Clinical trial NCT02175017
Conditions: Advanced Non-small Cell Lung Cancer (NSCLC)
Keywords: ONO-4538 Advanced non-small cell lung cancer (NSCLC) nivolumab
Sponsor: Ono Pharmaceutical Co. Ltd
Start date: 2014-06-01; Completion date: 2021-02-01
Enrollment: 104 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of the study is to investigate the efficacy and safety of ONO-4538 in subjects with stage IIIB/IV or recurrent non-small cell lung cancer unsuited to radical radiotherapy and resistant to a platinum-based chemotherapeutic regimen.

Detailed description:

Arms: arm 1: In each treatment cycle, patients received an intravenous infusion of nivolumab (ONO-4538) at a dose of 3 mg/kg every 2 weeks for 6 weeks. Changes in dose were not allowed. Radiological assessments (computed tomography/ magnetic resonance imaging) were conducted every 6 weeks. Patients entered subsequent treatment cycles unless they met discontinuation criteria, including disease progression, unacceptable adverse events, and consent withdrawal. Patients who were discontinued for any of these reasons entered the follow-up phase. arm 2: In each treatment cycle, patients received an intravenous infusion of nivolumab (ONO-4538) at a dose of 3 mg/kg every 2 weeks for 6 weeks. Changes in dose were not allowed. Radiological assessments (computed tomography/ magnetic resonance imaging) were conducted every 6 weeks. Patients entered subsequent treatment cycles unless they met discontinuation criteria, including disease progression, unacceptable adverse events, and consent withdrawal. Patients who were discontinued for any of these reasons entered the follow-up phase.
Interventions: intervention 1: ONO-4538 intervention 2: ONO-4538
Intervention descriptions: intervention 1: ONO-4538 Study in Patients With Squamous NSCLC intervention 2: ONO-4538 Study in Patients With Non-Squamous NSCLC

Protocol documents:
Prot_000.pdf: 
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Release date: November 2, 2020 
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ONO-4538 
 
 
Multicenter, open-label, uncontrolled, Phase II study in 
advanced non-small cell lung cancer 
 
Subtitle: A multicenter, open-label, uncontrolled Phase II study to evaluate safety and efficacy 
of ONO-4538 in stage IIIB/IV or recurrent non-small cell lung cancer patients who are unsuited 
to radical radiotherapy and resistant to a platinum-base chemotherapeutic regimen. 
 
Protocol 
 
 
 
 
 
 
 
 
 
Ono Pharmaceutical Co., Ltd. 
 
 
 
Protocol no. ONO-4538-09 
English Version 11.0 
Release date: November 2, 2020 
 
 


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Contact Information for Adverse Event Reports 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This protocol is to be disseminated to the principal investigator, subinvestigators, 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. 
 
 


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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.  
 
 
 


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Protocol Synopsis 
 
1. Study Objectives 
The objective of the study is to investigate the efficacy and safety of ONO-4538 in stage IIIB/IV or 
recurrent non-small cell lung cancer unsuited to radical radiotherapy and resistant to a platinum-based 
chemotherapeutic regimen in a multicenter, open-label, uncontrolled study.  
 
2. Study Design 
Multicenter, open label, uncontrolled study 
 
3. Disease Studied 
3.1 Disease Studied 
Stage IIIB/IV or recurrent non-small cell lung cancer unsuited to radical radiotherapy and resistant to 
a platinum-based chemotherapeutic regimen  
 
3.1.1 Subject Inclusion Criteria 
Patients satisfying all the following criteria will be included: 
1. 
Male or female.  
2. 
≥ 20 years of age (at time of enrollment).  
3. 
Histologically or cytologically confirmed non-small cell lung cancer.  
4. 
Diagnosis of NSCLC in stage IIIB/IV unsuited to radical radiotherapy according to UICC-TNM 
classification (7th edition) or recurrent NSCLC.  
5. 
Has at least one measurable lesion, as defined by the RECIST guideline (version 1.1) (Appendix 
1), in diagnostic imaging performed 14 or fewer days before enrollment. (Patients who have 
received radiotherapy for a measurable lesion must have confirmed progress in diagnostic imaging 
following radiotherapy.)  
6. 
Has a history of prior treatment with any of the following systemic anti-cancer products (e.g., 
chemotherapy, molecular targeted therapy, immunotherapy): 
1） History of prior platinum-based chemotherapy and up to 1 regimen of prior treatment for 
patients negative for or with unknown EGFR activity mutation or ALK gene translocation 
2） History of prior platinum-based chemotherapy and an EGFR tyrosine kinase inhibitor, and up 
to 2 regimens of prior treatment, for patients positive for EGFR activity mutation 


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3） History of prior platinum-based chemotherapy and an ALK inhibitor, and up to 2 regimens of 
prior treatment, for patients positive for ALK gene translocation 
7. 
ECOG Performance Status (Appendix 2) is 0 to 1.  
8. 
Life expectancy is ≥ 90 days.  
9. 
Women of childbearing potential (including women who are amenorrheic due to chemical 
menopause or for another medical reason) must agree to engage in contraception from the time of 
informed consent to at least 5 months after the final dose of the investigational product. Women 
must not be breastfeeding from the time of informed consent to at least 5 months after the final 
dose of the investigational product. 
10. Men must agree to use a contraceptive from the start of study treatment until at least 7 months 
following the last dose of investigational product. 
11. Percutaneous oxygen saturation by pulse oximetry performed 7 or fewer days before enrollment is 
≥ 94% in the absence of oxygen supplementation.  
12. Most recently determined laboratory values, determined 7 or fewer days before enrollment, satisfy 
the 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 
- 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 
 
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 safety evaluation of the 
investigational product. 
3. 
Active autoimmune disease or history of chronic or recurring autoimmune disease (Appendix 3).  


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4. 
Current or prior interstitial lung disease or pulmonary fibrosis diagnosed based on diagnostic 
imaging or clinical findings. (Radiation pneumonitis allows to be enrolled as long as not acute 
phase with fibrosis or without symptoms.) 
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. 
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. 
Pain associated with bone metastases and others not controllable 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. Uncontrollable diabetes. 
14. 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. 
15. Has received an anti-cancer product (e.g., chemotherapy, molecular targeted therapy, and 
immunotherapy) 28 or fewer days before enrollment. 
16. Has undergone surgery for pleural, pericardial, or similar adhesion 28 or fewer days before 
enrollment.  
17. Has undergone surgical treatment accompanying general anesthesia 28 or fewer days before 
enrollment.  


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18. Has undergone surgical treatment accompanying local or surface anesthesia 14 or fewer days 
before enrollment.  
19. Has received radiotherapy 28 or fewer days before enrollment or thoracic radiotherapy or a 
radiopharmaceutical agent (except when the radiopharmaceutical agent is used for testing or 
diagnostic purposes) 56 or fewer days before enrollment.  
20. Has undergone gamma knife or CyberKnife treatment 14 or fewer days before enrollment.  
21. Has a systemic infection that requires treatment.  
22. Has tested positive for HIV-1 antibody, HIV-2 antibody, HTLV-1 antibody, HBs antigen, or HCV 
antibody.  
23. 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. 
24. Is pregnant, nursing, or possibly pregnant.  
25. Has received another investigational product 28 or fewer days before enrollment.  
26. 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.  
27. Is found incapable of giving consent due to dementia or another such condition.  
28. Patients otherwise found by the principal or sub investigator to be ineligible. 
29. Patients who have received a live/attenuated vaccine 28 or fewer days before enrollment. 
 
4. Study Schedule and Observations 
The study consists of a screening phase, treatment phase, and follow-up phase (see Figure 4-1).  
 




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MRI) whenever possible until beginning subsequent treatment for non-small cell lung cancer or until 
developing PD or recurrence.  
Even after the conclusion of the tests performed on discontinuation, all treatment-related adverse 
events will be followed every 2 weeks whenever possible until resolution or improvement or when no 
further follow-up is necessary due to symptom stability. Laboratory tests or diagnostic imaging will be 
repeated and other measures taken as necessary to adequately ensure subject safety.  
 
4.4 Determination of Outcome  
Follow-up to determine survival status (and, if the subject has died, the date and cause of death) will 
be performed every 6 months or so beginning 6 months after the first day of treatment of the last subject 
enrolled in the study. Outcome information may be obtained by phone, letter, or another means. The 
use, start dates, and types of any subsequent treatments for NSCLC will also be investigated whenever 
possible.  
 






 
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Table 4-2 Study schedule (Cycles 2 and beyond) 
Category 
Treatment phase (Cycles 2 and beyond) 
Study day 
15 
15 
29 
 
435 
 
 
Before administration 
After administration  
 
Allowable range (days) 
1 
-3 to +7  
-6 to +7 
-6 to +7 
Visit 
V n-1 
V n-2 
V n-3 
V n-4 
Investigational product 
administration 1 
○ 
○ 
○ 
 
Performance Status 
○6, 7 
 
 
○ 
Vital signs/weight/percutaneous 
oxygen saturation 
○6, 7 
○8 
 
○7, 8 
○ 
Chest X-ray2 
 
 
 
○ 
12-lead ECG 
○6, 7, 9 
 
 
○9 
Hematology tests, blood 
biochemistry tests, urinalysis  
○6, 7 
 
 
○ 
Immunology/hormone tests 
 
 
 
○ 
Serum drug concentration 3 
○7, 10 
○11 
○11, 12 
 
 
Anti-ONO-4538 antibody 3 
○7, 10 
○11 
 
 
 
Tumor markers 4 
○ 
Diagnostic imaging (e.g., CT, 
MRI) 
 
 
 
○13 
Concomitant drugs/adverse events 
 
 
 


 
13 / 106 
 
 
1. 
Administer the investigational product after at least 10 days have passed since the most recent dose.  
2. 
Also perform at unscheduled times as necessary if, during the study (from the time of informed consent to the completion of the final tests (other than the 
determination of outcome) specified in the protocol), signs, subjective and objective symptoms, or test findings suggest respiratory disease.  
3. 
To be collected until the end of the 1-year period after the start of investigational drug administration (i.e., Cycle 9).  
4. 
Analyze tumor markers whenever possible in each subject with a tumor marker at a level exceeding the normal range. Perform tumor marker analysis when 
required.  
5. 
For subjects again proceeding to the treatment phase, administer the investigational product on Day 1 of the next cycle within the Day 43 allowable range (i.e., 
Days 37 to 50). Proceed to the follow-up phase (Table 4-3) on completing the treatment phase.  
6. 
Unless medically necessary, vital signs will be measured no sooner than 2 days, and other tests will be performed no sooner than 8 days after the previous 
measurement.  
7. 
Perform before administering the investigational product.  
8. 
Other than weight.  
9. 
Perform only in Cycle 4.  
10. Perform only in Cycles 2, 4, 5, 7, and 9.  
11. Perform only in Cycle 3.  
12. Collect sample immediately before the completion of investigational product administration.  
13.  Perform every cycle (every 6 weeks) between Cycle 2 and 29 and every 2 cycles (every 12 weeks) after Cycle 30. 






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5. Dose and Administration, and Duration of Treatment 
ONO-4538 is administered at a 3 mg/kg dose with a 2-week dosing interval. One cycle consists of 6 
weeks. ONO-4538 administration will continue until the development of PD as identified by the 
investigator or sub investigator according to the RECIST guideline (version 1.1). The appropriate dose 
of ONO-4538 will be diluted with physiological saline or dextrose 5% in water to a total amount of 
approximately not less than 60 mL before use (so that the solution drug concentration 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 ~ 1.20 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 or dextrose 5% in water. The ONO-4538 dose will not 
be reduced. The administration of ONO-4538 infusion must be completed within 24 hours of preparation. 
If not used immediately, the infusion solution may be stored under refrigeration condition (2°-8°C, 36°-
46°F) for up to 24 hours , and a maximum of 8 hours of the total 24 hours can be at room temperature 
(20°-25°C, 68°-77°F) and room light. The maximum 8-hour period under room temperature and room 
light conditions includes the product administration period. 
The dose will be changed if the body weight of the subject changes by at least 10% relative to the 
weight at enrollment. Each subsequent 10% or greater change in body weight is to be handled in a 
similar manner.  
 
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 
completion of the final tests (other than the determination of outcome) specified in the protocol).  
1. 
Immunosuppressants and corticosteroids 
2. 
Anti-cancer agents (e.g., chemotherapy, molecular targeted therapy, immunotherapy) 
3. 
Surgical treatment for a malignant tumor 
4. 
Radiotherapy 
5. 
Radiopharmaceuticals 
6. 
Bisphosphonate products and anti-RANKL antibodies 
7. 
Transplant therapy 
8. 
Any live/attenuated vaccine (eg, varicella, zoster, yellow fever, rotavirus, oral polio and measles, 
mumps, rubella [MMR]) 
9. 
Any other investigational product  


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6.2 Prophylactic Drug Use 
Prophylactic pretreatment with acetaminophen and diphenhydramine before ONO-4538 
administration is recommended for subjects who develop an infusion related reaction to a previous dose 
of ONO-4538.  
 
 
7. Investigational Product Discontinuation Criteria  
Subjects satisfying any of the following criteria in the treatment phase will be discontinued the 
investigational product and proceed to the follow-up phase.  
1. 
The development of PD is identified by the principal or sub investigator according to the RECIST 
guideline (version 1.1).  
2. 
A 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, rash) or uveitis occurs whose causal relationship with the 
investigational product cannot be ruled out.  
6. 
An adverse event or other events delay the administration of the investigational product by more 
than 6 weeks.  
7. 
The investigator or sub-investigator otherwise determines that continuing to administer the 
investigational product is inappropriate due to an efficacy- or safety-related reason.  
 
