Conditions: Advanced Solid Tumors Recurrent Solid Tumors
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 18
Healthy volunteers: no

Brief summary:
The objective of the study is to investigate the pharmacokinetics of ONO-4538 administered to Korean patients with advanced or recurrent solid tumors who are refractory or intolerant to standard therapy or for whom no appropriate treatment is available.

Detailed description:

Arms:
arm 1: ONO-4538 water-soluble injection, 100 mg/vial, 1mg/kg, single dose arm 2: ONO-4538 water-soluble injection, 100 mg/vial, 3mg/kg, single dose arm 3: ONO-4538 water-soluble injection, 100 mg/vial, 10mg/kg, single dose

Interventions: intervention 1: ONO-4538
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
Protocol no. ONO-4538-13                                         English Version 1.1 
Release date: January 8, 2015 
1 / 13 
 
 
 
 
 
ONO-4538 
 
 
Multicenter, open-label, uncontrolled, Phase I study in 
solid tumor 
 
Subtitle: A multicenter, open-label, uncontrolled Phase I study to evaluate the pharmacokinetics 
of ONO-4538 administered to Korean patients with advanced or recurrent solid tumors who are 
refractory or intolerant to standard therapy or for whom no appropriate treatment is available. 
 
Protocol 
 
 
 
 
 
 
 
 
 
Ono Pharmaceutical Co., Ltd. 
 
 
 
Protocol no. ONO-4538-13 
English Version: 1.1 
Release date: January 8, 2015 


Protocol no. ONO-4538-13                                         English Version 1.1 
Release date: January 8, 2015 
 
 
 
2 / 13 
 
 
 
Contact Information for Adverse Event Reports 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This protocol is to be disseminated to the principal investigator, sub investigators, clinical 
research coordinators, clinical trial pharmacist, medical laboratory technologist and institutional 
review boards etc. All information contained in this protocol should be treated as confidential and 
may not be disclosed to any third party.  
 
Note 
ONO-4538 is co-developed by Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb (BMS) 
(BMS code: BMS-936558). ONO-4538 is described in this document as a compound code. 
 
 


Protocol no. ONO-4538-13                                         English Version 1.1 
Release date: January 8, 2015 
 
 
 
3 / 13 
 
Ethics 
 
This study will be conducted in compliance with the ethical principles that have their origin in the 
Declaration of Helsinki, the study protocol, standards stipulated under ICH Good Clinical Practice 
Guidelines (GCPs), the applicable local regulatory requirements and revised ordinances and relevant 
notifications.  
This protocol will be amended when revision is needed to ensure the safety conduct of the study.  
 
 
 


Protocol no. ONO-4538-13                                         English Version 1.1 
Release date: January 8, 2015 
 
 
 
4 / 13 
 
Protocol Synopsis 
 
1. Study Objectives 
The objective of the study is to investigate the pharmacokinetics of ONO-4538 administered to 
Korean patients with advanced or recurrent solid tumors who are refractory or intolerant to standard 
therapy or for whom no appropriate treatment is available.  
 
2. Study Design 
Multicenter, open label, uncontrolled study 
 
3. Disease Studied 
3.1 Disease 
Advanced or recurrent solid tumors 
 
3.1.1 Subject Inclusion Criteria 
Patients satisfying all the following criteria will be included: 
1. 
Male or female (Korean)  
2. 
≥ 20 years of age (at time of obtaining the Informed Consent)  
3. 
Histologically or cytologically confirmed solid tumor 
4. 
Patients with advanced or recurrent solid tumors who are refractory or intolerant to standard 
therapy or for whom no appropriate treatment is available 
5. 
ECOG Performance Status (Appendix 2) is 0 to 1  
6. 
Life expectancy is ≥ 90 days at time of patient enrollment  
7. 
Women of childbearing potential (including women who are amenorrheic due to chemical 
menopause or for another medical reason) *1 must agree to engage in contraception*2 from the 
time of informed consent to at least 400 days after the final dose of the investigational product.  
8. 
Men must agree to use a contraceptive from the start of study treatment until at least 400 days 
following the last dose of investigational product. 
9. 
Most recently determined laboratory values, within 7 days before patient enrollment on this study, 
satisfy the criteria listed below. If all the laboratory values were obtained over 7 days before the 
ONO-4538 initial treatment, the laboratory test has to be performed within 7 days before the 
ONO-4538 initial treatment and the laboratory values have to meet the all criteria listed below. 


Protocol no. ONO-4538-13                                         English Version 1.1 
Release date: January 8, 2015 
 
 
 
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Laboratory testing must be performed with no granulocyte colony stimulating factor (G-CSF) 
treatment or blood transfusion having taken place 14 or fewer days before testing.  
- WBC count ≥ 2,000/mm3 and neutrophil count ≥ 1,500/mm3 
- Platelet count ≥ 100,000/mm3 
- Hemoglobin ≥ 9.0 g/dL 
- AST (GOT) and ALT (GPT) ≤ 3.0 times the upper limit of normal range of each institute 
- Total bilirubin ≤ 2.0 times the upper limit of normal range of each institute 
- Creatinine ≤ 1.5 mg/dL or creatinine clearance (raw or estimated using Cockcroft/Gault 
formula) > 45 mL/min 
 
*1  The term “women of childbearing potential” includes all women who have experienced 
menarche but have not undergone a sterilization procedure (e.g., hysterectomy, bilateral tubal 
ligation, bilateral oophorectomy) or experienced menopause. Menopause is constituted by 
having been amenorrheic for at least 12 months without a notable reason. Women who use an 
oral contraceptive, an intrauterine device, the barrier method, or other mechanical method of 
contraception are considered to be of childbearing potential.  
*2  The subject must consent to use any two of the following methods of contraception: vasectomy 
or condom for patients who are male or their partner and tubal ligation, contraceptive 
diaphragm, intrauterine device, or oral contraceptive for patients who are female or their 
partner. 
 
 
3.1.2 Subject Exclusion Criteria 
Patients satisfying any of the following criteria will be excluded: 
1. 
Current or prior severe hypersensitivity to another antibody product  
2. 
Adverse drug reactions due to prior treatments or remaining effects of surgical therapy that, in 
the principal or sub investigator’s opinion, may interfere with the evaluation of the 
investigational product 
3. 
Active autoimmune disease or history of chronic or recurring autoimmune disease (Appendix 3).  
4. 
Current or prior interstitial lung disease or pulmonary fibrosis diagnosed based on diagnostic 
imaging or clinical findings. 
5. 
Active diverticulitis or symptomatic gastrointestinal ulcerative disease 


Protocol no. ONO-4538-13                                         English Version 1.1 
Release date: January 8, 2015 
 
 
 
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6. 
Multiple primary cancers (except for completely resected basal cell cancer, stage I squamous cell 
carcinoma, carcinoma in situ, intramucosal carcinoma, or superficial bladder cancer or any other 
cancer from which the patient has been recurrence-free for at least 5 years)  
7. 
Original cancer or metastases to the brain or meninges (unless such lesions are asymptomatic and 
do not require treatment) 
8. 
Pericardial effusion, pleural effusion, or ascites requiring treatment  
9. 
Cancer pain not stable with a fixed regimen of an analgesic  
10. History of transient ischemic attack, cerebrovascular accident, thrombosis, or thromboembolism 
(pulmonary arterial embolism or deep vein thrombosis) within 180 days of enrollment.  
11. Any of the following cardiovascular diseases that are uncontrollable or severe:  
- Myocardial infarction within 180 days of enrollment 
- Uncontrollable angina pectoris within 180 days of enrollment 
- New York Heart Association (NYHA) Grade III or IV congestive cardiac failure 
- Hypertension (systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 90 mmHg 
persisting for ≥ 24 hours) despite appropriate treatment 
- Arrhythmia requiring treatment 
12. On anticoagulant therapy (other than antiplatelet therapy with low-dose aspirin) or having a 
disease requiring anticoagulant therapy.  
13. A serious concomitant disease such as liver failure, renal failure or uncontrollable diabetes. 
14. Patients requiring transplantation or with a history of transplantation except autotransplantation  
15. Has received a systemic corticosteroid (unless temporarily for testing, prophylaxis, or a similar 
purpose unrelated to an autoimmune disease) or an immune suppressant 28 or fewer days before 
enrollment. 
16. Has received an anti-cancer product (e.g., chemotherapy, molecular targeted therapy, and 
immunotherapy) 28 or fewer days before enrollment. 
17. Has undergone surgery for pleural, pericardial, or similar adhesion 28 or fewer days before 
enrollment.  
18. Has undergone surgical treatment accompanying general anesthesia 28 or fewer days before 
enrollment.  
19. Has undergone surgical treatment accompanying local or surface anesthesia 14 or fewer days 
before enrollment.  
20. Has received radiotherapy 28 or fewer days before enrollment or has received radiotherapy for 
relief of cancer symptoms 14 or fewer days before enrollment. 


