Clinical trial NCT02569242
Conditions: Esophageal Cancer
Sponsor: Ono Pharmaceutical Co. Ltd
Start date: 2015-12-14; Completion date: 2020-10-23
Enrollment: 419 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of study is to evaluate the efficacy and safety of Nivolumab in unresectable advanced or recurrent esophageal cancer patients who have failed in standard chemotherapies.

Detailed description:

Arms: arm 1: Nivolumab 240 mg/body solution intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends arm 2: Docetaxel: Intravenously administered at a dose of 75 mg/m2 every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends

OR

Paclitaxel: Intravenously administered at a dose of 100 mg/m2 weekly for 6 weeks followed by 2-week drug holiday until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends
Interventions: intervention 1: Nivolumab intervention 2: Docetaxel/Paclitaxel
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
 1 
ONO-4538 Phase III Study 
A Multicenter, Randomized, Open-label Study in Patients 
with esophageal Cancer refractory or intolerant to 
Combination Therapy with Fluoropyrimidine and 
Platinum-based Drugs 
Protocol 
Ono Pharmaceutical Co., Ltd. 
This study is being conducted in collaboration with co-development partner, Bristol-Myers Squibb 
(BMS): BMS IND Number: 126,406; EUDRACT Number: 2015-003339-36. 
Protocol No.: ONO-4538-24/BMS CA209473 
Version No.: 9.0 
Date of preparation: November 7, 2017 


 
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Confidentiality Statement 
This document is confidential and proprietary information of the company sponsoring the study and 
its global affiliates. By reviewing this document, you agree to keep it confidential and to use and 
disclose it solely for the purpose of assessing whether your organization will participate in and/or 
perform the proposed study. Any permitted disclosures will be made only on a confidential “need to 
know” basis within your organization or to your independent ethics committee(s).  
Any other use, copying, disclosure or dissemination of information in this document is strictly 
prohibited unless expressly authorized in writing by the sponsor. Any supplemental information 
(e.g., amendments) that may be added to this document is also confidential and proprietary to the 
sponsor and must be kept confidential in the same manner as the contents of this document. Any 
person who receives this document without due authorization from the sponsor is requested to 
return it to the sponsor or promptly destroy it. All other rights reserved. References to the sponsor 
in this protocol may apply to partners to which the sponsor has transferred obligations, e.g., a 
contract research organization (CRO). 
 


 
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Protocol Synopsis 
 
1 
Objective of the Study 
This is a multicenter, randomized, open-label, docetaxel- or paclitaxel-controlled study to evaluate the 
efficacy and safety of ONO-4538 in patients with esophageal cancer refractory or intolerant to 
combination therapy with fluoropyrimidine and platinum-based drugs. 
 
2 
Study Design 
A multicenter, randomized, open-label study 
 
2.1 Study Design 
This is a multicenter, randomized, open-label, docetaxel- or paclitaxel-controlled study where ONO-
4538 is administered at 2-week intervals for the treatment of patients with esophageal cancer 
refractory or intolerant to combination therapy with fluoropyrimidine and platinum-based drugs, with 
1 prior regimen to evaluate the efficacy and safety of ONO-4538. Patients will be randomized in a 1:1 
ratio to the ONO-4538 group or control group (docetaxel or paclitaxel), and will be stratified by 
region (Japan vs. rest of world) and number of organs with metastases (≤1 vs. ≥2) and expression of 
PD-L1 (≥1% vs. <1% or indeterminate). After randomization, the ONO-4538 group will receive 
ONO-4538 (240 mg at 2-week intervals) and the control group will receive docetaxel (75 mg/m2 at 3-
week intervals) or paclitaxel (100 mg/m2 weekly for 6 weeks in succession followed by a 2-week drug 
holiday). The primary endpoint is OS, based on which the superiority of ONO-4538 over the control 
group will be investigated. The study design overview is presented in Figure 2-1. 
 
 


 
5 
 
Figure 2-1 
Outline of Study Design 
 
3 
Subjects 
3.1 Subjects 
Patients with esophageal cancer who are refractory or intolerant to combination therapy with 
fluoropyrimidine and platinum-based drugs will be enrolled. 
 
3.2 Inclusion Criteria 
Having provided written consent before participation in the study, patients must fulfill all of the 
following criteria to be eligible for randomization. If a randomized subject does not meet any one of 
the following criteria before the first dose of the investigational product after randomization, the 
subject will not be started on the study treatment and will be withdrawn from the study. 
1. 
Sex: Male or female 
2. 
Age (at the time of informed consent): 20 years and older 
3. 
Patients with esophageal cancer and whose major lesion in the esophagus (if already resected, the 
major lesion in the esophagus prior to resection) satisfies the following criteria. For patients with 
multiple lesions, the deepest invasion by clinical diagnosis should be considered the major lesion. 
Lesions other than the major lesion should be considered as secondary lesions. Esophageal 
cancer in this study is defined as a cancer that has primarily developed from the esophagus. 
• 
Patients with a major lesion located in the cervical esophagus or thoracic esophagus (upper, 
middle, or lower thoracic region; including the esophagogastric junction) 
• 
Patients whose histological type of major lesion was pathologically proven squamous cell 
carcinoma or adenosquamous cell carcinoma (pathological diagnosis of secondary lesions 
in the esophagus is not mandatory). Note: adenosquamous is defined as an uncommon 
malignant esophageal neoplasm containing coexisting elements of infiltrating squamous 
cell carcinoma (SCC) and adenocarcinoma (AC) 
4. 
Patients who are refractory or intolerant to combination therapy with fluoropyrimidine and 
platinum-based drugs for esophageal cancer, have previously received 1 treatment regimen, and 
are not indicated for a radical resection. The definition of refractory should be defined as follows; 
and a therapy applicable to the following should be counted as 1 regimen. 
• 
Patients whose PD or recurrence was confirmed by imaging during their initial 
chemotherapy (including chemoradiation) or within 8 weeks after the last dose#1 of 
chemotherapy will be assessed as “refractory.” 


 
6 
 
• 
Patients who underwent a radical resection (R0 resection confirmed) in conjunction with 
chemotherapy including neo-adjuvant/adjuvant therapy and chemoradiation (including 
patients who underwent chemoradiation followed by salvage surgery) whose recurrence was 
confirmed by imaging within 24 weeks after the last dose#1 of chemotherapy will be 
determined as “refractory.” 
• 
If a CR (≥2 consecutive CRs confirmed by imaging after an interval of ≥4 weeks) was 
assessed as a result of the initial chemotherapy (including chemoradiation), patients whose 
recurrence was confirmed by imaging during the initial chemotherapy (including 
chemoradiation) or within 24 weeks after the last dose#1 of chemotherapy will be determined 
as “refractory.” 
#1 In case of chemoradiation, this will be the last dose of chemotherapy or the last radiation 
treatment, whichever occurs later.  
5. 
Patients who have at least 1 measurable or non-measurable lesion per the RECIST Guideline Ver. 
1.1 as confirmed by imaging within 28 days before randomization. The following requirements 
should also be satisfied: 
• 
The primary esophageal cancer should be deemed to be non-measurable lesion. 
• 
If patients only have lesions that were previously treated with radiation, the lesion should be 
limited to one with confirmed aggravation by imaging after radiation. 
• 
If patients have pericardial or pleural effusion or ascites only, the lesion should be limited to 
one with cytologically confirmed malignancy. 
6. 
ECOG Performance Status Score (see Appendix 3) 0 or 1 
7. 
Patients with a life expectancy of at least 3 months 
8. 
Patients must provide tumor tissue (stored tissue or tissue from the last biopsy) for analysis of 
PD-L1 expression. For patients who are unable to undergo another biopsy, stored tissue can be 
used for analysis. Tissue specimens must contain at least 100 evaluable tumor cells and must be 
available before the randomization. 
9. 
Patients whose latest laboratory data meet the below criteria within 7 days before randomization. 
If the date of the laboratory tests at the time of randomization is not within 7 days before the first 
dose of the investigational product, testing must be repeated within 7 days before the first dose of 
the investigational product, and these latest laboratory tests must meet the following criteria. Of 
note, laboratory data will not be valid if the patient has received a granulocyte colony-stimulating 
factor (G-CSF) or blood transfusion within 14 days before testing. 
• 
White blood cells ≥2,000/mm3 and neutrophils ≥1,500/mm3 


 
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• 
Platelets ≥100,000/mm3 
• 
Hemoglobin ≥9.0 g/dL 
• 
AST (GOT) and ALT (GPT) ≤3.0-fold the upper limit of normal (ULN) of the study site (or 
≤5.0-fold the ULN of the study site in patients with liver metastases) 
• 
Total bilirubin ≤1.5-fold the ULN of the study site 
• 
Creatinine ≤1.5-fold the ULN of the study site or creatinine clearance (either the measured 
or estimated value using the Cockcroft-Gault equation) >45 mL/min 
10. Women of childbearing potential (including women with chemical menopause or no 
menstruation for other medical reasons)#1 must agree to use contraception#2 from the time of 
informed consent until 5 months or more after the last dose of the investigational product. Also, 
women must agree not to breastfeed from the time of informed consent until 5 months or more 
after the last dose of the investigational product. 
11. Men must agree to use contraception#2 from the start of study treatment until 7 months or more 
after the last dose of the investigational product. 
 
#1 Women of childbearing potential are defined as all women after the onset of menstruation who 
are not postmenopausal and have not been surgically sterilized (e.g., hysterectomy, bilateral 
tubal ligation, bilateral oophorectomy). Postmenopause is defined as amenorrhea for ≥12 
consecutive months without specific reasons. Women using oral contraceptives, intrauterine 
devices, or mechanical contraception such as contraceptive barriers are regarded as having 
childbearing potential. 
#2 The subject must consent to use any two of the following methods of contraception: vasectomy 
or condom for patients who are male or female subject’s partner and tubal ligation, 
contraceptive diaphragm, intrauterine device, spermicide, or oral contraceptive for patients 
who are female or male subject’s partner.  
 
3.3 Exclusion Criteria 
Patients meeting any of the following criteria at the time of assessment for randomization will be 
excluded. If patients meet any of the following criteria prior to the first dose of the investigational 
product after randomization, the study treatment should not be initiated. 
 


 
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1. 
Patients with significant malnutrition. Patients will be excluded if they are receiving intravenous 
hyperalimentation, or require continuous infusion therapy with hospitalization. Patients whose 
nutrition has been well controlled for ≥28 days prior to randomization may be enrolled. 
2. 
Patients with apparent tumor invasion on organs located adjacent to the esophageal disease (e.g., 
the aorta or respiratory tract). Patients will be excluded if they are receiving stent therapy in 
esophagus or respiratory tract. 
3. 
Patients with multiple primary cancers (with the exception of completely resected basal cell 
carcinoma, stage I squamous cell carcinoma, carcinoma in situ, intramucosal carcinoma, or 
superficial bladder cancer, or any other cancer that has not recurred for at least 5 years) 
4. 
Patients with residual adverse effects of prior therapy or effects of surgery that would affect the 
safety evaluation of the investigational product in the opinion of the investigator or 
subinvestigator 
5. 
Patients with current or past history of severe hypersensitivity to any other antibody products 
6. 
Patients with concurrent autoimmune disease or history of chronic or recurrent autoimmune 
disease (see Appendix 4) 
7. 
Patients with a current or past history of interstitial lung disease or pulmonary fibrosis diagnosed 
based on imaging or clinical findings. Patients with radiation pneumonitis may be randomized if 
the radiation pneumonitis has been confirmed as stable (beyond acute phase) without any 
concerns about recurrence. 
8. 
Patients with concurrent diverticulitis or symptomatic gastrointestinal ulcerative disease 
9. 
Patients with any metastasis in the brain or meninx that is symptomatic or requires treatment. 
Patients may be randomized if the metastasis is asymptomatic and requires no treatment.  
10. 
Patients with pericardial fluid, pleural effusion, or ascites requiring treatment 
11. 
Patients with uncontrollable, tumor-related pain 
12. 
Patients who have experienced a transient ischemic attack, cerebrovascular accident, thrombosis, 
or thromboembolism (pulmonary arterial embolism or deep vein thrombosis) within 180 days 
before randomization 
13. 
Patients with a history of uncontrollable or significant cardiovascular disease meeting any of the 
following criteria: 
・ Myocardial infarction within 180 days before randomization 
・ Uncontrollable angina pectoris within 180 days before randomization 
・ New York Heart Association (NYHA) Class III or IV congestive heart failure 


 
9 
 
・ Uncontrollable hypertension despite appropriate treatment (e.g., systolic blood pressure 
≥150 mmHg or diastolic blood pressure ≥90 mmHg lasting 24 hours or more) 
・ Arrhythmia requiring treatment 
14. 
Patients receiving or requiring anticoagulant therapy for a disease. Patients receiving antiplatelet 
therapy including low-dose aspirin may be enrolled. 
15. 
Patients with uncontrollable diabetes mellitus 
16. 
Patients with systemic infections requiring treatment 
17. 
Patients with ≥ Grade 2 peripheral neuropathy 
18. 
Patients who have received systemic corticosteroids (except for temporary use, e.g., for 
examination or prophylaxis of allergic reactions) or immunosuppressants within 28 days before 
randomization 
19. 
Patients who have received antineoplastic drugs (e.g., chemotherapy agents, molecular-targeted 
therapy agents, or immunotherapy agents) within 28 days before randomization 
20. 
Patients who have undergone surgical adhesion of the pleura or pericardium within 28 days 
before randomization 
21. 
Patients who have undergone surgery under general anesthesia within 28 days before 
randomization 
22. 
Patients who have undergone surgery involving local or topical anesthesia within 14 days before 
randomization 
23. 
Patients who have received radiotherapy within 28 days before randomization, or radiotherapy to 
bone metastases within 14 days before randomization 
24. 
Patients who have received any radiopharmaceuticals (except for examination or diagnostic use 
of radiopharmaceuticals) within 56 days before randomization 
25. 
Patients with a positive test result for any of the following: HIV-1 antibody, HIV-2 antibody, 
HTLV-1 antibody, HBs antigen, or HCV antibody 
26. 
Patients with a negative HBs antigen test but a positive test result for either HBs antibody or HBc 
antibody with a detectable level of HBV-DNA 
27. 
Women who are pregnant or breastfeeding, or possibly pregnant 
28. 
Patients who have received any other unapproved drug (e.g., investigational use of drugs, 
unapproved combined formulations, or unapproved dosage forms) within 28 days before 
randomization 
29. 
Patients who have previously received taxane agents to treat esophageal cancer. Patients who 
were not proven refractory (see the definition of refractory in inclusion criteria 4) or intolerant to 


 
10 
 
taxane-based combination therapy and subsequently received fluoropyrimidine and platinum-
based combination therapy, and then proven refractory (see the definition of refractory in 
inclusion criteria 4) or intolerant may be randomized.  
30. 
Patients who are contraindicated to docetaxel and paclitaxel 
31. 
Patients who have previously received ONO-4538 (MDX-1106 or BMS-936558), anti-PD-1 
antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody, anti-CTLA-4 antibody 
or other therapeutic antibodies or pharmacotherapies for regulation of T-cells 
32. 
Patients judged to be incapable of providing consent for reasons such as concurrent dementia 
33. 
Other patients judged by the investigator or subinvestigator to be inappropriate as subjects of this 
study 
 
4 
Investigational Product 
4.1 Dosage, Administration, and Treatment Duration 
4.1.1 
Dosage, Administration, and Treatment Duration of ONO-4538 
ONO-4538 240 mg will be intravenously administered over 30 minutes at 2-week intervals. Six weeks 
will count as 1 cycle of treatment. Treatment will be continued until PD is assessed by the investigator 
or subinvestigator according to the RECIST Guideline Ver. 1.1. ONO-4538 will be administered at 
240 mg without any increase or decrease of the dose and when 11 or more days have passed since the 
last dose, i.e., at an interval of 10 days or more. 
For information regarding appropriate storage, handling, dispensing, and administration of ONO-4538, 
refer to the latest Investigator's Brochure and/or Reference Sheet for Pharmacy. 
 