Even when Criterion 1 is applicable, investigational product treatment may be continued if it is 
determined through consultation with the sponsor that no worsening of clinical symptoms attributable 
to disease progression occurs, continued treatment is expected to provide a clinical benefit, and the 
investigational product can continue to be safely administered. If the investigational product is to be 
continued, the subject should first be consulted about his or her willingness to continue receiving 
treatment, and this process should be documented in the medical records. Laboratory tests will be 
frequently repeated and other measures taken to adequately ensure subject safety. Any subject who is 


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found to have again developed PD according to the RECIST guideline (version 1.1)based on a point 
where a decision is made to continue investigational product treatment must cease using the 
investigational product regardless of whether clinical symptoms have worsened or not.  
 
8. Endpoints 
8.1 Efficacy  
1. 
Primary endpoint: Response rate (centrally assessed) 
2. 
Secondary endpoints: Response rate (study site assessment by investigator), overall survival, 
progression free survival, time to progression, duration of response, time to response, best overall 
response, and percent change in tumor diameter 
 
8.2 Safety 
1. 
Adverse events  
2. 
Laboratory tests (hematology, blood biochemistry, qualitative urinalysis, immunology tests, 
hormone tests) 
3. 
Vital signs (systolic blood pressure/diastolic blood pressure, pulse, body temperature), body weight, 
percutaneous oxygen saturation (SpO2)  
4. 
12-lead ECG 
5. 
Chest X-ray 
6. 
Performance Status (ECOG) 
 
8.3 Pharmacokinetics  
1. 
Serum ONO-4538 concentrations 
 
8.4 Anti-drug Antibodies 
1. 
Anti-ONO-4538 antibody  
 
 
 
 
 
 
 
 
 
 
 


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9. Planned Number of Subjects 
Total of 93 subjects (41 subjects with squamous NSCLC and 52 subjects with non-squamous NSCLC) 
10 Investigational Product Supply Restrictions 
Each subject to whom the investigational product discontinuation criteria and individual subject 
discontinuation criteria are not applicable is eligible to receive the investigational product from the 
sponsor. The sponsor will stop supplying the investigational product if:  
1. 
Ministry of Food and Drug Safety rejects the application for approval for the present indication.  
2. 
The study is cancelled due to safety concerns.  
3. 
The subject is able to receive the drugs through public or private health insurance.  
4. 
An alternative therapy becomes available.  
 
11. Planned Study Period 
 January 2014 to December 2021 
The data cut-off may be performed based on progress of the clinical studies.  

SAP_001.pdf: 
1 
Statistical Analysis Plan 
Protocol No.: ONO-4538-09 
Multicenter, open-label, uncontrolled, Phase II study 
in advanced non-small cell lung cancer 
Sponsor: Ono Pharmaceutical Co., Ltd. 
 
 
 
 
Protocol Version: ONO-4538-09-version 3.0, 20-Mar-2015 
SAP Version No & Date: SAP_ONO-4538-09_version 3.0, 29-Jul-2021 


 
 
 
 
2 
 
Signature Page 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
3 
 
History of Revision 
 
Study No 
ONO-4538-09 
Sponsor 
Ono Pharmaceutical Co., Ltd. 
 
 
 
 
 
 
 
 
 
 
 
Approval 
Date 
Amended 
Version 
Original 
Amendment 
Reason 
09 Apr 2015 
SAP_ONO-4538-
09_version 2.0, 
08 Apr 2015 
Section 1 
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. PD-1 ligand is 
also expressed in various 
human cancer tissues other than 
antigen presentation cells.  
Changed to: 
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. In Japan, it 
obtained manufacturing and 
marketing approval for 
indications of unresectable 
malignant melanoma. PD-1 (or 
CD279), a 55-kilodalton Type 1 
transmembrane protein, is a 
member of the CD28 family of T-
cell co-stimulatory receptors that 
include immunoglobulin super 
family members CD28, CTLA-4, 
ICOS, and BTLA. PD-1 is highly 
expressed on activated T-cells 
and B-cells. PD-1 expression 
can also be detected on memory 
T-cell subsets with variable 
levels of expression. Two 
ligands specific for PD-1 have 
been identified: PD-L1 (also 
known as B7-H1 or CD274) and 
PD-L2 (also known as B7-DC or 
CD273). PD-L1 and PD-L2 have 
been shown to down-regulate T-
cell activation upon binding to 
PD-1 in both murine and human 
systems. The product is made 
with recombinant technology 
using CHO cells. 
Protocol update 
Section 3.2.2 
6. Has a history of prior 
treatment with any of the 
following systemic anti-cancer 
products 
Changed to: 
6. Has a history of prior 
treatment with any of the 
following systemic anti-cancer 
agents 
Typo 
Section 3.2.2  12 
- AST (GOT) and ALT (GPT) ≤ 
3.0 times the upper limit of 
normal rage of each institute 
- Total bilirubin ≤ 2.0 times the 
upper limit of normal rage of 
Changed to: 
- 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 
Typo 


 
 
 
 
4 
 
each institute 
each institute 
Section 3.2.3 
Patients who meet any of the 
following criteria will be excluded 
Changed to: 
Patients satisfying any of the 
following criteria will be excluded 
Typo 
Section 3.3 
Clinical Trial Schedule and 
Observations 
This clinical trial consists of the 
screening period, treatment 
period, and follow-up period, as 
is outlined in Figure 3.1. 
 
Screening period 
Treatment period 
Post-treatment follow-up period 
 
Figure 3.1 Schematic of the 
clinical trial design 
Changed to: 
Study Schedule and 
Observations 
The study consists of the 
screening phase, treatment 
phase, and follow-up phase, as 
is outlined in Figure 3.1. 
 
 
 
Screening phase 
Treatment phase 
Follow-up phase 
 
Figure 3.1 Summary of study 
design 
Typo 
Section 3.4 
ONO-4538 is administered at a 
3 mg/kg dose with a 2-week 
dosing interval. One cycle 
consists of 6 weeks. ONO-4538 
administration will continue until 
the development of PD as 
identified by the investigator or 
sub investigator according to the 
RECIST guideline (version 1.1). 
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 the solution drug 
concentration 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 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. 
The ONO-4538 dose will not be 
reduced. 
Changed to: 
ONO-4538 is administered at a 
3 mg/kg dose with a 2-week 
dosing interval. One cycle 
consists of 6 weeks. ONO-4538 
administration will continue until 
the development of PD as 
identified by the investigator or 
sub investigator according to the 
RECIST guideline (version 1.1). 
The appropriate dose of ONO-
4538 will be diluted with 
physiological saline or dextrose 
5% in water to a total amount of 
approximately not less than 60 
mL before use (so that the 
solution drug concentration 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 ~ 1.20 
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 or dextrose 
5% in water. The ONO-4538 
dose will not be reduced. The 
administration of ONO-4538 
infusion must be completed 
within 24 hours of preparation. If 
not used immediately, the 
Protocol update 


 
 
 
 
5 
 
infusion solution may be stored 
under refrigeration condition (2°-
8°C, 36°-46°F) for up to 24 
hours , and a maximum of 4 
hours of the total 24 hours can 
be at room temperature (20°-
25°C, 68°-77°F) and room light. 
The maximum 4-hour period 
under room temperature and 
room light conditions includes 
the product administration 
period. 
Section 3.7.2 
The threshold response rate (the 
null hypothesis) was set at 8.8% 
because the response rate of 
docetaxel, which was selected 
as a comparator in non-Korean 
Phase III studies (CA209017, 
CA209057), was 8.8% in the 
phase III trial in patients with 
NSCLC 7). Under the 
assumption of the threshold 
response rate of 8.8% and the 
expected response rate of 
23.1% and 21.4% for patients 
with squamous and non-
squamous NSCLC respecrively, 
Changed to: 
The threshold response rate (the 
null hypothesis) was set at 8.8% 
because the response rate of 
docetaxel, which was selected 
as a comparator in non-Korean 
Phase III studies (CA209017, 
CA209057), was 8.8% in the 
phase III trial in patients with 
NSCLC. Under the assumption 
of the threshold response rate of 
8.8% and the expected 
response rate of 23.1% and 
21.4% for patients with 
squamous and non-squamous 
NSCLC respectively, 
Typo 
Section 4.1 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. 
Changed to: 
This set will be defined as group 
of subjects who are included in 
ENR and have received at least 
one dose of the study drug. 
Typo 
Section 4.3 
1. Treatment Period 
Cycle 1 
 
29  
Changed to: 
1. Treatment Period 
Cycle 1, Cycles 2 and beyond 
 
29c) 
Typo 
Section 6.1 
 
Added: 
With regard to the analysis item 
(1) in 6.2 Analysis Items and 
Data Handling, the ENR will be 
the analysis set. 
Add for clarifying 
the analysis set. 
Section 8.2 
“TNM classification (screening), 
metastasis lesions and stage 
(screening)” 
 
“NSCLC treatment history  
(surgical history, radiotherapy 
history, medication history, 
others)” 
Changed to: 
“TNM classification (baseline), 
metastasis lesions and stage 
(baseline)” 
 
“NSCLC treatment history  
(surgical history, radiotherapy 
history, medication history, 
others, number of treatment 
regimens )” 
Correct for 
ensuring 
consistency with 
protocol. 


 
 
 
 
6 
 
Section 8.3  1) 
Change of classification :  
“To be decided by data review” 
 
 
 
 
 
 
 
 
“IIIB, IV, Recurrent, Unknown, 
Other” 
 
“1, 2” 
 
 
Changed to: 
“Height : <160.0, 160.0-<170.0, 
≥170.0” 
“Weight: <55.0, 55.0-<65.0, 
≥65.0” 
“BMI: <18.5 ,18.5-<25.0 ,≥25.0” 
“Time from diagnosis date of 
primary disease to first dose 
date of the investigational 
product: <180, 181-<360, ≥361” 
 
“IIIB, IV, Recurrence, Unknown, 
Other” 
 
“Yes, No” 
 
Added: 
“Item : NSCLC treatment History 
(Number of treatment regimens), 
Classification: 1, 2, Analysis 
method: Proportion by category” 
Define 
classifications. 
Section 8.3  2) 
 
Added: 
“NSCLC treatment history 
(medication) will be summarized. 
Agents and medication will be 
reported using the generic 
name.” 
Add for 
evaluating the 
demographic in 
more detail. 
Section 9.2.4  2) 
“A Kaplan-Meier curve will be 
plotted for each analysis 
variable. The median and its 
95% confidence interval will be 
estimated by Kaplan-Meier 
method.” 
 
Changed to: 
“A Kaplan-Meier curve will be 
plotted for each analysis 
variable. The median and its 
95% confidence interval and 
overall survival rates at 6 
months and its 95% confidence 
interval will be estimated by 
Kaplan-Meier method.” 
 
Added: 
“6 months will be calculated 
assuming 30.4375 days for one 
month.” 
 
Add for 
evaluating the 
efficacy in more 
detail. 
Section 9.2.4  3) 
“Two Kaplan-Meier curve will be 
plotted based on the 
interpretation by the image 
central analysis laboratory and 
that by a investigator at the trial 
site. The median progression 
free survival, its 95% confidence 
interval and progression free 
survival rates at 3 and 6 months 
will be estimated by Kaplan-
Meier method.” 
Changed to: 
“Two Kaplan-Meier curves will 
be plotted based on the 
interpretation by the image 
central analysis laboratory and 
that by an investigator at the trial 
site. The median progression 
free survival, its 95% confidence 
interval and progression free 
survival rates at 3 and 6 months 
and its 95% confidence interval 
will be estimated by Kaplan-
Meier method. “ 
 
Add for 
evaluating the 
efficacy in more 
detail. 


 
 
 
 
7 
 
Added: 
“6 months will be calculated 
assuming 30.4375 days for one 
month.” 
 
Section 9.2.4  4) 
“The median and its 95% 
confidence interval will be 
estimated by Kaplan-Meier 
method.” 
Changed to: 
“The median and its 95% 
confidence interval and duration 
of response rates at 6 months 
and its 95% confidence interval 
will be estimated by Kaplan-
Meier method.” 
 
Added: 
“6 months will be calculated 
assuming 30.4375 days for one 
month.” 
Add for 
evaluating the 
efficacy in more 
detail. 
Section 9.2.4  7) 
 
Added: 
“In addition, a plot of individual 
subjects' percent change in 
tumor diameter of target lesion 
will be displayed at individual 
time point.” 
Add for 
evaluating the 
efficacy in more 
detail. 
Section 9.2.5  3) 
 
Added: 
“and totality” 
Add for 
clarification. 
Section 10 
Added: 
“Unless otherwise noted, safety 
data to be tabulated will be 
those observed during the 
period for 28 days after the final 
dose (or until the start of 
subsequent anti-cancer therapy 
for non-small-cell lung cancer 
after the final dose, whichever 
comes first).” 
Add for 
evaluating the 
safety properly. 
Section 10.1.2  2) 
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 
final dose (or until the start of 
subsequent anti-cancer therapy 
for non-small-cell lung cancer, 
whichever comes first after the 
final dose). 
Added: 
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 
final dose (or until the start of 
subsequent anti-cancer therapy 
for non-small-cell lung cancer 
after the final dose, whichever 
comes first after the final dose). 
Add for 
evaluating the 
safety properly. 
Section 10.1.2  2) 
 
Deleted: 
“For event counting in such 
cases, the same adverse events 
Typo 


 
 
 
 
8 
 
will be considered as different 
events.” 
Section 10.1.2  2) 
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. 
Changed to: 
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/incapacitating’) or 
grade 5 (‘Death related to 
adverse event’) based on the 
maximum intensity. 
Correct for 
ensuring 
consistency with 
protocol. 
Section 10.1.3  1) (1) 
 
Added: 
“and totality” 
Add for 
clarification. 
Section 10.1.3  2) (2) 
“Adverse events will be 
summarized by SOC, PT and 
CTCAE grade. The data will be 
displayed as “subject number 
(incidence of subjects (%))”.” 
Changed to: 
“Adverse events and adverse 
drug reactions will be 
summarized by SOC, PT and 
CTCAE grade (grade 1, 2, 3, 4, 
and 5). The data will be 
displayed as “subject number 
(incidence of subjects (%))”.” 
Add for 
evaluating the 
safety in more 
detail. 
Section 10.1.3  2) (3) 
“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.” 
Changed to: 
“Incidences of adverse events 
and adverse drug reactions by 
SOC and PT will be 
summarized. In addition, 
incidences of adverse events 
and adverse drug reactions will 
be summarized by SOC, PT and 
CTCAE grade (any grade, grade 
3 or 4, grade 5). And adverse 
events and adverse drug 
reactions with an incidence at or 
above a certain level will be 
summarized by SOC, PT and 
CTCAE grade (any grade, grade 
3 or 4, grade 5).” 
Add for 
evaluating the 
safety in more 
detail. 
Section 10.1.3  2) (5) 
“Incidences of adverse events 
and adverse drug reactions 
leading to discontinuation of the 
study treatment will be 
summarized by SOC and PT.” 
 