Protocol no. ONO-4538-13                                         English Version 1.1 
Release date: January 8, 2015 
 
 
 
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21. Has received a radiopharmaceutical agent (except when the radiopharmaceutical agent is used for 
testing or diagnostic purposes) 56 or fewer days before enrollment.  
22. Has undergone gamma knife or CyberKnife treatment 14 or fewer days before enrollment.  
23. Has a systemic infection that requires treatment.  
24. Has tested positive for HIV-1 antibody, HIV-2 antibody, HTLV-1 antibody, HBs antigen, or 
HCV antibody.  
25. Has tested positive for HBs antibody or HBc antibody and has a result of at least detectable in 
HBV-DNA assay despite testing negative for HBs antigen. 
26. Is pregnant, nursing, or possibly pregnant.  
27. Has received another investigational product 28 or fewer days before enrollment.  
28. Has previously received ONO-4538 (MDX-1106 or BMS-936558), an anti-CTLA-4 antibody, or 
other antibody therapy or drug therapy intended to control T-cells.  
29. Is found incapable of giving consent due to dementia or another such condition.  
30. Patients otherwise found by the principal or sub investigator to be ineligible. 
 
4. Study Schedule and Observations 
The study consists of a screening phase, treatment phase, and follow-up phase (see Figure 4).  
 
 
Figure 4 Summary of study design 
 
4.1 Screening Phase 
Patients who satisfy all of the subject inclusion criteria and none of the subject exclusion criteria 
and who are found eligible by the principal or sub investigator can be enrolled and then moved to the 
treatment phase.  


Protocol no. ONO-4538-13                                         English Version 1.1 
Release date: January 8, 2015 
 
 
 
8 / 13 
 
 
4.2 Treatment Phase 
ONO-4538 will be administered once. Subjects who will meet any of the Criteria for Entering the 
Follow-Up phase will move to the Follow-Up phase. The subjects who complete the treatment phase 
in this study and not meet all of the Criteria for Entering the Follow-Up phase, and will satisfy all 
inclusion criteria and not meet all of the exclusion criteria in the ONO-4538-14 study may move to the 
ONO-4538-14 study, otherwise the subjects will move to the Follow-Up phase. 
 
4.3 Follow-up Phase 
Those subjects receiving the investigational product who satisfy any of the Criteria for Entering the 
Follow-Up phase will proceed to the Follow-Up phase. 


 
9 / 13 
 
Table 4 Study schedule 
Follow-Up phase
2
3
4
8
15
22
After the start of the
administration
1 hr
2 hr
8 hr
-7 to -1
±2
+3
±7
○1
○
○2
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○6
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○2
●
Diagnostic imaging (e.g., CT, MRI)9
Tumor marker10
Concomitant drugs/adverse events
○:essential, ●: optional
○
○
Hematology tests/urinalysis
○
/blood biochemistry tests
Immunology/hormone tests
Serum drug concentration7
Anti-ONO-4538 antibody
Performance Status
Chest X-ray5
12-lead ECG
○4
○4
○4
Pregnancy test3
Vital signs/weight
○
○4
○4
/percutaneous oxygen saturation
Demographics
Allowable range (days)
-
±3
Written informed consent
Inclusion/exclusion criteria
Virus tests
ONO-4538 administration
○
Category
Screening
Phase
Study day
1
Before
administration
After the end of the
administration
Treatment Phase
28 days after the
discontinuation or the Day
22 only if the subjects will
not join the ONO-4538-14.
○
○
●
At
discontinuation
○4
○
○4
○4
○4
○4
○
 


 
10 / 13 
 
 
1. 
Begin administering the investigational product within 30 days of informed consent. 
2.  The data from virus tests performed within 1 year of enrollment, diagnostic imaging (e.g., CT, MRI) performed within 14 days of enrollment will be included. 
3. 
Women of childbearing potential will undergo a serum pregnancy test in the screening phase and subsequently undergo urine pregnancy testing.  
4. 
Other than weight. 
5. 
Also perform at unscheduled visits as necessary if, during the study (from the time of informed consent to the end of the subjects’ schedule), signs, subjective and 
objective symptoms, or test findings suggest respiratory disease.  
6. 
SP-D and KL-6 will be measured in the screening phase and, as necessary, in the treatment phase. 
7. 
Collect blood sample at 24, 48 and 72 hours after the completion of the administration on 2nd, 3rd and 4th day, respectively.  
 
 
9. 
Check for brain metastases with head CT/MRI. Check for bone metastases with X-ray imaging, FDG-PET, or bone scintigraphy as required by the clinical 
symptoms. 
10. Perform tumor marker assessment according to the cancer type of patient when required at Investigator’s discretion. 
 


Protocol no. ONO-4538-13                                         English Version 1.1 
Release date: January 8, 2015 
11 / 13 
5. Dose and Administration, and Duration of Treatment 
Patients will be assigned any of the following groups in order of increasing dose and ONO-4538 is 
administered at a dose level of 1, 3 or 10 mg/kg (See Table 5) 
 
Table 5. ONO-4538 Dose 
Group 
Treatment phase 
Subjects number 
Dose (mg/kg) 
A 
1 
6 
B 
3 
6 
C 
10 
6 
 
ONO-4538 will be administered once in the treatment phase and each subject will be observed for 3 
weeks. The appropriate dose of ONO-4538 will be diluted with physiological saline to a total amount 
of approximately not less than 60 mL before use (so that concentration of diluted solution of 
ONO-4538 is no less than 0.35 mg/mL). The entire dose of ONO-4538 will be administered as an 
intravenous infusion over approximately 60 minutes through a 0.20 or 0.22 μm in-line filter. The 
lower limit of the infusion time is 54 minutes. The target upper limit is 90 minutes. At the end of the 
infusion, the line will be flushed with a sufficient quantity of physiological saline. Regarding the 
calculation of the dosage amount, the dose can be rounded off to the nearest tenth.  
 
6. Prior and Concomitant Therapies 
6.1 Therapies Prohibited During the Study 
The therapies listed below are prohibited during the study (from the time of informed consent to the 
end of the subjects’ schedule).  
1. 
Immunosuppressants and corticosteroids *1 
2. 
Anti-cancer products (e.g., chemotherapy, molecular targeted therapy, immunotherapy*2) 
3. 
Surgical treatment for a malignant tumor 
4. 
Radiotherapy 
5. 
Radiopharmaceuticals*3 and anti-androgen receptor therapy 
6. 
Bisphosphonate products and anti-RANKL antibodies *4 
7. 
Transplant therapy 
8. 
Any other investigational product  


 
12 / 13 
*1 Subjects are permitted to use a local corticosteroid such as topical, intra-articular, intranasal, ocular, 
inhalational administration, or otherwise temporal systemic corticosteroid for the treatment or 
prevention of a contrast media allergy or an adverse event.  
*2 This includes local therapies.  
*3 The use of a radiopharmaceutical for a testing or diagnostic purpose is permitted.  
*4 Bisphosphonate products and anti-RANKL antibodies may be used only when the dosage regimen 
used before study enrollment is maintained. 
 
 
7. Criteria for Entering the Follow-Up phase 
Subjects satisfying any of the following criteria in the treatment phase will proceed to the follow-up 
phase. Only when the subjects do not satisfy all of the following criteria in the treatment phase, the 
subjects may move to the ONO-4538-14 study. 
1. 
The development of PD is identified by the principal or sub investigator according to the 
RECIST guideline (version 1.1) only in case in which the unplanned tumor assessment with 
diagnostic imaging is performed in the treatment phase.  
2. 
It is determined that continuing the treatment is not appropriate because the worsening of clinical 
symptoms attributed to disease progression occurs.  
3. 
The subject develops Grade 2 or higher interstitial lung disease, regardless of the causal 
relationship to the investigational product.  
4. 
Grade 2 or greater eye pain, or visual acuity reduced occurs whose causal relationship with the 
investigational product cannot be ruled out and does not improve to Grade 1 severity with local 
treatment.  
5. 
Grade 3 or greater bronchospasm, hypersensitivity reaction, infusion reaction (e.g., pyrexia, chills, 
nausea, pain, headache, cough, pruritus, and rash) or uveitis occurs whose causal relationship 
with the investigational product cannot be ruled out.  
6. 
The investigator or sub-investigator otherwise determines that continuing to administer the 
investigational product is inappropriate.  
 
