ONO-4538 Multicenter, Open-label, Uncontrolled, Phase II Study in Advanced Non-small Cell Lung Cancer
Phase: PHASE2
Conditions: Advanced Non-small Cell Lung Cancer (NSCLC)
Sponsor: Ono Pharmaceutical Co., Ltd.

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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 
 
 
 

 
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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.