed after termination of the treatment protocol until 
the subject dies, or up to 2 year 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 


 
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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. 


 
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9. DATA 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, and 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. 


 
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10. REPORTING OF ADVERSE EVENTS 
10.1. Evaluation of AEs 
10.1.1. Definition of AE 
An adverse event (AE) is any unfavorable and unintended sign (including an 
abnormal laboratory value), symptom, or disease occurred in a patient administered 
the investigational drug, whether or not considered related to the investigational drug. 
When ≥ Grade 1 subjective symptom or objective finding has been observed since 
before treatment initiation (at baseline evaluation), it will be handled as an AE only 
when the grade of the concerned AE worsened from the baseline value. 
 
10.1.2. Method for Recording AEs 
When grading an AE, the closest definition should be selected among the definitions of 
Grades 0 to 5. 
When a sign (including an abnormal laboratory value) or symptom is included in a 
diagnosis, the diagnostic term based on the CTCAE should be entered in the CRF to the 
extent possible instead of individual signs or symptoms. 
Abnormalities of laboratory values or vital sign alone should be reported as AEs only when 
the investigator determined that they fall into any of the following cases: 
(1) Where a clinical sign or symptom is induced; 
(2) Where it is judged to be clinically important; 
(3) Where requiring treatment; 
(4) Where requiring an additional test (excluding a retest only); or 
(5) Where requiring treatment discontinuation or dose reduction for the investigational 
drug. 
 
10.1.3. Items to Be Recorded for AEs 
For AEs occurred, the following information should be reported in the CRF: 
(1) AE term; 
(2) Severity (CTCAE Grade 0 to 5 and serious/non-serious); 
(3) Causal relationship with the each drug; 
(4) Date of onset, date of outcome and outcome; and 
(5) Presence or absence of therapeutic action. 
 
10.1.4. Assessment of the Causal Relationship 
The causal relationship with the each investigational drug should be assessed on the 
following two categories: 


 
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“Definite,” “probable,” “p 
Possible” or “unassessable” → “The causal relationship cannot be ruled out.” 
“Unlikely” or “not related” → “The causal relationship can be ruled out.” 
 
Table 10.1.4  Classification of causal relationship 
Classification 
Definition 
Definite (certain) 
The causal relationship with the protocol treatment is 
plausible and cannot be explained based on the 
progression of the primary disease, complications, other 
drugs/treatments, etc. 
Probable (likely) 
The causal relationship with the protocol treatment is 
reasonable and is unlikely to be due to the progression 
of 
the 
primary 
disease, 
complications, 
other 
drugs/treatments, etc. 
possible 
The causal relationship with the protocol treatment is 
reasonable and can be explained based on the 
progression of the primary disease, complications, other 
drugs/treatments, etc. 
unlikely 
The causal relationship with the protocol treatment is 
improbable and can be explained based on the 
progression of the primary disease, complications, other 
drugs/treatments, etc. 
not related (unrelated) 
There is no causal relationship with the protocol 
treatment, and it can be clearly explained based on the 
progression of the primary disease, complications, other 
drugs/treatments, etc. 
unassessable (conditional) 
An AE on which data to be assessed are insufficient, for 
which more detailed data are necessary (conditional), or 
which is difficult to assess. 
 
10.1.5. Follow-up of the Clinical Course at the Onset of AEs 
When an AE occurred, the investigator should immediately take an appropriate 
therapeutic action. 
A symptom (laboratory value) should be followed up until resolution or remission is 
confirmed even after the AE evaluation period is ended (see the Section 10.1.6). However, 
the follow-up of an AE may be terminated if falling into at least any one of the following 
cases: 
* In the case of terminating the follow-up of an AE: 
1) Where it is not an SAE, is assessed that the causal relationship can be ruled out, 
and occurred at least 30 days after the day of the last dose; 


 
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2) Where the principal investigator determined that the symptom is stable and is not 
of a medically significant concern; 
3) Where subsequent treatment was implemented so that the causal relationship 
with the investigational drug is unassessable; 
4) Where the clinical course cannot be followed up due to reasons such as transfer 
to another hospital;  
5) Where the patient refused to be followed up; or 
6) Where the patient died. 
 
10.1.6. AE Evaluation Period  
In this study, the AE evaluation period will be from the “the start day of the 
administration of the investigational drug” to “30 days after the day of the last dose of 
the investigational drug, or if subsequent treatment is initiated before that, before the 
start of the subsequent treatment, whichever comes earlier.” AEs occurring this period 
will be collected. 
Even if it is 31 days after the last dose of the investigational drug, AEs assessed as 
related to the protocol treatment should be collected. 
After PD is conformed, it is unnecessary to collet newly occurred AEs associated with 
the progression of the primary disease. 
 
10.2. Reporting of Serious Adverse Events (SAEs) 
10.2.1. Definition of SAE 
Of the AEs specified in the Section “10.1 Evaluation of AEs” AEs falling into any of the 
following items are defined as “SAEs.” 
(1) An event that results in death or is life-threatening; 
(2) An event that results in persistent or significant disability/incapacity; 
(3) An event that is a congenital anomaly/congenital defect; or 
(4) An event that requires inpatient hospitalization or prolongation of existing 
hospitalization 
However, excluding the following events: 
- Hospitalization or death due to the primary disease after PD is confirmed; 
- Hospitalization or prolongation of existing hospitalization for reducing a burden to a 
patient who visits the hospital from a remote place; 
- Hospitalization or prolongation of existing hospitalization planned beforehand; 
- Hospitalization or prolongation of existing hospitalization not related to AEs; or 
- Hospitalization or prolongation of existing hospitalization for no more than 24 hours 
only for following up of the course. 
(5) Medically important events are defined as those which possibly jeopardize the 


 
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patient or require a medical or surgical intervention to prevent the outcomes listed 
above. 
Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, must be reported within 24 hours 
to the Sponsor and within 2 working days of but not longer than three 3 calendar 
days of receipt of the information to Merck Global Safety Providerz to meet certain 
local requirements. Therefore, these events are considered serious by Provider for 
collection purposes. 
 