4.1.2 
Dosage, Administration, and Treatment Duration of Docetaxel 
The initial dose of docetaxel is 75 mg/m2, which will be intravenously administered at 3-week 
intervals. Each cycle of treatment lasts 3 weeks. Treatment will be continued until PD is assessed by 
the investigator or subinvestigator according to the RECIST Guideline Ver 1.1. If the subject has had 
a ≥10% change in body weight from that measured at the initial dose, the dose should be adjusted. If 
the change is observed on the day of administration, the dose can be adjusted from the next 
administration onwards. Each dose should be similarly adjusted if a further body weight change of 
≥10% is observed after the previous change. The dose (mg) will be rounded to one decimal place. The 
recommended procedures for docetaxel administration are described below; however, it can be 
administered in accordance with the study site procedures. Docetaxel will be administered 
intravenously over at least 60 minutes in accordance with the package insert. Adverse reactions to 


 
11 
 
docetaxel must be treated appropriately with reference to local standards, such as the package insert 
and treatment guidelines. 
 
4.1.3 
Dosage, Administration, and Treatment Duration of Paclitaxel 
The initial dose of paclitaxel is 100 mg/m2, which will be administered once weekly for 6 consecutive 
weeks, followed by a 2-week drug holiday. This treatment cycle will be repeated until PD is assessed 
by the investigator or subinvestigator according to the RECIST Guideline Ver 1.1. There should be an 
interval of at least 5 days between the doses of paclitaxel. The dose on Day 1 of each cycle should be 
continued throughout that cycle as a rule. If the subject has had a ≥10% change in body weight from 
that measured at the initial dose, the dose should be adjusted. If the change is observed on the day of 
administration, the dose can be adjusted from the next administration onwards. Each dose should be 
similarly adjusted if a further body weight change of ≥10% is observed after the previous change. The 
dose (mg) will be rounded to one decimal place. The recommended procedures for paclitaxel 
administration are described below; however, it can be administered in accordance with the study site 
procedures. 
Paclitaxel will be administered intravenously through an in-line filter using a membrane filter of ≤0.22 
μm over 60 minutes in accordance with the package insert. Adverse reactions to paclitaxel must be 
treated appropriately with reference to local standards, such as the package insert and treatment 
guidelines. 
 
5 
Prior and Concomitant Therapies 
5.1 Prohibited Therapies During the Study Period 
5.1.1 
Prohibited Therapies During the Study Period (ONO-4538 Group) 
The following treatments are prohibited throughout the study period (i.e., after informed consent and 
until completion of the final examination stipulated by the protocol [with the exception of the outcome 
investigation]), unless absolutely necessary for medical reasons even after the examination at the end 
of the treatment phase (at discontinuation) has been completed. 
 
1. 
Immunosuppressants and corticosteroids1, 5 
2. 
Any antitumor therapies5 (including chemotherapy, molecular target therapy, and 
immunotherapy2) 
3. 
Surgical treatment for malignant tumors5 
4. 
(Chemo) radiotherapy5 


 
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5. 
Radiopharmaceuticals3, 5 
6. 
Bisphosphonates and anti-RANKL antibody products4 
7. 
Transplantation 
8. 
Other unapproved drugs5 (e.g., investigational use of drugs, unapproved combined formulations, 
and unapproved dosage forms) 
 
1 Corticosteroids may only be used topically (e.g., external, intra-articular, intranasal, ophthalmic, or 
inhalational use) or temporarily (e.g., for the treatment or prophylaxis of contrast medium allergy or 
AEs). 
2 These include local therapeutic agents such as picibanil. 
3 Use for examination or diagnostic use of radiopharmaceuticals is allowed. 
4 Treatment with bisphosphonates or anti-RANKL antibody products that has been ongoing since 
before the subject’s first dose of study treatment may be continued only if there are no changes 
made to the dosage and mode of administration. 
5 Before randomization, these therapies may be used unless they are performed in the respective 
periods specified in the exclusion criteria #18～24, 28. 
 
5.1.2 
Prohibited Therapies During the Study Period (Control Group) 
The following treatments are prohibited throughout the study period (i.e., after informed consent and 
until completion of the final examination stipulated by the protocol [with the exception of the outcome 
investigation]), unless absolutely necessary for medical reasons even after the examination at the end 
of the treatment phase (at discontinuation) has been completed. 
 
1. 
Immunosuppressants and corticosteroids1, 5 
2. 
Any antitumor therapies5 (including chemotherapy, molecular target therapy, and immunotherapy 
2) 
3. 
Surgical treatment for malignant tumors5 
4. 
(Chemo) radiotherapy5 
5. 
Radiopharmaceuticals3, 5 
6. 
Bisphosphonates and anti-RANKL antibody products4 
7. 
Transplantation 
8. 
Disulfiram, cyanamide, carmofur, and procarbazine hydrochloride (for the paclitaxel group only) 


 
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9. 
Other unapproved drugs5 (e.g., investigational use of drugs, unapproved combined formulations, 
and unapproved dosage forms) 
 
1 
Corticosteroids may only be used topically (e.g., external, intra-articular, intranasal, ophthalmic, or 
inhalational use) or temporarily (e.g., for the treatment or prophylaxis of contrast medium allergy 
or AEs). 
2 
These include local therapeutic agents such as picibanil. 
3 
Use for examination or diagnostic use of radiopharmaceuticals is allowed. 
4 
Treatment with bisphosphonates or anti-RANKL antibody products that has been ongoing since 
before the subject’s first dose of study treatment may be continued only if there are no changes 
made to the dosage and mode of administration. 
5 
Before randomization, these therapies may be used unless they are performed in the respective 
periods specified in the exclusion criteria #18～24, 28. 
 
5.2 Prophylactic Premedication 
5.2.1 
ONO-4538 Group 
In subjects who may experience infusion-related reactions to ONO-4538, prophylactic premedication 
with acetaminophen or diphenhydramine is recommended before administration of ONO-4538 for 
subjects who have experienced infusion reaction previously. 
 
5.2.2 
Docetaxel Group 
Follow recommendations per local SmPC/Package Insert. 
 
5.2.3 
Paclitaxel Group 
The following pretreatments are recommended to prevent the occurrence of serious hypersensitivity 
symptoms caused by paclitaxel. 
The following premedication should be completed approximately ≥30 minutes prior to administration 
of paclitaxel: intravenous doses of dexamethasone sodium phosphate injection (dexamethasone 8 mg), 
either ranitidine hydrochloride injection (ranitidine 50 mg) or famotidine injection (famotidine 20 mg), 
and oral diphenhydramine hydrochloride tablet (diphenhydramine hydrochloride 50 mg). 
The initial dose of dexamethasone is 8 mg. If hypersensitivity symptoms do not occur until the next 
administration or are not clinically significant, the dexamethasone dose may be reduced to half the 
initial dose (4 mg) from Week 2. If hypersensitivity symptoms are absent or clinically insignificant in 


 
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the subsequent weeks of administration, the dexamethasone dose may be further reduced by half, 
down to 1 mg. 
 
6 
Study Schedule and Observation Items 
6.1 Screening phase 
The screening phase will start when the subject has signed the informed consent form. Subjects who 
have provided consent will be enrolled in the study. Among the enrolled subjects, the investigator or 
subinvestigator will proceed with randomization of those fulfilling the criteria in Section 4.2 
“Inclusion Criteria” and not meeting any of the criteria in Section 4.3 “Exclusion Criteria” judged to 
be appropriate as subjects in this study. Protocol-specified evaluations and their schedule during this 
period are specified in Table 6-1, Table 6-2, and Table 6-3 (ONO-4538, docetaxel, and paclitaxel 
groups, respectively) in the protocol synopsis section. 
 
6.2 Treatment phase 
6.2.1 
ONO-4538 Group 
During the treatment phase, ONO-4538 will be administered every 2 weeks up to 3 doses. These 6 
weeks will count as one cycle. Study treatment may be repeated in subjects fulfilling the criteria in 
Section 7.1.2.1 “Criteria for Administration of ONO-4538” and not meeting any of the criteria in 
Section 7.1.4.1 “Criteria for Discontinuation of ONO-4538.” Protocol-specified evaluations and their 
schedule during this period are specified in Table 6-1 in the protocol synopsis section. 
6.2.2 
Docetaxel Group 
During the treatment phase, docetaxel will be administered every 3 weeks. This is defined as 1 cycle. 
Study treatment may be repeated in subjects fulfilling the criteria in Section 7.1.2.2 “Criteria for 
Administration of Docetaxel” and not meeting any of the criteria in Section 7.1.4.2 “Discontinuation 
Criteria for Docetaxel or Paclitaxel.” Protocol-specified evaluations and their schedule during this 
period are specified in Table 6-2 in the protocol synopsis section. 
 
6.2.3 
Paclitaxel Group 
Paclitaxel will be administered once weekly for 6 consecutive weeks, followed by a 2-week drug 
holiday. This is defined as 1 cycle. Study treatment may be repeated in subjects fulfilling the criteria 
in Section 7.1.2.3 “Criteria for Administration of Paclitaxel” and not meeting any of the criteria in 
Section 7.1.4.2 “Discontinuation Criteria for Docetaxel or Paclitaxel.” Protocol-specified evaluations 
and their schedule during this period are specified in Table 6-3 in the protocol synopsis section. 


 
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6.3 Follow-up phase 
All subjects meeting any of the criteria in Section 7.1.4 “Discontinuation Criteria” after administration 
of 
the 
investigational 
product 
will 
undergo 
end-of-treatment 
examination 
(at 
completion/discontinuation) and proceed to the follow-up phase. Protocol-specified evaluations and 
their schedule during the follow-up phase are specified in Table 6-1, Table 6-2, and Table 6-3 (ONO-
4538, docetaxel, and paclitaxel groups, respectively) in the protocol synopsis section. 


 
 
 
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6.4 Study Schedule 
Table 6-1 
Study Schedule for the ONO-4538 Group 
Item 
Screening 
phase1 
Treatment phase 
Post-treatment  
observation period 
Cycle 1 
Cycle ≥2 
End (or 
discontinuation) of the 
treatment phase2 
Examination 
28 days after 
the end of 
treatment 
phase2, 3 
Follow-up 
investigation 
Study day 
1 
8 
15 
29 
43 
1 
15, 29 
43 
Predose Postdose 
Allowable window (day/days) 
-7 to -1 
±0 
-3 to +3 
-3 to +7 
-6 to +7 
-6 to +7 
±0 
-6 to +7 
-6 to +7 
±3 
±7 
－ 
Written informed consent 
○4 
 
 
 
 
 
 
 
 
 
 
 
Demographic data, Eligibility check 
○ 
 
 
 
 
 
 
 
 
 
 
 
Administration of the investigational 
product5 
 
○ 
 
○ 
○ 
 
○6 
○ 
 
 
 
 
Viral tests 
○ 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testing7 
○ 
○ 
 
 
 
 
 
○8 
 
 
○ 
○ 
 
Performance Status 
○ 
 
○ 
○8 
○8 
○ 
○6, 8 
○8 
○ 
○ 
○ 
 
Vital signs and body weight measurement 
○ 
○2 
○9 
○9 
○8, 9 
○8, 9 
○ 
○6, 8 
○8, 9 
○ 
○ 
○ 
 
Chest X-ray10 
○ 
 
 
 
 
○ 
 
 
○ 
○ 
○ 
 
12-lead ECG 
○ 
○ 
 
 
 
○ 
○8, 11 
 
○11 
○ 
○ 
 
Hematology, biochemistry, and urinalysis 
○ 
 
○ 
○8 
○8 
○ 
○6, 8 
 
○ 
○ 
○ 
 
Immunological and hormone tests12 
○ 
 
 
 
 
○ 
 
 
○ 
○ 
○ 
 
Serum drug concentration 
 
○ 
 
 
○8 
 
○8, 13 
 
 
 
○14 
●15 
Anti-ONO-4538 antibody 
 
○ 
 
 
 
○8 
 
○8, 13 
 
 
 
○14 
●15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor tissue examination (PD-L1) 
○18 
 
 
 
 
 
 
 
 
●19 
 
 
 
 
 
 
 
 
 
 
Imaging (e.g., CT, MRI) 20 
○21 
○22 
○ 
○23 
○23 
Tumor markers24 
As needed 
Concomitant treatment and AE monitoring 
 
 
←→ 
○23, 25 
Outcome investigation 
 
○26 
Patient Reported Outcomes /  
Healthcare Resource Utilization 
○ 
 
 
 
 
 
○ 
 
 
○27 
○ 
 
○27 
○ indicates mandatory items; ● indicates optional items. 


 
 
 
17 
1. 
For viral tests, the latest available results obtained within 1 year before randomization may be used as an alternative. For immunological tests and hormone tests, the latest available results obtained within 
14 days before randomization may be used as an alternative. For imaging examinations (except chest X-ray), the latest available images obtained within 28 days before randomization may be used as an 
alternative. Tumor tissue must be obtained for analysis of PD-L1 expression. For the tumor tissue examination after informed consent, no allowable window is set for the timing of tumor tissue specimen 
collection and assessment before the start of study treatment, but a specimen collected after the end of prior treatment should be submitted as far as possible. 
 
2. 
The previous test results may be used as an alternative if the previous assessment has been done at the end of the treatment phase (at discontinuation) or within the allowable window of 28 days after the end 
of the treatment phase, unless new measurements are medically required. However, the data will be newly obtained if ≥2 days have passed since the previous vital signs measurement, ≥15 days have passed 
for imaging examinations (except chest X-ray), or ≥8 days have passed for other tests. Tests will be performed whenever medically indicated. 
3. 
If post-study treatment for esophageal cancer is started due to clinical necessity until 28 days after the end of the treatment phase, an examination 28 days after the end of the treatment phase will be 
conducted prior to the initiation of the post-study treatment. 
4. 
Administration of the investigational product should be started within 60 days after informed consent. 
5. 
There should be an interval of at least 10 whole days between 2 doses of the investigational product. Considering the day following a dose as the first day, the next dose may be administered on the 11th day 
or later. 
6. 
When continuation to the next cycle is decided based on examinations performed on Day 43 of the previous cycle, the next cycle should be started within the allowable window for the Day 43 time point of 
the previous cycle. The available data on Performance Status, vital signs, body weight, hematology tests, biochemistry tests, and urinalysis obtained on Day 43 of the previous cycle may be used as an 
alternative, unless new measurements are medically required. However, data will be newly obtained if ≥2 days have passed for vital signs or ≥8 days have passed for other tests. Tests will be performed 
whenever medically indicated. 
7. 
Women of childbearing potential will undergo serum or urine pregnancy testing, and the same testing method should be used throughout the study as far as possible. From Cycle 2 onwards, pregnancy 
testing will be performed within 7 days before administration of the investigational product. 
8. 
To be assessed before administration of the investigational product. 
9. 
No body weight measurement will be required. 
10. 
As necessary, unscheduled X-rays should be performed whenever an onset of respiratory disease is suspected based on clinical symptoms or findings or laboratory findings during the study period (i.e., 
after informed consent and until completion of the final examination stipulated by the protocol [with the exception of the outcome investigation]). 
11. 
To be performed only in Cycle 4. 
12. 
SP-D and KL-6 measurements at time points of evaluation as specifed in the screening, treatment and follow-up phases will be mandatory, but SP-D and KL-6 may be measured as necessary at other time 
points than these time points of evaluation in three phases. 
13. 
To be performed on Day 1 of Cycles 4 and 9. 
14. 
To be performed only in subjects proceeding to the follow-up phase by the end of Cycle 9. 
15. 
To be also measured at 6-12 weeks after the last dose of the investigational product as far as possible. 
16. 
 