Changed to: 
“Incidences of adverse events 
and adverse drug reactions 
leading to discontinuation of the 
study treatment will be 
summarized by SOC, PT and 
CTCAE grade (any grade, grade 
3 or 4, grade 5).” 
Add for 
evaluating the 
safety in more 
detail. 
Section 10.1.3  2) (6) 
“Incidences of adverse events 
and adverse drug reactions 
leading to interruption of the 
investigational product will be 
summarized by SOC and PT.” 
 
Changed to: 
“Incidences of adverse events 
and adverse drug reactions 
leading to interruption of the 
investigational product will be 
summarized by SOC, PT and 
CTCAE grade (any grade, grade 
3 or 4, grade 5).” 
Add for 
evaluating the 
safety in more 
detail. 


 
 
 
 
9 
 
Section 10.1.3  2) (7) 
“Incidences of serious adverse 
events and adverse drug 
reactions will be summarized by 
SOC and PT.” 
 
Changed to: 
“Incidences of serious adverse 
events and adverse drug 
reactions will be summarized by 
SOC, PT and CTCAE grade 
(any grade, grade 3 or 4, grade 
5).” 
Add for 
evaluating the 
safety in more 
detail. 
Section 10.1.3  2) (8) 
“Incidences of select, Grade 3 or 
higher, adverse events and 
adverse drug reactions will be 
summarized by categories and 
PT.” 
 
Changed to: 
“Incidences of select adverse 
events and adverse drug 
reactions will be summarized by 
categories, PT and CTCAE 
grade (any grade, grade 3 or 4, 
grade 5).” 
Add for 
evaluating the 
safety in more 
detail. 
Section 10.1.3  2) 
Added: 
“(9) Incidences of select adverse 
events and adverse drug 
reactions leading to 
discontinuation will be 
summarized by categories, PT 
and CTCAE grade (any grade, 
grade 3 or 4, grade 5). 
(10) Incidences of serious select 
adverse events will be 
summarized by categories, PT 
and CTCAE grade (any grade, 
grade 3 or 4, grade 5).” 
Add for 
evaluating the 
safety in more 
detail. 
Section 10.1.4 
 
Added: 
“and totality” 
Add for 
clarification. 
Section 10.2.3 
 
Added: 
“and the change from baseline” 
Add for 
evaluating the 
safety in more 
detail. 
Section 10.3.3  1) 
 
Added: 
“and the change from baseline” 
Add for 
evaluating the 
safety in more 
detail. 
Section 10.3.3  3) 
Added: 
“and totality” 
Add for 
clarification. 
Section 10.4.3  2) 
“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.” 
Changed to: 
“Summary statistics (no. of 
subjects, mean, standard 
deviation, median, minimum, 
and maximum) will be provided 
for each hormonal test 
parameter value and the change 
from baseline by the time of 
measurement.” 
Add for 
evaluating the 
safety in more 
detail. 
Section 10.6.2  2) 
 
Added: 
QTcF will be calculated using the 
following compensation formula. 
QTcF (ms) = QT interval / (RR 
interval)1/3. 
Add the formula. 
Section 10.6.3  2) 
For 12-lead ECG parameters 
(observed values of RR interval, 
Added: 
For 12-lead ECG parameters 
(observed values of RR interval, 
Add for 
clarification. 


 
 
 
 
10 
 
QT interval, Fridericia's 
corrected QT interval [QTcF], 
QRS width, and PR interval, and 
their changes [ΔQTcF, ΔQRS, 
and ΔPR]), observed value (HR) 
and change (ΔHR) of heart rate, 
summary statistics and 
frequency distr bution for each 
category will be summarized at 
each time point. 
QT interval, Fridericia's 
corrected QT interval [QTcF], 
QRS width, and PR interval, and 
their changes from baseline 
[ΔQTcF, ΔQRS, and ΔPR]), 
observed value (HR) and 
change from baseline (ΔHR) of 
heart rate, summary statistics 
and frequency distribution for 
each category will be 
summarized at each time point. 
Section 10.6.3 
“P-R (ms) (observed value)” 
Changed to: 
“PR (ms) (observed value)” 
Typo 
Section 10.6.3 
“ΔQTcF (ms) 
(change)” 
Added:  
“ΔQTcF (ms) 
(change from baseline)” 
Add for 
clarification. 
Section 11.2  2) (1) [1] 
Added: 
Subjects with at least one 
baseline neutralizing positive 
sample for anti-ONO-4538 
antibodies including baseline 
positive ones. 
Clarify the 
definition. 
Section 11.2  2) (2) [2] 
Persistent positive: Subjects with 
two or more samples collected 
at consecutive time points after 
the first dose of the 
investigational product and 
testing positive for anti-ONO-
4538 antibodies with a minimum 
interval of 16 weeks between the 
first and last positive samples. 
Change to: 
Persistent positive: Subjects with 
two or more samples collected 
at consecutive time points after 
the first dose of the 
investigational product and 
testing positive for anti-ONO-
4538 antibodies with a minimum 
interval of 16 weeks (there is a 
time window for one week) 
between the first and last 
positive samples. 
Add for 
evaluating the 
anti-drug 
antibody 
properly. 
Section 11.3 
Added: 
“and totality” 
Add for 
clarification. 
Section 12.3  Background 
factors and efficacy endpoint 
 
Added: 
Percent change in tumor 
diameter of target lesion (%) 
Add for 
clarification. 
Section 12.3  Vital signs 
 
Deleted: 
Respiratory rate(beats/min) 
Typo 
Section 12.3  12-lead ECG 
QRS complex (ms) 
Change to: 
QRS width (ms) 
Typo 
Section 12.4 
“Metastatic Lesion” 
“To be decided by data review” 
“surgery” 
“radiotherapy” 
“Medication” 
 
"IIIB, IV, recurrent, unknown or 
other" 
Change to: 
“Brain metastasis” 
“Yes, No” 
“Surgery” 
“Radiotherapy” 
“Number of treatment regimens” 
 
"IIIB, IV, recurrence, unknown or 
other" 
 
Deleted: 
“Item: Location of Initial 
Occurrence” 
Modify the 
subgroup item 
and its name. 


 
 
 
 
11 
 
 
Added: 
“Item: Bone metastasis, 
Classification: Yes, No” 
“Item: Presence of the anti-
ONO-4538 ant body, 
Classification: Positive 
(Persistent positive/ Only the last 
sample positive, Other positive) , 
Baseline positive, Negative” 
Section 14.3  1) (1) 
Deleted: 
“Subject Disposition and” 
Reflect the result 
of data review 
analysis 
Section 14.3  1) (2) 
Response rate and progression-
free survival (centrally assessed) 
Change to: 
Response rate and progression-
free survival (investigator-
assessed) 
Reflect the result 
of data review 
analysis 
Section 14.4  3) 
The response rate (centrally 
assessed) and its 95% 
confidence interval (Wilson) will 
be calculated to examine the 
appropriateness of the analysis 
method. In addition, missingness 
will be evaluated as necessary. 
Change to: 
The response rate (investigator-
assessed) and its 95% 
confidence interval (Wilson) will 
be calculated to examine the 
appropriateness of the analysis 
method. In addition, missingness 
will be evaluated as necessary. 
Reflect the result 
of data review 
analysis 
Section 14.4  
 
Added: 
“4) For progression-free survival 
(investigator-assessed), a 
Kaplan-Meier curve will be 
presented. In addition, using the 
Kaplan-Meier method, the 
median and its 95% confidence 
interval and progression free 
survival rates at 3 and 6 months 
and its 95% confidence interval 
will be estimated for the 
validation of the analysis 
methods or handling of data.” 
Add progression 
free survival 
analysis in data 
review. 
Section 14 
Added: 
“The above analyses were 
performed using the data 
obtained from 96 subjects 
treated with the study drug as of 
Feb. 27, 2015.” 
Reflect the result 
of data review 
analysis 
Section 15 
“NA” 
Changed to: 
“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 
Add contents of 
change from 
protocol. 


 
 
 
 
12 
 
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, 
analysis of the development of 
tumor diameter and evaluation 
of baseline characteristics will be 
performed.” 
Section Addendum 1 
Added: 
Subcategory, Preferred Term 
Add for 
evaluating the 
safety properly. 
29Jul2021 
SAP_ONO-4538-
09_version 3.0, 
29Jul2021 
Section 9.2.4  2)  
 
A Kaplan-Meier curve will be 
plotted for each analysis 
variable. The median and its 
95% confidence interval and 
overall survival rates at 6 
months and its 95% confidence 
interval will be estimated by 
Kaplan-Meier method. 6 months 
will be calculated assuming 
30.4375 days for one month. 
Change to: 
A Kaplan-Meier curve will be 
plotted for each analysis 
variable. The median and its 
95% confidence interval and 
overall survival rates at 6, 12, 18 
and 24 months and its 95% 
confidence interval will be 
estimated by Kaplan-Meier 
method. 6, 12, 18 and 24 
months will be calculated 
assuming 30.4375 days for one 
month. 
Add for 
evaluation of the 
overall survival 
rate at 12, 18 
and 24 months. 
 
 
Section 9.2.4  3) 
The median progression free 
survival, its 95% confidence 
interval and progression free 
survival rates at 3 and 6 months 
and its 95% confidence interval 
will be estimated by Kaplan-
Meier method. 3 and 6 months 
will be calculated assuming 
30.4375 days for one month. 
Change to: 
The median progression free 
survival, its 95% confidence 
interval and progression free 
survival rates at 3, 6, 9 and 12 
months and its 95% confidence 
interval will be estimated by 
Kaplan-Meier method. 3, 6, 9 
and 12 months will be calculated 
assuming 30.4375 days for one 
month. 
Add for 
evaluation of the 
progression free 
survival rates at 
9 and 12 months 
 
 
Section 9.2.4  4) 
The median and its 95% 
confidence interval and duration 
of response rates at 6 months 
and its 95% confidence interval 
will be estimated by Kaplan-
Meier method. 6 months will be 
calculated assuming 30.4375 
days for one month. 
Change to: 
The median and its 95% 
confidence interval and duration 
of response rates at 6 and 12 
months and its 95% confidence 
interval will be estimated by 
Kaplan-Meier method. 6 and 12 
months will be calculated 
assuming 30.4375 days for one 
month. 
Add for 
evaluation of the 
duration of 
response rates 
at 12 months 
 
 
 
 
 


 
 
 
 
13 
 
 List of Contents 
Pages 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................................... 17 
1 INTRODUCTION........................................................................................................................... 19 
2 STUDY OBJECTIVES ................................................................................................................... 21 
3 INVESTIGATIONAL PLAN ......................................................................................................... 22 
3.1 
Study Design ............................................................................................................................ 22 
3.2 
Target ....................................................................................................................................... 22 
3.2.1 
Target .............................................................................................................................. 22 
3.2.2 
Subject Inclusion Criteria ................................................................................................ 22 
3.2.3 
Subject Exclusion Criteria .............................................................................................. 23 
3.3 
Study Schedule and Observations ............................................................................................ 25 
3.3.1 
Screening Phase .............................................................................................................. 26 
3.3.2 
Treatment Phase .............................................................................................................. 26 
3.3.3 
Follow-up Phase .............................................................................................................. 26 
3.3.4 
Determination of Outcome .............................................................................................. 27 
3.4 
Dose and Administration, and Duration of Treatment ............................................................. 33 
3.5 
Prior and Concomitant Therapies ............................................................................................. 33 
3.5.1 
Therapies Prohibited During the Study ........................................................................... 33 
3.5.2 
Prophylactic Drug Use .................................................................................................... 34 
3.6 
Investigational Product Discontinuation Criteria ..................................................................... 34 
3.7 
Sample size determination ....................................................................................................... 35 
3.7.1 
Planned Number of Subjects ........................................................................................... 35 
3.7.2 
Rationale for Number of Subjects ................................................................................... 35 
4 ANALYSIS SETS ........................................................................................................................... 37 
4.1 
Definitions of Groups ............................................................................................................... 37 
4.2 
Criteria for Subject Handling ................................................................................................... 37 
4.3 
Criteria for Handling Evaluation Time Points ......................................................................... 38 
5 DOCUMENTATION OF STATISTICAL METHOD ................................................................... 39 
5.1 
Efficacy Endpoints ................................................................................................................... 39 
5.1.1 
Primary Endpoint ............................................................................................................ 39 
5.1.2 
Secondary Endpoint ........................................................................................................ 39 
5.2 
Safety Endpoints ...................................................................................................................... 40 


 
 
 
 