- Is a new cancer (that is not a condition of the study); 
- Is associated with an overdose 
 
For the time period beginning when the consent form is signed until treatment, any 
serious adverse event, or follow up to a serious adverse event, including death due to 
any cause that occurs to any participant must be reported within 24 hours to the 
Sponsor and within 2 working days of but not longer than three 3 calendar days of 
receipt of the information to Merck Global Safety if it causes the participant to be 
excluded from the trial, or is the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
For the time period beginning at treatment through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the participant initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a 
serious adverse event, including death due to any cause whether or not related to the 
Provider product, must be reported within 24 hours to the Sponsor and within 2 working 
days of but not longer than three 3 calendar days of receipt of the information to Merck 
Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a 
qualified physician to be related to Provider product that is brought to the attention of 
the investigator at any time following consent through the end of the specified safety 
follow-up period specified in the paragraph above, or at any time outside of the time 
period specified in the previous paragraph also must be reported immediately to Merck 
Global Safety. 
All participants with serious adverse events must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded to 
the Merck Global Safety facsimile number:  +81-3-6272-0077 
 


 
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10.2.2. . Reporting Obligation of the Investigator and Reporting Procedures 
1) 
Report to the head of the study site and the coordinating committee 
① Initial report 
When an SAE (see the Section “10.2”) occurred, the investigator should immediately 
take an appropriate action. The subinvestigators should promptly report it to the 
principal investigator. 
The investigator should reported an SAE occurred in writing (e-mail* or fax) or orally 
(telephone) to the head of the study site and the coordinating committee within 24 
hours after learning its onset. When the initial report is made without using the “SAE 
Report,” a report should be promptly made using the said form (e-mail or fax). 
In addition, the details of the SAE should be reported in writing to the head of the study 
site and the coordinating committee within 2 business days after learning its onset. 
* Reporting by e-mail is recommended. 
 
② Additional report 
The principal investigator should follow up the SAE (see the Section “10.2”). 
Additional information should be recorded in the “SAE Report” (additional report) and 
promptly sent to the head of the study site and the coordinating committee within 2 
days after learning its onset. 
 
Contact information of the coordinating committee: Clinical Study 
Coordinating Secretariat 
E-mail: ctu_dc@east.ncc.go.jp 
Tel: 04-7133-1111 (extension: 5200) Fax: 04-7134-6860 
 
The investigator should provide further information upon request of the coordinating 
committee, the head of the study site, the institutional review board (IRB) and the 
investigational drug suppliers. 
 
10.2.3. Reporting Obligation of the Coordinating Committee and Reporting Procedures 
The coordinating committee should determine the seriousness, causal relationship, 
expectedness and the necessity for reporting to the regulatory authority (Pharmaceuticals 
and Medical Devices Agency (PMDA)) (pursuant to “Article 80-2, Paragraph 6 of the 
Pharmaceutical Affairs Law (PAL)” and “Article 273 of the Enforcement Regulations of the 
PAL”) for SAEs notified by initial and additional reports. 
The details of reporting procedures should be as specified in the “Procedures for Handling 


 
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of Safety Information.” 
 
1) 
Report to each principal investigator 
The coordinating committee should promptly report the notified SAE with the details 
of the abovementioned determinations to each principal investigator. Each principal 
investigator should, as necessary, report them as soon as possible to the head of the 
study site in accordance with rules at each study site. 
2) 
Report to the PMDA 
When reporting to the PMDA is found necessary, the coordinating committee should 
handle the matter in accordance with Article 273 of the Enforcement Regulations of 
the PAL and relevant notifications. 
3) 
Report to the efficacy and safety evaluation committee 
When a review of an SAE by the efficacy and safety evaluation committee is judged 
to be necessary, the coordinating committee should report it in writing and seek its 
opinions on the appropriateness of the comments of the principal investigator and 
coordinating committee on the AE and handling (assessments of the seriousness, 
causal relationship and expectedness of the AE) of the AE. 
4) 
Report to the investigational drug suppliers 
The coordinating committee should promptly notify SAEs reported by the investigator 
to the investigational drug suppliers. In addition, the coordinating committee should, 
as necessary, provide information other than the “SAE Report” to the investigational 
drug suppliers upon their request. 
 
10.2.4. Events of Clinical Interest  
10.2.4.1. Definition of ECI 
Events of clinical interest for this trial include: 
1. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value 
that is less than 2X the upper limit of normal, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. 
2. an overdose of Provider product, as defined in Section 7.2.1 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results. 
 
10.2.4.2.  Reporting of ECI 
Selection non serious and serious adverse events are also kown as Events of Clinical 
Interest (ECI) and must be reported within 2 working days of but not longer than 3 
calender days of receipt of imformation. But, if it shold be the serious adverse events, 
you don’t have any duty to report to the head of the institution. 
For the time period beginning at treatment through 90 days following cessation of 


 
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treatment, or 30 days following cessation of treatment if the participant initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or 
not related to Provider product, must be reported within 2 working days of but not 
longer than three 3 calendar days of receipt of the information. 
 