 
17. 
This is applicable only to subjects discontinuing the study treatment before Cycle 2. 
18. 
For determination of PD-L1 expression before randomization, a sample test should be performed by the central laboratory. Subjects with stored tumor tissue specimens collected prior to the start of the 
study treatment can provide the stored specimens to the sponsor. Results of the testing must be available prior to randomization and will be used for stratification through the IWRS. Results will not be 
made available to the investigator/site staff or the subject. 
19. 
This tumor tissue specimen will be collected after completion of efficacy assessments for the subject. 
20. 
Tumor response will be assessed based on a cervico-thoraco-abdomino-pelvic CT or other imaging examinations. The same method should be used for the assessment of tumor response throughout the 
study. The RECIST Guideline Ver. 1.1 will be used to assess tumor response. Depending on clinical symptoms, the brain or bone metastasis status should be assessed based on diagnostic imaging data.  
21. 
If a brain or bone metastasis is clinically suspected before enrollment, a head CT/MRI or FDG-PET (or bone scintigraphy) must be performed to determine the presence or absence of brain or bone 
metastasis (within 28 days before randomization). 
22. 
Imaging examinations will be performed every 6 weeks (-6 to +7 days) from the start of Cycle 1 during the treatment phase. After a period of one year from the start of Cycle 1 (after the end of Cycle 9), 
imaging examinations will be performed every 12 weeks (2 cycles). Depending on clinical symptoms, the brain or bone metastasis status should be assessed based on diagnostic imaging data. 
23. 
For subjects who have an response assessment other than PD in accordance with the RECIST Guideline Ver. 1.1 (see Appendix 2) and have discontinued the treatment phase for safety reasons, imaging 
examinations will be continued as far as possible until either initiation of post-study treatment for esophageal cancer or assessment of PD or recurrence while continuing the follow-up investigations to 
collect data on any post-study treatment for esophageal cancer and the details of the treatment. 
24. 
In subjects with tumor marker levels above the ULN range, measurements of the tumor marker will be continued as far as possible and as frequently as needed. 
25. 
Monitoring for any AEs and concomitant treatments will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE 
for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE and treatment for the event will be continued at appropriate intervals 
until the event resolves, improves, or stabilizes and thus is judged not to require further follow-up. SAEs, IMAEs and any treatment for IMAEs are to be collected during the treatment period and for 100 
days following the last dose of investigational product. 
26. 
Outcome investigation (with collection of data on the date of death and cause of death if the patient died) should be conducted by direct contact or other means such as by telephone or letter, roughly every 6 
to 8 weeks but as frequently as required based on the occurrence of events. Updated information on survival status will be entered into the eCRF. The follow-up investigation will also collect data on any 
post-study treatment for esophageal cancer,  start date, and  details as far as possible. 
27. 
The Patient Reported Outcomes and Healthcare Resource Utilization will be administered every 6 weeks (-6 to +7 days) from the start of Cycle 1 until the end of the treatment phase and subsequently every 
12 weeks (-14 to +14 days) during the follow-up phase. 


 
 
 
18 
Table 6-2 
Study Schedule for the Docetaxel Group 
Item 
Screening 
phase1 
Treatment phase 
Post-treatment  
observation period 
Cycle 1 
Cycle ≥2 
End (or 
discontinuation) 
of the treatment 
phase2 
Examination 
28 days after 
the end of 
treatment 
phase2, 3 
Follow-up 
investigation 
Study day 
1 
8 
22 
1 
22 
Pre 
dose 
Post 
dose 
Allowable window (day/days) 
-7 to -1 
±0 
-3 to +3 
-6 to +7 
±0 
-6 to +7 
±3 
±7 
－ 
Written informed consent 
○4 
 
 
 
 
 
 
 
 
Demographic data, Eligibility check 
○ 
 
 
 
 
 
 
 
 
Administration of the investigational 
product 
 
○ 
 
 
○5 
 
 
 
 
Serological tests 
○ 
 
 
 
 
 
 
 
 
Pregnancy testing6 
○ 
○ 
 
 
 
○7 
 
○ 
○ 
 
Performance Status 
○ 
 
○ 
○ 
○5, 7 
○ 
○ 
○ 
 
Vital signs and body weight 
○ 
○2 
○8 
○8 
○ 
○5, 7 
○ 
○ 
○ 
 
Chest X-ray 9 
○ 
 
 
○ 
 
○ 
○ 
○ 
 
12-lead ECG 
○ 
○ 
 
○ 
○7, 10 
○10 
○ 
○ 
 
Hematology, biochemistry, and 
urinalysis 
○ 
 
○ 
○ 
○5, 7 
○ 
○ 
○ 
 
Immunological and hormone tests11 
○ 
 
 
○ 
 
○ 
○ 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor tissue examination (PD-L1) 
○15 
 
 
 
 
 
●16 
 
 
 
 
 
 
 
Imaging (e.g., CT, MRI)17 
○18 
○19 
○ 
○20 
○20 
Tumor markers21 
As needed 
Concomitant treatment and AE 
monitoring 
 
 
←→ 
○20, 22 
Outcome investigation 
○23 
Patient Reported Outcomes /  
Healthcare Resource Utilization 
○ 
○24 
○ 
 
○24 
○ indicates mandatory items; ● indicates optional items. 


 
 
 
19 
1. 
For serological tests, the latest available results obtained within 1 year before randomization may be used as an alternative. For immunological tests and hormone tests, the latest available results obtained 
within 14 days before randomization may be used as an alternative. For imaging examinations (except chest X-ray), the latest available images obtained within 28 days before randomization may be used as 
an alternative. Tumor tissue must be obtained for analysis of PD-L1 expression. For the tumor tissue examination after informed consent, no allowable window is set for the timing of tumor tissue specimen 
collection and assessment before the start of study treatment, but a specimen collected after the end of prior treatment should be submitted as far as possible. 
 
2. 
The previous test results may be used as an alternative if the previous assessment has been done at the end of the treatment phase (at discontinuation) or within the allowable window of 28 days after the end 
of the treatment phase, unless new measurements are medically required. However, the data will be newly obtained if ≥2 days have passed since the previous vital signs measurement, ≥15 days have passed 
for imaging examinations (except chest X-ray), or ≥8 days have passed for other tests. Tests will be performed whenever medically indicated. 
3. 
If post-study treatment for esophageal cancer is started due to clinical necessity until 28 days after the end of the treatment phase, an examination 28 days after the end of the treatment phase will be 
conducted prior to the initiation of the post-study treatment. 
4. 
Administration of the investigational product should be started within 60 days after informed consent. 
5. 
When continuation to the next cycle is decided based on examinations performed on Day 22 of the previous cycle, the next cycle should be started within the allowable window for the Day 22 time point of 
the previous cycle. The available data on Performance Status, vital signs, body weight, hematology tests, biochemistry tests, and urinalysis obtained on Day 22 of the previous cycle may be used as an 
alternative, unless new measurements are medically required. However, data will be newly obtained if ≥2 days have passed for vital signs or ≥8 days have passed for other tests. Tests will be performed 
whenever medically indicated. 
6. 
Women of childbearing potential will undergo serum or urine pregnancy testing, and the same testing method should be used throughout the study as far as possible. From Cycle 2 onwards, pregnancy 
testing will be performed within 7 days before administration of the investigational product. 
7. 
To be assessed before administration of the investigational product. 
8. 
No body weight measurement will be required. 
9. 
As necessary, unscheduled X-rays should be performed whenever an onset of respiratory disease is suspected based on clinical symptoms or findings or laboratory findings during the study period (i.e., 
after informed consent and until completion of the final examination stipulated by the protocol [with the exception of the outcome investigation]). 
10. 
To be performed only in Cycle 7. 
11. 
SP-D and KL-6 measurements at time points of evaluation as specifed in the screening, treatment and follow-up phases will be mandatory , but SP-D and KL-6 may be measured as necessary at other time 
points than these time points of evaluation in three phases. 
12. 
 
 
13. 
To be performed only in Cycle 2. 
14. 
To be performed only when the study treatment is discontinued by Day 22 of Cycle 2. 
15. 
For determination of PD-L1 expression before randomization, a sample test should be performed by the central laboratory. Subjects with stored tumor tissue specimens collected prior to the start of the 
study treatment can provide the stored specimens to the sponsor. Results of the testing must be available prior to randomization and will be used for stratification through the IWRS. Results will not be 
made available to the investigator/site staff or the subject. 
16. 
This tumor tissue specimen will be collected after completion of efficacy assessments for the subject. 
17. 
Tumor response will be assessed based on a cervico-thoraco-abdomino-pelvic CT or other imaging examinations. The same method should be used for the assessment of tumor response throughout the 
study. The RECIST Guideline Ver. 1.1 will be used to assess tumor response.  
18. 
If a brain or bone metastasis is clinically suspected before enrollment, a head CT/MRI or FDG-PET (or bone scintigraphy) must be performed to determine the presence or absence of brain or bone 
metastasis (within 28 days before randomization). 
19. 
Imaging examinations will be performed every 6 weeks (-6 to +7 days) from the start of Cycle 1 during the treatment phase and every 12 weeks (-14 to +14 days) after a period of one year from the start of 
Cycle 1. Depending on clinical symptoms, the brain or bone metastasis status should be assessed based on diagnostic imaging data. 
20. 
For subjects who have an response assessment other than PD in accordance with the RECIST Guideline Ver. 1.1 (see Appendix 2) and have discontinued the treatment phase for safety reasons, imaging 
examinations will be continued as far as possible until either initiation of post-study treatment for esophageal cancer or assessment of PD or recurrence while continuing the follow-up investigations to 
collect data on any post-study treatment for esophageal cancer and the details of the treatment. 
21. 
In subjects with tumor marker levels above the ULN range, measurements of the tumor marker will be continued as far as possible and as frequently as needed. 
22. 
Monitoring for any AEs and concomitant treatments will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE 
for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE and treatment for the event will be continued at appropriate intervals 
until the event resolves, improves, or stabilizes and thus is judged not to require further follow-up. SAEs, IMAEs and any treatment for IMAEs are to be collected during the treatment period and for 100 
days following the last dose of investigational product. 
23. 
Outcome investigation (with collection of data on the date of death and cause of death if the patient died) should be conducted by direct contact or other means such as by telephone or letter, roughly every 6 
to 8 weeks but as frequently as required based on the occurrence of events. Updated information on survival status will be entered into the eCRF. The follow-up investigation will also collect data on any 
post-study treatment for esophageal cancer, start date, and details as far as possible. 
24. 
The Patient Reported Outcomes and Healthcare Resource Utilization will be administered every 6 weeks (-6 to +7 days) from the start of Cycle 1 until the end of the treatment phase and subsequently every 
12 weeks (-14 to +14 days) during the follow-up phase.  
 


 
 
 
20 
Table 6-3 
Study Schedule for the Paclitaxel Group 
Item 
Screening 
phase1 
 
Treatment phase 
Follow-up phase 
 
Cycle 1 
Cycle ≥2 
End (or 
discontinuation) 
of the treatment 
phase2 
Examination 
28 days after 
the end of 
treatment 
phase2, 3 
Follow-up 
investigation
Study day 
1 
8 
 
15, 22, 
29, 36 
43 
50 
1 
8, 15, 22, 
29, 36 
50 
Pre 
dose 
Post 
dose 
Allowable window (day/days) 
-7 to -1 
±0 
-1 to +3 
-2 to +3 
-2 to +3 
-6 to +7 
±0 
-2 to +3 
-6 to +7 
±3 
±7 
－ 
Written informed consent 
○4 
 
 
 
 
 
 
 
 
 
 
 
Demographic data, Eligibility check 
○ 
 
 
 
 
 
 
 
 
 
 
 
Administration of the investigational 
product 5 
 
○ 
○ 
○ 
 
 
○6 
○ 
 
 
 
 
Serological tests 
○ 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testing7 
○ 
○ 
 
 
 
 
 
○8 
 
○ 
○ 
 
Performance Status 
○ 
 
○8 
 
 
○ 
○6, 8 
○ 
○ 
○ 
 
Vital signs and body weight 
○ 
○2 
○9 
○8, 9 
○8, 9, 10 
 
○ 
○6, 8 
○8, 9, 10 
○ 
○ 
○ 
 
Chest X-ray 11 
○ 
 
 
 
 
○ 
 
○ 
○ 
○ 
 
12-lead ECG 
○ 
○ 
 
 
 
○ 
○ 8, 12 
○12 
○ 
○ 
 
Hematology, biochemistry, and 
urinalysis 
○ 
 
○8, 10 
○8, 10 
 
○ 
○6, 8 
○8, 10 
○ 
○ 
○ 
 
Immunological and hormone tests13 
○ 
 
 
 
 
○ 
 
○ 
○ 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor tissue examination (PD-L1) 
○16 
 
 
 
 
 
 
 
 
●17 
 
 
 
 
 
 
 
 
 
 
Imaging (e.g., CT, MRI)18 
○19 
○20 
○ 
○21 
○21 
Tumor markers22 
 
As needed 
Concomitant treatment and AE 
monitoring 
 
 
←→ 
○21, 23 
Outcome investigation 
 
 
○24 
Patient Reported Outcomes /  
and Healthcare Resource Utilization 
○ 
○25 
○ 
 
○25 
○ indicates mandatory items; ● indicates optional items. 


 
 
 
21 
1. 
For serological tests, the latest available results obtained within 1 year before randomization may be used as an alternative. For immunological tests and hormone tests, the latest available results obtained 
within 14 days before randomization may be used as an alternative. For imaging examinations (except chest X-ray), the latest available images obtained within 28 days before randomization may be used as 
an alternative. Tumor tissue must be obtained for analysis of PD-L1 expression. For the tumor tissue examination after informed consent, no allowable window is set for the timing of tumor tissue specimen 
collection and assessment before the start of study treatment, but a specimen collected after the end of prior treatment should be submitted as far as possible. 
 
2. 
The previous test results may be used as an alternative if the previous assessment has been done at the end of the treatment phase (at discontinuation) or within the allowable window of 28 days after the end 
of the treatment phase, unless new measurements are medically required. However, the data will be newly obtained if ≥2 days have passed since the previous vital signs measurement, ≥15 days have passed 
for imaging examinations (except chest X-ray), or ≥8 days have passed for other tests. Tests will be performed whenever medically indicated. 
3. 
If post-study treatment for esophageal cancer is started due to clinical necessity until 28 days after the end of the treatment phase, an examination 28 days after the end of the treatment phase will be 
conducted prior to the initiation of the post-study treatment. 
4. 
Administration of the investigational product should be started within 60 days after informed consent. 
5. 
There should be an interval of at least 5 days between the doses. 
6. 
When continuation to the next cycle is decided based on examinations performed on Day 50 of the previous cycle, the next cycle should be started within the allowable window for the Day 50 time point of 
the previous cycle. The available data on Performance Status, vital signs, body weight, hematology tests, biochemistry tests, and urinalysis obtained on Day 50 of the previous cycle may be used as an 
alternative, unless new measurements are medically required. However, data will be newly obtained if ≥2 days have passed for vital signs or ≥8 days have passed for other tests. Tests will be performed 
whenever medically indicated. 
7. 
Women of childbearing potential will undergo serum or urine pregnancy testing, and the same testing method should be used throughout the study as far as possible. From Cycle 2 onwards, pregnancy 
testing will be performed within 7 days before administration of the investigational product. 
8. 
To be assessed before administration of the investigational product. 
9. 
No body weight measurement will be required. 
10. 
Check whether the dosing criteria and dose reduction criteria are met and whether the withdrawal criteria are fulfilled by performing vital signs measurements (systolic blood pressure, diastolic blood 
pressure, and body temperature), hematological tests (hemoglobin, white blood count, neutrophil count, and blood platelet count), and biochemical tests (albumin, AST, ALT, ALP, total bilirubin, Na, K, 
Ca, creatinine, and CRP) before treatment with the investigational product. 
11. 
As necessary, unscheduled X-rays should be performed whenever an onset of respiratory disease is suspected based on clinical symptoms or findings or laboratory findings during the study period (i.e., 
after informed consent and until completion of the final examination stipulated by the protocol [with the exception of the outcome investigation]). 
12. 
To be performed only in Cycle 3. 
13. 
SP-D and KL-6 measurements at time points of evaluation as specifed in the screening, treatment and follow-up phases will be mandatory, but SP-D and KL-6 may be measured as necessary at other time 
points than these time points of evaluation in three phases. 
14. 
 