8. Endpoints 
8.1 Safety 
1. 
Adverse events  


 
13 / 13 
2. 
Laboratory tests (hematology, blood biochemistry, qualitative urinalysis, immunology, hormone 
tests) 
3. 
Vital signs (systolic blood pressure/diastolic blood pressure, pulse rate, and body temperature), 
body weight, percutaneous oxygen saturation (SpO2)  
4. 
12-lead ECG 
5. 
Chest X-ray 
6. 
Performance Status (ECOG) 
 
8.2 Pharmacokinetics  
1. 
Serum ONO-4538 concentrations 
2. 
Pharmacokinetic parameters such as Cmax, Tmax, AUC, T1/2 
 
8.3 Anti-drug Antibodies 
1. 
Anti-ONO-4538 antibody  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9. Planned Number of Subjects 
Total 18 subjects (6 subjects in each group) 
 
10. Planned Study Period 
July 2014 to December 2015 

SAP_001.pdf: 
 
 
 
 
1 
 
 
 
 
 
 
Statistical Analysis Plan 
 
Protocol No.: ONO-4538-13 
 
  
 
 
Multicenter, open-label, uncontrolled,  
Phase I in solid tumor 
  
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor: Ono Pharmaceutical Co., Ltd. 
Author: LSK Global PS 
Protocol Version: ONO-4538-13-version 1.1, 08-Jan-2015 
SAP Version No & Date: SAP_ONO-4538-13_version 1.0, 13-Jan-2015 


 
 
 
 
2 
 
Signature Page 
 
 
Prepared by: 
 
Kwak, Hee Eun 
 
 
 
 
Project Statistician, LSK Global PS 
 
Date(dd-mmm-yyyy) 
 
Signature 
 
 
Reviewed by LSK Global PS:  
 
Jeong, Bong Hwang 
 
 
 
 
STAT Manager, LSK Global PS 
 
Date(dd-mmm-yyyy) 
 
Signature 
 
 
 
 
 
Park, Byeong Kwan 
 
 
 
 
STAT Director, LSK Global PS 
 
Date(dd-mmm-yyyy) 
 
Signature 
 
 
Approved by Ono Pharmaceutical Co., Ltd: 
 
Satoru Fukinbara 
 
 
 
 
Senior Director, Data Science, 
Development Headquarters 
 
Date(dd-mmm-yyyy) 
 
Signature 
 


 
 
 
 
3 
 
History of Revision 
 
Study No 
ONO-4538-13 
Sponsor 
Ono Pharmaceutical Co., Ltd. 
CRO 
LSK Global PS 
Prepared by 
Kwak, Hee Eun 
Approval Date 
Amended Version 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
4 
 
List of Contents 
Pages 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................................... 7 
1 INTRODUCTION............................................................................................................................. 9 
2 STUDY OBJECTIVES ................................................................................................................... 10 
3 INVESTIGATIONAL PLAN ......................................................................................................... 11 
3.1 
Study Design ............................................................................................................................ 11 
3.2 
Target ....................................................................................................................................... 11 
3.2.1 
Target .............................................................................................................................. 11 
3.2.2 
Subject Inclusion Criteria ................................................................................................ 11 
3.2.3 
Subject Exclusion Criteria .............................................................................................. 12 
3.3 
Study Schedule and Observations ............................................................................................ 14 
3.3.1 
Screening Phase .............................................................................................................. 14 
3.3.2 
Treatment Phase .............................................................................................................. 15 
3.3.3 
Follow-up Phase .............................................................................................................. 15 
3.4 
Dose and Administration, and Duration of Treatment ............................................................. 18 
3.5 
Prior and Concomitant Therapies ............................................................................................. 18 
3.5.1 
Therapies Prohibited During the Study ........................................................................... 18 
3.6 
Criteria for Entering the Follow-Up phase ............................................................................... 19 
3.7 
Sample size determination ....................................................................................................... 19 
3.7.1 
Planned Number of Subjects ........................................................................................... 19 
4 ANALYSIS SETS ........................................................................................................................... 21 
4.1 
Definitions of Groups ............................................................................................................... 21 
4.2 
Criteria for Subject Handling ................................................................................................... 21 
4.3 
Criteria for Handling Evaluation Time Points ......................................................................... 21 
5 DOCUMENTATION OF STATISTICAL METHOD ................................................................... 23 
5.1 
Safety Endpoints ...................................................................................................................... 23 
6 DISPOSITION AND PROTOCOL DEVIATIONS ....................................................................... 24 
6.1 
Assessment of Reliability of Clinical Trial .............................................................................. 24 
6.1.1 
Analysis Set .................................................................................................................... 24 
6.1.2 
Analysis Items and Data Handling .................................................................................. 24 
6.1.3 
Analysis Methods ............................................................................................................ 24 
7 Study Drug Exposure and Compliance ........................................................................................... 25 


 
 
 
 
5 
 
7.1.1 
Analysis Set .................................................................................................................... 25 
7.1.2 
Analysis Items and Data Handling .................................................................................. 25 
7.1.3 
Analysis Methods ............................................................................................................ 25 
8 DEMOGRAPHIC AND BASELINE CHARACTERISTICS ........................................................ 26 
8.1 
Analysis Set .............................................................................................................................. 26 
8.2 
Analysis Items and Data Handling ........................................................................................... 26 
8.3 
Analysis Methods and Classification ....................................................................................... 26 
9 SAFETY EVALUATION ............................................................................................................... 29 
9.1 
Adverse Events......................................................................................................................... 29 
9.1.1 
Analysis Set .................................................................................................................... 29 
9.1.2 
Analysis Items and Data Handling .................................................................................. 29 
9.1.3 
Analysis Methods ............................................................................................................ 30 
9.2 
Clinical Laboratory Evaluation ................................................................................................ 31 
9.2.1 
Analysis Set .................................................................................................................... 31 
9.2.2 
Analysis Items and Data Handling .................................................................................. 31 
9.2.3 
Analysis Methods ............................................................................................................ 31 
9.3 
Immunologic Test .................................................................................................................... 32 
9.3.1 
Analysis Set .................................................................................................................... 32 
9.3.2 
Analysis Items and Data Handling .................................................................................. 32 
9.3.3 
Analysis Methods ............................................................................................................ 32 
9.4 
Hormonal Test .......................................................................................................................... 32 
9.4.1 
Analysis Set .................................................................................................................... 32 
9.4.2 
Analysis Items and Data Handling .................................................................................. 32 
9.4.3 
Analysis Methods ............................................................................................................ 33 
9.5 
Vital Signs ................................................................................................................................ 33 
9.5.1 
Analysis Set .................................................................................................................... 33 
9.5.2 
Analysis Items and Data Handling .................................................................................. 33 
9.5.3 
Analysis Methods ............................................................................................................ 33 
9.6 
12-lead ECG ............................................................................................................................. 33 
9.6.1 
Analysis Set .................................................................................................................... 33 
9.6.2 
Analysis Items and Data Handling .................................................................................. 33 
9.6.3 
Analysis Methods ............................................................................................................ 34 
10 GENERAL PRESENTATION OF SUMMARIES AND ANALYSES ......................................... 35 


 
 
 
 
6 
 
10.1 Summary Statistics ................................................................................................................... 35 
10.2 Significance Level to Be Used ................................................................................................. 35 
10.3 Decimals ................................................................................................................................... 35 
10.4 Site Pooling Method ................................................................................................................. 37 
10.5 Software for Statistical Analysis .............................................................................................. 37 
11 INTERIM ANALYSIS ................................................................................................................... 37 
12 DATA REVIEW ............................................................................................................................. 38 
12.1 Objectives ................................................................................................................................. 38 
12.2 Analysis Set .............................................................................................................................. 38 
12.3 Analysis Items and Data Handling ........................................................................................... 38 
12.4 Analysis Methods ..................................................................................................................... 38 
13 CHANGE FROM PROTOCOL ...................................................................................................... 39 
14 SAS PROCEDURE FOR ANALYSIS ........................................................................................... 39 
15 REFERENCES ................................................................................................................................ 39 
 


 
 
 
 
7 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
ALP 
alkaline phosphatase  
ALT (GPT) 
Alanine aminotransferase 
(glutamic pyruvic transaminase) 
ANA 
anti-nuclear antibody 
AST (GOT) 
Aspartate aminotransferase 
(glutamate oxaloacetate transaminase) 
BMI 
body mass index 
BUN 
blood urea nitrogen  
CK (CPK) 
creatine kinase (creatine phosphokinase) 
Cl 
Chloride 
CRP 
C-reactive protein 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
CTLA-4 
cytotoxic T lymphocyte-associated antigen 4 
DNA 
deoxyribonucleic acid 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form  
G-CSF 
granulocyte colony stimulating factor 
GH 
growth hormone 
HBc 
hepatitis B virus core protein 
HBs 
hepatitis B virus surface protein 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV-1 
human immunodeficiency virus-1 
HIV-2 
human immunodeficiency virus-2 
HLA 
human leukocyte antigen 
IL 
interleukin 
IP 
interferon-inducible protein 
LDH 
Lactate dehydrogenase 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
NCI 
National Cancer Institute, United States 
NKT cell 
natural killer T cell 
NYHA 
New York Heart Association 


 
 
 
 