10.2.5. Duties of the Efficacy and Safety Evaluation Committee 
The efficacy and safety evaluation committee should examine the details of AE 
reports and advise, in writing, handling such as whether or not to continue the study 
and the necessity of protocol revisions to the coordinating committee. For their 
procedures, the separately stipulated “Procedures for the Efficacy and Safety 
Evaluation Committee” should be followed. 
 
10.3. Collection of Safety Information 
When safety information on the investigational drugs is received from the 
investigational drug suppliers, the coordinating committee should handle it in 
accordance with Article 273 of the Enforcement Regulations of the PAL and relevant 
notifications. The coordinating committee should report the safety information to 
each principal investigator. Each principal investigator should report it to the head 
of the study site as soon as possible in accordance with rules at each study site. 
For the details of reporting procedures, the “Procedures for Handling of Safety 
Information” should be followed. 
In addition, the necessity of revising the protocol and written information to patients 
as well as an explanation to the patients should be determined and implemented if 
needed. 
 
10.4. Reporting of Pregnancy and Lactation 
Although pregnancy and lactation are not considered adverse events, it is the 
responsibility of investigators or their designees to report any pregnancy (subject or 
partner of a male subject) or lactation in a subject (spontaneously reported to them) 
that occurs during the trial. 
Pregnancies and lactations that occur from the time of treatment enrollment 
through 120 days following cessation of Pembrolizumab, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is 
earlier, must be reported by the investigator. All reported pregnancies must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, 
fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious 


 
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events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported. 
 
Such events must be reported within 24 hours to the Principal Investigator. Such 
events must be reported to Eisai coorpolation andwithin 2 working days of but not 
longer than three 3 calendar days of receipt of the information to Merck Global 
Safety. (Attn: Worldwide Product Safety; FAX +81-3-6272-0077) 
 


 
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11. ASSESSMENT OF RESPONSE AND DEFINITIONS OF THE ENDPOINTS 
11.1. Assessment of Respons 
Assessments of tumor response should be made in accordance with the RECIST guideline 
Ver 1.1 (Appendices 2). 
Chest and abdomen and pelvic contrast CT or MRI (Simple CT or MRI is acceptable if the 
patients are allergic to contrast media.) should be performed in accordance with Table 8.b 
to make the assessments based on image measurements.   
 
11.2. Definitions of the Endpoints 
11.2.1. Objective response rate:ORR 
The ORR will be defined as the proportion of patients who achieved CR or PR for best 
overall response (confirmation required) according to irRECIST and RECIST v1.1. 
11.2.2. Progression free survival：PFS 
The period will be from the day of enrollment, as the starting date of the computation, to 
the day when progression is determined or the day of death of any cause, whichever comes 
earlier. 
 “Progression” will be PD based on diagnostic imaging according to overall response 
by RECIST v1.1. The day of the imaging test will be defined as the day of 
progression. When the treatement are discontinued due to clinical PD and 
digagnositic imaging can not be performed, the day of clinical PD will be defined as 
the day of progression. 
 Surviving patients, who are not assessed as progression will be censored on the 
last day when no progression is confirmed on imaging (last day of PFS confirmed) 
(If information on progression or progression-free is obtained from medical 
institutions to which the patients are transferred or referred, a statement on medical 
information provision documenting the rationales for a diagnosis should be received 
and retained. Notification only by telephone will not be acceptable.). 
 For patients who died without being assessed as progression, whether to consider 
to be an “event on the day of death” or “censoring on the last day of PFS confirmed” 
should be decided at the time of data review performed prior to data fixation. In 
principle, they should be “an “event on the day of death” unless the period from the 
last day of PFS confirmed to the day of death is long. 
 When another treatment is given as subsequent treatment in withdrawals due to 
AEs or refusal, they should be censored on the start day of the subsequent 
treatment. 
 The development of secondary cancer (asynchronous double cancer) should not be 
handled as an event or censoring but as PFS until other events are observed. 
 
11.2.3. Disease control rate：DCR 
The DCR will be defined as the proportion of patients who achieved CR or PR, or SD 


 
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for best overall response according to RECIST v1.1. 
 
11.2.4. Overall survival：OS 
The period will be from the day of enrollment, as the starting date of the computation, 
to the day of death of any cause. 
Surviving patients should be censored on the last day of PFS confirmed 
(Confirmation of survival by telephone inquiry will be acceptable. However, the fact of 
confirming survival should be documented in medical records.). 
Patients who are lost to follow up should be censored on the last day when their 
survival is confirmed before being lost to follow up. 
 
11.2.5. Incidence of AEs 
All treated patients will be defined as a denominator, and the frequency of the worst 
grade according to the CTCAE v4.0-JCOG during all cycles will be calculated for each 
AE associated with the below mentioned protocol treatment. 
 
 


 
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12. STATISTICAL MATTERS 
The Statistical Analysis Plan is summarized below. The details are presented in the 
separately prepared “Statistical Analysis Plan. 
 
12.1. Handling of the Patients 
 
The handling of the patients will be decided in accordance with the criteria for patient 
handling. The criteria for patient handling will be developed based on a data review. 
 