 
15. 
To be performed only when the study treatment is discontinued by Day 43 of Cycle 1. 
16. 
For determination of PD-L1 expression before randomization, a sample test should be performed by the central laboratory. Subjects with stored tumor tissue specimens collected prior to the start of the 
study treatment can provide the stored specimens to the sponsor. Results of the testing must be available prior to randomization and will be used for stratification through the IWRS. Results will not be 
made available to the investigator/site staff or the subject. 
17. 
This tumor tissue specimen will be collected after completion of efficacy assessments for the subject. 
18. 
Tumor response will be assessed based on a cervico-thoraco-abdomino-pelvic CT or other imaging examinations. The same method should be used for the assessment of tumor response throughout the 
study. The RECIST Guideline Ver. 1.1 will be used to assess tumor response. Depending on clinical symptoms, the brain or bone metastasis status should be assessed based on diagnostic imaging data. 
19. 
Imaging examinations will be performed every 6 weeks (-6 to +7 days) from the start of Cycle 1 during the treatment phase and every 12 weeks (-14 to +14 days) after a period of one year from the start of 
Cycle 1. Depending on clinical symptoms, the brain or bone metastasis status should be assessed based on diagnostic imaging data. 
20. 
After a lapse of one year from the start of Cycle 1 (after the end of Cycle 9), imaging examinations will be performed every 12 weeks (2 cycles). 
21. 
For subjects who have an response assessment other than PD in accordance with the RECIST Guideline Ver. 1.1 (see Appendix 2) and have discontinued the treatment phase for safety reasons, imaging 
examinations will be continued as far as possible until either initiation of post-study treatment for esophageal cancer or assessment of PD or recurrence while continuing the follow-up investigations to 
collect data on any post-study treatment for esophageal cancer and the details of the treatment. 
22. 
In subjects with tumor marker levels above the ULN range, measurements of the tumor marker will be continued as far as possible and as frequently as needed. 
23. 
Monitoring for any AEs and concomitant treatments will be continued until 28 days after the end of the treatment phase. In subjects who, at the time of initiation of the follow-up investigation, have any AE 
for which a causal relationship to the investigational product cannot be ruled out or which led to discontinuation, investigation of the AE and treatment for the event will be continued at appropriate intervals 
until the event resolves, improves, or stabilizes and thus is judged not to require further follow-up. SAEs, IMAEs and any treatment for IMAEs are to be collected during the treatment period and for 100 
days following the last dose of investigational product. 
24. 
Outcome investigation (with collection of data on the date of death and cause of death if the patient died) should be conducted by direct contact or other means such as by telephone or letter, roughly every 6 
to 8 weeks but as frequently as required based on the occurrence of events. Updated information on survival status will be entered into the eCRF. The follow-up investigation will also collect data on any 
post-study treatment for esophageal cancer, start date, and details as far as possible. 
25. 
The Patient Reported Outcomes and Healthcare Resource Utilization will be administered every 6 weeks (-6 to +7 days) from the start of Cycle 1 until the end of the treatment phase and subsequently every 
12 weeks (-14 to +14 days) during the follow-up phase.  


 
 
22 
 
7 
Endpoints 
7.1 Efficacy Endpoints - Primary Endpoint 
Overall survival (OS) 
 
7.2 Efficacy Endpoints - Secondary Endpoints 
1. 
Objective response rate (ORR) 
2. 
Disease control rate (DCR) 
3. 
Progression free survival (PFS) 
4. 
Duration of response 
5. 
Time to response 
6. 
Best overall response (BOR) 
7. 
Maximum percent change from baseline in the sum of diameters of the target lesion 
 
7.3   Safety Endpoints 
1. 
Adverse events 
2. 
Clinical laboratory tests 
3. 
Vital signs 
4. 
12-lead ECG 
5. 
Chest X-ray 
6. 
Performance Status (ECOG) 
 
7.4 Pharmacokinetic Endpoint 
Serum ONO-4538 concentrations (for the ONO-4538 group only) 
 
7.5 Anti-drug Antibody Endpoint 
Anti-ONO-4538 antibody (for the ONO-4538 group only) 
 
7.6 Exploratory Biomarkers 
 
 
 
  
 
  
 
 
 
 


 
 
23 
 
6. 
Tumor tissue examination (PD-L1 expression analysis, essential; 
) 
 
7.7 Other Test Variables 
1. Tumor markers 
2. Patient reported outcomes (PROs) 
3. Healthcare Resource Utilization 
 
8 
Planned Sample Size 
The planned sample size for this study is 195 for each group, totaling 390.
 
 
 


 
 
24 
 
Table of Contents 
1 Background ..................................................................................................................................... 34 
1.1 
Introduction .............................................................................................................................. 34 
1.2 
Summary of Important Findings from Non-clinical and Clinical Studies ................................ 36 
1.2.1 
Summary of Non-clinical Data ....................................................................................... 36 
1.2.2 
Summary of Clinical Data and Summary of Known and Potential Risks and Benefits 
to Subjects ....................................................................................................................... 38 
2 Study Organization and Roles ......................................................................................................... 40 
3 Objective of the Study ..................................................................................................................... 40 
3.1 
Primary Objective of the Study ................................................................................................ 40 
3.2 
Secondary Objectives of the Study .......................................................................................... 40 
4 Subjects ........................................................................................................................................... 41 
4.1 
Subjects .................................................................................................................................... 41 
4.2 
Inclusion Criteria ...................................................................................................................... 41 
4.3 
Exclusion Criteria ..................................................................................................................... 44 
5 Study Methods ................................................................................................................................ 47 
5.1 
Study Design ............................................................................................................................ 47 
5.1.1 
Study Design ................................................................................................................... 47 
5.1.2 
Planned Sample Size ....................................................................................................... 48 
5.2 
Method of Assigning Subjects to Treatment Groups ............................................................... 50 
5.2.1 
Method for investigational product allocation ................................................................ 50 
5.3 
Subject Enrollment Procedures ................................................................................................ 51 
5.4 
Blinding .................................................................................................................................... 52 
5.5 
Endpoints ................................................................................................................................. 52 
5.5.1 
Efficacy Endpoints .......................................................................................................... 52 
5.5.1.1 
Primary Endpoint ..................................................................................................... 52 
5.5.1.2 
Secondary Endpoints ................................................................................................ 52 
5.5.2 
Safety Endpoints ............................................................................................................. 52 
5.5.3 
Pharmacokinetic Endpoint .............................................................................................. 53 
5.5.4 
Anti-drug Antibody Endpoint ......................................................................................... 53 
5.5.5 
Exploratory Biomarkers .................................................................................................. 53 
5.5.6 
Other Test Variables ....................................................................................................... 53 
6 Investigational Products .................................................................................................................. 53 


 
 
25 
 
6.1 
Handling and Supply of Investigational Product ..................................................................... 54 
6.2 
Procedures for Investigational Product Accountability and Return of Unused 
Investigational products ........................................................................................................... 55 
6.2.1 
Investigational Product Storage and Management .......................................................... 55 
6.2.2 
Disposal of Investigational Products ............................................................................... 56 
6.2.3 
Return of Unused Investigational Products ..................................................................... 57 
7 Study Plan ....................................................................................................................................... 57 
7.1 
Investigational Product ............................................................................................................. 57 
7.1.1 
Dosage, Administration, and Treatment Duration .......................................................... 57 
7.1.1.1 
Dosage, Administration, and Treatment Duration of ONO-4538 ............................ 57 
7.1.1.2 
Dosage, Administration, and Treatment Duration of Docetaxel .............................. 59 
7.1.1.3 
Dosage, Administration, and Treatment Duration of Paclitaxel ............................... 59 
7.1.2 
Criteria for Administration of Investigational Product ................................................... 60 
7.1.2.1 
Criteria for Administration of ONO-4538 ................................................................ 60 
7.1.2.2 
Criteria for Administration of Docetaxel ................................................................. 61 
7.1.2.3 
Criteria for Administration of Paclitaxel .................................................................. 62 
7.1.3 
Dosage Reduction Criteria .............................................................................................. 63 
7.1.3.1 
Dosage Reduction Criteria for ONO-4538 ............................................................... 63 
7.1.3.2 
Dose Reduction Criteria for Docetaxel .................................................................... 63 
7.1.3.3 
Dose Reduction Criteria for Paclitaxel ..................................................................... 64 
7.1.4 
Discontinuation Criteria .................................................................................................. 64 
7.1.4.1 
Criteria for Discontinuation of ONO-4538 .............................................................. 64 
7.1.4.2 
Discontinuation Criteria for Docetaxel or Paclitaxel ............................................... 66 
7.2 
Prior and Concomitant Therapies ............................................................................................. 67 
7.2.1 
Prohibited Therapies During the Study Period ............................................................... 67 
7.2.1.1 
Prohibited Therapies During the Study Period (ONO-4538 Group) ........................ 67 
7.2.1.2 
Prohibited Therapies During the Study Period (Control Group) .............................. 68 
7.2.2 
Prophylactic Premedication ............................................................................................ 69 
7.2.2.1 
ONO-4538 Group ..................................................................................................... 69 
7.2.2.2 
Docetaxel Group ...................................................................................................... 69 
7.2.2.3 
Paclitaxel Group ....................................................................................................... 69 
7.3 
Discontinuation of the Supply of the Investigational Product .................................................. 70 
7.4 
Post-Study Access to Therapy .................................................................................................. 70 


 
 
26 
 
8 Study schedule and Observation Items ........................................................................................... 70 
8.1 
Study Schedule ......................................................................................................................... 70 
8.1.1 
Screening Phase .............................................................................................................. 70 
8.1.2 
Treatment Phase .............................................................................................................. 71 
8.1.2.1 
ONO-4538 Group ..................................................................................................... 71 
8.1.2.2 
Docetaxel Group ...................................................................................................... 71 
8.1.2.3 
Paclitaxel Group ....................................................................................................... 71 
8.1.3 
Follow-up Phase .............................................................................................................. 71 
8.2 
Observation Items .................................................................................................................... 72 
8.2.1 
Patient Demographics and Other Background Characteristics ....................................... 72 
8.2.2 
Details of Study Treatment and Concomitant Treatments .............................................. 73 
8.2.2.1 
Details of administration of the investigational product .......................................... 73 
8.2.2.2 
Details of Administration of Other Drugs and Concomitant Therapies ................... 73 
8.2.3 
Items related to Efficacy ................................................................................................. 73 
8.2.3.1 
Imaging Examination (with Measurements of Tumor Diameters and Assessment 
of Tumor Response) ................................................................................................. 74 
8.2.4 
Items related to Safety ..................................................................................................... 75 
8.2.4.1 
Vital Signs, Body Weight, and 12-lead ECG ........................................................... 75 
8.2.4.2 
Chest X-ray .............................................................................................................. 77 
8.2.4.3 
Laboratory Tests ....................................................................................................... 78 
8.2.4.4 
Pregnancy Testing (Only in Women of Childbearing Potential).............................. 80 
8.2.4.5 
Viral Tests ................................................................................................................ 81 
8.2.4.6 
ECOG Performance Status Score ............................................................................. 81 
8.2.4.7 
Adverse Events ......................................................................................................... 82 
8.2.5 
Serum Drug Concentration Measurements (ONO-4538 group only) ............................. 83 
8.2.6 
Anti-drug Antibody Measurements (ONO-4538 group only) ......................................... 84 
8.2.7 
Tumor Markers (As needed) ........................................................................................... 84 
8.2.8 
Patient Reported Outcomes (PROs), Healthcare Resource Utilization ........................... 85 
8.2.9 
Exploratory Biomarkers .................................................................................................. 85 
 
 
 
 
 
 
 
 


 
 
27 
 
 
 
8.2.9.6 
Tumor Tissue Examinations (some are essential) .................................................... 88 
8.2.10 
Follow-up Investigation .................................................................................................. 89 
8.2.11 
Lost to Follow-up ............................................................................................................ 90 
9 Adverse Events and Matters to Ensure the Safety of Subjects ........................................................ 90 
9.1 
Definition of Adverse Events ................................................................................................... 90 
9.2 
Definition of Immune-mediated Adverse Events ..................................................................... 91 
9.3 
Definition of Serious Adverse Events ...................................................................................... 92 
9.4 
Grading Criteria of Adverse Events ......................................................................................... 93 
9.5 
Assessment Criteria of Causal Relationship to the Investigational Product............................. 93 
9.6 
Event Outcome ......................................................................................................................... 94 
9.7 
Action Taken with the Investigational Product ........................................................................ 94 
9.8 
Any Treatment for Adverse Events .......................................................................................... 95 
9.9 
Actions to be Taken Following Onset of Any Serious Adverse Event .................................... 95 
9.10 Actions to be Taken Following Pregnancy .............................................................................. 96 
9.11 Actions to be Taken Following Overdose ................................................................................ 96 
9.12 Other Safety Considerations..................................................................................................... 97 
9.13 Provision of New Information .................................................................................................. 97 
10 Statistical Analysis .......................................................................................................................... 97 
10.1 Description of Statistical Analysis Methods including the Interim Analysis ........................... 97 
10.2 Independent Data Monitoring Committee ................................................................................ 97 
10.3 Significance Level to be Used .................................................................................................. 98 
10.3.1 
Efficacy ........................................................................................................................... 98 
10.3.2 
Safety .............................................................................................................................. 98 
10.4 Determination of Subjects included in Analysis ...................................................................... 98 
10.4.1 
Definitions of Analysis Sets ............................................................................................ 98 
10.4.1.1 
Enrolled Set（ENR） .............................................................................................. 98 
10.4.1.2 
Randomized Set（RND）／ITT ............................................................................. 98 
10.4.1.3 
SAF .......................................................................................................................... 98 
10.4.1.4 
ADA ......................................................................................................................... 98 
10.4.2 
Criteria for Handling of Subjects .................................................................................... 99 
10.4.2.1 
Disqualified Subjects ................................................................................................ 99 
10.4.2.2 
GCP Noncompiant Subjects ..................................................................................... 99 


 
 
28 
 
10.4.2.3 
Untreated Subjects .................................................................................................... 99 
10.4.2.4 
Incomlete Anti-Drug Antibody Subjects .................................................................. 99 
10.4.3 
Criteria for Handling of Time Points of Evaluation ........................................................ 99 
10.5 Analysis Methods ................................................................................................................... 100 
10.5.1 
Reliability of the Study ................................................................................................. 100 
10.5.1.1 
Inclusion and Exclusion for Analyses .................................................................... 100 
10.5.1.2 
Withdrawals and Dropouts ..................................................................................... 100 
10.5.2 
Details of Treatment with the Investigational Product .................................................. 100 
10.5.3 
Distribution of Patient Background Factors .................................................................. 100 
10.5.3.1 
Demographic Variables .......................................................................................... 100 
10.5.3.2 
Patient Background Characteristics ........................................................................ 100 
10.5.3.3 
Baseline Values of Observation ............................................................................. 101 
10.5.3.4 
Concomitant drugs and therapies ........................................................................... 101 
10.5.4 
Primary Efficacy Endpoint ............................................................................................ 101 
10.5.4.1 
Purpose of Analysis ................................................................................................ 101 
10.5.4.2 
Hypothesis .............................................................................................................. 101 
10.5.4.3 
Analytical Item and Data Handling ........................................................................ 101 
10.5.4.4 
Analytical Methods ................................................................................................ 101 
10.5.5 
Secondary Efficacy Endpoints ...................................................................................... 102 
10.5.5.1 
Purpose of Analysis ................................................................................................ 102 
10.5.5.2 
Analytical Items and Data Handling ...................................................................... 102 
10.5.5.3 
Analytical Methods, ............................................................................................... 104 
10.5.6 
Interaction Analysis ...................................................................................................... 105 
10.5.7 
Adjusted Analysis ......................................................................................................... 105 
10.5.8 
Analysis of safety .......................................................................................................... 105 
10.5.8.1 
Purpose of Analysis ................................................................................................ 105 
10.5.8.2 
Analytical methods ................................................................................................. 105 
10.5.9 
Data Reviews ................................................................................................................ 106 
10.5.10 Other Issues ................................................................................................................... 106 
11 Ethical Conduct of the Study ........................................................................................................ 106 
11.1 Good Clinical Practice ........................................................................................................... 106 
11.2 Institutional Review Board or Independent Ethics Committee (IRB/IEC) ............................ 107 
11.3 Privacy Protection for Subjects .............................................................................................. 107 


 
 
29 
 
12 Subject Informed Consent ............................................................................................................. 107 
12.1 Informed Consent ................................................................................................................... 107 
12.2 Withdrawal of Consent .......................................................................................................... 109 
13 Rules or Criteria for Withdrawing Individual Subjects from the Study or Discontinuing Parts 
of the Study or Entire Study .......................................................................................................... 109 
13.1 Rules or Criteria for Withdrawing Individual Subjects from the Study ................................. 109 
14 Study Management ........................................................................................................................ 110 
14.1 Compliance with the Protocol and Protocol Amendments ..................................................... 110 
15 Completion of Electronic Case Report Forms (eCRFs) ................................................................ 110 
15.1 eCRF ...................................................................................................................................... 110 
16 Monitoring .................................................................................................................................... 111 
17 Procedures to Ensure Compliance of Subject Medication and Other Stipulations ....................... 111 
18 Retention of Essential Documents ................................................................................................ 111 
18.1 Record Retention .................................................................................................................... 111 
19 Publication of Study Results ......................................................................................................... 112 
20 Literature references ...................................................................................................................... 113 
 