8 
 
PD-1 
Programmed cell death-1 
PD-L1 
Programmed cell death-ligand 1 
PD-L2 
Programmed cell death-ligand 2 
Performance Status 
Performance Status 
PT 
preferred term 
QRS 
ventricular activation time 
QT 
electrocardiogram QT interval (electrical ventricular contraction 
time) 
QTcF 
QT interval corrected for heart rate according to Fridericia’s formula 
RA 
rheumatoid factor 
RANKL 
Receptor activator of NF-κB ligand 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
SAF 
Safety Analysis Set 
SOC 
System Organ Class 
SP-D 
pulmonarysurfactant protein D 
SpO2 
percutaneous oxygen saturation 
TSH 
thyroid stimulating hormone 
UICC-TNM 
Union InternationaleContre Le Cancer TNM 
γ-GTP 
Gamma-glutamyltranspeptidase 
 


 
 
 
 
9 
 
1 
INTRODUCTION 
ONO-4538 (Bristol-Myers Squibb [BMS] developmental code: BMS-936558, ex-Medarex 
developmental code: MDX-1106) is a fully human monoclonal antibody to human programmed cell 
death-1 (PD-1 [also known as CD279]), made by Ono Pharmaceutical Co., Ltd. and Medarex Inc. The 
product is made with recombinant technology using CHO cells. PD-1 is a receptor of the CD28 family 
(a molecular group that positively and negatively regulates the activation of T cells in supplementary 
fashion), which is expressed on activated lymphocytes (T cells, B cells and NKT cells) and myeloid 
cells. PD-1 binds to PD-1 ligands (PD-L1 [also known as B7-H1 and CD274] and PD-L2 [also known 
as B7-DC and CD273]), which are expressed on antigen-presenting cells, and transmits regulatory 
stimuli to lymphocytes to down-modulate the activation of lymphocytes 1). PD-1 ligands are expressed 
on various cancer tissues 2), in addition to antigen-presenting cells. Based on some non-clinical 
pharmacological studies, the proliferation and the activation of antigen-specific T cells have been 
shown as the result of the inhibition to binding of PD-1 on PD-1 ligand by ONO-4538.  
Ono is clinically developing the ONO-4538 in Korea and Japan. BMS is clinically developing that 
in other regions. 
We have planned to conduct a clinical trial to investigate the pharmacokinetics of ONO-4538 in 
patient with solid tumor in Korea.  In addition to the pharmacokinetics, the safety and 
pharmacological action will be evaluated. The data from this study will be included in the documents 
for the new drug administration of ONO-4538 in Korea. 
 


 
 
 
 
10 
 
2 
STUDY OBJECTIVES 
The objective of the study is to investigate the pharmacokinetics of ONO-4538 administered to 
Korean patients with advanced or recurrent solid tumors who are refractory or intolerant to standard 
therapy or for whom no appropriate treatment is available. 


 
 
 
 
11 
 
3 
INVESTIGATIONAL PLAN 
 
3.1 
Study Design  
Multi-center, open-label, uncontrolled study 
 
3.2 
Target 
3.2.1 
Target  
Advanced or recurrent solid tumors who are refractory or intolerant to standard therapy or for 
whom no appropriate treatment are available. 
 
3.2.2 
Subject Inclusion Criteria   
Patients satisfying all the following criteria will be included: 
1. 
Male or female (Korean)  
2. 
≥ 20 years of age (at time of obtaining the Informed Consent)  
3. 
Histologically or cytologically confirmed solid tumor 
4. 
Patients with advanced or recurrent solid tumors who are refractory or intolerant to standard therapy 
or for whom no appropriate treatment is available 
5. 
ECOG Performance Status (Appendix 2) is 0 to 1  
6. 
Life expectancy is ≥ 90 days at time of patient enrollment  
7. 
Women of childbearing potential (including women who are amenorrheic due to chemical menopause 
or for another medical reason) *1 must agree to engage in contraception*2 from the time of informed 
consent to at least 400 days after the final dose of the investigational product.  
8. 
Men must agree to use a contraceptive from the start of study treatment until at least 400 days 
following the last dose of investigational product. 
9. 
Most recently determined laboratory values, within 7 days before patient enrollment on this study, 
satisfy the criteria listed below. If all the laboratory values were obtained over 7 days before the ONO-
4538 initial treatment, the laboratory test has to be performed within 7 days before the ONO-4538 
initial treatment and the laboratory values have to meet the all criteria listed below. Laboratory testing 
must be performed with no granulocyte colony stimulating factor (G-CSF) treatment or blood 
transfusion having taken place 14 or fewer days before testing.  
- WBC count ≥ 2,000/mm3 and neutrophil count ≥ 1,500/mm3 
- Platelet count ≥ 100,000/mm3 
- Hemoglobin ≥ 9.0 g/dL 


 
 
 
 
12 
 
- AST (GOT) and ALT (GPT) ≤ 3.0 times the upper limit of normal range of each institute 
- Total bilirubin ≤ 2.0 times the upper limit of normal range of each institute 
- Creatinine ≤ 1.5 mg/dL or creatinine clearance (raw or estimated using Cockcroft/Gault formula) > 45 
mL/min 
 
*1 The term “women of childbearing potential” includes all women who have experienced menarche but 
have not undergone a sterilization procedure (e.g., hysterectomy, bilateral tubal ligation, bilateral 
oophorectomy) or experienced menopause. Menopause is constituted by having been amenorrheic for at 
least 12 months without a notable reason. Women who use an oral contraceptive, an intrauterine device, 
the barrier method, or other mechanical method of contraception are considered to be of childbearing 
potential.  
*2 The subject must consent to use any two of the following methods of contraception: vasectomy or 
condom for patients who are male or their partner and tubal ligation, contraceptive diaphragm, 
intrauterine device, or oral contraceptive for patients who are female or their partner. 
 
3.2.3 
Subject Exclusion Criteria   
Patients satisfying any of the following criteria will be excluded: 
1. 
Current or prior severe hypersensitivity to another antibody product  
2. 
Adverse drug reactions due to prior treatments or remaining effects of surgical therapy that, in 
the principal or sub investigator’s opinion, may interfere with the evaluation of the 
investigational product 
3. 
Active autoimmune disease or history of chronic or recurring autoimmune disease (Appendix 3).  
4. 
Current or prior interstitial lung disease or pulmonary fibrosis diagnosed based on diagnostic 
imaging or clinical findings. 
5. 
Active diverticulitis or symptomatic gastrointestinal ulcerative disease 
6. 
Multiple primary cancers (except for completely resected basal cell cancer, stage I squamous cell 
carcinoma, carcinoma in situ, intramucosal carcinoma, or superficial bladder cancer or any other 
cancer from which the patient has been recurrence-free for at least 5 years)  
7. 
Original cancer or metastases to the brain or meninges (unless such lesions are asymptomatic and 
do not require treatment) 
8. 
Pericardial effusion, pleural effusion, or ascites requiring treatment  
9. 
Cancer pain not stable with a fixed regimen of an analgesic  
10. History of transient ischemic attack, cerebrovascular accident, thrombosis, or thromboembolism 


 
 
 
 
13 
 
(pulmonary arterial embolism or deep vein thrombosis) within 180 days of enrollment.  
11. Any of the following cardiovascular diseases that are uncontrollable or severe:  
- Myocardial infarction within 180 days of enrollment 
- Uncontrollable angina pectoris within 180 days of enrollment 
- New York Heart Association (NYHA) Grade III or IV congestive cardiac failure 
- Hypertension (systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 90 mmHg 
persisting for ≥ 24 hours) despite appropriate treatment 
- Arrhythmia requiring treatment 
12. On anticoagulant therapy (other than antiplatelet therapy with low-dose aspirin) or having a 
disease requiring anticoagulant therapy.  
13. A serious concomitant disease such as liver failure, renal failure or uncontrollable diabetes. 
14. Patients requiring transplantation or with a history of transplantation except autotransplantation  
15. Has received a systemic corticosteroid (unless temporarily for testing, prophylaxis, or a similar 
purpose unrelated to an autoimmune disease) or an immune suppressant 28 or fewer days before 
enrollment. 
16. Has received an anti-cancer product (e.g., chemotherapy, molecular targeted therapy, and 
immunotherapy) 28 or fewer days before enrollment. 
17. Has undergone surgery for pleural, pericardial, or similar adhesion 28 or fewer days before 
enrollment.  
18. Has undergone surgical treatment accompanying general anesthesia 28 or fewer days before 
enrollment.  
19. Has undergone surgical treatment accompanying local or surface anesthesia 14 or fewer days 
before enrollment.  
20. Has received radiotherapy 28 or fewer days before enrollment or has received radiotherapy for 
relief of cancer symptoms 14 or fewer days before enrollment. 
21. Has received a radiopharmaceutical agent (except when the radiopharmaceutical agent is used for 
testing or diagnostic purposes) 56 or fewer days before enrollment.  