12.2. Definitions of Analysis Populations 
Each analysis population is defined as follows: 
 
Abbreviation Analysis population 
Definition 
All Enrolled 
Patients 
(ITT) 
Intention to treat 
Analysis target group based on the principle 
of Intention to treat. A population of enrolled 
patients excluding those with overlapping or 
incorrect enrollment 
SP 
Safety Population 
A population of all enrolled patients who 
received at least one dose of the protocol 
treatment 
FAS 
Full Analysis Set 
A population of all enrolled patients who met 
the entry criteria and received protocol 
treatment 
 
 
12.3. Data Handling 
Data handling (e.g., conditions for including in the analysis populations) will be 
decided by the coordinating committee upon discussion with the principal investigator. 
The details of data handling will be presented in the Statistical Analysis Plan. 
 
12.3.1. Handling of Missing Data and Outliers 
In principle, no imputation of missing data or analysis for outliers will be carried out. 
However, in the case where it is found that there are missing data and outliers, which 
may significantly affect analysis results, before data fixation, actions for such will be 
described in the Statistical Analysis Plan. 


 
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12.3.2. Actions for Additional Analyses 
Analyses performed after the finalization of the Statistical Analysis Plan will be 
positioned as additional analyses. The results of the additional analyses should be 
reported in a manner that they are analyses not planned beforehand or by preparing a 
separate report of the additional analysis results. 
 
12.4. Positioning of Analyses and Analysis Methods 
In this study, no future decision-making criteria or development policy will be clearly 
specified. However, if the study statistically shows that “the primary endpoint ORR in 
accordance with the RECIST ver.1.1 is higher than the threshold of 10%,” and 
furthermore, improvement in the efficacy and safety in the secondary endpoints is 
confirmed, the study treatment will be judged to be promising treatment. 
 
In this trial, we perform the following three analyzes. 
1) Intermediate analysis: After the ORR has become evaluatable for FAS (10 cases) 
required for intermediate analysis to determine the ineffectiveness in the first stage, the 
analysis to be performed 
2) Main analysis: After reaching FAS (29 cases) necessary for the main analysis, 
analysis to be performed on the ORR 
3) Final analysis: analysis performed after the main analysis and after the 
observation period (12 months after the last case registration date) 
 
12.5. Efficacy Analyses 
12.5.1. Analysis of the Primary Endpoint 
The analysis set for the primary endpoint is the Full Analysis Set (FAS). The statistical 
criteria for main analysis will be based on the number of patients with the best overall 
response of Complete Response (CR) or Partial Response (PR) according to RECIST 
guideline version 1.1. In the first stage, if two or more objective response (CR or PR) was 
observed among 10 patients (no confirmation required), the study will proceed to the second 
stage. If objective response (CR or PR) was less than two, the study will not proceed to the 
second stage and we will consider discontinuation of this trial. on the basis of a precise 
method based on the binomial distribution 
In the second stage 19 patients will be enrolled. If there are ≥ 6 patients with objective 
response (CR or PR), the main objective of this trial will be achieved. An accurate 
confidence interval based on a binomial distribution is used for calculating the proportion of 


 
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confidence intervals. 
If subgroup analyses are conducted, therapeutic efficacy between subgroups should be 
summarized using appropriate statistical procedures such as the Fisher’s exact probability 
test and logistic regression model. 
12.5.2. Analysis secondary endpoint 
Analyses of the secondary efficacy endpoints are specified as follows: 
(1) PFS 
A survival function will be estimated using the Kaplan-Meier method. The median PFS with 
the 95% CI and monthly survival rate with the 95% CI will be estimated. 
If subgroup analyses are implemented, therapeutic efficacy between subgroups should be 
summarized using appropriate survival analysis procedures such as the log-rank test and 
Cox proportional hazard model. 
(2) OS 
The same analysis as that for PFS will be carried out. 
(3) ORR by irRECIST and DCR 
Based on the definitions set forth in the Section 11.2, the DCR and ORR will be calculated. 
Exact 95% CIs based on the binomial distribution will be composed. If subgroup analyses 
are conducted, therapeutic efficacy between subgroups should be summarized using 
appropriate statistical procedures such as the Fisher’s exact probability test and logistic 
regression model. 
 
12.6. Safety Analyses 
The safety analysis will be performed on the SP. The summary of frequency of each 
AE will be reported as the incidence of AEs. If necessary, 95% CIs using accurate 
methods based on the binomial distribution and spaghetti plots summarizing changes 
over time in laboratory values, etc. will be reported. 
 
12.7. Planned Sample Size 
[First stage] 10 patients as the FAS 
[Second stage] A total 29 patienst as the FAS  
 
12.8. Rationales for Determination 
See the Section 2.10.2 Planned Number of Enrollment. 
 


 
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12.9. Interim Analysis 
    Position the first stage of Simon's Optimal two-stage design as an intermediate analysis. 
Based on the matters specified below, interim analysis will be carried out in principle. 
 
12.9.1. Object and Timing of Intermediate Analysis 
 Intermediate analysis will be carried out to judge whether to proceed to the second stage 
to exam futility stopping when 10 patienst are confirmed to be included in the FAS. 
 
12.9.2. Method of Intermediate Analysis 
The statistical criteria for main analysis will be based on the number of patients with the best 
overall response of Complete Response (CR) or Partial Response (PR) according to 
RECIST guideline version 1.1. In the first stage, if two or more objective response (CR or 
PR) was observed among 10 patients (no confirmation required), the study will proceed to 
the second stage. If objective response (CR or PR) was less than two, the study will not 
proceed to the second stage and we will consider discontinuation of this trial. 
However, whether or not two or more objective response (CR or PR) would be observed 
among 10 patients (no confirmation required) may be grasped at the time of study 
monitoring. In such a case, enrollment should not be terminated, and the study should be 
continued. If it cannot be grasped at the time of study monitoring, enrollment should be 
stopped at the time when 10 patients in the FAS are confirmed, and the follow-up should be 
continued until whether or not two or more objective response (CR or PR) would be 
observed among 10 patients can be confirmed. If at least 6 patients with CR/PR are 
identified in the first stage, it means that the threshold for the ORR in the final analysis has 
been achieved. In such a case, however, there may be problems such as no mature data 
on AEs, PFS, OS, etc., can be obtained. Thus, in principle, enrollment will be continued until 
“29 patients in the FAS” are achieved. When the study is to be terminated early based on 
efficacy, its appropriateness should be discussed with the coordinating committee. 
 