14 
 
5.3 
Other Endpoints ....................................................................................................................... 40 
5.3.1 
Anti-drug Antibody Endpoint ......................................................................................... 40 
6 DISPOSITION AND PROTOCOL DEVIATIONS ....................................................................... 41 
6.1 
Analysis Set .............................................................................................................................. 41 
6.2 
Analysis Items and Data Handling ........................................................................................... 41 
6.3 
Analysis Methods ..................................................................................................................... 41 
7 STUDY DRUG EXPOSURE AND COMPLIANCE ..................................................................... 42 
7.1 
Analysis Set .............................................................................................................................. 42 
7.2 
Analysis Items and Data Handling ........................................................................................... 42 
7.3 
Analysis Methods ..................................................................................................................... 42 
8 DEMOGRAPHIC AND BASELINE CHARACTERISTICS ........................................................ 44 
8.1 
Analysis Set .............................................................................................................................. 44 
8.2 
Analysis Items and Data Handling ........................................................................................... 44 
8.3 
Analysis Methods and Classification ....................................................................................... 44 
9 EFFICACY EVALUATION .......................................................................................................... 46 
9.1 
Primary Efficacy Analysis ....................................................................................................... 46 
9.1.1 
Objective ......................................................................................................................... 46 
9.1.2 
Analysis Set .................................................................................................................... 46 
9.1.3 
Analysis Items and Data Handling .................................................................................. 46 
9.1.4 
Analysis Methods ............................................................................................................ 46 
9.2 
Secondary Efficacy Analysis ................................................................................................... 46 
9.2.1 
Objective ......................................................................................................................... 46 
9.2.2 
Analysis Set .................................................................................................................... 46 
9.2.3 
Analysis Items and Data Handling .................................................................................. 47 
9.2.4 
Analysis Methods ............................................................................................................ 50 
9.2.5 
Subgroup Analysis of Efficacy Endpoint ........................................................................ 51 
10 SAFETY EVALUATION ............................................................................................................... 52 
10.1 Adverse Events......................................................................................................................... 52 
10.1.1 
Analysis Set .................................................................................................................... 52 
10.1.2 
Analysis Items and Data Handling .................................................................................. 52 
10.1.3 
Analysis Methods ............................................................................................................ 53 
10.1.4 
Subgroup Analysis of Safety Endpoints ......................................................................... 55 
10.2 Clinical Laboratory Evaluation ................................................................................................ 55 


 
 
 
 
15 
 
10.2.1 
Analysis Set .................................................................................................................... 55 
10.2.2 
Analysis Items and Data Handling .................................................................................. 55 
10.2.3 
Analysis Methods ............................................................................................................ 56 
10.3 Immunologic Test .................................................................................................................... 56 
10.3.1 
Analysis Set .................................................................................................................... 56 
10.3.2 
Analysis Items and Data Handling .................................................................................. 56 
10.3.3 
Analysis Methods ............................................................................................................ 57 
10.4 Hormonal Test .......................................................................................................................... 57 
10.4.1 
Analysis Set .................................................................................................................... 57 
10.4.2 
Analysis Items and Data Handling .................................................................................. 57 
10.4.3 
Analysis Methods ............................................................................................................ 57 
10.5 Vital Signs ................................................................................................................................ 58 
10.5.1 
Analysis Set .................................................................................................................... 58 
10.5.2 
Analysis Items and Data Handling .................................................................................. 58 
10.5.3 
Analysis Methods ............................................................................................................ 58 
10.6 12-lead ECG ............................................................................................................................. 58 
10.6.1 
Analysis Set .................................................................................................................... 58 
10.6.2 
Analysis Items and Data Handling .................................................................................. 59 
10.6.3 
Analysis Methods ............................................................................................................ 59 
11 Anti-drug Antibody Analysis .......................................................................................................... 60 
11.1 Analysis Set .............................................................................................................................. 60 
11.2 Analysis Items and Data Handling ........................................................................................... 60 
11.3 Analysis Methods ..................................................................................................................... 61 
12 GENERAL PRESENTATION OF SUMMARIES AND ANALYSES ......................................... 62 
12.1 Summary Statistics ................................................................................................................... 62 
12.2 Significance Level to Be Used ................................................................................................. 62 
12.3 Decimals ................................................................................................................................... 62 
12.4 Subgroup Definitions ............................................................................................................... 64 
12.5 Site Pooling Method ................................................................................................................. 64 
12.6 Software for Statistical Analysis .............................................................................................. 64 
13 INTERIM ANALYSIS ................................................................................................................... 64 
14 DATA REVIEW ............................................................................................................................. 65 
14.1 Objectives ................................................................................................................................. 65 


 
 
 
 
16 
 
14.2 Analysis Set .............................................................................................................................. 65 
14.3 Analysis Items and Data Handling ........................................................................................... 65 
14.4 Analysis Methods ..................................................................................................................... 65 
15 CHANGE FROM PROTOCOL ...................................................................................................... 67 
16 SAS PROCEDURE FOR ANALYSIS ........................................................................................... 67 
16.1 95% confidence interval (Wilson) ............................................................................................ 67 
16.2 Kaplan-Meier curve ................................................................................................................. 67 
17 REFERENCES ................................................................................................................................ 67 
Addendum 1 List of Select Adverse Events .......................................................................................... 68 
 






 
 
 
 
19 
 
1 
INTRODUCTION 
Lung cancer is the leading cause of cancer-related deaths globally. An estimated 221,130 new cases 
of lung cancer will be diagnosed in 2011. The majority of subjects (approximately 78%) are diagnosed 
with advanced or metastatic disease. Progression after first-line therapy occurred in nearly all of these 
subjects and the 5 year survival rate is only 3.6% in the refractory setting.  
Leading a treatment guidelines (National Comprehensive Cancer Network Guidelines) recommend 
combination therapy with a platinum agent and a third-generation anticancer agent (e.g., 
carboplatin/paclitaxel, cisplatin/gemcitabine, cisplatin/pemetrexed) as first-line drug therapy for 
patients with stage IIIB/IV non-small cell lung cancer (NSCLC) unsuited to radical radiotherapy who 
are negative for or with unknown EGFR mutation and have an ECOG Performance Status of 0 to 2. For 
patients with stage IIIB/IV NSCLC unsuited to radical radiotherapy who are positive for EGFR mutation 
and have an ECOG Performance Status of 0 to 2, these guidelines recommend either combination 
therapy with a platinum agent and a third-generation anticancer agent or treatment with an EGFR 
tyrosine kinase inhibitor such as erlotinib as first-line treatment. These first-line therapies of 
combination therapy with a platinum agent and a third-generation anticancer agent, however, provide a 
median progression free survival of 4.5 to 6.2 months and median overall survival of 10.3 to 12.3 months. 
Moreover, docetaxel for patients with NSCLC with disease resistance to the first-line therapies confers 
a median progression free survival of 2.3 to 3.1 months and median overall survival of 7.2 to 10.0 
months. These figures show the efficacy of the existing treatments to be insufficient in patients with 
stage IIIB/IV NSCLC unsuited to radical radiotherapy. The need for new drug therapies for these 
patients is great.  
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. In 
Japan, it obtained manufacturing and marketing approval for indications of unresectable malignant 
melanoma. PD-1 (or CD279), a 55-kilodalton Type 1 transmembrane protein, is a member of the CD28 
family of T-cell co-stimulatory receptors that include immunoglobulin super family members CD28, 
CTLA-4, ICOS, and BTLA. PD-1 is highly expressed on activated T-cells and B-cells. PD-1 expression 
can also be detected on memory T-cell subsets with variable levels of expression. Two ligands specific 
for PD-1 have been identified: PD-L1 (also known as B7-H1 or CD274) and PD-L2 (also known as B7-
DC or CD273). PD-L1 and PD-L2 have been shown to down-regulate T-cell activation upon binding to 
PD-1 in both murine and human systems. The product is made with recombinant technology using CHO 
cells. PD-L1 is expressed at 19.4 to 95.2% and PD-L2 at 50.0% in the cancer tissue of NSCLC. Various 


 
 
 
 
20 
 
nonclinical pharmacology studies have demonstrated that ONO-4538 inhibits the binding of PD-1 and 
PD-1 ligands to enhance the growth and activity of antigen-specific T cells. Ono Pharmaceutical within 
Japan and BMS outside the country are clinically developing ONO-4538. Antitumor activity was 
assessed according to the RECIST guideline (version 1.1) using data obtained to the March18, 2013 
cutoff point in a non-Japanese phase I repeated dose study (Study CA209003). Twenty-two of the 129 
study subjects, who had NSCLC resistant to standard treatment, achieved a response. This finding 
highlights the potential of ONO-4538, which inhibits binding between PD-1 and PD-1 ligand, to become 
a NSCLC drug therapy with a novel mechanism of action. To investigate this potential, Ono 
Pharmaceutical planned this phase II study of ONO-4538 in patients with stage IIIB/IV NSCLC 
unsuited to radical radiotherapy or recurrent NSCLC.  
  


 
 
 
 
21 
 
2 
STUDY OBJECTIVES 
The objective of the study is to investigate the efficacy and safety of ONO-4538 in stage IIIB/IV or 
recurrent non-small cell lung cancer unsuited to radical radiotherapy and resistant to a platinum-based 
chemotherapeutic regimen in a multicenter, open-label, uncontrolled study.  
The primary efficacy endpoint is response rate (centrally assessed). The secondary efficacy endpoints 
are response rate (study site assessment by investigator), overall survival, progression free survival, time 
to progression, duration of response, time to response, best overall response, and percent change in 
tumor diameter.  
  


 
 
 
 
22 
 
3 
INVESTIGATIONAL PLAN 
 
3.1 
Study Design  
Multi-center, open-label, uncontrolled study 
 
3.2 
Target 
3.2.1 
Target  
Stage IIIB/IV or recurrent non-small cell lung cancer unsuited to radical radiotherapy and resistant to 
a platinum-based chemotherapeutic regimen 
 
3.2.2 
Subject Inclusion Criteria   
Patients satisfying all the following criteria will be included: 
1. 
Male or female.  
2. 
≥ 20 years of age (at time of enrollment).  
3. 
Histologically or cytologically confirmed non-small cell lung cancer.  
4. 
Diagnosis of NSCLC in stage IIIB/IV unsuited to radical radiotherapy according to UICC-TNM 
classification (7th edition) or recurrent NSCLC.  
5. 
Has at least one measurable lesion, as defined by the RECIST guideline (version 1.1) in diagnostic 
imaging performed 14 or fewer days before enrollment. (Patients who have received radiotherapy 
for a measurable lesion must have confirmed progress in diagnostic imaging following 
radiotherapy.)  
6. 
Has a history of prior treatment with any of the following systemic anti-cancer agents (e.g., 
chemotherapy, molecular targeted therapy, immunotherapy): 
1） History of prior platinum-based chemotherapy and up to 1 regimen of prior treatment for patients 
negative for or with unknown EGFR activity mutation or ALK gene translocation 
2） History of prior platinum-based chemotherapy and an EGFR tyrosine kinase inhibitor, and up to 2 
regimens of prior treatment, for patients positive for EGFR activity mutation 
3） History of prior platinum-based chemotherapy and an ALK inhibitor, and up to 2 regimens of prior 
treatment, for patients positive for ALK gene translocation 
7. 
ECOG Performance Status is 0 to 1.  


 
 
 
 
23 
 
8. 
Life expectancy is ≥ 90 days.  
9. 
Women of childbearing potential (including women who are amenorrheic due to chemical 
menopause or for another medical reason) must agree to engage in contraception from the time of 
informed consent to at least 320 days after the final dose of the investigational product.  
10. Men must agree to use a contraceptive from the start of study treatment until at least 320 days 
following the last dose of investigational product. 
11. Percutaneous oxygen saturation by pulse oximetry performed 7 or fewer days before enrollment is 
≥ 94% in the absence of oxygen supplementation.  
12. Most recently determined laboratory values, determined 7 or fewer days before enrollment, satisfy 
the 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 
- 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 
 
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 safety evaluation of the 
investigational product. 
3. 
Active autoimmune disease or history of chronic or recurring autoimmune disease.  
4. 
Current or prior interstitial lung disease or pulmonary fibrosis diagnosed based on diagnostic 
imaging or clinical findings. (Radiation pneumonitis allows to be enrolled as long as not acute 


 
 
 
 
24 
 
phase with fibrosis or without symptoms.) 
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. 
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. 
Pain associated with bone metastases and others not controllable 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. Uncontrollable diabetes. 
14. 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. 
15. Has received an anti-cancer product (e.g., chemotherapy, molecular targeted therapy, and 
immunotherapy) 28 or fewer days before enrollment. 
16. Has undergone surgery for pleural, pericardial, or similar adhesion 28 or fewer days before 
enrollment.  
17. Has undergone surgical treatment accompanying general anesthesia 28 or fewer days before 


 
 
 
 
25 
 
enrollment.  
18. Has undergone surgical treatment accompanying local or surface anesthesia 14 or fewer days 
before enrollment.  
19. Has received radiotherapy 28 or fewer days before enrollment or thoracic radiotherapy or a 
radiopharmaceutical agent (except when the radiopharmaceutical agent is used for testing or 
diagnostic purposes) 56 or fewer days before enrollment.  
20. Has undergone gamma knife or CyberKnife treatment 14 or fewer days before enrollment.  
21. Has a systemic infection that requires treatment.  
22. Has tested positive for HIV-1 antibody, HIV-2 antibody, HTLV-1 antibody, HBs antigen, or HCV 
antibody.  
23. 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. 
24. Is pregnant, nursing, or possibly pregnant.  
25. Has received another investigational product 28 or fewer days before enrollment.  
26. 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.  
27. Is found incapable of giving consent due to dementia or another such condition.  
28. Patients otherwise found by the principal or sub investigator to be ineligible.   
 
3.3 
Study Schedule and Observations 
The study consists of the screening phase, treatment phase, and follow-up phase, as is outlined in 
Figure 3.1. 
 




 
 
 
 
27 
 
MRI) whenever possible until beginning subsequent treatment for non-small cell lung cancer or until 
developing PD or recurrence.  
Even after the conclusion of the tests performed on discontinuation, all treatment-related adverse 
events will be followed every 2 weeks whenever possible until resolution or improvement or when no 
further follow-up is necessary due to symptom stability. Laboratory tests or diagnostic imaging will be 
repeated and other measures taken as necessary to adequately ensure subject safety. 
 
3.3.4 
Determination of Outcome  
Follow-up to determine survival status (and, if the subject has died, the date and cause of death) will 
be performed every 6 months or so beginning 6 months after the first day of treatment of the last subject 
enrolled in the study. Outcome information may be obtained by phone, letter, or another means. The 
use, start dates, and types of any subsequent treatments for NSCLC will also be investigated whenever 
possible.  
 