List of Tables 
Table 6-1 
Study Schedule for the ONO-4538 Group ............................................................... 16 
Table 6-2 
Study Schedule for the Docetaxel Group ................................................................ 18 
Table 6-3 
Study Schedule for the Paclitaxel Group ................................................................. 20 
Table 1 
List of abbreviations ................................................................................................ 31 
Table 6-1 
Description of Investigational Products ................................................................... 54 
Table 7.1.1.1-1 Exposure of ONO-4538 at steady state .................................................................... 58 
Table 7.1.3.2-1 Dose Criteria for Docetaxel ..................................................................................... 63 
Table 7.1.3.2-2 Dose Reduction Criteria for Docetaxel .................................................................... 63 
Table 7.1.3.3-1 Dose Criteria for Paclitaxel ..................................................................................... 64 
Table 7.1.3.3-2 Dose Reduction Criteria for Paclitaxel .................................................................... 64 
Table 9.2-1 
Preferred Terms of IMAEs ................................................................................... 91 
* Irrespective of being treated with immunosuppressive medications or not. .................................... 91 
 
List of Figures 
Figure 2-1 
Outline of Study Design ............................................................................................ 5 


 
 
30 
 
 
Appendix 1: Criteria and Definitions Used in This Study 
Appendix 2: Tumor Response Assessment Criteria Used in This Study 
Appendix 3: Performance Status Score (ECOG) 
Appendix 4: List of Autoimmune Diseases
 


 
 
31 
 
Table 1 List of abbreviations 
Abbreviation 
Unabbreviated term 
ACTH 
Adrenocorticotropic hormone 
ADCC 
Antibody-dependent cellular toxicity 
ADL 
Activities of daily living 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
(GPT) 
Alanine aminotransferase 
(glutamic pyruvic transaminase) 
ANA 
Antinuclear antibody 
AST 
(GOT) 
Aspartate aminotransferase 
(glutamic oxaloacetic transaminase) 
AUC 
Area under the plasma concentration-time curve 
BMI 
Body mass index 
BOR 
Best overall response 
BUN 
Blood urea nitrogen 
CD 
Cluster of differentiation 
CDC 
Complement-dependent cytotoxicity 
C3 
Beta-1C/beta-1A globulin 
C4 
Beta-1E globulin 
CHO 
Chinese hamster ovary 
CH50 
50% hemolytic complement 
CK(CPK) 
Creatine kinase (creatine phosphokinase) 
Cmax 
Maximum plasma concentration 
CR 
Complete response 
CRP 
C-reactive protein 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T lymphocyte-associated antigen 4 
DCR 
Disease control rate 
DNA 
Deoxyribonucleic acid 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EMR 
Endoscopic mucosal resection 
ENR 
Enrolled Set 
ESD 
Endoscopic submucosal dissection 
FDG-PET 
18F-fluorodeoxy glucose positron emission tomography 
free T3 
Free triiodothyronine 
free T4 
Free thyroxine 
GAD 
Glutamic acid decarboxylase 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony-stimulating factor 
HBc 
Hepatitis B core 
HBs 
Hepatitis B surface 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV-1 
Human immunodeficiency virus-1 
HIV-2 
Human immunodeficiency virus-2 


 
 
32 
 
Abbreviation 
Unabbreviated term 
 
 
 
 
 
 
 
 
 
 
HR 
Heart rate 
HTLV-1 
Human T-lymphotropic virus-1 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IFN-γ 
Interferon-gamma 
IgA 
Immunoglobulin A 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
IWRS 
Interactive Web Response System 
JCOG 
Japan Clinical Oncology Group 
KD 
Dissociation constant 
KL-6 
Krebs von den Lungen-6 
La 
Anti-SSB antibody 
LDH 
Lactate dehydrogenase 
LKM 
Liver kidney microsome 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MLR 
Human mixed lymphocyte reaction 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NYHA 
New York Heart Association 
OS 
Overall survival 
ORR 
Objective response rate 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PD-1 
Programmed cell death-1 
PD-L1 
Programmed cell death-ligand 1 
PD-L2 
Programmed cell death-ligand 2 
PS 
Performance status 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PK/PD 
Pharmacokinetics/pharmacodynamics 
PR 
Partial response 
PR interval 
PR interval on an electrocardiogram (atrioventricular conduction time) 
PT 
Preferred term 
QRS width 
QRS width on an electrocardiogram (ventricular activation time) 
QT interval 
QT interval on an electrocardiogram (duration of ventricular electrical 
systole) 
RA 
Rheumatoid factor 
RANKL 
Receptor activator of NF-κB ligand 
RECIST 
Response Evaluation Criteria in Solid Tumors 


 
 
33 
 
Abbreviation 
Unabbreviated term 
RNA 
Ribonucleic acid 
RND 
Randomized set 
Ro 
Anti-SSA antibody 
RR 
Ventricular rate 
SAE 
Serious adverse event 
SAF 
Safety set 
SD 
Stable disease 
SOC 
System organ class 
SP-D 
Pulmonary surfactant protein D 
SSA 
Sjogren syndrome A 
SSB 
Sjogren syndrome B 
TNM 
Tumor node metastasis 
TSH 
Thyroid-stimulating hormone 
UICC 
Unio Internationalis Contra Cancrum 
γ-GTP 
Gamma-glutamyl transpeptidase 
 


 
 
34 
 
1 
Background 
1.1 
Introduction 
The global number of deaths due to malignant tumors was estimated to have exceeded 8,200,000 in 
2012, of which the number of deaths due to esophageal cancer was 400,000, ranking 6th after lung, 
liver, gastric, colorectal, and breast cancers 1). The number of deaths due to malignant tumors in Japan, 
which ranks first among the causes of deaths in the country, was 364,872 (2013). Among these, the 
number of deaths due to esophageal cancer was 11,543 (2013), accounting for 3.2% of the total 
number of deaths due to malignant tumors 2). Esophageal cancer has a higher incidence in men than 
women at a ratio of about 6:1, and follows lung, gastric, colorectal, liver, and pancreatic cancers in 
terms of crude death rates in men. The number of patients with esophageal cancer was 23,119 in 2011 
3), with high rates in patients in their 60s to 70s of age, accounting for approximately 68% of the 
overall incidence 4). The numbers of deaths and patients are expected to increase in both sexes, up to 
13,100 and 24,900, respectively, from 2025-2029 5). Moreover, epidemiological information in Korea 
and Taiwan reveals that the estimated number of patients with esophageal cancer in Korea was 8314 
(2013) 6), and the annual number of newly-diagnosed patients in Taiwan was 2238 (2010) 7). These 
numbers are reportedly increasing. 
There are regional differences in the histological type and location of lesions of esophageal cancer. In 
Japan, the dominant histological type is squamous cell carcinoma, accounting for 88.7% of all 
esophageal cancers, and locations of lesions are most commonly found in the middle thoracic 
esophagus at a rate of 46.9% 4). Squamous cell carcinoma is also reportedly common in Asia including 
Taiwan. In contrast, adenocarcinomas are increasing in Western countries, which account for more 
than half of all histological types. The common locations of lesions include those of the lower chest, 
abdominal esophagus, and esophagogastric junction. Prognosis of squamous cell carcinoma is 
considered to be poorer than that of adenocarcinoma. The main risk factors of squamous cell 
carcinoma are drinking and smoking, and the risk is known to increase by a combination of both 8)-12). 
On the other hand, the main risk factors of adenocarcinoma are obesity and reflux esophagitis. It has 
been noted that adenocarcinomas may also be increasing in Japan due to its westernized lifestyle, etc 
13). 
To diagnose and treat esophageal cancer, various imaging tests on the depth of tumor invasion, lymph 
node metastasis, and distal metastasis are performed to determine disease progression (stage and type), 
and multimodal treatments with a combination of endoscopic treatment, surgical treatment, 
chemotherapy, and radiotherapy are provided. Treatment in patients without distal metastases is aimed 
at a radical cure by methods appropriate for their stage of cancer. Meanwhile, for patients with distal 


 
 
35 
 
metastases or those with a postoperative distant recurrence, combination therapy with cisplatin and 5-
FU (FP therapy) is recommended as the standard treatment, but it is not proven to prolong survival 15). 
Survival prolongation by docetaxel or paclitaxel commonly used as second-line treatment has been 
confirmed in esophageal adenocarcinoma but not in esophageal squamous cell carcinoma in 
comparative studies13) 16)-18) 27). The prognosis of patients treated solely by chemotherapy is poor with 
a 5-year survival rate of 8.6% 4). Comparing the 5-year relative survival rate in patients with distal 
metastases by cancer type, the survival rate of all cancer types is 11.8%, while that of esophageal 
cancer is as low as 4.3% followed by pancreatic, biliary/bile duct, hepatic/intrahepatic bile duct, and 
lung cancers 14). A triple-agent combination therapy with the addition of docetaxel to FP therapy has 
been recently investigated; however, chemotherapies including combination chemotherapy have their 
limits in terms of efficacy, so chemotherapy alone is only applied to patients with unresectable 
metastases 13). There are no other standard therapies for esophageal cancer if a patient becomes 
refractory or intolerant to standard therapies including FP therapy. Hence, a new agent for esophageal 
cancer is needed. 
ONO-4538, a human monoclonal antibody to the PD-1 (Programmed cell death-1, also known as 
CD279), was developed by Ono Pharmaceutical Co., Ltd. (Ono Pharmaceutical) and Medarex, Inc. 
(currently, Bristol-Myers Squibb Company [BMS]), and is now in the phase of clinical development 
by Ono Pharmaceutical and BMS. The PD-1 (or CD279) is a 55 kDa type 1 transmembrane protein 
and belongs to the CD28 immunoglobulin superfamily of T-cell co-stimulatory receptors including 
CD28, CTLA-4, ICOS, and BTLA. PD-1 is highly expressed on activated T-cells and B cells and is 
also expressed in varying degrees on memory T cell subsets. Two specific ligands for PD-1 have been 
identified: PD-L1 (also called B7-H1 or CD274) and PD-L2 (also called B7-DC or CD273). The 
binding of PD-1 with either of its ligands PD-L1 or PD-L2 has been suggested to negatively control 
the activation of T-cells in mice and humans 19)-21). ONO-4538 is approved for malignant melanoma 
and other indications in Japan, Korea, the US, Europe and so on, and also under development for 
various cancer types.  
PD-L1 and PD-L2 are expressed in tumor tissues in 43.9% of patients with esophageal cancer. 
Patients with PD-L1 and PD-L2 expression are reported to show poorer prognoses than those without 
expression 22). Based on phase I studies conducted in Japan and the US (ONO-4538-01 and 
CA209003), ONO-4538 is suggested to be effective for a wide range of tumor histological types, 
including squamous cell carcinomas and adenocarcinomas, the major histological types of esophageal 
cancer. A Japanese phase II study of ONO-4538 in patients with esophageal cancer refractory or 
intolerant to standard therapies (ONO-4538-07) is currently ongoing. This study has suggested that the 


 
 
36 
 
antitumor effect of ONO-4538 in esophageal cancer is sustainable for a long duration as in other types 
of cancer.  
Based on the above, ONO-4538 is suggested to demonstrate a long-term, persistent tumor response to 
esophageal cancer refractory or intolerant to standard therapies, and thus is expected to prolong 
survival. Therefore, we believe ONO-4538, that inhibits the binding of PD-1 with its ligand, can be a 
therapeutic agent for esophageal cancer with a novel mode of action, and planned this study to 
confirm the efficacy and safety of ONO-4538 in patients with esophageal cancer. 
 
1.2 
Summary of Important Findings from Non-clinical and Clinical Studies 
1.2.1 
Summary of Non-clinical Data 
ONO-4538 is a human monoclonal antibody that targets the human PD-1 receptor and is produced in 
Chinese hamster ovarian (CHO) cells via genetical combination technology. The drug substance is an 
aqueous solution of ONO-4538 that is clear or opalescent and colorless or pale yellow; fine particles 
may be slightly observed in the solution. The drug product is an aqueous injection containing 100 mg 
ONO-4538 in each vial and is stored away from light at 2 to 8°C. (refer to the Investigator’s Brochure 
for details).  
ONO-4538 specifically binds to the PD-1 receptor and has shown high affinity to human PD-1 and 
simian PD-1 with KD values of 3.06 nmol/L and 3.92 nmol/L, respectively. ONO-4538 in vitro 
inhibited the binding of PD-1 with PD-1 ligands (i.e., PD-L1 and PD-L2), and human mixed 
lymphocyte reaction (MLR) showed increases in T-cell proliferation and IFN-gamma production. In 
an evaluation system in which human peripheral blood mononuclear cells (PBMCs) collected from 
donors previously infected with cytomegalovirus (CMV) were re-stimulated with CMV antigen, 
ONO-4538 increased the antigen-induced production of IFN-gamma in a concentration-dependent 
manner. In monkeys vaccinated with HBsAg, SKMel and DNP-Ficoll, ONO-4538 increased anti-
SKMel cell specific antibody titers.  
In multiple models of allogeneic tumor-bearing mice, an anti-mouse PD-1 antibody, 4H2, 
demonstrated a delay of tumor growth, thereby documenting the antitumor effect of anti-PD-1 
antibody that blocks PD-1 ligand from binding to PD-1.  
On the basis of the above, ONO-4538 is believed to exert its antitumor effect by inhibiting the binding 
between PD-1 and PD-1 ligand, thereby enhancing the activity of antigen-specific T-cells, resulting in 
an increased immune response. 
 


 
 
37 
 
Effects of ONO-4538 on the central nervous system and cardiovascular system were studied in 
conscious monkeys with single-dose intravenous administration up to 50 mg/kg, which showed no 
effects on the general conditions, body temperature, heart rate, blood pressure or electrocardiogram. 
Also in multiple-dose toxicity studies in monkeys with administration of ONO-4538 either once 
weekly for 4 weeks or twice weekly for 13 weeks, no effects were shown on the general condition, 
body temperature, heart rate, blood pressure or electrocardiogram up to the highest dose of 50 mg/kg. 
Effects of ONO-4538 on the respiratory system were studied in the 4-week multiple-dose toxicity 
study and the 13-week multiple-dose intravenous toxicity study in monkeys, which showed no effects 
up to the highest dose of 50 mg/kg.  
 
After a single intravenous dose of ONO-4538 at 1, 10 and 50 mg/kg in monkeys, the AUC of ONO-
4538 in serum increased in a near dose-proportional manner. The steady-state volume of distribution 
(Vss) was similar to the volume of plasma, thereby indicating the distribution of ONO-4538 primarily 
in circulating blood. Serum ONO-4538 concentrations over time were lower in the anti-ONO-4538 
antibody-positive animals than in the anti-ONO-4538 antibody-negative animals. In a reproductive 
toxicity study in pregnant monkeys, ONO-4538 was detected in serum samples of neonates, indicating 
transmission of ONO-4538 to fetuses via the placenta of the mother.  
 
In a single-dose toxicity study in monkeys, no deaths or toxic changes were observed with ONO-4538 
up to the highest dose of 10 mg/kg. In a multiple-dose intravenous toxicity study in monkeys, no toxic 
changes were observed with ONO-4538 50 mg/kg administered once weekly for 4 weeks or twice 
weekly for 13 weeks. Thus, the no-observed-adverse-effect level in the 4-week and 13-week multiple 
dose toxicity studies was considered to be 50 mg/kg. In these studies, no changes suggestive of local 
irritation were observed at or around the intravenous administration site of ONO-4538 10 mg/mL 
given once weekly or twice weekly.  
 
In expanded prenatal and postnatal development studies using pregnant monkeys, ONO-4538 at 10 
mg/kg and above increased embryonic and fetal mortality during the third semester of gestationor 
increased neonatal mortality. However, no teratogenicity was observed, and no effects were shown on 
neonatal growth, behaviors, or immune function.  
 