12.10. Final Analysis 
In the final analysis, all the endpoints will be analyzed. After completing the final 
analysis, a report of statistical analysis results should be prepared in accordance with 
the Statistical Analysis Plan. 
 
12.11. Special Notes 
12.11.1. Other Exploratory Analysis 
1) 
Demographic and other baseline characteristics 


 
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They will be summarized using appropriate descriptive statistical procedures. 
2) 
Tabulation of treatment compliance data 
Details of a summary of treatment course and tabulations of, for example, reasons for 
discontinuation will be specified in the Statistical Analysis Plan. 
3) 
Sub group analysis 
 
The sub group analysis of efficacy will be performed exploratory regarding the 
following items. 
These analyses will not be performed ensuring sufficient detection power, and not be 
adjusted multiplicity. The analysis results of sub group should be interpreted as 
exploratory results. 
･ Sex (male/ female) 
･ Age (＜65 years of age, ≧65 years of age) 
･ PS (0/1) 
･ Gastrectomy (No/Yes) 
･ Primary site (Junction / the other) 
･ Histology (Intestinal type/Diffuse type) 
･ Number of metastatic site (1/ 2 or more) 
･ Peritoneal dissemination (absence/ presence) 
･ Liver metastatis (absence/presence) 
･ Number of pretreatment regimens (1/2/3 or more) 
･ PD-L1 (positive/negative) 
･ EBV (positive/negative) 
･ MMR (Proficient/Deficient) 
 
4) 
Form items covered in the clinical study report 
The following items will be covered in the clinical study report. 
< Efficacy evaluation (Target: All patients enrolled and FAS)> 
･ 11.2 Demographic data 
･ 11.4.1.1 Objective response rate（ORR） 
･ 11.4.1.2 Objective response rate（ORR） by irRECIST 
･ 11.4.1.3 Disease control rate（DCR） 
･ 11.4.1.4 Progression free survival（PFS） 
･ 11.4.1.5 Overall survival（OS） 
< Safety evaluation (Target: SP)> 
･ 12.2.1 Incidence of DLT; incidence of adverse events (Number of onset and 
incidence by the worst grade) 


 
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･ 12.4.2 Summary statistics and change of laboratory values 
＜Forms that are cited but not included in the main text of the clinical study report＞ 
･ 14.3.2 List of deaths, other serious adverse events, and significant adverse events 
･ 14.3.4 List of laboratory values by patient 


 
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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 
The investigator should give the written information to patients approved by the IRB to 
the patients and orally explain the following information in detail: 
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 
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 


 
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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. 
 
13.3. 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 


 
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Use 
1) 
Information that can identify individuals 
Subjects identification number, registration number 
2) 
Supervision of de-identification and correspondence table  
When providing personal information outside clinical trial medical institution is 
implemented, we provide it after making it anonymous. The subject identification 
number and the case number are used as "information capable of identifying an 
individual" as the minimum necessary information for identifying the subject. Under 
the responsibility of the investigator of each clinical trial medical institution, the 
correspondence table between the information such as the name of the patient 
and the case number is managed appropriately according to the policy of clinical 
trial medical institution. 
That is, the medical institution, such as the name of the subject, which can 
independently identify individuals without a correspondence table does not inform 
the outside. 
 
3) 
Handling methods 
The personal information 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. 
 
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. 


 
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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. 
 
13.5. Changes in the Contents of the Protocol 
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. 
 
13.5.1. Categories of Changes in the Contents of the Protocol 
In this study, changes in the contents of the protocol should be handles as follows: 
1) 
Revision 
A revesion refers to a change in the contents of the protocol. Approval of the IRB 
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 obtained. 
2) 
Notification letter 
Notification letter will be issued when deficiency is finded in the protocol and 
determined that it is required to disseminate to study related persons. The 
coordinating investigator determines whether approval of the IRB is required or 


 
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not. 
3) 
Q&A 
Q&A about the interpretation in the contents of the protocol will be issued to 
disseminate it to study related persons. 
 
13.5.2. 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. 
 
13.6. 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 will not involve in any essential part of the study 
such as the operation of the study and the interpretation of results. 
 
13.7. 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. 


 
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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) 
 
14.3. Audit 
Auditors will carry out audits in accordance with the “Audit procedures” and “Audit 
plan” and check that the clinical study is properly implemented and the reliability of data 


 
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is adequately kept through direct access to source documents. 
 
14.4. Direct Access 
The study site should collaborate in monitoring, audits and inspections by the IRB 
and regulatory authority and, as necessary, provide all study-related records such as 
source documents for direct access. 
 


 
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15. SPECIAL NOTES 
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. 
 


 
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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. Associated 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. 
 
 


 
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16. STUDY ORGANIZATION 
This is a multicenter, investigator-initiated clinical study so that the coordinating 
committee will be organized. 
 
16.1. Study Implementation Structure 
See Sttachment 1. 
 
16.2. Funding Source of the Study 
The present trial is conducted with Eisai and MSD in part of the investigational fund 
and/or free of investigationa drugs 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). 
   