 
 
 
 
28 
 
 Table 3-1 Study schedule (Cycle 1)  
Category 
Screening 
phase 
Treatment phase (Cycle 1) 
Study day 
1 
8 
15 
29 
 
436 
 
Before 
administration 
After 
administration 
 
 
 
Allowable range (days) 
-7 to -1 
1 
±3 
-3 to +7 
-6 to +7 
-6 to + 7 
Visit 
V 1-0 
V 1-1 
V 1-2 
V 1-3 
V 1-4 
V 1-5 
Written informed consent 
○7 
 
 
 
 
 
Demographics and 
inclusion/exclusion criteria 
○ 
 
 
 
 
 
Investigational product 
administration 1 
 
○ 
 
○ 
○ 
 
Virus tests 
○8 
 
 
 
 
 
Pregnancy test2 
○8 
○ 
 
 
 
 
 
Performance Status 
○8 
 
○ 
○9 
○9 
○ 
Vital signs/weight/percutaneous 
oxygen saturation 
○8 
○10 
○10 
○10 
○9, 10 
○9, 10 
○ 
Chest X-ray3 
○8 
 
 
 
 
○ 
12-lead ECG 
○8 
○ 
○11 
 
 
 
○ 
Hematology tests, blood 
biochemistry tests, urinalysis 
○8 
 
○ 
○9 
 
○ 
Immunology/hormone tests 
○8, 12 
 
 
 
 
○ 
Serum drug concentration 
 
○ 
○13 
 
○9 
○9 
 
Anti-ONO-4538 antibody 
 
○ 
 
 
○9 
○9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Diagnostic imaging  
(e.g., CT, MRI) 
○8, 14 
 
 
 
 
○ 
Concomitant drugs 
/adverse events 
 
 
←→ 
1. Administer the investigational product after at least 10 days have passed since the most recent 
dose.  
2. Women of childbearing potential will undergo a serum pregnancy test in the screening phase and 
subsequently undergo urine pregnancy testing.  
3. Also perform at unscheduled visits as necessary if, during the study (from the time of informed 
consent to the completion of the final tests (other than the survey for ‘determination of outcome’) 
specified in the protocol), signs, subjective and objective symptoms, or test findings suggest 
respiratory disease.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
  
6. For subjects again proceeding to the treatment phase, administer the investigational product on 
Day 1 of the next cycle within the Day 43 allowable range (i.e., Days 37 to 50). Proceed to the 
follow-up phase (Table 3-3) on completing the treatment phase.  
7. Begin administering the investigational product within 30 days of informed consent.  


 
 
 
 
29 
 
8. The data from virus tests performed within 1 year of enrollment, diagnostic imaging (e.g., CT, 
MRI) performed within 14 days of enrollment, and other tests performed within 7 days of 
enrollment will be included.  
9. Perform before administering the investigational product.  
10. Other than weight.  
11. Perform immediately before collecting the sample for serum drug concentration analysis.  
12. SP-D and KL-6 will be measured in the screening phase and, as necessary, in the treatment phase.  
13. Collect sample immediately before the completion of investigational product administration.  
14. 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.  


 
 
 
 
30 
 
Table 3-2 Study schedule (Cycles 2 and beyond) 
Category 
Treatment phase (Cycles 2 and beyond) 
Study day 
15 
15 
29 
 
435 
 
 
Before 
administration 
After 
administration 
 
Allowable range (days) 
1 
-3 to +7 
-6 to +7 
-6 to +7 
Visit 
V n-1 
V n-2 
V n-3 
V n-4 
Investigational product 
administration 1 
○ 
○ 
○ 
 
Performance Status 
○6, 7 
 
 
○ 
Vital 
signs/weight/percutaneous 
oxygen saturation 
○6, 7 
○8 
 
○7, 8 
○ 
Chest X-ray2 
 
 
 
○ 
12-lead ECG 
○6, 7, 9 
 
 
○9 
Hematology tests, blood 
biochemistry tests, 
urinalysis 
○6, 7 
 
 
○ 
Immunology/hormone tests 
 
 
 
○ 
Serum drug concentration 3 
○7, 10 
○11 
○11, 12 
 
 
Anti-ONO-4538 antibody 3 
○7, 10 
○11 
 
 
 
Tumor markers 4 
○ 
Diagnostic imaging  
(e.g., CT, MRI) 
 
 
 
○ 
Concomitant drugs/adverse 
events 
←→ 
1. Administer the investigational product after at least 10 days have passed since the most recent 
dose.  
2. Also perform at unscheduled times as necessary if, during the study (from the time of informed 
consent to the completion of the final tests (other than the determination of outcome) specified in 
the protocol), signs, subjective and objective symptoms, or test findings suggest respiratory 
disease.  
3. To be collected until the end of the 1-year period after the start of investigational drug 
administration (i.e., Cycle 9).  
4. Analyze tumor markers whenever possible in each subject with a tumor marker at a level 
exceeding the normal range. Perform tumor marker analysis when required.  
5. For subjects again proceeding to the treatment phase, administer the investigational product on 
Day 1 of the next cycle within the Day 43 allowable range (i.e., Days 37 to 50). Proceed to the 
follow-up phase (Table 3-3) on completing the treatment phase.  
6. Unless medically necessary, vital signs will be measured no sooner than 2 days, and other tests 
will be performed no sooner than 8 days after the previous measurement.  
7. Perform before administering the investigational product.  
8. Other than weight.  
9. Perform only in Cycle 4.  
10. Perform only in Cycles 2, 4, 5, 7, and 9.  
11. Perform only in Cycle 3.  
12. Collect sample immediately before the completion of investigational product administration.  


 
 
 
 
31 
 
Table 3-3 Study schedule (for subjects completing the treatment phase) 
Category 
At end of treatment 
phase 6 
Follow-up phase 
Study day 
28 days after final dose or on discontinuation 
28 or fewer days after final dose 6 
Follow-up7 
Allowable range (days) 
-3 to +3 
-7 to +7 
- 
Visit 
V f-0 
V f-1 
V f-n 
Pregnancy test1 
○8 
○ 
 
Performance Status 
○ 
○ 
 
Vital signs/weight/percutaneous 
oxygen saturation 
○ 
○ 
 
Chest X-ray 
○ 
○ 
 
12-lead ECG 
○8 
○ 
 
Hematology tests, blood 
biochemistry tests, urinalysis  
○ 
○ 
 
Immunology/hormone tests 
○ 
○ 
 
Serum drug concentration 2 
○8 
○ 
 
Anti-ONO-4538 antibody 2 
○8 
○ 
 
Diagnostic imaging (e.g., CT, MRI) 
○ 
○ 
○ 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
Concomitant drugs/adverse events 5 
←→ 
 
1. 
Women of childbearing potential will undergo urine pregnancy testing. 
2. 
Perform only if the subject proceeds to the follow-up phase within 1 year after the start of 
investigational product administration (by Cycle 9). Collect sample if possible 6 to12 weeks after 
the final investigational product dose. 
 
 
 
 
 
  
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
5. 
Investigate all adverse events and concomitant treatments to the completion of the final tests (other 
than the survey for ‘determination of outcome’) specified in the protocol. Beyond the completion of 
the final tests (other than the survey for ‘determination of outcome’) specified in the protocol, follow 
any persisting adverse event for which a causal relationship with the investigational product cannot 
be ruled out, adverse events that resulted in discontinuation, and the concomitant treatments 
associated with those events until the events resolve, improve, or are determined to be permanent or 


 
 
 
 
32 
 
no further follow-up is necessary. And all treatment-related adverse events will be followed every 2 
weeks if possible. 
6. 
Information from a prior measurement may be included if the day of that measurement falls within 
the acceptable range at the end of the treatment phase or discontinuation. Unless medically necessary, 
vital signs will be measured no sooner than 2 days, diagnostic imaging (e.g., CT, MRI) performed 
no sooner than 15 days, and other tests no sooner than 8 days after the previous measurement. 
7. 
Those subjects who are CR, PR, or SD at the time of discontinuation of the investigational product 
will undergo follow-up whenever possible with diagnostic imaging and to determine the use and 
types of any subsequent treatments for non-small cell lung cancer until a subsequent therapy for non-
small cell lung cancer is begun or the subject experiences PD or recurrence. 
8. 
Perform only when the test after 28 days of the final investigational product dosage or on 
discontinuation within 28 days after the final investigational product dosage is not performed due to 
withdrawal or other reasons. Perform 12-lead ECG also at the discontinuation of treatment phase if 
the treatment phase is discontinue in Cycle 1 or 4. 
 
 
  
  
 
 
  
  
  
  
 
 
 
 
 
 
 
  
  
  
  


 
 
 
 
33 
 
3.4 
Dose and Administration, and Duration of Treatment  
ONO-4538 is administered at a 3 mg/kg dose with a 2-week dosing interval. One cycle consists of 6 
weeks. ONO-4538 administration will continue until the development of PD as identified by the 
investigator or sub investigator according to the RECIST guideline (version 1.1). The appropriate dose 
of ONO-4538 will be diluted with physiological saline or dextrose 5% in water to a total amount of 
approximately not less than 60 mL before use (so that the solution drug concentration 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 ~ 1.20 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 or dextrose 5% in water. The ONO-4538 dose will not 
be reduced. The administration of ONO-4538 infusion must be completed within 24 hours of preparation. 
If not used immediately, the infusion solution may be stored under refrigeration condition (2°-8°C, 36°-
46°F) for up to 24 hours , and a maximum of 4 hours of the total 24 hours can be at room temperature 
(20°-25°C, 68°-77°F) and room light. The maximum 4-hour period under room temperature and room 
light conditions includes the product administration period. 
The dose will be changed if the body weight of the subject changes by at least 10% relative to the 
weight at enrollment. Each subsequent 10% or greater change in body weight is to be handled in a 
similar manner.  
 
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 
completion of the final tests (other than the determination of outcome) specified in the protocol).  
1. Immunosuppressants and corticosteroids 
2. Anti-cancer agents (e.g., chemotherapy, molecular targeted therapy, immunotherapy) 
3. Surgical treatment for a malignant tumor 
4. Radiotherapy 
5. Radiopharmaceuticals 
6. Bisphosphonate products and anti-RANKL antibodies 
7. Transplant therapy 
8. Any other investigational product  
 


 
 
 
 
34 
 
3.5.2 
Prophylactic Drug Use  
Prophylactic pretreatment with acetaminophen and diphenhydramine before ONO-4538 
administration is recommended for subjects who develop an infusion related reaction to a previous dose 
of ONO-4538.  
 
3.6 
Investigational Product Discontinuation Criteria  
Subjects satisfying any of the following criteria in the treatment phase will be discontinued the 
investigational product and proceed to the follow-up phase.  
1. The development of PD is identified by the principal or sub investigator according to the RECIST 
guideline (version 1.1).  
2. A 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, rash) or uveitis occurs whose causal relationship with the 
investigational product cannot be ruled out.  
6. An adverse event or other events delay the administration of the investigational product by more 
than 6 weeks.  
7. The investigator or sub investigator otherwise determines that continuing to administer the 
investigational product is inappropriate due to an efficacy- or safety-related reason.  
 
Even when Criterion 1 is applicable, investigational product treatment may be continued if it is 
determined through consultation with the sponsor that no worsening of clinical symptoms attributable 
to disease progression occurs, continued treatment is expected to provide a clinical benefit, and the 
investigational product can continue to be safely administered. If the investigational productis to be 
continued, the subject should first be consulted about his or her willingness to continue receiving 
treatment, and this process should be documented in the medical records. Laboratory tests will be 
frequently repeated and other measures taken to adequately ensure subject safety. Any subject who is 
found to have again developed PD according to the RECIST guideline (version 1.1) based on a point 


 
 
 
 
35 
 
where a decision is made to continue investigational product treatment must cease using the 
investigational product regardless of whether clinical symptoms have worsened or not.  
 
3.7 
Sample size determination 
3.7.1 
Planned Number of Subjects  
Total of 93 subjects (41 subjects with squamous NSCLC and 52 subjects with non-squamous 
NSCLC) 
 
3.7.2 
Rationale for Number of Subjects  
The objective of the study is to investigate the efficacy of ONO-4538 in patients with stage IIIB/IV 
or recurrent NSCLC unsuited to radical radiotherapy using centrally assessed response rates as the 
primary endpoint. The sample size for each histology is calculated in order to confirm anti-tumor 
response of ONO-4538 in Korean population.  
From efficacy data of non-Korean phase I multiple-dose study (CA209003) as of March 18, 2013 
(Table 3-4), the expected response rate for ONO-4538 in patients with squamous NSCLC was set at 
23.1% because responses of 22% (4/18) and 24% (5/21) were achieved in patients with squamous 
NSCLC in the 3 and 10 mg/kg group, respectively. Similarly, the expected response rate for ONO-4538 
in patients with non-squamous NSCLC was set at 21.4% because responses of 26% (5/19) and 19% 
(7/37) were achieved in patients with non-squamous NSCLC in the 3 and 10 mg/kg group, respectively.  
The threshold response rate (the null hypothesis) was set at 8.8% because the response rate of docetaxel, 
which was selected as a comparator in non-Korean Phase III studies (CA209017, CA209057), was 8.8% 
in the phase III trial in patients with NSCLC. Under the assumption of the threshold response rate of 
8.8% and the expected response rate of 23.1% and 21.4% for patients with squamous and non-squamous 
NSCLC respectively, 41 subjects for squamous and 52 subjects for non-squamous will provide a 
statistical power of at least 80% in a binomial test (normal approximation) with an one-sided 
significance level of 2.5% (two-sided significance level of 5.0%). The sample sizes (i.e., 41 subjects 
with squamous NSCLC and 52 subjects with non-squamous NSCLC) were calculated using the formula 
as follows. 
2
0
1
1
1
1
0
0
1
)
1(
)
1(








−
−
+
−
=
−
−
p
p
p
p
z
p
p
z
N
β
α
 
N: the number of subjects 
p0: threshold response rate 
p1: expected response rate 


 
 
 
 
36 
 
z1-α: (1 – α)100 quantile of the standard normal distribution 
z1-β: (1 – β) 100 quantile of the standard normal distribution 
α: one-sided significance level 
1 - β: statistical power 
 
Table 3-4 Objective Response Rate per RECIST 1.0 in Non-small Cell Lung Cancer 
Subjects (CA209003) 
Dose 
(mg/kg) 
N 
Histology 
ORR 
No. of Subjects (%) 
95% CI of ORR 
1.0 
15 
SQ 
0 
0 
18 
NSQ 
1 (6) 
0.1 - 27 
3.0 
18 
SQ 
4 (22) 
6 - 48 
19 
NSQ 
5 (26) 
9 - 51 
10.0 
21 
SQ 
5 (24) 
8 - 47 
37 
NSQ 
7 (19) 
8 - 35 
CI: confidence interval, NSQ: non-squamous, ORR: objective response rate; SQ: squamous 
 
 


 
 
 
 
37 
 
4 
ANALYSIS SETS 
The “Full Analysis Set (FAS)” will be the primary analysis set to be used in the efficacy endpoint 
evaluation. 
The analysis set for the safety endpoint evaluation will be the “Safety Analysis Set (SAF)”.  
The analysis set for the evaluation of the production of anti-ONO-4538 antibodies will be the “Anti-
drug Antibody Analysis Set (ADAS)”. 
 