 
 
 
 
14 
 
22. Has undergone gamma knife or CyberKnife treatment 14 or fewer days before enrollment.  
23. Has a systemic infection that requires treatment.  
24. Has tested positive for HIV-1 antibody, HIV-2 antibody, HTLV-1 antibody, HBs antigen, or 
HCV antibody.  
25. Has tested positive for HBs antibody or HBc antibody and has a result of at least detectable in 
HBV-DNA assay despite testing negative for HBs antigen. 
26. Is pregnant, nursing, or possibly pregnant.  
27. Has received another investigational product 28 or fewer days before enrollment.  
28. Has previously received ONO-4538 (MDX-1106 or BMS-936558), an anti-CTLA-4 antibody, or 
other antibody therapy or drug therapy intended to control T-cells.  
29. Is found incapable of giving consent due to dementia or another such condition.  
30. Patients otherwise found by the principal or sub investigator to be ineligible. 
 
3.3 
Study Schedule and Observations 
The study consists of a screening phase, treatment phase, and follow-up phase (see Figure 3). 
 
 
Figure 3 Summary of study design 
 
3.3.1 
Screening Phase  
Patients who satisfy all of the subject inclusion criteria and none of the subject exclusion criteria 
and who are found eligible by the principal or sub investigator can be enrolled and then moved to the 
treatment phase. 


 
 
 
 
15 
 
 
3.3.2 
Treatment Phase  
ONO-4538 will be administered once. Subjects who will meet any of the Criteria for Entering the 
Follow-Up phase will move to the Follow-Up phase. The subjects who complete the treatment phase 
in this study and not meet all of the Criteria for Entering the Follow-Up phase, and will satisfy all 
inclusion criteria and not meet all of the exclusion criteria in the ONO-4538-14 study may move to the 
ONO-4538-14 study, otherwise the subjects will move to the Follow-Up phase. 
 
3.3.3 
Follow-up Phase 
Those subjects receiving the investigational product who satisfy any of the Criteria for Entering the 
Follow-Up phase will proceed to the Follow-Up phase. 
 


 
 
 
16 
Table 3 Study schedule 
Follow-Up phase
2
3
4
8
15
22
After the start of the
administration
1 hr
2 hr
8 hr
-7 to -1
±2
+3
±7
○1
○
○2
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○6
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
○
Blood cytokines
○
○
HLA test
micro RNA exp.
○
○
Tumor tissue
●8
○2
●
28 days after the
discontinuation or the Day
22 only if the subjects will
not join the ONO-4538-14.
○
○
●
●
At
discontinuation
○4
○
○4
○4
○4
○4
○
Category
Screening
Phase
Study day
1
Before
administration
After the end of the
administration
Treatment Phase
Demographics
Allowable range (days)
-
±3
Written informed consent
Inclusion/exclusion criteria
Virus tests
ONO-4538 administration
○
Pregnancy test3
Vital signs/weight
○
○4
○4
/percutaneous oxygen saturation
Performance Status
Chest X-ray5
12-lead ECG
○4
○4
○4
Exploratory
biomarker
examination
○
○
○
Hematology tests/urinalysis
○
/blood biochemistry tests
Immunology/hormone tests
Serum drug concentration7
Anti-ONO-4538 antibody
○
○
Diagnostic imaging (e.g., CT, MRI)9
Tumor marker10
Concomitant drugs/adverse events
○:essential, ●: optional


 
 
 
 
17 
 
1. Begin administering the investigational product within 30 days of informed consent. 
2. The data from virus tests performed within 1 year of enrollment, diagnostic imaging (e.g., CT, 
MRI) performed within 14 days of enrollment will be included. 
3. Women of childbearing potential will undergo a serum pregnancy test in the screening phase 
and subsequently undergo urine pregnancy testing.  
4. Other than weight. 
5. Also perform at unscheduled visits as necessary if, during the study (from the time of informed 
consent to the end of the subjects’ schedule), signs, subjective and objective symptoms, or test 
findings suggest respiratory disease.  
6. SP-D and KL-6 will be measured in the screening phase and, as necessary, in the treatment 
phase. 
7. Collect blood sample at 24, 48 and 72 hours after the completion of the administration on 2nd, 
3rd and 4th day, respectively.  
8. No allowance range will be applied. 
9. Check for brain metastases with head CT/MRI. Check for bone metastases with X-ray imaging, 
FDG-PET, or bone scintigraphy as required by the clinical symptoms. 
10. Perform tumor marker assessment according to the cancer type of patient when required at 
Investigator’s discretion. 


 
 
 
 
18 
 
3.4 
Dose and Administration, and Duration of Treatment  
Patients will be assigned any of the following groups in order of increasing dose and ONO-4538 is 
administered at a dose level of 1, 3 or 10 mg/kg (See Table 5) 
 
Table 5. ONO-4538 Dose 
Group 
Treatment phase 
Subjects number 
Dose (mg/kg) 
A 
1 
6 
B 
3 
6 
C 
10 
6 
 
ONO-4538 will be administered once in the treatment phase and each subject will be observed for 3 
weeks. The appropriate dose of ONO-4538 will be diluted with physiological saline to a total amount 
of approximately not less than 60 mL before use (so that concentration of diluted solution of ONO-
4538 is no less than 0.35 mg/mL). The entire dose of ONO-4538 will be administered as an 
intravenous infusion over approximately 60 minutes through a 0.20 or 0.22 μm in-line filter. The 
lower limit of the infusion time is 54 minutes. The target upper limit is 90 minutes. At the end of the 
infusion, the line will be flushed with a sufficient quantity of physiological saline. Regarding the 
calculation of the dosage amount, the dose will be rounded off to the nearest tenth. 
 
3.5 
Prior and Concomitant Therapies  
3.5.1 
Therapies Prohibited During the Study  
The therapies listed below are prohibited during the study (from the time of informed consent to the 
end of the subjects’ schedule).  
1. Immunosuppressants and corticosteroids *1 
2. Anti-cancer products (e.g., chemotherapy, molecular targeted therapy, immunotherapy*2) 
3. Surgical treatment for a malignant tumor 
4. Radiotherapy 
5. Radiopharmaceuticals*3 and anti-androgen receptor therapy 
6. Bisphosphonate products and anti-RANKL antibodies *4 
7. Transplant therapy 
8. Any other investigational product  
 


 
 
 
 
19 
 
*1 Subjects are permitted to use a local corticosteroid such as topical, intra-articular, intranasal, 
ocular, inhalational administration, or otherwise temporal systemic corticosteroid for the 
treatment or prevention of a contrast media allergy or an adverse event.  
*2 This includes local therapies.  
*3 The use of a radiopharmaceutical for a testing or diagnostic purpose is permitted.  
*4 Bisphosphonate products and anti-RANKL antibodies may be used only when the dosage 
regimen used before study enrollment is maintained. 
 
3.6 
Criteria for Entering the Follow-Up phase 
Subjects satisfying any of the following criteria in the treatment phase will proceed to the follow-up 
phase. Only when the subjects do not satisfy all of the following criteria in the treatment phase, the 
subjects may move to the ONO-4538-14 study. 
1. The development of PD is identified by the principal or sub investigator according to the 
RECIST guideline (version 1.1) only in case in which the unplanned tumor assessment with 
diagnostic imaging is performed in the treatment phase.  
2. It is determined that continuing the treatment is not appropriate because the worsening of 
clinical symptoms attributed to disease progression occurs.  
3. The subject develops Grade 2 or higher interstitial lung disease, regardless of the causal 
relationship to the investigational product.  
4. Grade 2 or greater eye pain, or visual acuity reduced occurs whose causal relationship with the 
investigational product cannot be ruled out and does not improve to Grade 1 severity with local 
treatment.  
5. Grade 3 or greater bronchospasm, hypersensitivity reaction, infusion reaction (e.g., pyrexia, 
chills, nausea, pain, headache, cough, pruritus, and rash) or uveitis occurs whose causal 
relationship with the investigational product cannot be ruled out.  
6. The investigator or sub-investigator otherwise determines that continuing to administer the 
investigational product is inappropriate. 
 
3.7 
Sample size determination 
3.7.1 
Planned Number of Subjects  
Total 18 subjects (6 subjects in each group) 
 
 


 
 
 
 
20 
 
Rationale 
ONO-4538 is a fully human IgG4 monoclonal antibody and it is reported that there is no great 
distinction between Japanese and non-Japanese regarding the pharmacokinetics of monoclonal 
antibody. Therefore the sample size which the pharmacokinetics can be evaluated is set at 6 subjects 
in each group in this study. 


 
 
 
 
21 
 
4 
ANALYSIS SETS 
The “Safety Analysis Set (SAF)” will be used in the safety endpoint evaluation. 
 
4.1 
Definitions of Groups  
These sets will be defined as a group of subjects who have provided informed consent. Definitions 
of the individual groups are shown below.  
1) Enrolled Set (ENR) 
This set will be defined as group of subjects who have been enrolled. 
2) SAF 
This set will be defined as group of subjects who included in ENR and have received at least one 
dose of the study drug. 
 