Crossreactivity with monkey and human normal tissues, antibody-dependent cellular toxicity (ADCC) 
activity, complement-dependent cytotoxicity (CDC) activity, and cytokine production in human whole 


 
 
38 
 
blood were studied. The study on crossreactivity using monkey and human normal tissues showed 
positive reactions of the lymphocyte membrane of humans and monkeys known to express PD-1, and 
also showed unexpected positive reactions of the cytoplasm of pituitary hormone-producing cells in 
monkeys and humans. However, ONO-4538, which is an antibody product and thus does not pass 
through the cell membrane, is not considered to have direct action on the cytoplasm of pituitary 
hormone-producing cells. Moreover, the 4-week and 13-week multiple-dose toxicity studies in 
monkeys showed no abnormalities in pituitary hormone levels (TSH), pituitary weight, or 
histopathological findings of the pituitary gland.  
 
ONO-4538 did not show ADCC activity or CDC activity in activated human CD4-positive T-cells in 
the presence of effector cells (from human PBMCs) and human complements. ONO-4538 did not 
cause the production of cytokines in human whole blood.  
 
In monkeys given ONO-4538 in combination with a human anti-CTLA-4 monoclonal antibody 
ipilimumab or an anti-LAG-3 monoclonal antibody BMS-986016 repeatedly for 4 weeks, 
inflammatory changes were observed in the large intestine or the central nervous system, which were 
not observed with ONO-4538 alone. These findings indicate that co-administration of a T-cell 
activating agent with ONO-4538 can lead to excessive potentiation of T-cell immune response. 
 
1.2.2 
Summary of Clinical Data and Summary of Known and Potential Risks and 
Benefits to Subjects 
The efficacy, safety and pharmacokinetics (PK) of ONO-4538 have been evaluated in patients with 
cancers, including non-small-cell lung carcinoma, malignant melanoma, renal cell carcinoma, and 
esophageal carcinoma in phase I, II, and III studies sponsored by Ono Pharmaceutical or BMS. 
Ongoing clinical studies are evaluating ONO-4538 as monotherapy or in combination with 
chemotherapy agents, molecular-targeted agents or other immunotherapy agents.  
 
After single-dose administration, the PK of ONO-4538 was linear with dose-proportional increase 
within the dose range of 0.3 to 10 mg/kg. After multiple doses, the PK of ONO-4538 was linear with 
dose-proportional increase of the exposure within the dose range of 0.1 to 10 mg/kg. The elimination 
and distribution of ONO-4538 were similar across different doses. A PPK analysis (interim data) 
indicated no dependence of the clearance of ONO-4538 on tumor types within the dose range of 0.1 to 
10 mg/kg.  


 
 
39 
 
To date, approximately 8,600 subjects have received ONO-4538 as either monotherapy or in 
combination with other therapies. The safety profile of ONO-4538 monotherapy has been similar 
across different tumor types, and no dose dependency has been shown in the incidence of adverse 
events, severity, or causal relationship to the investigational product. However, inflammatory lung 
disease as an adverse event has been numerically more common in subjects with non-small-cell lung 
cancer than in subjects with other cancer types, in part because the relationship between ONO-4538 
and lung symptoms or changes in imaging findings on X-ray could be equivocal in some subjects with 
non-small-cell lung cancer.  
 
Ongoing clinical studies are evaluating the safety of the combination use of ONO-4538 with other 
agents, including ipilimumab, cytotoxic chemotherapy agents, angiogenesis inhibitors, and molecular-
targeted agents. Of these, the one being most actively developed is the combination of ONO-4538 
with ipilimumab for patients with non-small cell lung cancer, malignant melanoma and renal cell 
carcinoma. According to the data available to date, the safety profile of the combination therapy with 
ONO-4538 plus ipilimumab has been similar to that of either drug alone, but the incidence of adverse 
events was occasionally higher with the combination use of the two drugs.  
 
Efficacy and safety data from completed and ongoing Japanese and overseas clinical studies are 
provided in the current investigator’s brochure.  
 
Some subjects have been reported to have required long-term high-dose corticosteroid therapy or 
immunosuppressive therapy for the treatment of adverse events that could be related to ONO-4538, 
with rare onset of opportunistic infection after immunosuppressive therapy in 3 subjects. One of these 
3 subjects was a man with non-small-cell lung cancer, and during the use of ONO-4538 in 
combination with chemotherapy, he experienced corticosteroid-responsive pneumonitis. Immediately 
after completion of corticosteroid therapy, respiratory symptoms recurred, and a subsequent lung 
biopsy led to a diagnosis of invasive aspergillosis, without findings of pulmonary inflammation 
(pneumonitis). He died one week after the diagnosis of invasive aspergillosis. The second patient was 
a woman with non-small-cell lung cancer who, after receiving ONO-4538 monotherapy for more than 
24 weeks, experienced corticosteroid-responsive pneumonitis. Subsequently, respiratory symptoms 
recurred and a lung biopsy led to a diagnosis of Aspergillus pneumonia, without findings of 
pulmonary inflammation (pneumonitis). Aspergillus pneumonia resolved after antifungal treatment. 
The remaining patient was a man with renal cell carcinoma who, during the use of ONO-4538 in 


 
 
40 
 
combination with pazopanib, experienced corticosteroid-responsive pneumonitis. High-dose 
corticosteroid therapy was given with dose tapering for more than 2 months. Subsequently, symptoms 
recurred, and a specimen collected during bronchoscopy led to a diagnosis of Pneumocystis jirovecii 
pneumonia, which completely resolved after antimicrobial therapy. 
 
1. 
Japanese phase II study in patients with esophageal cancer (ONO-4538-07) 
ONO-4538-07 is a Phase 2, multicenter, open-label, uncontrolled study of nivolumab (3 mg/kg Q2W) 
in esophageal cancer refractory or intolerant to combination therapy with fluoropyrimidine, platinum, 
and taxane-based drugs conducted solely in Japan. As of the data cut-off date of 28-Feb-2015, efficacy 
has been evaluated in 64 treated subjects. ORR according to RECIST v1.1 was 15.7% (10 of 64 
subjects) by a central imaging assessment. The best overall response resulted in 1 CR (1.6%), 9 PR 
(14.1%), 17 SD (26.6%), 29 PD (45.3%), and 8 not estimable (12.5%) by central assessment at ONO 
imaging facilities. 
 
2 
Study Organization and Roles 
See Annex 1 “Study Organization.” 
Any revisions to Annex 1 will be made separately from protocol amendments. 
 
3 
Objective of the Study 
This is a multicenter, randomized, open-label, docetaxel- or paclitaxel-controlled study to evaluate the 
efficacy and safety of ONO-4538 in patients with esophageal cancer refractory or intolerant to 
combination therapy with fluoropyrimidine and platinum-based drugs. 
 
3.1 
Primary Objective of the Study 
To compare overall survival (OS) between the ONO-4538 group and control group (docetaxel or 
paclitaxel) in patients with esophageal cancer refractory or intolerant to combination therapy with 
fluoropyrimidine and platinum-based drugs 
 
3.2 
Secondary Objectives of the Study 
• 
To compare progression-free survival (PFS) between the ONO-4538 group and control group 
(docetaxel or paclitaxel) in patients with esophageal cancer refractory or intolerant to 
combination therapy with fluoropyrimidine and platinum-based drugs. 


 
 
41 
 
• 
To compare objective response rates between the ONO-4538 group and control group 
(docetaxel or paclitaxel) in patients with esophageal cancer refractory or intolerant to 
combination therapy with fluoropyrimidine and platinum-based drugs. 
 
4 
Subjects 
4.1 
Subjects 
Patients with esophageal cancer who are refractory or intolerant to combination therapy with 
fluoropyrimidine and platinum-based drugs will be enrolled. 
 
4.2 
Inclusion Criteria 
Having provided written consent before participation in the study, patients must fulfill all of the 
following criteria to be eligible for randomization. If a randomized subject is found not to meet any of 
the following criteria before the first dose of the investigational product, the subject will not be started 
on the study treatment and will be withdrawn from the study. 
1. 
Sex: Male or female 
2. 
Age (at the time of informed consent): 20 years and older 
3. 
Patients with esophageal cancer and whose major lesion in the esophagus (if already resected, the 
major lesion in the esophagus prior to resection) satisfies the following criteria. For patients with 
multiple lesions, the deepest invasion by clinical diagnosis should be considered the major lesion. 
Lesions other than the major lesion should be considered as secondary lesions. Esophageal 
cancer in this study is defined as a cancer that has primarily developed from the esophagus. 
• 
Patients with a major lesion located in the cervical esophagus or thoracic esophagus (upper, 
middle, or lower thoracic region; including the esophagogastric junction) 
• 
Patients whose histological type of major lesion was pathologically proven squamous cell 
carcinoma or adenosquamous cell carcinoma (pathological diagnosis of secondary lesions in 
the esophagus is not mandatory). Note: adenosquamous is defined as an uncommon 
malignant esophageal neoplasm containing coexisting elements of infiltrating squamous cell 
carcinoma (SCC) and adenocarcinoma (AC) 
4. 
Patients who are refractory or intolerant to combination therapy with fluoropyrimidine and 
platinum-based drugs for esophageal cancer, have previously received 1 treatment regimen, and 
are not indicated for a radical resection. The definition of refractory should be defined as follows; 
and a therapy applicable to the following should be counted as 1 regimen. 


 
 
42 
 
• 
Patients whose PD or recurrence was confirmed by imaging during their initial 
chemotherapy (including chemoradiation) or within 8 weeks after the last dose#1 of 
chemotherapy will be assessed as “refractory.” 
• 
Patients who underwent a radical resection (R0 resection confirmed) in conjunction with 
chemotherapy including neo-adjuvant/adjuvant therapy and chemoradiation (including 
patients who underwent chemoradiation followed by salvage surgery) whose recurrence was 
confirmed by imaging within 24 weeks after the last dose#1 of chemotherapy will be 
determined as “refractory.” 
• 
If a CR (≥2 consecutive CRs confirmed by imaging after an interval of ≥4 weeks) was 
assessed as a result of the initial chemotherapy (including chemoradiation), patients whose 
recurrence was confirmed by imaging during the initial chemotherapy (including 
chemoradiation) or within 24 weeks after the last dose#1 of chemotherapy will be 
determined as “refractory.” 
#1  In case of chemoradiation, this will be the last dose of chemotherapy or the last radiation 
treatment, whichever occurs later. 
5. 
Patients who have at least 1 measurable or non-measurable lesion per the RECIST Guideline Ver. 
1.1 as confirmed by imaging within 28 days before randomization. The following requirements 
should also be satisfied: 
• 
The primary esophageal cancer should be deemed to be non-measurable lesion. 
• 
If patients only have lesions that were previously treated with radiation, the lesion should be 
limited to one with confirmed aggravation by imaging after radiation. 
• 
If patients have pericardial or pleural effusion or ascites only, the lesion should be limited to 
one with cytologically confirmed malignancy. 
6. 
ECOG Performance Status Score 0 or 1 
7. 
Patients with a life expectancy of at least 3 months 
8. 
Patients must provide tumor tissue (stored tissue or tissue from the last biopsy) for analysis of 
PD-L1 expression. For patients who are unable to undergo another biopsy, stored tissue can be 
used for analysis. Tissue specimens must contain at least 100 evaluable tumor cells and must be 
available before the randomization. 
9. 
Patients whose latest laboratory data meet the below criteria within 7 days before randomization. 
If the date of the laboratory tests at the time of randomization is not within 7 days before the first 
dose of the investigational product, testing must be repeated within 7 days before the first dose of 
the investigational product, and these latest laboratory tests must meet the following criteria. Of 


 
 
43 
 
note, laboratory data will not be valid if the patient has received a granulocyte colony-stimulating 
factor (G-CSF) or blood transfusion within 14 days before testing. 
• 
White blood cells ≥2,000/mm3 and neutrophils ≥1,500/mm3 
• 
Platelets ≥100,000/mm3 
• 
Hemoglobin ≥9.0 g/dL 
• 
AST (GOT) and ALT (GPT) ≤3.0-fold the upper limit of normal (ULN) of the study site (or 
≤5.0-fold the ULN of the study site in patients with liver metastases) 
• 
Total bilirubin ≤1.5-fold the ULN of the study site 
• 
Creatinine ≤1.5-fold the ULN of the study site or creatinine clearance (either the measured 
or estimated value using the Cockcroft-Gault equation) >45 mL/min 
10. 
Women of childbearing potential (including women with chemical menopause or no 
menstruation for other medical reasons)#1 must agree to use contraception#2 from the time of 
informed consent until 5 months or more after the last dose of the investigational product. Also, 
women must agree not to breastfeed from the time of informed consent until 5 months or more 
after the last dose of the investigational product. 
11. 
Men must agree to use contraception#2 from the start of study treatment until 7 months or more 
after the last dose of the investigational product. 
 
#1 Women of childbearing potential are defined as all women after the onset of menstruation 
who are not postmenopausal and have not been surgically sterilized (e.g., hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy). Postmenopause is defined as amenorrhea for 
≥12 consecutive months without specific reasons. Women using oral contraceptives, 
intrauterine devices, or mechanical contraception such as contraceptive barriers are regarded 
as having childbearing potential. 
#2 The subject must consent to use any two of the following methods of contraception: 
vasectomy or condom for patients who are male or female subject’s partner and tubal ligation, 
contraceptive diaphragm, intrauterine device, spermicide, or oral contraceptive for patients 
who are female or male subject’s partner.  
 
Rationale 
1. 
No need to limit the gender of study subjects was considered and set. 
2. 
The age limit was set at the age of voluntary consent to participate in the study. 


 
 
44 
 
3. 
This criterion was set to select patients with primary esophageal cancer as the subjects of the 
study, and those with esophageal cancer of a histological type amenable to efficacy and safety 
evaluation. 
4. 
This criterion was set to include patients who do not benefit from chemotherapy with 
fluoropyrimidine and platinum-based drugs. 
5. 
This criterion was set to identify patients evaluable for efficacy in this study. 
6. 
This criterion was set to enroll patients with a favorable performance status. 
7. 
This criterion was set to select patients evaluable for efficacy and safety in this study. 
8. 
This criterion was set to select patients evaluable for PD-L1 expression. 
9. 
This criterion was set to select patients with adequate functioning of major organs. 
10, 11. The safety of ONO-4538 in pregnant women and fetuses has not been established. 
 