4.1 
Definitions of Groups  
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 are included in ENR and have received at least one 
dose of the study drug. 
3) FAS 
This set will be defined as a full group of subjects who are included in SAF. 
4) ADAS 
This set will be defined as a group of subjects included in SAF and for whom the anti-ONO-4538 
antibody level was determined once at baseline and at least once after the start of the study treatment. 
 
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. 
2) Subjects with Incomplete Anti-drug Antibody Data 
Subjects with incomplete anti-drug antibody data will be defined as those for whom a baseline level 
of anti-ONO-4538 antibodies was not determined or for whom the levels of anti-ONO-4538 antibodies 
were never determined after the start of the study treatment. 
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. 
 


 
 
 
 
38 
 
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, except for those from diagnostic imaging, only when they are measured within 
the following criteria. To count days of the treatment period, the day of the start of each cycle will be 
defined as Day 1. 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. 
 
1. Treatment Period  
Item 
Treatment period 
Cycle 1, Cycles 2 and beyond 
Trial day 
1 
8b) 
15c) 
29c) 
43 
Before 
dosing a) 
After 
dosing b) 
Time window (days) 
1 
5 - 11 
12 - 22 
23 - 36 
37 - 50 
a) In Cycle 1, Performance Status and laboratory test results which have been obtained within seven 
days before enrollment will be accepted. In Cycle 2 and subsequent cycles, the following data will 
be accepted: for vital signs, those within 1 day before administration, and for the other 
examinations, those within seven days before administration. 
b) Will only apply to Cycle 1.  
c) Data before administration will be accepted, except for serum drug concentrations. 
 
2. Post-treatment Follow-up Period (subjects who have terminated the treatment period) 
Item 
End of 
treatment 
period 
Post-treatment follow-up period 
Trial day 
Discontinuation at or within 
28 days after the final dose 
Follow-up 
Time window (days) 
-3 - +3 
-7 - +7 
- 
 
 
 


 
 
 
 
39 
 
5 
DOCUMENTATION OF STATISTICAL METHOD 
 
5.1 
Efficacy Endpoints 
5.1.1 
Primary Endpoint 
1. 
Response rate (centrally assessed) 
The response rate is the percentage of subjects given a best overall response assessment of CR or PR 
by the central imaging analysis facility.  
In the overall response order of CR > PR > SD > PD > NE, the following criteria will be used to 
assess the best overall response from the overall response assessments made to the completion of the 
study. When the definitions of more than one response category are satisfied, the better of the two will 
be selected as the best overall response according to the order of CR > PR > SD > PD > NE.  
∙ CR: Assessment of CR at least 2 consecutive times in intervals of 4 weeks (28 days) or longer.  
∙ PR: Assessment of PR or greater (CR or PR) at least 2 consecutive times in intervals of 4 
weeks (28 days) or longer.  
∙ SD: The best overall response is neither CR nor PR but no overall response of PD is assessed 
6 or more weeks after the start of treatment and at least one overall response of SD or better 
is assessed.  
∙ PD: The best overall response is not CR, PR, or SD, and the overall response is PD. 
∙ NE: The best overall response, which is not CR, PR, SD, or PD, is not evaluable.  
∙ Without target lesions: there is target lesion in investigator assessment but not in central 
assessment. 
 
The following overall responses will not be used to assess the best overall response: 
∙ Overall response following the start or the end of follow-up of a subsequent NSCLC therapy  
∙ Overall responses after an assessment of PD is made 
 
5.1.2 
Secondary Endpoint 
1 
Response rate (investigator-assessed) 
2 
Overall survival 
3 
Progression free survival (centrally assessed and investigator-assessed) 
4 
Time to progression (centrally assessed) 
5 
Duration of response (centrally assessed) 
6 
Time to response (centrally assessed) 


 
 
 
 
40 
 
7 
Best overall response (centrally assessed and investigator-assessed) 
8 
Percent change in tumor diameter of target lesion (investigator-assessed) 
 
5.2 
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) 
 
5.3 
Other Endpoints 
5.3.1 
Anti-drug Antibody Endpoint 
1 
Anti-ONO-4538 antibody 
 


 
 
 
 
41 
 
6 
DISPOSITION AND PROTOCOL DEVIATIONS 
 
6.1 
Analysis Set  
Analysis will be performed in SAF. With regard to the analysis item (1) in 6.2 Analysis Items and 
Data Handling, the ENR will be the analysis set. 
 
6.2 
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) Reason for discontinuation or dropout of the clinical trial 
(4) Participants in the clinical trial per institution 
2) Data Handling 
There will be no special handling. 
 
6.3 
Analysis Methods  
1) The analysis results will be summarized by squamous NSCLC and non-squamous NSCLC separately 
and totality. 
2) Classification of subjects will be indicated according to subject criteria. 
3) Frequency of subjects who have terminated the treatment period and frequency by reason for 
termination will be summarized.  
4) Frequency of subjects who have discontinued and dropped out of the clinical trial and frequency by 
reason for discontinuation and drop out will be summarized.  
5) Frequency of participants in the clinical trial per institution will be summarized. 
 
  
  
 


 
 
 
 
42 
 
7 
STUDY DRUG EXPOSURE AND COMPLIANCE 
 
7.1 
Analysis Set 
Analysis will be performed in SAF.  
 
7.2 
Analysis Items and Data Handling  
1) Analysis Items 
(1) Number of doses 
(2) Number of cycles 
(3) Duration of treatment (days) 
(4) Total dose (mg/kg) 
(5) Relative dose intensity (%) 
2) Data Handling 
(1) The number of doses will be the count of doses at all time points. 
(2) The number of cycles will refer to all cycles started, including those discontinued or temporarily 
suspended. 
(3) The duration of treatment will be calculated using the following formula. 
 Duration of treatment (days) = (the final dose date of investigational product ) – (the first dose 
date of investigational product ) + 1 
(4) The total dose (mg/kg) will be the sum of doses at all time points. The dose at each time point will 
be calculated using the following formula. 
 Dose at each time point (mg/kg) = (actual dose [mg]) / (body weight immediately before 
dosing [kg]) 
(5) The relative dose intensity will be calculated using the following formula. 
 Relative dose intensity (%) = total dose (mg/kg) / {(the final dose date of investigational 
product – the first dose date of investigational product + 14[days]) × 3 (mg/kg)/14 (days)} × 
100 
 
7.3 
Analysis Methods 
1) The analysis results will be summarized by squamous NSCLC and non-squamous NSCLC separately 
and totality. 
2) Frequency distribution and summary statistics of the number of doses will be calculated. 
3) Frequency distribution and summary statistics of the number of cycles will be calculated. 


 
 
 
 
43 
 
4) Frequency distribution and summary statistics of the duration of treatment will be calculated. 
5) Summary statistics of the total dose will be calculated. 
6) Frequency distribution and summary statistics of the relative dose intensity will be calculated. 
 
 


 
 
 
 
44 
 
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 disease to first dose date of the investigational product, histologic 
type, location of initial occurrence, TNM classification (baseline), metastasis lesions and stage 
(baseline), past medical history, concurrent diseases, NSCLC treatment history (surgical history, 
radiotherapy history, medication history, others, number of treatment regimens), drinking history, 
smoking history, performance status (ECOG). 
 
2) Data Handling 
Data will be analyzed as observed without imputing missing data. The cancer treatment history will 
refer to non-small-cell lung cancer. 
The time from diagnosis date of primary disease to first dose date of the investigational product will 
be calculated using the following formula. 
 
Time from diagnosis date of primary disease to first dose date of the investigational 
product (days) = (the first dose date of investigational product) – (the diagnosis date of 
primary disease) + 1 
 
8.3 
Analysis Methods and Classification  
1) For the background factors shown in 1) under Section 8.2Analysis 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. 
 


 
 
 
 
45 
 
Item 
Classification 
Analysis method 
Sex 
Male or female 
Proportion by category 
Age 
<65，65 - <75, ≥75 
Summary statistics and 
proportion by category 
Height 
<160.0, 160.0-<170.0, ≥170.0 Summary statistics and 
proportion by category 
Weight 
<55.0, 55.0-<65.0, ≥65.0 
Summary statistics and 
proportion by category 
BMI 
<18.5 ,18.5-<25.0, ≥25.0 
Summary statistics and 
proportion by category 
Time from diagnosis date of primary 
disease to first dose date of the 
investigational product 
<180, 181-<360, ≥361 
Summary statistics and 
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 
Histologic type 
Squamous cell carcinoma, 
Adenocarcinoma, Large cell 
carcinoma or Other 
Proportion by category 
Location of Initial Occurrence 
LUL, LLL, RUL, RML, RLL, 
Unknown, Other 
Proportion by category 
TNM classification (T) 
X, 0, is, 1a, 1b, 2a, 2b, 3, 4, 
Other 
Proportion by category 
TNM classification (N) 
X, 0, 1, 2, 3, Other 
Proportion by category 
TNM classification (M) 
X, 0, 1a, 1b, Other 
Proportion by category 
Metastatic Lesion 
Lung(LUL, LLL, RUL, RML, 
RLL, Unknown, Other), 
Lymph Node, Liver, Bone, 
Brain or Other, No 
Proportion by category 
Stage 
IIIB, IV, Recurrence, 
Unknown, Other 
Proportion by category 
Past Medical History 
Yes, No 
Proportion by category 
Concurrent diseases 
Yes, No 
Proportion by category 
NSCLC treatment History (Surgery) 
Yes, No 
Proportion by category 
NSCLC treatment History 
(Radiotherapy) 
Yes, No 
Proportion by category 
NSCLC treatment History (Medication) Yes, No 
Proportion by category 
NSCLC treatment History (Others) 
Yes, No 
Proportion by category 
NSCLC treatment History (Number of 
treatment regimens) 
1, 2 
Proportion by category 
 
The analysis results will be summarized by squamous NSCLC and non-squamous NSCLC separately 
and totality. 
 
2) NSCLC treatment history (medication) will be summarized. Agents and medication will be reported 
using the generic name. 
 


 
 
 
 
46 
 
9 
EFFICACY EVALUATION 
 
9.1 
Primary Efficacy Analysis 
9.1.1 
Objective 
To confirm the efficacy of ONO-4538 in stage IIIB/IV or recurrent NSCLC unsuited to radical 
radiotherapy and resistant to a platinum-based chemotherapeutic regimen using the response rate 
assessed by the central imaging analysis facility (centrally assessed) as the primary efficacy endpoint. 
 
9.1.2 
Analysis Set 
Analysis will be performed in FAS. 
 
9.1.3 
Analysis Items and Data Handling  
1) Analysis Items  
Response rate (centrally assessed). 
2) Data Handling 
The response rate (centrally assessed) is defined as the number of subjects whose confirmed best 
overall response determined by the central imaging analysis facility (RECIST guideline version 1.1) is 
a CR or PR divided by the number of FAS. The subject whose confirmed best overall response is missed 
will be defined as the non-responder. 
 
9.1.4 
Analysis Methods  
Response rate (centrally assessed) and its 95% confidence interval (Wilson) will be calculated. The 
analysis results will be summarized by squamous NSCLC and non-squamous NSCLC separately and 
totality. 
 
9.2 
Secondary Efficacy Analysis 
9.2.1 
Objective 
To perform the exploratory analyses in the endpoints other than the primary endpoint and evaluate 
the efficacy of investigational product from various viewpoints 
 
9.2.2 
Analysis Set  
Analysis will be performed in FAS. 
 


 
 
 
 
47 
 
9.2.3 
Analysis Items and Data Handling  
1) Analysis Items 
(1) Response rate (investigator-assessed) 
(2) Overall survival 
(3) Progression-free survival (centrally assessed and investigator-assessed) 
(4) Time to progression (centrally assessed) 
(5) Duration of response (centrally assessed) 
(6) Time to response (centrally assessed) 
(7) Best overall response (centrally assessed and investigator-assessed) 
(8) Percent change in tumor diameter of target lesion (investigator-assessed) 
 
2) Data Handling 
Overall response and best overall response will be defined as diagnostic imaging results evaluated in 
compliance with RECIST guideline version 1.1 and will not include clinical deterioration. Evaluable 
diagnostic imaging will be defined as diagnostic imaging which provides assessment other than NE. 
(1) The response rate (investigator-assessed) is defined as the number of subjects whose confirmed 
best overall response determined by the study site investigator is a CR or PR divided by the 
number of FAS. The subject whose objective response is missed will be defined as the non-
responder. 
(2) Overall survival will be calculated using the following formula. 
 