 
 


 
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17. ATTRIBUTION OF STUDY RESULTS AND PUBLICATION OF STUDY 
RESULTS 
Study results will belong to the National Cancer Center. The presentation or 
publication of study results at academic conferences or in papers will be decided by the 
coordinating committee upon discussion with the principal investigators and other 
relevant persons at the time of presentation or publication. 


 
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18. REFERENCES 
1.  http://www.mhlw.go.jp/toukei/list/81-1.html 
2.  http://ganjoho.ncc.go.jp/professional/statistics/ 
3.  GLOBOCAN http://globocan.iarc.fr/ 
4.  NCCN guideline 
5.  Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with 
chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric 
or gastro-oesophageal junction cancer (TOGA): a phase 3, open-label, randomised 
controlled trial. Lancet 2010; 376:687-697 
6.  Thuss-Patience PC, Kretzschmar A, Bichev D, et al. Survival advantage for irinotecan 
versus best supportive care as second-line chemotherapy in gastric cancer - A randomised 
phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 
2011 Oct;47(15):2306-14. 
7.  S. H. Park, D. H. Lim, K. Park, et al. A multicenter randomized phase III trial comparing 
second-line chemotherapy (SLC) plus best supportive care (BSC) with BSC alone for 
pretreated advanced gastric cancer (AGC). J Clin Oncol 29: 2011 (suppl; abstr 4004)  
8.  Wilke H, et al.Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with 
previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma 
(RAINBOW): a double-blind, randomised phase 3 trial: Lancet Oncol., 2014; 15: 1224-35． 
9. Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current 
vaccines. Nature medicine. 2004;10:909-915. 
10. 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. 
11. Yoon-Koo Kang, et al. Nivolumab (ONO-4538/BMS-936558) as salvage treatment after  
second or later-line chemotherapy for advanced gastric or gastro-esophageal junction 
cancer (AGC): A double-blinded, randomized, phase III trial. 
12. Wada J, Suzuki H, Fuchino R, et al. The contribution of vascular endothelial growth factor 
to the induction of regulatory T-cells in malignant effusions. Anticancer research. 
2009;29:881-888. 
13. Shrimali RK, Yu Z, Theoret MR, et al. Antiangiogenic agents can increase lymphocyte 
infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. 
Cancer research. 2010;70:6171-6180. 
14. Manzoni M, Rovati B, Ronzoni M, et al. Immunological effects of bevacizumab-based 
treatment in metastatic colorectal cancer. Oncology. 2010;79:187-196. 
15. Osada T, Chong G, Tansik R, et al. The effect of anti-VEGF therapy on immature myeloid 
cell and dendritic cells in cancer patients. Cancer immunology, immunotherapy: CII. 
2008;57:1115-1124. 
16. Voron T, Colussi O, Marcheteau E, et al. VEGF-A modulates expression of inhibitory 
checkpoints on CD8+ T cells in tumors. J Exp Med. 2015.212(2):139-48. 
17. Pan PY, Wang GX, Yin B, et al. Reversion of immune tolerance in advanced malignancy: 
modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor 
function. Blood.2008.111(1):219-28. 
18. Yamamoto Y, Matsui J, Matsushima T, et al. Lenvatinib, an angiogenesis inhibitor targeting 
VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models 
associated with microvessel density and pericyte coverage. Vasc Cell. 2014 
19. Nakamichi S, Nokihara H, Yamamoto N, et al. A phase 1 study of lenvatinib, multiple 
receptor tyrosine kinase inhibitor, in Japanese patients with advanced solid tumors. Cancer 
Chemother Pharmacol.2015.76(6):1153-61. 
20. Muro K, Chung HC, Shankaran V, et al: Pembrolizumab for patients with PD-L1-postive 
advanced gastric cancer (KEYNOTE-012):a multicentere, open-label, phase 1b trial. 
Lancet oncol. 2016.17(6):717-26. 
21. Kato Y, Matsui J. Effects of Lenvatinib on Tumor-Associated Macrophages Enhance 


 
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Antitumor Activity of PD-1 Signal Inhibitors. JCA. 2015. 
22. Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. 
Immunity. 2014;41:49-61. 
23. Simon R. Optimal two-stage designs for phase II clinical trials. Controlled clinical trials 
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24. Shukui Qin, et al. Phase III Study of Apatinib in Metastatic Gastric Cancer: A Randomized, 
Double-blind, Placebo-controlled Trial. JCO. 2014. supl;abstr 4003. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendix 1) Performance Status (Eastern Cooperative Oncology Group (ECOG) 
Classification) 
 
PS 
Contents 
0 
Fully active. Being able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendix 2) 
New Response Evaluation Criteria in Solid Tumors (Revised RECIST 
guideline) version 1.1 
 
The following sections are excerpts from the “New Response Evaluation Criteria in Solid 
Tumors (Revised RECIST guideline) version 1.1 - Japanese Translation by the Japan 
Clinical Oncology Group (JCOG) -: Revised RECIST guideline (version 1.1).” 
 
2-1. 
Baseline Evaluation 
In accordance with the test schedule, tumor lesions will be identified by chest and 
abdomen/pelvic contrast CT or abdominal/pelvic contrast MRI prior to enrollment. Each 
lesion will be categorized “measurable” or “non-measurable.” 
A tumor diameter will be measured by cross-sectional CT or MRI. No measurement by a 
method to reconstruct three-dimensional sagittal or coronal images will be used. 
 