4.3 
Exclusion Criteria 
Patients who meet any of the following criteria at the time of assessment for randomization will be 
excluded. If a randomized subject is found to meet any of the following criteria before the first dose of 
the investigational product, the subject will not be started on the study treatment and will be 
withdrawn from the study. 
1. 
Patients with significant malnutrition. Patients will be excluded if they are receiving intravenous 
hyperalimentation, or require continuous infusion therapy with hospitalization. Patients whose 
nutrition has been well controlled for ≥28 days prior to randomization may be enrolled. 
2. 
Patients with apparent tumor invasion on organs located adjacent to the esophageal disease (e.g., 
the aorta or respiratory tract). Patients will be excluded if they are receiving stent therapy in 
esophagus or respiratory tract. 
3. 
Patients with multiple primary cancers (with the exception of completely resected basal cell 
carcinoma, stage I squamous cell carcinoma, carcinoma in situ, intramucosal carcinoma, or 
superficial bladder cancer, or any other cancer that has not recurred for at least 5 years) 
4. 
Patients with residual adverse effects of prior therapy or effects of surgery that would affect the 
safety evaluation of the investigational product in the opinion of the investigator or 
subinvestigator 
5. 
Patients with current or past history of severe hypersensitivity to any other antibody products 
6. 
Patients with concurrent autoimmune disease or history of chronic or recurrent autoimmune 
disease (see Appendix 4) 


 
 
45 
 
7. 
Patients with a current or past history of interstitial lung disease or pulmonary fibrosis diagnosed 
based on imaging or clinical findings. Patients with radiation pneumonitis may be randomized if 
the radiation pneumonitis has been confirmed as stable (beyond acute phase) without any 
concerns about recurrence. 
8. 
Patients with concurrent diverticulitis or symptomatic gastrointestinal ulcerative disease 
9. 
Patients with any metastasis in the brain or meninx that is symptomatic or requires treatment. 
Patients may be randomized if the metastasis is asymptomatic and requires no treatment.  
10. 
Patients with pericardial fluid, pleural effusion, or ascites requiring treatment 
11. 
Patients with uncontrollable, tumor-related pain 
12. 
Patients who have experienced a transient ischemic attack, cerebrovascular accident, thrombosis, 
or thromboembolism (pulmonary arterial embolism or deep vein thrombosis) within 180 days 
before randomization 
13. 
Patients with a history of uncontrollable or significant cardiovascular disease meeting any of the 
following criteria: 
・ Myocardial infarction within 180 days before randomization 
・ Uncontrollable angina pectoris within 180 days before randomization 
・ New York Heart Association (NYHA) Class III or IV congestive heart failure 
・ Uncontrollable hypertension despite appropriate treatment (e.g., systolic blood pressure 
≥150 mmHg or diastolic blood pressure ≥90 mmHg lasting 24 hours or more) 
・ Arrhythmia requiring treatment 
14. 
Patients receiving or requiring anticoagulant therapy for a disease. Patients receiving antiplatelet 
therapy including low-dose aspirin may be enrolled. 
15. 
Patients with uncontrollable diabetes mellitus 
16. 
Patients with systemic infections requiring treatment 
17. 
Patients with ≥ Grade 2 peripheral neuropathy 
18. 
Patients who have received systemic corticosteroids (except for temporary use, e.g., for 
examination or prophylaxis of allergic reactions) or immunosuppressants within 28 days before 
randomization 
19. 
Patients who have received antineoplastic drugs (e.g., chemotherapy agents, molecular-targeted 
therapy agents, or immunotherapy agents) within 28 days before randomization 
20. 
Patients who have undergone surgical adhesion of the pleura or pericardium within 28 days 
before randomization 
21. 
Patients who have undergone surgery under general anesthesia within 28 days before 


 
 
46 
 
randomization 
22. 
Patients who have undergone surgery involving local or topical anesthesia within 14 days before 
randomization 
23. 
Patients who have received radiotherapy within 28 days before randomization, or radiotherapy to 
bone metastases within 14 days before randomization 
24. 
Patients who have received any radiopharmaceuticals (except for examination or diagnostic use 
of radiopharmaceuticals) within 56 days before randomization 
25. 
Patients with a positive test result for any of the following: HIV-1 antibody, HIV-2 antibody, 
HTLV-1 antibody, HBs antigen, or HCV antibody 
26. 
Patients with a negative HBs antigen test but a positive test result for either HBs antibody or HBc 
antibody with a detectable level of HBV-DNA 
27. 
Women who are pregnant or breastfeeding, or possibly pregnant 
28. 
Patients who have received any other unapproved drug (e.g., investigational use of drugs, 
unapproved combined formulations, or unapproved dosage forms) within 28 days before 
randomization 
29. 
Patients who have previously received taxane agents to treat esophageal cancer. Patients who 
were not proven refractory (see the definition of refractory in inclusion criteria 4) or intolerant to 
taxane-based combination therapy and subsequently received fluoropyrimidine and platinum-
based combination therapy, and then proven refractory or intolerant may be randomized.  
30. 
Patients who are contraindicated to docetaxel and paclitaxel 
31. 
Patients who have previously received ONO-4538 (MDX-1106 or BMS-936558), anti-PD-1 
antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody, anti-CTLA-4 antibody 
or other therapeutic antibodies or pharmacotherapies for regulation of T-cells 
32. 
Patients judged to be incapable of providing consent for reasons such as concurrent dementia 
33. 
Other patients judged by the investigator or subinvestigator to be inappropriate as subjects of this 
study 
 
Rationale 
1 to 17. These criteria were set to secure the safety of patients and to avoid possible effects on 
evaluations of the efficacy and safety of ONO-4538. 
18 to 24. These criteria were set to avoid possible effects of prior and concomitant treatments on 
evaluations of the efficacy and safety of ONO-4538. 


 
 
47 
 
25, 26. 
These criteria were set to secure the safety of patients and to avoid possible effects on 
evaluations of the efficacy and safety of ONO-4538. 
27. 
The safety of ONO-4538 in pregnant women, fetuses, and infants has not been established. 
28. 
This criterion was set to avoid effects of unapproved drugs with unestablished drug efficacy. 
29, 31. 
This criterion was set to avoid possible effects on the efficacy evaluation. 
30. 
This criterion was set to avoid possible effects on the safety evaluation. 
32. 
This criterion was set to protect patients’ human rights. 
33. 
This criterion was set to exclude patients not meeting any of the exclusion criteria 1 to 27 
but who are inappropriate for other reasons. 
 
5 
Study Methods 
5.1 
Study Design 
5.1.1 
Study Design 
This is a multicenter, randomized, open-label, docetaxel- or paclitaxel-controlled study where ONO-
4538 is administered at 2-week intervals for the treatment of subjects with esophageal cancer 
refractory or intolerant to combination therapy with fluoropyrimidine and platinum-based drugs, with 
up to 1 prior regimen to evaluate the efficacy and safety of ONO-4538. 
 
<Rationale for the Study Design> 
This study will be conducted in patients with esophageal cancer refractory or intolerant to 
combination therapy with fluoropyrimidine and platinum-based drugs, the standard chemotherapy 
treatment for esophageal cancer, with up to 1 prior regimen. 
Esophageal cancer patients without distal metastases are currently provided according to their stage of 
cancer with endoscopic treatment, surgical treatment, radiation therapy, and chemotherapy selected in 
a multimodal manner for radical cure. On the other hand, esophageal cancer patients with unresectable 
distal metastases are treated mainly with chemotherapy in which a combination of fluoropyrimidine 
and a platinum-based drug, 5-FU and cisplatin (FP therapy) is recommended as the standard therapy. 
Second-line treatments after FP therapy are generally taxanes such as docetaxel and paclitaxel. 
Among patients with esophageal cancer for which chemotherapy is indicated, those with esophageal 
adenocarcinoma benefit from docetaxel in terms of survival prolongation; however, no chemotherapy 
shown to prolong survival in esophageal squamous cell carcinoma currently exists. 
Currently, a phase II multicenter, open-label, uncontrolled study (ONO-4538-07) is underway to 
explore the efficacy and safety of multiple-dose intravenous administration of ONO-4538 (3 mg/kg) at 


 
 
48 
 
2-week intervals in patients with esophageal cancer refractory or intolerant to fluoropyrimidine-, 
platinum-, or taxane-based standard therapy. This study has suggested that the antitumor effect of 
ONO-4538 in esophageal cancer is sustainable for a long duration, as in other types of cancer. In 
addition, since squamous cell carcinoma is the major histological type of esophageal cancer in Asia, a 
global phase III study of ONO-4538 (CA209017) was conducted on a similar histological type, 
squamous non-small cell lung cancer, where the target population was patients with stage IIIB/IV or 
recurrent squamous non-small cell lung cancer who received prior platinum-containing chemotherapy. 
The study demonstrated that ONO-4538 has a significantly higher prolongation of survival (HR=0.59; 
p=0.00025) over existing therapy (docetaxel). Based on the above, a randomized open-label study, 
with docetaxel and paclitaxel controls that are widely used in 2nd-line treatment, is planned in patients 
with esophageal cancer after FP therapy to evaluate the efficacy and safety of ONO-4538. 
 
5.1.2 
Planned Sample Size 
195 subjects in each group, totaling 390 subjects 
 
<Rationale for the Sample Size> 
This study is intended to verify the superiority of ONO-4538 group over the control groups (docetaxel 
or paclitaxel) in terms of OS, the primary endpoint, in patients with esophageal cancer refractory or 
intolerant to fluoropyrimidine and platinum-based agents, the standard chemotherapy regimen for the 
treatment of esophageal cancer. Subjects will be randomized to either the ONO-4538 group or the 
control group in a 1:1 ratio and stratified by region (Japan vs. rest of world) and number of organs 
with metastases (≤1 vs. ≥2) and PD-L1 expression (≥1% vs. <1% or indeterminate) 22)-24). 
As for OS, assuming an exponential distribution for the control group (7.2 months median OS) and a 
piecewise mixture model for the ONO-4538 group with 5.0% long term survival rate (the ratio that 
long term survival is expected due to the effect of ONO-4538), the hazard ratio of the ONO-4538 
group relative to the control group was assumed to be 1.0 for the first 3 months and 0.65 for non-long 
term survival population thereafter (10.0 months overall median OS for the ONO-4538 group), the 
expected average hazard ratio of the ONO-4538 group to the control groups was assumed to be 0.70 in 
this study. The number of events required to detect superiority of the ONO-4538 group over the 
control groups with two-sided significance level of 5% and 90% or more power by the log-rank test 
was calculated to be 331. 
Assuming the enrollment period to be 16 months and the follow-up period after the last patient’s 
enrollment to be 18 months, the number of subjects required to ensure the required 331 events was 


 
 
49 
 
estimated to be 390. For the calculation of the required events and sample size at the time of planning 
the study, the statistical analysis software SAS (version 9.3) was used. 
 
<Rationale for assuming the median OS in the control group to be 7.2 months> 
The phase II single-arm study of docetaxel and the retrospective study of paclitaxel as 2nd-line 
treatment for patients with esophageal cancer reported that the median OS of docetaxel and paclitaxel 
was 5.5-8.1 months and 6.1-10.4 months, respectively, 17), 18), 25), 26). Based on this information, the 
median OS in the control groups of this study is assumed to be 7.2 months. 
 
<Rationale for assuming long term survival rate (the ratio that long term survival is expected due to 
the effect of ONO-4538) as 5.0% and the hazard ratio of the ONO-4538 group relative to the control 
groups was assumed to be 1.0 for the first 3 months> 
We set long term survival rate and the hazard ratio referring to the results of a randomized phase 3 
clinical trial of nivolumab vs investigator’s choice in recurrent or metastatic platinum-refractory 
squamous cell carcinoma of the head and neck (CA209141) 28) and a phase 2 uncontrolled study of 
nivolumab in esophageal cancer refractory or intolerant to standard therapy (ONO-4538-07)29). 
 
<Rationale for setting the hazard ratio of the ONO-4538 group relative to the control groups was 
assumed to be 0.65 after first 3 months in non-long term survival population> 
In the global phase III study conducted in patients with stage IIIB/IV or recurrent squamous non-small 
cell lung cancer who received a prior platinum-containing chemotherapy regimen (CA209017) to 
verify the superiority of ONO-4538 over docetaxel, one of the controls in this study, the hazard ratio 
of ONO-4538 relative to docetaxel was 0.59 [96.85% confidence interval: 0.43, 0.81]. 
If the same histological type of cancer and control are used in the present study, the efficacy on 
ONO-4538 is expected to be similar. However, this study includes paclitaxel as well as docetaxel as 
controls. Efficacy data on ONO-4538 vs. paclitaxel has not been obtained previously. Based on these 
reasons, the expected average hazard ratio of the ONO-4538 group to the control groups was assumed 
to be 0.70 in this study. 
In this study, since we assumed that 5.0% of long term survival rate and the hazard ratio of the ONO-
4538 group relative to the control group was to be 1.0 for the first 3 months, the hazard ratio of the 
ONO-4538 group relative to the control groups after first 3 months in non-long term survival 
population was calculated as 0.65 to become the expected average hazard ratio of the ONO-4538 
group relative to the control groups was 0.70.  


 
 
50 
 
5.2 
Method of Assigning Subjects to Treatment Groups 
5.2.1 
Method for investigational product allocation 
Subjects who meet all inclusion criteria will be assigned to the ONO-4538 group or control group 
(docetaxel group or paclitaxel group) in a 1:1 ratio using the following assignment factors. 
∙ Location (Japan vs. rest of world) 
∙ Number of organs with metastases (≤1 vs. ≥2) (at randomization) 
∙ Expression of PD-L1 (≥1% vs. <1% or indeterminate ) 
 
Location (Japan vs. rest of world) was used as a stratification factor in order to uniformly assign 
subjects to the ONO-4538 or control group (docetaxel group or paclitaxel group) in each location. The 
number of organs with metastases (≤1 vs. ≥2) and PD-L1 expression (≥1% vs. <1% or indeterminate) 
were selected based on a published report on prognostic factors in esophageal cancer patients 22)-24) as 
well as specialist advice.  
Stratified randomization will be carried out using a permuted block method. Administration of the 
investigational product (ONO-4538, docetaxel, or paclitaxel) will be started within 7 days after the 
randomization. 
 


 
 
51 
 
5.3 
Subject Enrollment Procedures 
Subjects will be enrolled according to the following procedures. 
 
 
 
 
 
 
 
Each subject who has provided written informed consent will be enrolled in the study by the IWRS 
(enrollment). Detailed procedures for the use of the IWRS will be specified in a separate document 
provided to each study site. The investigator or designee will enroll subjects according to 
predetermined procedures. The following data are required for enrollment after informed consent: 
• 
Date of informed consent 
• 
Date of birth 
• 
Sex 
 
Subjects who meet all inclusion criteria after enrollment are eligible for randomization by the IWRS 
(randomization). The following data are required for randomization. 
• 
Subject identification code (ID) 
• 
Date of birth 
• 
Location (Japan vs. rest of world) 
• 
Number of organs with metastases (≤1 or ≥2) (at randomization) 
• 
PD-L1 expression (≥1% vs. <1% or indeterminate ) 
 
Administration of the investigational product must be started within 7 days following randomization. 
If an enrolled subject is withdrawn without randomization, the investigator or designee will 
communicate the withdrawal before randomization using IWRS. If an eligible subject is withdrawn 
after randomization for specific reasons before administration of the investigational product, the 
investigator or designee will communicate the withdrawal before administration of study drug using 
IWRS. 
 
 
*: See Section 12 Subject Informed Consent 
*Written informed consent 
Enrollment 
Randomization 
Study Drug Allocation 
Start of treatment 


 
 
52 
 
5.4 
Blinding 
Not applicable. 
 
5.5 
Endpoints 
5.5.1 
Efficacy Endpoints 
5.5.1.1 
Primary Endpoint 
Overall survival (OS) 
 
Rationale 
OS is defined as the time from randomization until death from any cause. OS was selected as the 
primary endpoint of this study because it is generally regarded as the most reliable cancer endpoint 
and is usually the preferred endpoint for studies that can be conducted to adequately assess survival. 
 
5.5.1.2 
Secondary Endpoints 
1. Objective response rate (ORR) 
2. Disease control rate (DCR) 
3. Progression free survival (PFS) 
4. Duration of response 
5. Time to response 
6. Best overall response (BOR) 
7. Maximum percent change from baseline in the sum of diameters of the target lesion 
 
Rationale 
These endpoints were set to assess the efficacy of ONO-4538 and docetaxel or paclitaxel from various 
perspectives in patients with esophageal cancer. 
 
5.5.2 
Safety Endpoints 
1. Adverse events 
2. Clinical laboratory tests 
3. Vital signs 
4. 12-lead ECG 
5. Chest X-ray 
6. Performance Status (ECOG) 


 
 
53 
 
Rationale 
These endpoints were set to assess the safety of ONO-4538 and docetaxel or paclitaxel from various 
perspectives in patients with esophageal cancer. 
 
5.5.3 
Pharmacokinetic Endpoint 
Serum ONO-4538 concentrations (for the ONO-4538 group only) 
 
5.5.4 
Anti-drug Antibody Endpoint 
Anti-ONO-4538 antibody (for the ONO-4538 group only) 
 
5.5.5 
Exploratory Biomarkers 
 
  
  
 
 
6. Tumor tissue examination (PD-L1 expression analysis, essential; 
) 
 
5.5.6 
Other Test Variables 
1. Tumor markers 
2. Patient reported outcomes (PROs) 
3. Healthcare Resource Utilization 
 
Rationale 
These variables have been employed for exploratory examination of biomarkers that may be related to 
the efficacy or safety of ONO-4538, including PD-L1 expression, 
 
 
 
6 
Investigational Products 
An investigational product, also known as an investigational medicinal product in some regions, is 
defined as a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with marketing authorization but used or assembled 


 
 
54 
 
(formulated or packaged) differently from the authorized form or used for an unauthorized indication, 
or when used to gain further information about the authorized form.  
The investigational product should be stored in a secure area according to local regulations. The 
investigator has the responsibility to ensure that investigational product is only dispensed to study 
subjects. The investigational product must be dispensed only from official study sites by authorized 
personnel according to local regulations. 
In this protocol, the investigational products are ONO-4538 (nivolumab), docetaxel, and paclitaxel. 
 