Overall survival (days) = (the date of death due to any cause) - (the first dose date of 
investigational product) + 1 
A subject who has not died will be censored at last known date alive. 
(3) Progression-free survival (centrally assessed and investigator-assessed) will be calculated using 
the following formula. 
 
Progression free survival (days) = (the earlier date of the first documented PD or death 
due to any cause) - (the first dose date of investigational product) + 1  
Clinical deterioration will not be included as an event in progression-free survival when progression-
free survival is evaluated based on diagnostic imaging results interpreted by the image central analysis 
laboratory; it will be included, however, when progression-free survival is evaluated based on diagnostic 
imaging results interpreted by a physician at the trial site. 
In addition, event/censoring assessment will be performed according to Table 9-1. 


 
 
 
 
48 
 
Table 9-1 Criteria for event/censoring assessment in progression-free survival (centrally assessed and 
investigator-assessed) 
 
Status 
Event or censoring date 
Result 
Subjects for whom diagnostic imaging 
was missed at baseline. 
Date of starting the study treatment 
Censoring 
Subjects for whom evaluable 
diagnostic imaging has not been 
performed and who are alive 
Date of starting the study treatment 
Censoring 
Subjects who received subsequent 
anti-cancer therapy for non-small-cell 
lung cancer before he/she died or 
were assessed as having PD  
Date when the last evaluable diagnostic 
imaging was performed before starting 
subsequent anti-cancer therapy for non-
small-cell lung cancer 
Censoring 
Subjects for whom the outcome 
follow-up for non-small-cell lung 
cancer was ended before death or 
assessment as PD 
Date when the last evaluable diagnostic 
imaging was performed before the end of 
the outcome follow-up for non-small-cell 
lung cancer 
Censoring 
Subjects who are alive and have not 
been assessed as having PD 
Date when the last evaluable diagnostic 
imaging was performed 
Censoring 
Subjects who died or have been 
assessed as having PD 
Date of death or date when the first 
diagnostic imaging to provide assessment 
as PD was performed, whichever comes 
first 
Event 
Subjects who died before initial 
evaluable diagnostic imaging 
Date of death 
Event 
 
(4) Time to progression (centrally assessed) will be calculated based on assessment by the central 
imaging analysis facility with the following formula: 
 
Time to progression (days) = (the date of the first documented PD) - (the first dose date 
of investigational product) + 1 
In addition, event/censoring assessment will be performed according to Table 9-2. 
 
Table 9-2 Criteria for aggravation/censoring assessment in time to progression (centrally assessed 
and investigator-assessed) 
 
Status 
Event or censoring date 
Result 
Subjects for whom diagnostic 
imaging was missed at baseline. 
Date of start of the study treatment 
Censoring 
Subjects for whom evaluable 
diagnostic imaging has not been 
performed  
Date of start of the study treatment 
Censoring 
Subjects who received subsequent 
anti-cancer therapy for non-small-cell 
lung cancer before assessment as PD 
Date when the last evaluable diagnostic 
imaging was performed before starting 
subsequent anti-cancer therapy for non-
small-cell lung cancer 
Censoring 


 
 
 
 
49 
 
Status 
Event or censoring date 
Result 
Subjects for whom the outcome 
follow-up for non-small-cell lung 
cancer was ended before death or 
assessment as PD 
Date when the last evaluable diagnostic 
imaging was performed before the end of 
the outcome follow-up for non-small-cell 
lung cancer 
Censoring 
Subjects who have not been assessed 
as having PD 
Date when the last evaluable diagnostic 
imaging was performed 
Censoring 
Subjects who have been assessed as 
having PD 
Date when the first diagnostic imaging to 
provide assessment as PD was performed 
Event 
 
(5) Duration of response (centrally assessed) will be calculated based on assessment by the central 
imaging analysis facility with the following formula: 
 
Duration of response (days) = (the date of the first documented PD or death due to any 
cause after response is confirmed) - (the date of the first confirmed CR or PR) + 1 
Subjects without documented PD and who did not die will be censored at the last evaluable tumor 
assessment. Subjects who are not evaluated a confirmed CR or PR at any time during the study will be 
excluded from this analysis. 
(6) Time to response (centrally assessed) will be calculated based on assessment by the central 
imaging analysis facility with the following formula: 
 
Time to response (days) = (the date of the first confirmed CR or PR) - (the first dose date 
of investigational product) + 1 
Subjects who are not evaluated confirmed CR or PR at any time during the study will be excluded 
from this analysis. 
 (7) Percent change in tumor diameter of target lesion (investigator-assessed) 
With regard to the tumor diameter (sum of the longest diameters of target lesions) evaluated by a 
investigator at the trial site according to RECIST guideline version 1.1, the best percent change and 
percent change at each time point will be calculated using the following formulas. 
The calculation of the best percent change will not include the longest diameters of target lesions 
measured after the overall response is assessed as PD; any subsequent anti-cancer therapy is performed 
for non-small-cell lung cancer; or subsequent anti-cancer therapy follow-up is ended. The percent 
change at each time point will be calculated also after the overall response is assessed as PD but will 
not after any subsequent anti-cancer therapy for non-small-cell lung cancer or the outcome follow-up is 
ended. 
 Best percent change = 
Smallest tumor diameter after first dose – Baseline tumor diameter 
x 100 
Baseline tumor diameter 


 
 
 
 
50 
 
 Percent change = 
Tumor diameter at evaluation point – Baseline tumor diameter 
x 100 
Baseline tumor diameter 
Subjects without measurable lesion or without any tumor assessment after first dose will be excluded 
from this analysis. 
 
9.2.4 
Analysis Methods  
With regard to the analysis items shown in 1) under Section 9.1.3 Analysis Items and Data Handling, 
the following analyses will be performed. The analysis results will be summarized by squamous NSCLC 
and non-squamous NSCLC separately and totality. 
1)  Response rate (investigator-assessed) and its 95% confidence interval (Wilson) will be calculated. 
2)  The following analyses will be performed for overall survival and time to progression. 
 
A Kaplan-Meier curve will be plotted for each analysis variable. The median and its 95% confidence 
interval and overall survival rates at 6, 12, 18 and 24 months and its 95% confidence interval will 
be estimated by Kaplan-Meier method. 6, 12, 18 and 24 months will be calculated assuming 30.4375 
days for one month. 
3)  The following analyses will be performed for progression free survival.  
 
Two Kaplan-Meier curves will be plotted based on the interpretation by the image central analysis 
laboratory and that by an investigator at the trial site. The median progression free survival, its 95% 
confidence interval and progression free survival rates at 3, 6, 9 and 12 months and its 95% 
confidence interval will be estimated by Kaplan-Meier method. 3, 6, 9 and 12 months will be 
calculated assuming 30.4375 days for one month. 
4)  Summary statistics will be calculated for duration of response. The median and its 95% confidence 
interval and duration of response rates at 6 and 12 months and its 95% confidence interval will be 
estimated by Kaplan-Meier method. 6 and 12 months will be calculated assuming 30.4375 days for 
one month. 
5)  Summary statistics will be calculated for time to response. The median and its 95% confidence 
interval will be estimated by Kaplan-Meier method. 
6)  For best overall response, the percentages of CR, PR, SD, PD, and NE will be calculated based on 
the interpretation by the image central analysis laboratory and that by an investigator at the trial site. 
In addition, the 95% confidence intervals (Wilson) will be calculated in CR, PR and SD. 
7)  Waterfall plot will be displayed for best percent change in tumor diameter of target lesion. In 
addition, a plot of individual subjects' percent change in tumor diameter of target lesion will be 
displayed at individual time point.  


 
 
 
 
51 
 
 
9.2.5 
Subgroup Analysis of Efficacy Endpoint  
The response rate (centrally assessed) as the primary endpoint will be analyzed in subgroups defined 
by risk factors. 
1) Analysis Item 
Response rate (centrally assessed) 
2) Data Handling 
Background factors shown in Section 12.4 Subgroup Definitions will be used as risk factors. 
Classification according to risk factors will be based on clinical significance or dividing the sample size 
into two or three nearly equal parts etc. 
3) Analysis Methods 
The response rate (centrally assessed) and its 95% confidence intervals (Wilson) will be calculated 
for each subgroup. The analysis results will be summarized by squamous NSCLC and non-squamous 
NSCLC separately and totality. 
 
 
 


 
 
 
 
52 
 
10 
SAFETY EVALUATION 
Unless otherwise noted, safety data to be tabulated will be those observed during the period for 28 
days after the final dose (or until the start of subsequent anti-cancer therapy for non-small-cell lung 
cancer after the final dose, whichever comes first). 
 
10.1 
Adverse Events 
10.1.1 
Analysis Set 
Analysis will be performed in SAF. 
 
10.1.2 
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 final dose (or until the start of subsequent anti-
cancer therapy for non-small-cell lung cancer after the final dose, whichever comes first after the final 
dose). In addition, all adverse events that occur during the treatment period or the subsequent anti-cancer 
therapy 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/incapacitating’) or grade 5 (‘Death related to adverse event’) based on 
the maximum intensity. With respect to the relationship to study drug, ‘Related’ will be regarded as 


 
 
 
 
53 
 
related, and ‘Not related’ will be regarded as unrelated. If the relationship is unclear due to a missing, 
the relationship to study drug is considered as ‘Related’. 
(1) Time to a Grade 3 or higher adverse event will be calculated using the following formula. 
 Time to a Grade 3 or higher adverse event (days) = (date of the onset of the Grade 3 or higher 
adverse event, or the date of worsening to Grade 3 or higher, whichever comes first) - (the 
first dose date of investigational product) + 1 
 
Data will be censored if the subject has no Grade 3 or higher adverse event at 28 days after 
the final dose (or at the start of subsequent anti-cancer therapy for non-small-cell lung cancer 
after the final dose, whichever comes first). 
(2) Time to a Grade 3 or higher adverse drug reaction will be also calculated in the same manner. 
(3) 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). 
Time to a select adverse event will be calculated by category using the following formula. 
 
Time to select adverse event (days) = (date of the onset of the earliest select adverse event 
in the category) – (the first dose date of investigational product) + 1 
 
Data will be censored if the subject has no select adverse event in any of the categories at 28 
days after the final dose (or at the start of subsequent anti-cancer therapy for non-small-cell 
lung cancer after the final dose, whichever comes first). 
(4) Time to select adverse drug reaction will be also calculated in the same manner. 
(5) Number of deaths 
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 final dose (or until the start of 
subsequent anti-cancer therapy for non-small-cell lung cancer after the final dose, whichever 
comes first). 
 
10.1.3 
Analysis Methods  
1) Overall Adverse Events, Adverse Drug Reactions and Number of Deaths 
(1) The analysis results will be summarized by squamous NSCLC and non-squamous NSCLC 
separately and totality. 


 
 
 
 
54 
 
(2) The number of subjects (incidence rate) of the overall incidence will be provided for all adverse 
events and adverse drug reactions). The data will be displayed as “subject number (incidence of 
subjects (%))”. 
(3) 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) The analysis results will be summarized by squamous NSCLC and non-squamous NSCLC 
separately and totality. 
(2) Adverse events and adverse drug reactions will be summarized by SOC, PT and CTCAE grade 
(grade 1, 2, 3, 4, and 5). The data will be displayed as “subject number (incidence of subjects 
(%))”.  
(3) Incidences of adverse events and adverse drug reactions by SOC and PT will be summarized. In 
addition, incidences of adverse events and adverse drug reactions will be summarized by SOC, 
PT and CTCAE grade (any grade, grade 3 or 4, grade 5). And adverse events and adverse drug 
reactions with an incidence at or above a certain level will be summarized by SOC, PT and 
CTCAE grade (any grade, grade 3 or 4, grade 5). 
(4) Incidences of adverse events and adverse drug reactions leading to death will be summarized by 
SOC and PT. 
(5) Incidences of adverse events and adverse drug reactions leading to discontinuation of the study 
treatment will be summarized by SOC, PT and CTCAE grade (any grade, grade 3 or 4, grade 5). 
(6) Incidences of adverse events and adverse drug reactions leading to interruption of the 
investigational product will be summarized by SOC, PT and CTCAE grade (any grade, grade 3 
or 4, grade 5). 
(7) Incidences of serious adverse events and adverse drug reactions will be summarized by SOC, PT 
and CTCAE grade (any grade, grade 3 or 4, grade 5).  
(8) Incidences of select adverse events and adverse drug reactions will be summarized by categories, 
PT and CTCAE grade (any grade, grade 3 or 4, grade 5). 
(9) Incidences of select adverse events and adverse drug reactions leading to discontinuation will be 
summarized by categories, PT and CTCAE grade (any grade, grade 3 or 4, grade 5). 
(10) Incidences of serious select adverse events will be summarized by categories, PT and CTCAE 
grade (any grade, grade 3 or 4, grade 5). 


 
 
 
 
55 
 
(11) Kaplan-Meier curves will be presented for time to onset of select adverse events and adverse 
drug reactions. Kaplan-Meier curves will also be displayed for time to onset of Grade 3 or higher 
adverse events and adverse drug reactions. 
 
10.1.4 
Subgroup Analysis of Safety Endpoints 
Incidences of select adverse events and adverse drug reactions will be analyzed in subgroups. Risk 
factors and classification methods using these factors will be based on items established in Section 9.2.5 
Subgroup Analysis of Efficacy Endpoint. The analysis results will be summarized by squamous NSCLC 
and non-squamous NSCLC separately and totality. 
 
10.2 
Clinical Laboratory Evaluation 
10.2.1 
Analysis Set 
Analysis will be performed in SAF.  
 
10.2.2 
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. The analysis period of clinical 
laboratory evaluation is treated as well as adverse events. 


 
 
 
 
56 
 
Any laboratory values that fall below the detection or quantification limit will be imputed to be the 
detection or quantification limit. The laboratory values will be summarized by Grade, if necessary, 
according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-
CTCAE) version 4.0. 
 