 
2-2. 
Definitions of measurable lesions 
A lesion falling into any of the following definitions is measurable (measurable lesion): 
3) 
A lesion other than malignant lymph nodes (non-nodal lesions) meeting any of the 
following definitions: 
(1) 
When CT or MRI with a slice thickness of ≤ 5 mm is used, the longest diameter of 
the lesion must be ≥ 10 mm. 
(2) 
When CT or MRI with a slice thickness of > 5 mm is used, the longest diameter of 
the lesion must be at least twice the slice thickness. 
(3) 
Osteolytic bone metastasis with soft tissue components meeting the Item (1) or (2) 
(4) 
Absence of other measurable non-cystic lesions and the presence of a cystic 
lesion meeting the Item (1) or (2) 
 
4) 
A lymph node must be ≥ 15 mm in short axis when assessed by CT with a slice 
thickness of ≤ 5 mm. 
(A lymph node with ≥ 10 mm to < 15 mm in short axis is a non-target lesion, and a lymph 
node with < 10 mm in short axis is not a lesion.) 
5) 
When chest X-ray is used, the longest diameter of the lesion must be ≥ 20 mm, and the 
lesion must be surrounded by the lung parenchyma (not adjacent to the mediastinum 
or thoracic wall) 
6) 
For clinical lesions (e.g., superficial skin lesions), the longest diameter must be ≥ 10 
mm as documented by color photography including a ruler 


 
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All lesions other than those listed above are non-measurable (non-measurable lesions). 
 
Attention should be paid that non-measurable lesions include the following lesions 
irrespective of imaging technique or lesion size: 
 
Bone lesions (excluding osteolytic lesions with measurable soft tissue components) 
Cystic lesions (excluding measurable lesions defined in the above Item 1)-(4)) 
Lesions previously locally treated with radiation therapy 
Leptomeningeal disease 
Ascites, pleural or pericardial effusion 
Lymphangitic involvement of skin or lung 
Abdominal masses/abdominal organomegaly that is palpable but not      measurable by 
imaging techniques 
 
3-3. 
Selection and Baseline Documentation of Target Lesions 
In this study, of measurable lesions identified at enrollment, 10 lesions at a maximum or 5 
lesions at a maximum per organ will be selected in the order of the largest diameter (longest 
axis for non-nodal lesions; and short axis for malignant lymph nodes) and defined as target 
lesions. When selecting lesions, representative of all involved organs should be included to 
the extent possible, and reproducible repeated measurements should be taken into 
consideration (Even if the diameter is large, a lesion difficult to measure should be avoided.). 
For the selected target lesions, the sites in the order from the head to the caudal end of the 
body, test method, date of test, longest axis for non-nodal lesions, short axis for malignant 
lymph nodes, and the sum of diameters of all the target lesions (hereinafter referred to as 
the sum of diameters) will be recorded in the case report form (CRF). 
 
3-4. 
Baseline Documentation of Non-target Lesions 
All lesions other than those selected as target lesions should be identified as non-target 
lesions, irrespective of measurability. Their sites, test method and date of test will be 
recorded in the CRF. Multiple non-target lesions involving the same organ may be 
documented as a single lesion (e.g., multiple enlarged pelvic lymph nodes or multiple liver 
metastases). 
 
3-5. 
Assessment of Tumor Response 
The target and non-target lesions will be assessed using the same test method as that used 


 
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at the time of enrollment. The diameters of the target lesions, and whether the non-target 
lesions disappeared or progressed will be recorded in the CRF. 
 
3-6. 
Response Criteria for Target Lesions 
Complete Response (CR) 
Disappearance of all non-nodal target lesions. All nodal target lesions must have reduction 
in short axis to < 10 mm. If nodal target lesions are selected at baseline, even if the sum of 
diameters is not 0 mm, the target lesions may be assessed as CR. 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). The 
sum must also demonstrate an absolute increase of at least 5 mm. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking 
as reference the smallest sum diameters while on study. 
Not all Evaluated 
No test can be performed for some reason, or lesions cannot be assessed as any of CR, 
PR, PD or SD. 
 
Percent reduction in the sum of diameters = (Pre-treatment sum of diameters - sum of 
diameters at assessment) /(Pre-treatment sum of diameters) × 100% 
 
Percent increase in the sum of diameters = (Sum of diameters at assessment – smallest 
sum of diameters) /(Smallest sum of diameters) × 100% 
 
* All target lesions should have their actual measurements recorded whenever they are 
measurable (e.g., even when < 5 mm). However, if target lesions are reported as “too small 
to measure,” irrespective of CT slice thickness, the diameter will be recorded as 0 mm if the 
lesion has likely disappeared, or as 5 mm if the lesion is faintly seen but too small to measure. 
* When the percent reduction meets the criteria for PR, and the percent increase meets the 
criteria for PD at the same time, PD should be determined. 
* For lesions that split during treatment, the fragmented portions should be added together 
to calculate the sum of diameters. 


 
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* If multiple lesions have coalesced during treatment and they are no longer separable, the 
diameter of the coalesced lesion should be added to calculate the sum of diameters. If 
lesions coalesce, and a plane between them may be maintained, the diameter of each 
individual lesion should be added to calculate the sum of diameters. 
 