4.2 
Criteria for Subject Handling  
Details of subject handling are shown below. 
1) Subject without Administration 
Subject without Administration will be defined as those who have never administered the 
investigational product. 
How to handle subjects with other unexpected problems in the analyses will be decided by the 
sponsor before data lock through discussions about the details with the medical expert. 
 
4.3 
Criteria for Handling Evaluation Time Points  
If the actual date of examination is not the protocol-specified date of examination, the examination 
data will be accepted, only when they are measured within the following criteria. If multiple data are 
present within the time window of a given time point, data which are obtained at a time point nearest 
the specified timing of examination will be preferred. If multiple safety data are obtained before and 
after the specified date and the lengths of time from the specified date and time are identical, those 
obtained after the specified date and time will be preferred.  
 
 
 
 
 
 


 
 
 
 
22 
 
1. Treatment Period  
Item 
Treatment period 
Trial day 
1 
2,3,4 
8 
15 
22 
Before 
administrationa) 
After the start of 
the administration 
After the end of the 
administration 
1 hr 
2 hr 
8 hr 
Time window 
(days) 
1 
±10 min 
±15 min ±30 min 
1 
-2 - +2 -3 - +3 -3 - +3 
a) Performance Status and laboratory test results which have been obtained within seven days before 
enrollment will be accepted. 
 
2. Post-treatment Follow-up Period (subjects who have terminated the treatment period) 
Item 
At Discontinuation 
Follow-up during 28 days after the 
discontinuation or 22 days only  
if the subjects will not join ONO-4538-14 
Trial day 
Time window 
(days) 
+3 
-7 - +7 
 


 
 
 
 
23 
 
5 
DOCUMENTATION OF STATISTICAL METHOD 
 
5.1 
Safety Endpoints 
1. Adverse events 
2. Laboratory tests: 
Hematology: RBC, MCV, MCH, MCHC, hemoglobin, hematocrit, WBC, differential WBC 
(neutrophils, lymphocytes, eosinophils, basophils, and monocytes) and platelet count 
Blood biochemistry: Albumin, ALP, AST (GOT), ALT (GPT), total bilirubin, direct bilirubin, γ-
GTP, total protein, creatinine, blood glucose, LDH, BUN, uric acid, CK (CPK), P, Ca, Na, K, and 
Cl 
Qualitative urinalysis: Specific gravity, protein, glucose, occult blood, and sediment (WBC and 
RBC) 
Immunology: Rheumatoid factor (RA), C-reactive protein (CRP), antinuclear antibody (ANA), SP-
D, KL-6 
Hormone tests: Thyroid-stimulating hormone (TSH), free triiodothyronine (free T3), and free 
thyroxine (free T4) 
3. Vital signs (systolic blood pressure/diastolic blood pressure, pulse rate, body temperature), body 
weight, percutaneous oxygen saturation (SpO2) 
4. 12-lead ECG 
5. Chest X-ray 
6. Performance Status (ECOG) 
 


 
 
 
 
24 
 
6 
DISPOSITION AND PROTOCOL DEVIATIONS 
 
6.1 
Assessment of Reliability of Clinical Trial  
6.1.1 
Analysis Set  
Analysis will be performed in SAF. With regard to the analysis item (1) in 6.1.2 Analysis Items and 
Data Handling, the ENR will be the analysis set. 
 
6.1.2 
Analysis Items and Data Handling  
1) Analysis Items 
(1) Reason for exclusion from the analysis set 
(2) Reason for termination of the treatment period 
(3) Participants in the clinical trial per institution 
2) Data Handling 
There will be no special handling. 
 
6.1.3 
Analysis Methods  
The analysis results will be summarized by dose level groups separately and totality. 
1) Classification of subjects will be indicated according to 4.1 Definitions of Groups. 
2) Frequency of subjects who have terminated the treatment period and frequency by reason for 
termination will be summarized.  
3) Frequency of participants in the clinical trial per institution will be summarized. 
  
 
  
  
 


 
 
 
 
25 
 
7 
Study Drug Exposure and Compliance 
 
7.1.1 
Analysis Set 
Analysis will be performed in SAF.  
 
7.1.2 
Analysis Items and Data Handling  
1) Analysis Items 
(1) Actual dose (mg/kg) 
2) Data Handling 
(1) The actual dose (mg/kg) will be calculated using the following formula. 
 Actual dose (mg/kg) = (actual dose [mg]) / (body weight immediately before dosing [kg]) 
 
7.1.3 
Analysis Methods 
The analysis results will be summarized by dose level groups separately and totality. 
1) Summary statistics of the actual dose will be calculated. 
 


 
 
 
 
26 
 
8 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS  
 
8.1 
Analysis Set  
Analysis will be performed in SAF. 
 
8.2 
Analysis Items and Data Handling  
1) Background Factors 
(1) Demographic Variables:  
Sex, age, height, weight, and body mass index (BMI). 
(2) Patient Characteristics: 
Time from diagnosis date of primary cancer to first dose date of the investigational product, 
Performance Status (ECOG), the type of primary cancer, stage classification and TNM classification 
(baseline) if applicable, medical history, concurrent diseases, cancer treatment history (surgical history, 
radiotherapy history, medication history, others, number of treatment regimens), drinking history, 
smoking history 
 
2) Data Handling 
Data will be analyzed as observed without imputing missing data. 
Time from diagnosis date of primary cancer to first dose date of the investigational product will be 
calculated using the following formula. 
 
Time from diagnosis date of primary cancer to first dose date of the investigational product 
(days) = (the first dose date of investigational product) – (diagnosis date of primary disease) 
+ 1 
 
8.3 
Analysis Methods and Classification  
For the background factors shown in 1) under Section 8.2 Analysis Items and Data Handling, the 
summary statistics and frequency distribution of each category will be calculated.   
The ordinal scale classification and continuous quantity classification will be decided by clinical 
significance or dividing the sample size into three, four, or five nearly equal parts etc. 
The level of measurement will be as shown below. 
 
 
Item 
Classification 
Analysis method 


 
 
 
 
27 
 
Sex 
Male or female 
Proportion by category 
Age 
<65，65 - <75, ≥75 
Summary statistics and 
proportion by category 
Height 
- 
Summary statistics 
Weight 
- 
Summary statistics 
BMI 
- 
Summary statistics 
Time from diagnosis date of primary 
cancer to first dose date of the 
investigational product 
- 
Summary statistics 
Primary cancer 
< According as collected 
data > 
Proportion by category 
Performance Status (ECOG) 
0, 1 
Proportion by category 
Smoking history 
Non-Smoker, Smoker or 
Ex-Smoker 
Proportion by category 
Drinking history 
Non-Drinker, Drinker or 
Ex-Drinker  
Proportion by category 
TNM classification (T) 
TX, T0, Tis, T1, T1a, T1b, 
T2, T2a, T2b, T3, T3a, T3b, 
T4, T4a, T4b 
Proportion by category 
TNM classification (N) 
NX, N0, N1, N1a, N1b, N2, 
N2a, N2b, N2c, N3 
Proportion by category 
TNM classification (M) 
MX, M0, M1, M1a, M1b, 
M1c 
Proportion by category 
Stage 
0, I, IIa, IIb, II, IIIa, IIIb, 
IIIc, III, IVa, IVb, IV, 
Unknown or Other 
Proportion by category 
Past Medical History 
Yes, No 
Proportion by category 
Concurrent diseases 
Yes, No 
Proportion by category 
Cancer treatment History (Surgery) 
Yes, No 
Proportion by category 
Cancer treatment History (Radiotherapy) Yes, No 
Proportion by category 
Cancer treatment History (Medication) 
Yes, No 
Proportion by category 
Cancer treatment History (Others) 
Yes, No 
Proportion by category 
Cancer treatment History (Number of 
treatment regimens) 
1, 2, 3, 4, 5, 6 
Proportion by category 
Proportion by category: The frequency by category and the proportion will be calculated. 
Summary statistics: Summary statistics will be calculated. 
 


 
 
 
 
28 
 
The analysis results will be summarized by dose level groups separately and totality. 