10.2.3 
Analysis Methods  
1) The analysis results will be summarized by squamous NSCLC and non-squamous NSCLC separately 
and totality. 
2) For laboratory values and the change from baseline 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, while frequency distribution will be created for 
laboratory values on an ordinal scale.  
3)  Frequency distribution of abnormal laboratory values will be calculated at each time point. 
4) A Grade shift table will be prepared for changes in hemoglobin, platelet count, white blood cell count, 
neutrophil count, lymphocyte count, ALT (GPT), AST (GOT), ALP, total bilirubin and creatinine 
from baseline to the worst value observed during the period from the first dose of the study drug 
until 28 days after the final dose (or until the start of subsequent anti-cancer therapy for non-small-
cell lung cancer after the final dose, whichever comes first). 
5) Frequency distribution will be calculated for subjects whose liver function test values meet any of 
the following criteria. 
(1) ALT or AST > 3 times ULN (Upper Limit of Normal), 5 times ULN, 10 times ULN, 20 times 
ULN 
(2) Total bilirubin > 2 times ULN 
(3) ALT or AST > 3 times ULN and total bilirubin within 1 day > 2 times ULN 
(4) ALT or AST > 3 times ULN and total bilirubin within 30 days > 2 times ULN 
(5) ALT or AST > 3 times ULN, total bilirubin within 1 day ≥ 2 times ULN, and ALP < 2 times ULN 
 
 
10.3 
Immunologic Test 
10.3.1 
Analysis Set 
Analysis will be performed in SAF. 
 
10.3.2 
Analysis Items and Data Handling  
1)  Analysis Items 


 
 
 
 
57 
 
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. The analysis period of 
immunologic test is treated as well as adverse events. 
Any immunologic test values that fall below the detection or quantification limit will be imputed to 
be the detection or quantification limit. 
10.3.3 
Analysis Methods  
1) Summary statistics (no. of subjects, mean, standard deviation, median, minimum, and maximum) 
will be provided for immunologic test values and the change from baseline as continuous quantities, 
while frequency distribution will be created for those on an ordinal scale. 
2) Frequency distribution of abnormal immunologic test values will be calculated at each time point.  
3) The analysis results will be summarized by squamous NSCLC and non-squamous NSCLC separately 
and totality.  
 
10.4 
Hormonal Test 
10.4.1 
Analysis Set 
Analysis will be performed in SAF. 
 
10.4.2 
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. The analysis period of hormonal 
test is treated as well as adverse events. 
Any hormonal test values that fall below the detection or quantification limit will be imputed to be 
the detection or quantification limit. 
 
10.4.3 
Analysis Methods  
1) The analysis results will be summarized by squamous NSCLC and non-squamous NSCLC separately 
and totality.  
2) Summary statistics (no. of subjects, mean, standard deviation, median, minimum, and maximum) 
will be provided for each hormonal test parameter value and the change from baseline by the time 
of measurement. 


 
 
 
 
58 
 
3) Frequency distribution of abnormal hormonal test values will be calculated at each time point. 
4) Frequency distribution will be calculated for subjects whose thyroid function test values meet any of 
the following criteria. 
(1) TSH > ULN 
(2) TSH > ULN with TSH ≤ ULB at Baseline 
(3) TSH > ULN with at least one FT3/FT4 test values < LLN (Lower Limit of Normal) 
(4) TSH > ULN with all other FT3/FT4 test values ≥ LLN 
(5) TSH > ULN with FT3/FT4 test missing 
(6) TSH < LLN 
(7) TSH < LLN with TSH ≥ LLN at Baseline 
(8) TSH < LLN with at least one FT3/FT4 test values > ULN 
(9) TSH < LLN with all other FT3/FT4 test values ≤ ULN 
(10) TSH < LLN with FT3/FT4 test missing 
 
10.5 
Vital Signs  
10.5.1 
Analysis Set 
Analysis will be performed in SAF.  
 
10.5.2 
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.  
 
10.5.3 
Analysis Methods  
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. The analysis results will be 
summarized by squamous NSCLC and non-squamous NSCLC separately and totality. 
 
10.6 
12-lead ECG 
10.6.1 
Analysis Set 
Analysis will be performed in SAF.  


 
 
 
 
59 
 
 
10.6.2 
Analysis Items and Data Handling  
1)  Analysis Items 
Heart rate, RR interval, QT interval, QTcF, PR interval, QRS width. 
2)  Data Handling 
12-lead ECG data will be analyzed as observed without imputing missing data. 
QTcF will be calculated using the following compensation formula. 
QTcF (ms) = QT interval / (RR interval)1/3. 
 
10.6.3 
Analysis Methods  
1) The analysis results will be summarized by squamous NSCLC and non-squamous NSCLC separately 
and totality. 
2) For 12-lead ECG parameters (observed values of RR interval, QT interval, Fridericia's corrected QT 
interval [QTcF], QRS width, and PR interval, and their changes from baseline [ΔQTcF, ΔQRS, and 
ΔPR]), observed value (HR) and change from baseline (ΔHR) of heart rate, summary statistics and 
frequency distribution for each category will be summarized at each time point. 
3) 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 
PR (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, QTcF (ms) 
(observed value) 
≤450, >450–480  
>480–500, >500 
ΔQTcF (ms) 
(change from baseline) 
≤30, >30–60, >60 


 
 
 
 
60 
 
11 
Anti-drug Antibody Analysis 
 
11.1 
Analysis Set 
Analysis will be performed in the Anti-drug Antibody Analysis Set. 
 
11.2 
Analysis Items and Data Handling  
1) Analysis Items 
Presence of the anti-ONO-4538 antibody 
2) Data Handling 
(1) Handling per sample 
Samples will be handled as follows. 
[1] Baseline positive samples 
Samples testing positive for anti-ONO-4538 antibodies at baseline. Subjects with at least one baseline 
neutralizing positive sample for anti-ONO-4538 antibodies including baseline positive ones. 
[2] Anti-ONO-4538 antibody-positive samples 
Samples were obtained within 100 days of final dose meeting either of the following criteria: 
1. Samples after the first dose of the investigational product (collected from subjects who 
tested negative for anti-ONO-4538 antibodies at baseline) testing positive for anti-ONO-
4538 antibodies. 
2. Samples after the first dose of the investigational product (collected from subjects who 
tested positive for anti-ONO-4538 antibodies at baseline) testing positive for anti-ONO-
4538 antibodies and with titers at least 4-hold higher than those at baseline. 
[3] Anti-ONO-4538 antibody-negative sample 
Samples after the first dose of the investigational product testing negative for anti-ONO-4538 
antibodies (excluding missing ones), including baseline negative samples (excluding missing ones). 
(2) Handling per subject 
[1] Baseline positive subjects 
Subjects with baseline positive samples as defined in (1) but subjects without any positive samples 
for anti-ONO-4538 antibodies after the first dose of the investigational product. And “baseline 
neutralizing positive” subjects with at least one positive sample for anti-ONO-4538 antibodies after the 
first dose of the investigational product including neutralizing ones within “baseline positive” subject. 
[2] Anti-ONO-4538 antibody-positive subjects 


 
 
 
 
61 
 
Subjects with at least one positive sample for anti-ONO-4538 antibodies after the first dose of the 
investigational product. They will be classified as follows. 
1. Persistent positive: Subjects with two or more samples collected at consecutive time points 
after the first dose of the investigational product and testing positive for anti-ONO-4538 
antibodies with a minimum interval of 16 weeks (there is a time window for one week) 
between the first and last positive samples. 
2. Only the last sample positive: Subjects for whom only the last sample is positive for anti-
ONO-4538 antibodies. 
3. Other positive: Other subjects (not meeting 1 or 2) with samples positive for anti-ONO-
4538 antibodies. 
4. Neutralizing positive: Subjects with at least one positive sample for anti-ONO-4538 
antibodies including neutralizing ones. 
[3] Anti-ONO-4538 antibody-negative subjects 
Subjects without any positive sample for anti-ONO-4538 antibodies after the first dose of the 
investigational product. 
 
11.3 
Analysis Methods  
The following will be calculated: the proportions of baseline positive subjects, anti-ONO-4538 
antibody-positive subjects and anti-ONO-4538 antibody-negative subjects in the Anti-drug Antibody 
Analysis Set; the proportions of “persistent positive” subjects, “only the last sample positive” subjects 
and "other positive" subjects among anti-ONO-4538 antibody-positive subjects; and if necessary, the 
proportion of “baseline neutralizing positive” subjects and “neutralizing positive” subjects among anti-
ONO-4538 antibody-positive subjects. The analysis results will be summarized by squamous NSCLC 
and non-squamous NSCLC separately and totality. 
 
 
 


 
 
 
 
62 
 
12 
GENERAL PRESENTATION OF SUMMARIES AND ANALYSES 
 
12.1 
Summary Statistics 
As summary statistics, mean, standard deviation, median, maximum, and minimum will be calculated 
unless otherwise noted. 
 
12.2 
Significance Level to Be Used  
No significance level is defined because no tests will be performed. 
 
12.3 
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 
Two decimal places 
Time from diagnosis date of primary disease 
to first dose date of the investigational 
product (days) 
Age (years) 
Height (cm) 
Weight (kg） 
BMI (kg/m2) 
Percent change in tumor diameter 
of target lesion (%) 
 


 
 
 
 
63 
 
∙ Laboratory values 
Integer value 
(No decimal places) 
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) 
Temperature (ºC) 
SpO2 (%) 
 
 
 
∙ 12-lead ECG  
Integer value 
(No decimal places) 
Heart rate (beats/min) 
RR interval (ms) 
QT interval (ms) 
QTcF (ms) 
PR interval (ms) 
QRS width (ms) 
 
 
 


 
 
 
 
64 
 
12.4 
Subgroup Definitions 
 
Item 
Classification 
Age (years) 
<65, 65 - <75, ≥75 
Sex 
Male or female 
Performance Status (ECOG) 
0, 1 
Brain metastasis 
Yes, No 
Bone metastasis 
Yes, No 
Stage 
IIIB, IV, recurrence, unknown or other 
NSCLC treatment history (Surgery) 
Yes, No 
NSCLC treatment history (Radiotherapy) 
Yes, No 
NSCLC treatment history (Number of 
treatment regimens) 
1, 2 
Presence of the anti-ONO-4538 antibody 
Positive(Persistent positive/ Only the last 
sample positive, Other positive), Baseline 
positive, Negative 
 
12.5 
Site Pooling Method 
NA 
 
12.6 
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.  
 
 
13 
INTERIM ANALYSIS 
No interim analysis will be performed 
 
 
 


 
 
 
 
65 
 
14 
DATA REVIEW 
 
14.1 
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. 
 
14.2 
Analysis Set 
Analysis will be performed in subjects receiving the study drug. 
 
14.3 
Analysis Items and Data Handling 
1)  Analysis Items 
(1) Background factors 
Demography  
(2) Efficacy endpoints 
Response rate and progression-free survival (investigator-assessed) 
(3) Safety endpoints 
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. 
 
14.4 
Analysis Methods 
1) The analysis results will be summarized by squamous NSCLC and non-squamous NSCLC separately 
and totality. 
2) Summary statistics and frequency distribution of background factors will be calculated, and 
classification will be decided. 
3) The response rate (investigator-assessed) and its 95% confidence interval (Wilson) will be calculated 
to examine the appropriateness of the analysis method. In addition, missingness will be evaluated 
as necessary. 
4) For progression-free survival (investigator-assessed), a Kaplan-Meier curve will be presented. In 
addition, using the Kaplan-Meier method, the median and its 95% confidence interval and 


 
 
 
 
66 
 
progression free survival rates at 3 and 6 months and its 95% confidence interval will be estimated 
for the validation of the analysis methods or handling of data. 
5) Incidences of adverse events will be calculated. In addition, incidences of adverse events by SOC or 
by PT will be summarized according to Grade.  
 
The above analyses were performed using the data obtained from 96 subjects treated with the study 
drug as of Feb. 27, 2015. 
 
 
 


 
 
 
 
67 
 
15 
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, analysis of the development of tumor diameter and evaluation of 
baseline characteristics will be performed. 
 
16 
SAS PROCEDURE FOR ANALYSIS 
16.1 
95% confidence interval (Wilson) 
PROC FREQ DATA=[Analysis data set]; 
 
TABLES [Binary data] / BINOMIAL(WILSON) alpha=0.05; 
 
BY [Histologic type]; 
RUN; 
 
16.2 
Kaplan-Meier curve 
PROC LIFETEST DATA= [Analysis data set] METHOD=KM CONFTYPE=LOGLOG; 
TIME [Time to onset of initial event or censoring] * [Censoring variable]([Censoring value]); 
STRATA [Histologic type]; 
RUN; 
 
17 
REFERENCES 
NA 
 
 


 
 
 
 
68 
 
Addendum 1 List of Select Adverse Events 
Category 
Subcategory 
Preferred Term 
Endocrine Adverse 
Events 
Adrenal disorder 
Adrenal insufficiency 
Adrenal suppression 
Blood corticotrophin decreased 
Blood corticotrophin increased 
Hypothalamic pituitary adrenal axis suppression 
Secondary adrenocortical insufficiency 
Diabetes 
Diabetes mellitus 
Diabetic ketoacidosis 
Latent autoimmune diabetes in adults 
Pituitary disorder 
Hypophysitis 
Thyroid disorder 
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 


 
 
 
 
69 
 
Hepatic Adverse Events 
Acute hepatic failure 
Alanine aminotransferase increased 
Aspartate aminotransferase increased 
Autoimmune hepatitis 
Bilirubin conjugated increased 
Blood bilirubin increased 
Drug-induced liver injury 
Gamma-glutamyltransferase increased 
Hepatic enzyme increased 
Hepatic failure 
Hepatitis 
Hepatitis acute 
Hepatotoxicity 
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 


 
 
 
 
70 
 
Skin Adverse Events 
Blister 
Dermatitis 
Dermatitis exfoliative 
Drug eruption 
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