3-7. 
Response Criteria for Non-target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and all lymph nodes must be non-pathological in 
size (< 10 mm short axis). 
Non-CR/non-PD 
Persistence of one or more non-target lesion(s) (including persistence of non-target lymph 
nodes measuring ≥ 10 mm in short axis) 
Progressive Disease (PD) 
“Unequivocal progression” of existing non-target lesions (including recurrence). 
When the patient also has measurable disease: In this setting, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit discontinuation 
of therapy. When the response of target lesions is SD or PR, an increase in the tumor burden 
of a non-target lesion much higher than a decrease in the tumor burden is considered to be 
“unequivocal progression.” If not, it is assessed as Non-CR/non-PD. 
When the patient has only non-measurable disease: As an idea, “unequivocal progression” 
is an increase in a non-target lesion that is determined to clearly exceed the tumor burden 
representing a 20% increase in the diameter and an additional 73% increase in volume. 
Not all Evaluated 
No test can be performed for some reason or when lesions cannot be assessed as any of 
CR, Non-CR/non-PD or PD. 
 
 
3-8. 
Presence or absence of new lesions 
When a lesion, which was not present at baseline, is identified after the start of treatment, 
it should be considered to be the appearance of a “new lesion.” 
The finding of a “new lesion” should be unequivocal: Not attributable to any difference from 
baseline in scanning technique, change in imaging modality or findings thought to represent 
something other than tumor. For example, necrosis of a liver metastatic lesion appeared as 
a new cystic lesion should not be handled as a new lesion. A lesion identified on a follow-


 
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up examination in an anatomical location that was not required to be scanned at baseline 
(pre-enrollment evaluation) is handled as a new lesion. 
If a lesion disappears and reappears at a subsequent time point, it should continue to be 
measured. However, the patient’s response at the point in time when the lesion reappears 
will depend upon the status of his/her other lesions. For example, if the patient’s tumor had 
reached a CR status and the lesion reappeared, then the patient would be considered PD 
at the time of reappearance. In contrast, if the tumor status was a PR or SD and one lesion 
which had disappeared then reappears, its maximal diameter should be added to the sum 
of the remaining lesions for a calculated response: in other words, the reappearance of an 
apparently “disappeared” single lesion amongst many which remain is not in itself enough 
to qualify for PD: that requires the sum of all lesions to meet the PD criteria. The rationale 
for such a categorization is based upon the realization that most lesions do not actually 
“disappear” but are not visualized because they are beyond the resolving power of the 
imaging modality employed. 
If a lesion may be new but equivocal, the lesion should not be recorded as a new lesion, 
but imaging examination should be repeated after a clinically appropriate interval. If a repeat 
imaging test confirms that it is a new lesion, then a new lesion should be declared using the 
date of the imaging test when it is confirmed to be a new lesion. 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD for 
overall response based on a new lesion (a positive FDG-PET scan lesion means one which 
is FDG avid with an uptake greater than twice that of the surrounding tissue on the 
attenuation corrected image). No FDG-PET at baseline and a positive FDG-PET at follow-
up: If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT of MRI, and if the positive FDG-PET confirms a lesion not identified on CT or MRI at 
baseline, this is a new lesion. 
 
 
3-9. 
Overall Response 
Overall response will be assessed based on a combination of the response of target lesions, 
response of non-target lesions and the appearance of a new lesion in accordance with Table 
9.a. below. If no non-target lesion is present at baseline, overall response will be assessed 
based on the target lesions and the appearance of a new lesion. If no target lesion is present 
at baseline, overall response will be assessed based on the non-target lesions and the 
appearance of a new lesion in accordance with Table 9.b. 
Table 9a Overall response at each time point: Patients with target lesions 
Target lesions 
Non-target lesions 
New lesions 
Overall 


 
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response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD 
or 
not 
all 
evaluated 
No 
PR 
SD 
Non-PD 
or 
not 
all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Table 9b Overall response at each time point: Patients with non-target lesions only 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
PR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
3-10. 
Best Overall Response 
Overall response will be considered “good” in the order of CR > PR > SD > PD > NE. Best 
overall response will be assessed based on the overall response during the entire study 
period in accordance with the criteria specified below. When corresponding to the definitions 
of multiple categories, a better category should be chosen in the order of CR > PR > SD > 
PD > NE. 
Complete Response (CR): 
The CR status for overall response is maintained in at least two consecutive tests performed 
at intervals of 4 weeks (28 days) or more. The day of confirming CR for overall response in 
the second test is considered to be the “day of confirming CR.” 
Partial Response (PR):The PR or higher status for overall response (CR or PR) is 
maintained in at least two consecutive tests performed at intervals of 4 weeks (28 days) or 
more. The day of confirming the PR or higher status for overall response in the second test 
and PR is confirmed for best overall response is considered to be the “day of confirming 
PR.” 


 
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Stable Disease (SD): 
No CR or PR is achieved for best overall response, but PD is not assessed for overall 
response before 6 weeks after the start of treatment, and SD or higher is assessed in at 
least one test for overall response. 
Progressive Disease (PD): 
No CR, PR or SD is assessed for best overall response and but is confirmed to be PD for 
overall response. 
Not Evaluable (NE): 
All overall responses were NE. 
Table 9c Best overall response 
First overall response 
Second 
overall 
response 
Third 
overall 
response 
Best 
overall 
response 
Either PR or CR 
SD 
PD 
SD 
Either PR or CR 
SD 
NE 
SD 
Either PR or CR 
PD 
- 
PD 
Either PR or CR 
NE 
NE 
NE 
Either PR or CR 
NE 
SD 
SD 
SD 
PD 
- 
PD 
SD 
SD 
PD 
SD 
SD 
NE 
PD 
PD 
NE 
NE 
PD 
PD 
NE 
NE 
NE 
NE 
NE 
NE 
PD 
PD