 
 
 
 
29 
 
9 
 SAFETY EVALUATION 
 
9.1 
Adverse Events 
9.1.1 
Analysis Set 
Analysis will be performed in SAF.  
 
9.1.2 
Analysis Items and Data Handling  
1) Analysis Items 
(1) Overall adverse events, adverse drug reactions and number of deaths. 
(2) Classification of adverse events  
2) Data Handling 
An adverse event is any unfavorable or unintended sign (including an abnormal laboratory finding), 
symptom or disease during a clinical trial, whether or not related to the investigational product. Of 
note, tabulation will include adverse events whose symptoms have occurred/worsened during the 
period from the first dose of the study drug until 28 days after the discontinuation or Day 22 only if 
subjects will not join the ONO-4538-14 study (or until the start of subsequent anti-cancer therapy, 
whichever comes first). In addition, all adverse events that occur during the treatment period or the 
post-treatment follow-up period will be listed and reported. 
All adverse events reported in this clinical study will be coded by SOC (System Organ Class) and 
PT (Preferred Term) using MedDRA (Current version). Treatment-emergent adverse events are those 
events that occur or worsen on or after the first dose of study treatment up until end of study treatment. 
For the analysis of adverse events, only treatment-emergent adverse events (TEAEs) will be 
included in the summary tables. 
In case the same adverse events in terms of SOC and PT occurs to one subject more than once, it 
will be considered as a single event, and the highest severity and relationship status among all events 
will be taken into account.  
Severity of adverse events will be classified using NCI-CTCAE, and where NCI-CTCAE is 
inapplicable, it will be classified as grade 1 (‘Mild’), grade 2 (‘Moderate’), grade 3 (‘Severe’), grade 4 
(‘Life-threatening or disabling’) or grade 5 (‘Death’) based on the maximum intensity. With respect to 
the relationship to study drug, ‘Related’ will be regarded as related, and ‘Not related’ will be regarded 
as unrelated. 
 
(1) Number of deaths 


 
 
 
 
30 
 
The number of deaths will be defined as the total number of subjects who have died during the 
period from the first dose of the study drug until 28 days after the discontinuation or 22 days 
only if subjects will not join the 4538-14 study (or until the start of subsequent anti-cancer 
therapy, whichever comes first). 
Select adverse events will be defined as adverse events to be coded as PTs in any of the 
categories specified in Addendum 1 List of Select Adverse Events (i.e., Endocrine Adverse 
Events, Hypersensitivity/Infusion Reactions, Gastrointestinal Adverse Events, Hepatic Adverse 
Events, Pulmonary Adverse Events, Renal Adverse Events and Skin Adverse Events). 
 
9.1.3 
Analysis Methods  
The analysis results will be summarized by dose level groups separately and totality. 
1) Overall Adverse Events, Adverse Drug Reactions and Number of Deaths 
(1) The number of subjects (incidence rate) will be provided for all adverse events and adverse drug 
reactions). The data will be displayed as “subject number (incidence of subjects (%))”. 
(2) The numbers of deaths, subjects with Grade 3 or higher adverse events and adverse drug 
reactions, and serious adverse events and adverse drug reactions, and discontinuations due to 
adverse events and adverse drug reactions, and adverse events and adverse drug reactions led to 
death will be summarized. 
 
2) Classification of Adverse Events  
(1) Adverse events will be summarized by SOC and PT. The data will be displayed as “subject 
number (incidence of subjects (%))”.  
(2) Incidences of adverse events and adverse drug reactions by SOC and PT will be summarized 
according to Grade. In addition, incidences of Grade 3 or higher adverse events and adverse 
drug reactions will be summarized by SOC and PT. 
(3) Incidences of adverse events and adverse drug reactions led to death will be summarized by 
SOC and PT. 
(4) Incidences of adverse events and adverse drug reactions leading to discontinuation of the study 
treatment will be summarized by SOC and PT. 
(5) Incidences of serious adverse events and adverse drug reactions will be summarized by SOC 
and PT. 


 
 
 
 
31 
 
(6) Incidences of select adverse events and adverse drug reactions will be summarized by categories 
and PT. In addition, incidences of select, Grade 3 or higher adverse events and adverse drug 
reactions will be summarized by categories and PT. 
 
9.2 
Clinical Laboratory Evaluation 
9.2.1 
Analysis Set 
Analysis will be performed in SAF.  
 
9.2.2 
Analysis Items and Data Handling  
1) Analysis Items 
(1) Hematology 
Red blood cell count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), 
mean corpuscular hemoglobin concentration (MCHC), hemoglobin, hematocrit, white blood cell count, 
differential white blood cell count (neutrophils, lymphocytes, eosinophils, basophils, and monocytes), 
and platelet count. 
(2) Blood biochemistry 
Albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST) (glutamic oxaloacetic 
transaminase [GOT]), alanine aminotransferase (ALT) (glutamic pyruvic transaminase [GPT]), total 
bilirubin, direct bilirubin, gamma-glutamyl transpeptidase (γ-GTP), total protein, creatinine, blood 
glucose, lactate dehydrogenase (LDH), blood urea nitrogen (BUN), uric acid, creatine kinase (CK) 
(creatine phosphokinase [CPK]), phosphorus (P), calcium (Ca), sodium (Na), potassium (K), and 
chloride (Cl). 
(3) Urinalysis (qualitative)   
Specific gravity, protein, glucose, occult blood, and sediment (white blood cells and red blood cells). 
 
2) Data Handling 
Data will be analyzed as observed without imputing missing data. 
Any laboratory values that fall below the detection or quantification limit will be imputed to be the 
detection or quantification limit.  
 
9.2.3 
Analysis Methods  
The analysis results will be summarized by dose level groups separately and totality. 


 
 
 
 
32 
 
1) For laboratory values as continuous quantities, summary statistics (no. of subjects, mean, standard 
deviation, median, minimum, and maximum) will be provided for each laboratory parameter by the 
time of measurement, and frequency distribution will be created for laboratory values on ordinal 
scale parameters. 
 
9.3 
Immunologic Test 
9.3.1 
Analysis Set 
Analysis will be performed in SAF.  
 
9.3.2 
Analysis Items and Data Handling  
1)  Analysis Items 
Rheumatoid factor (RA), C-reactive protein (CRP), antinuclear antibody (ANA), SP-D, and KL-6. 
2)  Data Handling 
Data will be analyzed as observed without imputing missing data.  
Any immunologic test values that fall below the detection or quantification limit will be imputed to 
be the detection or quantification limit. 
 
9.3.3 
Analysis Methods  
The analysis results will be summarized by dose level groups separately and totality. 
1) Summary statistics (no. of subjects, mean, standard deviation, median, minimum, and maximum) 
will be provided for immunologic test values as continuous quantities, while frequency distribution 
will be created for those on an ordinal scale. 
 
9.4 
Hormonal Test 
9.4.1 
Analysis Set 
Analysis will be performed in SAF.  
 
9.4.2 
Analysis Items and Data Handling  
1)  Analysis Items 
Thyroid-stimulating hormone (TSH), free triiodothyronine (free T3), and free thyroxine (free T4). 
2)  Data Handling 
Data will be analyzed as observed without imputing missing data.  


 
 
 
 
33 
 
Any hormonal test values that fall below the detection or quantification limit will be imputed to be 
the detection or quantification limit. 
 
9.4.3 
Analysis Methods  
The analysis results will be summarized by dose level groups separately and totality. 
1) Summary statistics (no. of subjects, mean, standard deviation, median, minimum, and maximum) 
will be provided for each Hormonal test parameter by the time of measurement. 
 
9.5 
Vital Signs  
9.5.1 
Analysis Set 
Analysis will be performed in SAF.  
 
9.5.2 
Analysis Items and Data Handling  
1)  Analysis Items 
Systolic blood pressure/diastolic blood pressure, pulse rate, temperature, weight, and percutaneous 
oxygen saturation as measured using pulse oximetry (SpO2).  
2)  Data Handling 
Data will be analyzed as observed without imputing missing data. 
Any vital sign parameter values that fall below the detection or quantification limit will be imputed 
to be the detection or quantification limit. 
 
9.5.3 
Analysis Methods  
The analysis results will be summarized by dose level groups separately and totality. 
Summary statistics (no. of subjects, mean, standard deviation, median, minimum, and maximum) 
will be provided for each vital sign parameter by the time of measurement. 
 
9.6 
12-lead ECG 
9.6.1 
Analysis Set 
Analysis will be performed in SAF.  
 
9.6.2 
Analysis Items and Data Handling  
1)  Analysis Items 
Heart rate, RR interval, QT interval, QTcF, PR interval, QRS complex. 


 
 
 
 
34 
 
2)  Data Handling 
12-lead ECG data will be analyzed as observed without imputing missing data. 
Any 12-lead ECG parameter values that fall below the detection or quantification limit will be 
imputed to be the detection or quantification limit. 
 
QTcF will be calculated using the following compensation formula. 
QTcF (ms) = QT interval / (RR interval)1/3. 
 
9.6.3 
Analysis Methods  
The analysis results will be summarized by dose level groups separately and totality. 
1)  For 12-lead ECG parameters (observed values of RR interval, QT interval, Fridericia's corrected 
QT interval [QTcF], QRS complex, and PR interval, and their changes [ΔQTcF, ΔQRS, and 
ΔPR]), observed value (HR) and change (ΔHR) of heart rate, summary statistics and frequency 
distribution for each category will be summarized at each time point. 
2)  For maximum QTcF, maximum ΔQTcF, maximum QRS, maximum PR, and maximum heart rate 
of subjects, frequency distribution for each category will be calculated. 
 
 
Item 
Classification 
RR (ms) (observed value) 
≤600, >600–1200, >1200 
P-R (ms) (observed value) 
≤120, >120–200, >200 
QRS (ms) (observed value) 
≤60, >60–109, >109 
Heart rate (observed value) 
≤50, >50–100, >100 
QT interval, ΔQTcF (ms) 
(observed value) 
≤450, >450–480  
>480–500, >500 
ΔQTcF (ms) 
(change) 
≤30, >30–60, >60 
  


 
 
 
 
35 
 
10 
GENERAL PRESENTATION OF SUMMARIES AND ANALYSES 
 
10.1 
Summary Statistics 
As summary statistics, mean, standard deviation, median, maximum, and minimum will be 
calculated unless otherwise noted. 
 
10.2 
Significance Level to Be Used  
No significance level is defined because no tests will be performed. 
 
10.3 
Decimals 
When displaying the individual data, the number of significant figures will be as shown below. For 
the mean, standard deviation, and median, the number of significant figures will be the number of 
significant figures for the individual data + 1. For example, if the number of significant decimal places 
for individual items of data is 1, that for the mean, standard deviation, and median will be 2. 
 
∙ Background factors and efficacy endpoint 
Integer value 
(No decimal places) 
One decimal place 
Time from diagnosis date of primary cancer to first dose date 
of the investigational product (days) 
Age (years) 
Height (cm) 
Weight (kg） 
BMI (kg/m2) 
 


 
 
 
 
36 
 
∙ Laboratory values 
Integer value 
(Figures after the decimal point will not be 
displayed.) 
One decimal place 
White blood cell count (/mm3) 
Red blood cell count (104/mm3) 
MCV (fL) 
AST (GOT) (U/L) 
ALT (GPT) (U/L) 
ALP (U/L) 
γ-GTP (U/L) 
LDH (U/L) 
CK (CPK) (U/L) 
Blood glucose (mg/dL) 
BUN (mg/dL) 
Na (mEq/L) 
Cl (mEq/L) 
Neutrophil (/mm3) 
Lymphocyte (/mm3) 
Eosinophil (/mm3) 
Basophil (/mm3) 
Monocyte (/mm3) 
RA (IU/mL) 
KL-6 (U/mL) 
MCH (pg) 
MCHC (%) 
Hemoglobin (g/dL) 
Hematocrit (%) 
Platelet count (104/mm3) 
Albumin (g/dL) 
Total protein (g/dL) 
Total bilirubin (mg/dL) 
Direct bilirubin (mg/dL) 
Uric acid (mg/dL) 
K (mEq/L) 
Ca (mEq/L) 
P (mEq/L) 
CRP (mg/dL) 
SP-D (ng/mL) 
Two decimal places 
Three decimal places 
Creatinine (mg/dL) 
Free triiodothyronine (pg/mL) 
Free thyroxine (ng/dL) 
Urine specific gravity 
Thyroid-stimulating hormone (μIU/mL) 
 
∙ Vital signs 
Integer value 
(No decimal places) 
One decimal place 
Systolic blood pressure (mmHg) 
Diastolic blood pressure (mmHg) 
Pulse rate (bpm) 
Respiratory rate (beats/min) 
Temperature (ºC) 
SpO2 (%) 
 


 
 
 
 
37 
 
 
∙ 12-lead ECG  
Integer value 
(No decimal places) 
Heart rate (beats/min) 
RR interval (ms) 
QT interval (ms) 
QTcF (ms) 
PR interval (ms) 
QRS complex (ms) 
 
10.4 
Site Pooling Method 
NA 
 
10.5 
Software for Statistical Analysis 
To display analysis, tabulation, and part of figures and tables, SAS Ver. 9.3 or higher, SAS institute, 
Cary, NC, USA will be used. 
For lists, figures, and tables, Microsoft Word will be used.  
 
11 
INTERIM ANALYSIS 
No interim analysis will be performed 
 


 
 
 
 
38 
 
12 
DATA REVIEW 
12.1 
Objectives 
After data collection, a preliminary inspection will be performed using unlocked data to examine 
whether to accept data and subjects, possible variable transformation, definitions of outliers, 
classification by stratification factors, and others and thereby to decide an appropriate analysis method 
compatible with data. 
 
12.2 
Analysis Set 
Analysis will be performed in subjects receiving the study drug. 
 
12.3 
Analysis Items and Data Handling 
1)  Analysis Items 
(1) Background Demographic factors 
(2) Summary of TEAE and Incidence of TEAEs by SOC and PT 
2)  Data Handling 
All items will be handled as defined previously in the analysis policy. 
 
12.4 
Analysis Methods 
The analysis results will be summarized by dose level groups separately and totality. 
1) Summary statistics and frequency distribution of background factors will be calculated, and 
classification will be decided. 
2) Incidences of adverse events will be calculated. In addition, incidences of adverse events by SOC 
and PT will be summarized according to Grade. 
 
The above analyses included a total of 18 subjects for whom data entry was completed as of Dec 17, 
2014. 


 
 
 
 
39 
 
13 
CHANGE FROM PROTOCOL 
1) 4.1 Definitions of Groups 1) Enrolled Set (ENR) 
(1) Content of change 
The Enrolled Set (ENR) was added. 
(2) Reason for change 
The Enrolled Set (ENR) will be evaluated for subject without administration as an analysis 
population. 
2) 8.2 Analysis Items and Data Handling 1) Background Factors 
(1) Content of change 
Tumor diameter of target lesion was deleted. 
(2) Reason for change 
As part of the efficacy analysis in the ONO-4538-14, analysis of the development of tumor 
diameter and evaluation of baseline characteristics will be performed using data of ONO-4538-14 
study incorporated with data of this study. 
 
14 
SAS PROCEDURE FOR ANALYSIS 
NA 
 
15 
REFERENCES 
NA 
 


 
 
 
 
40 
 
Addendum 1 List of Select Adverse Events 
Category 
Preferred Term 
Endocrine Adverse Events 
Adrenal insufficiency 
Adrenal suppression 
Blood corticotrophin decreased 
Blood corticotrophin increased 
Hypothalamic pituitary adrenal axis suppression 
Secondary adrenocortical insufficiency 
Diabetes mellitus 
Latent autoimmune diabetes in adults 
Hypophysitis 
Autoimmune thyroiditis 
Blood thyroid stimulating hormone decreased 
Blood thyroid stimulating hormone increased 
Hyperthyroidism 
Hypothyroidism 
Thyroid function test abnormal 
Thyroiditis 
Thyroiditis acute 
Thyroxine decreased 
Thyroxine free decreased 
Thyroxine free increased 
Thyroxine increased 
Tri-iodothyronine uptake increased 
Hypersensitivity/Infusion Reactions 
Anaphylactic reaction 
Anaphylactic shock 
Bronchospasm 
Hypersensitivity 
Infusion related reaction 
Gastrointestinal Adverse Events 
Colitis 
Colitis ulcerative 
Diarrhoea 
Enteritis 
Enterocolitis 
Frequent bowel movements 
Gastrointestinal perforation 


 
 
 
 
41 
 
Hepatic Adverse Events 
Acute hepatic failure 
Alanine aminotransferase increased 
Aspartate aminotransferase increased 
Bilirubin conjugated increased 
Blood bilirubin increased 
Drug-induced liver injury 
Gamma-glutamyltransferase increased 
Hepatic enzyme increased 
Hepatic failure 
Hepatitis 
Hepatitis acute 
Hyperbilirubinaemia 
Liver disorder 
Liver function test abnormal 
Liver injury 
Transaminases increased 
Pulmonary Adverse Events 
Acute respiratory distress syndrome 
Acute respiratory failure 
Interstitial lung disease 
Lung infiltration 
Pneumonitis 
Renal Adverse Events 
Blood creatinine increased 
Blood urea increased 
Creatinine renal clearance decreased 
Hypercreatininaemia 
Nephritis 
Nephritis allergic 
Nephritis autoimmune 
Renal failure 
Renal failure acute 
Renal tubular necrosis 
Tubulointerstitial nephritis 
Urine output decreased 
Skin Adverse Events 
Blister 
Dermatitis 
Dermatitis exfoliative 
Drug eruption 


 
 
 
 
42 
 
Eczema 
Erythema 
Erythema multiforme 
Exfoliative rash 
Palmar-plantar erythrodysaesthesia syndrome 
Photosensitivity reaction 
Pruritus 
Pruritus allergic 
Pruritus generalised 
Psoriasis 
Rash 
Rash erythematous 
Rash generalised 
Rash macular 
Rash maculo-papular 
Rash papular 
Rash pruritic 
Skin exfoliation 
Skin hypopigmentation 
Skin irritation 
Stevens-Johnson syndrome 
Toxic epidermal necrolysis 
Urticaria 
Vitiligo 
 
MedDRA version 17.1