Table 6-1 
Description of Investigational Products 
Name and dosage 
form of the 
investigational 
product 
Contents of the 
primary 
packaging  
(small box) 
No. of vials in 
the secondary 
packaging 
(large box) 
Appearance 
Storage conditions 
(as per the 
indication on the 
label) 
ONO-4538 
(Nivolumab) 
For injection 
100 mg/10 mL 
Vials 
6 
Colorless to pale yellow 
clear to opalescent 
liquid, occasionally 
containing 
microparticles 
Store refrigerated at 
2 to 8°C with 
protection from 
light. 
Docetaxel 
For i.v. drip 
infusion 
 
80 mg/2 mL  
Vials 
3 
Yellow to orange–
yellow clear viscous 
liquid 
Store at 1 to 30°C 
with protection from 
light. 
(Accompanying 
reconstitution 
diluent) 
Ethanol 
764.4 mg/6 mL  
Vials 
3 
Colorless clear liquid 
Store at 1 to 30°C 
with protection from 
light. 
Paclitaxel 
For injection 
100 mg/16.7 mL 
Vials 
6 
Colorless to pale yellow 
clear, viscous oily liquid 
Store at 1 to 30°C 
with protection from 
light. 
Docetaxel 
concentrate for 
solution for 
infusion* 
80 mg/vial (10 
mg/mL) 
1 
Clear, pale yellow to 
brownish-yellow 
solution. 
Store below 25°C.  
Store in original 
package and protect 
from light. 
Paclitaxel Solution 
for Injection* 
100 mg/vial (6 
mg/mL) 
4 
Clear, colorless or 
slightly yellow viscous 
solution 
Store at 15 to 30°C.  
Protect from light. 
*Comparators used in “United States and European countries.  These products may be obtained by 
the investigational sites as local commercial product in certain countries if allowed by local 
regulations.  In these cases, product may be a different pack size/potency than listed in this table. 
 
6.1 
Handling and Supply of Investigational Product 
The investigational product will be supplied to individual study sites as listed in table 6-1. 
The investigator should confirm that the investigational products are being stored under the 
environmental conditions (temperature, light, and humidity) specified by the sponsor. If concerns arise 


 
 
55 
 
regarding the quality or appearance of the investigational product, the product should not be dispensed 
and the sponsor should be contacted immediately. 
The investigator should maintain investigational product documentation that includes all of the 
processes required to ensure that the investigational product is administered accurately. This will 
include documentation of investigational product storage, administration and, as applicable, storage 
temperatures, reconstitution, and use of required processes (e.g., a required diluent, administration 
sets). 
For further details regarding preparation/administration and storage of nivolumab, docetaxel, and 
paclitaxel please refer to the current Investigator Brochure, pharmacy reference sheet and/or 
appropriate package insert/SPC. 
It is the responsibility of the investigator/site to provide any supplies required to prepare/administer 
Investigational Product (e.g., filters, diluents, IV bags, administration sets) and any required pre-
medication treatments (e.g., for paclitaxel). 
 
6.2 
Procedures for Investigational Product Accountability and Return of Unused 
Investigational products 
6.2.1 
Investigational Product Storage and Management 
The investigator is responsible for ensuring that a current status record of the investigational product 
(supplied by the sponsor) is maintained at each study site where the investigational product is 
inventoried and dispensed. Records or logs must comply with applicable regulations and guidelines 
and should include: 
• 
amount received and placed in storage area 
• 
amount currently in storage area 
• 
label identification number or batch number 
• 
amount dispensed to and returned by each subject, including Subject Identification Codes 
• 
amount transferred to another area/site for dispensing or storage 
• 
non-study status (e.g., lost, wasted) 
• 
amount destroyed at study site, if applicable 
• 
amount returned to the sponsor 
• 
samples retained for bioavailability/bioequivalence, if applicable 
• 
dates and initials of person responsible for investigational product 
dispensing/accountability, as per the delegation of authority form 
 


 
 
56 
 
The sponsor will provide forms to facilitate inventory control if the study site does not have an 
established system that meets these requirements. 
 
6.2.2 
Disposal of Investigational Products 
In this study, the investigational products (those supplied by the sponsor or sourced by the 
investigator), such as partially used investigational product containers, vials and syringes, may be 
destroyed on site.  
Any unused investigational product will not be destroyed unless investigational product containers 
must be immediately destroyed as required for safety or to meet local regulations (e.g., cytotoxics or 
biologics).  
On-site destruction is allowed provided the following minimal standards are met: 
• 
On-site disposal practices must not expose humans to risks from the drug. 
• 
On-site disposal practices and procedures are in agreement with applicable laws and regulations, 
including any special requirements for controlled or hazardous substances. 
• 
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s Standard Operating Procedures (SOPs) and a copy provided to the sponsor 
upon request. 
• 
Records are maintained that enable the traceability of each container, including the date of 
disposal, quantity disposed, and the person disposing of the containers. The method of disposal, 
i.e., incinerator, licensed sanitary landfill, or licensed waste disposal vendor must be 
documented. 
• 
Investigational product accountability and disposal records must be complete, up-to-date, and 
accessible to the sponsor for review throughout the clinical study period. 
 
If the conditions for destruction of the investigational product cannot be met, the responsible monitor 
assigned by the sponsor will make arrangements to return the investigational product. 
Provided that procedures for proper disposal have been established according to applicable local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept, the 
investigator will arrange the disposal of all empty containers. 
 


 
 
57 
 
6.2.3 
Return of Unused Investigational Products 
If the investigational product will not be destroyed upon completion or termination of the study, all 
unused and/or partially used investigational product that was supplied by the sponsor must be returned 
to the sponsor.  
The investigator is responsible for arranging the disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable local and institutional 
guidelines and procedures, and provided that appropriate records of disposal are kept. 
 
7 
Study Plan 
7.1 
Investigational Product 
7.1.1 
Dosage, Administration, and Treatment Duration 
7.1.1.1 
Dosage, Administration, and Treatment Duration of ONO-4538 
ONO-4538 240 mg will be administered intravenously over 30 minutes at 2-week intervals. Six weeks 
will count as 1 cycle of treatment. Treatment will be continued until PD is assessed by the investigator 
or subinvestigator according to the RECIST Guideline Ver. 1.1. ONO-4538 will be administered at 
240 mg without any increase or decrease of the dose and when 11 or more days have passed since the 
last dose, i.e., at an interval of 10 days or more. For information regarding appropriate storage, 
handling, dispensing, and administration of ONO-4538, refer to the latest Investigator's Brochure 
and/or Reference Sheet for Pharmacy. 
 
<Rationale for Setting the Dosage and Administration of ONO-4538> 
In the global phase I multiple-dose study (CA209003), multiple doses of ONO-4538 at 0.1-10 mg/kg 
was intravenously administered every 2 weeks to 306 patients with malignant tumors, including non-
small-cell lung cancer, malignant melanoma, and renal cell carcinoma. Favorable antitumor effects 
with ONO-4538 ≥3 mg/kg have been shown in the study. 
In terms of safety, the tolerability of multiple intravenous doses of ONO-4538 monotherapy every 2 
weeks has been demonstrated up to 20 mg/kg in Japan and up to 10 mg/kg in overseas countries in 
phase I studies (ONO-4538-01 and CA209003). In the global phase I multiple-dose study (CA209003), 
the type, incidence, and severity of adverse events (AEs) for which a causal relationship to ONO-4538 
could not be ruled out were similar among the evaluated doses.  
These efficacy and safety data led to the use of ONO-4538 at a dose of 3 mg/kg every 2 weeks in 
ongoing phase II and III studies in patients with non-small-cell lung cancer, malignant melanoma, and 
renal cell carcinoma. 


 
 
58 
 
Based on these data taken together, “multiple intravenous doses of ONO-4538 at 3 mg/kg every 2 
weeks” was selected as the clinically recommended dosage for esophageal cancer, in line with the 
recommended dosage regimen for other cancer types. In addition, the ongoing Japanese phase II study 
of ONO-4538 3 mg/kg (given at a 2-week interval) in patients with esophageal cancer refractory or 
intolerant to standard therapies (ONO-4538-07) has suggested the efficacy and safety of this regimen 
in esophageal cancer.  
As described above, multiple clinical studies have been conducted in which ONO-4538 is 
administered at a dose per body weight (mg/kg). The results of population pharmacokinetic (PPK) 
analysis demonstrated a linear PK profile of ONO-4538 and a dose-proportional increase in exposure 
to ONO-4538 within the range of 0.1 to 10 mg/kg. No difference has been suggested in the PK of 
ONO-4538 among cancer types. The clearance and distribution volume of ONO-4538 increased as 
body weight increased; however, the increase in these parameters was less than proportional to the 
increase in body weight. On the other hand, considering that the PK of ONO-4538 correlates with 
body weight, administration of ONO-4538 at a fixed dose (mg), which is not adjusted for body weight, 
is expected to provide lower exposure in heavy subjects than in light subjects. The predicted trough, 
peak, and mean concentrations at steady state (Cminss, Cmaxss, and Cavgss, respectively) after 
administration of ONO-4538 at a dose of 3 mg/kg or 240 mg to patients with non-small-cell lung 
cancer (NSCLC) are shown in Table 7.1.1.1-1. The median body weight in the three phase II and III 
studies of ONO-4538 monotherapy (CA209017, CA209057, and CA209063) was approximately 80 
kg. ONO-4538 240 mg is equivalent to 3 mg/kg ONO-4538 in subjects weighing 80 kg. As shown in 
Table 7.1.1.1-1, the geometric means of the Cminss, Cmaxss, and Cavgss after administration of 
ONO-4538 at a fixed dose (240 mg) were slightly higher (<15%) than those at 3 mg/kg, and the 
variation coefficient at 240 mg was also slightly higher (<10%) than that at 3 mg/kg. Since no 
difference has been suggested in the PK of ONO-4538 among cancer types, the predicted values in 
patients with NSCLC in Table 7.1.1.1-1 are applicable to patients with other cancer types. 
 
Table 7.1.1.1-1 
Exposure of ONO-4538 at steady state 
Dose of ONO-4538 
Cminss 
[µg/mL] 
Cmaxss 
[µg/mL] 
Cavgss 
[µg/mL] 
240 mg 
61.5 (44.6) 
133.7 (35.0) 
84.2 (38.2) 
3 mg/kg 
54.7 (41.9) 
118.9 (31.8) 
73.3 (35.6) 
Geometric mean (variation coefficient %) 
 
The safety and tolerance of ONO-4538 have been confirmed up to 10 mg/kg. The relationship 
between the exposure and efficacy of ONO-4538 was relatively consistent at 3 mg/kg. The above PK, 


 
 
59 
 
safety, and efficacy data of ONO-4538 suggest that the safety and efficacy profile of ONO-4538 at 
240 mg is similar to that at 3 mg/kg. 
Based on the above information taken together, a dose of 240 mg (multiple-dose intravenous 
administration at a 2-week interval) was selected for global clinical studies of ONO-4538 in 
esophageal cancer. 
 
7.1.1.2 
Dosage, Administration, and Treatment Duration of Docetaxel 
Docetaxel will be intravenously administered at a dose of 75 mg/m2 every 3 weeks. Each treatment 
cycle lasts 3 weeks. Treatment will be continued until PD is assessed by the investigator or 
subinvestigator according to the RECIST Guideline Ver 1.1. To calculate the first dose of the 
docetaxel, the body weight measured at study enrollment can be used instead of that on the day of 
administration (predose). If the subject has had a ≥10% change in body weight from that measured at 
the initial dose, the dose should be adjusted. If the change is observed on the day of administration 
from the initial dose, the dose can be adjusted from the next administration onwards. Each dose should 
be similarly adjusted if a further body weight change of ≥10% is observed after the previous change. 
The dose (mg) will be rounded to one decimal place. Although administration should be performed 
per the procedure of the study site, the recommended procedure is as follows: Docetaxel will be 
intravenously administered over at least 60 minutes in accordance with the package insert. Adverse 
reactions to docetaxel must be treated appropriately with reference to local standards, such as the 
package insert and treatment guidelines. 
 
<Rationale for Setting Dosage and Administration of Docetaxel> 
The standardized dosing regimen of docetaxel was established for this study with reference to local 
standards, such as the package insert of docetaxel and treatment guidelines in each country. 
 
7.1.1.3 
Dosage, Administration, and Treatment Duration of Paclitaxel 
Paclitaxel will be administered at a 100 mg/m2 dose weekly for 6 weeks followed by a 2-week drug 
holiday. This treatment cycle will be repeated until PD is assessed by the investigator or 
subinvestigator in accordance with the RECIST Guideline Ver 1.1. There should be an interval of at 
least 5 days between the doses of paclitaxel. To calculate the first dose of paclitaxel, the body weight 
measured at study enrollment can be used instead of that on the day of administration (predose). The 
dose on Day 1 of each cycle should be continued throughout that cycle as a rule. If the subject has had 
a ≥10% change in body weight from that measured at the initial dose, the dose should be adjusted. If 


 
 
60 
 
the change is observed on the day of administration from the initial dose, the dose can be adjusted 
from the next administration onwards. Each dose should be similarly adjusted if a further body weight 
change of ≥10% is observed after the previous change. The dose (mg) will be rounded to one decimal 
place. Although administration should be performed per procedure of the study site, recommended 
procedure is as follows: 
Paclitaxel will be administered intravenously through an in-line filter using a membrane filter of ≤0.22 
μm over 60 minutes in accordance with the package insert. Adverse reactions to paclitaxel must be 
treated appropriately with reference to local standards, such as the package insert and treatment 
guidelines. 
 
<Rationale for Setting Dosage and Administration of Paclitaxel> 
The standardized dosing regimen of paclitaxel was established for this study with reference to local 
standards, such as the package insert of paclitaxel and treatment guidelines in each country. 
 
7.1.2 
Criteria for Administration of Investigational Product 
Subjects who meet all of the criteria for administration of the investigational product and meet none 
of the criteria for its discontinuation will be allowed to continue study treatment. 
The following terms are defined for the administration criteria. 
Discontinuation: The study treatment is discontinued permanently without resuming the treatment.  
Delay: The interval between administrations is extended; or administration is delayed from the 
predetermined schedule. 
Skip: Administration of the investigational products is skipped to the next dosing schedule. 
 
7.1.2.1 
Criteria for Administration of ONO-4538 
Before the start of each infusion, the subject must fulfill the following criteria to receive the dose on 
the basis of the latest data available at that time. If the subject does not meet any of the following 
criteria at the start of each infusion, the scheduled administration of ONO-4538 will be skipped. 
However, subjects will be allowed to continue study treatment if the treatment is expected to lead to 
clinical benefits and is assessed to be administered safely unless investigator-assessed disease 
progression is observed. In this case, the subject’s consent to continue study treatment must be 
obtained prior to the continuation of study treatment and recorded in the medical record. The 
continuation should be reported to the Sponsor as in a timely manner as possible. The protocol-


 
 
61 
 
specified diagnostic imaging for the assessment of tumor response and other examinations for safety 
assessment will be performed as scheduled, irrespective of the administration of ONO-4538. 
 
1. 
No Grade ≥3 adverse events for which a causal relationship to ONO-4538 cannot be ruled out 
(i.e., adverse drug reactions).  
2. No Grade ≥2 diarrhea or colitis for which a causal relationship to ONO-4538 cannot be ruled 
out. 
3. No Grade ≥2 creatinine increased for which a causal relationship to ONO-4538 cannot be ruled 
out. 
4. No Grade ≥2 neurotoxicity for which a causal relationship to ONO-4538 cannot be ruled out. 
5. No increase of ≥2 grades from baseline (predose of ONO-4538) in AST (GOT), ALT (GPT), or 
total bilirubin for which a causal relationship to ONO-4538 cannot be ruled out. 
6. No suspected autoimmune disease based on signs/symptoms or clinical laboratory tests.  
7. The investigator or subinvestigator judges that the dose of ONO-4538 may be administered to 
the subject. 
 
7.1.2.2 
Criteria for Administration of Docetaxel 
Before the start of each infusion, subjects must fulfill all of the following criteria to receive the dose 
on the basis of the latest data available at that time. At the start of the treatment cycles, if the subject 
does not meet any of the following criteria, the scheduled dose of docetaxel should be delayed.  
If no worsening of clinical symptoms determined due to disease progression is observed, and 
continuation of the study treatment is expected to lead clinical benefits, and the dose of docetaxel can 
be continued safely without contraindications, treatment with docetaxel may be continued. In this case, 
the subject’s willingness to continue with docetaxel treatment must be confirmed prior to continuation 
and must be documented in the medical record. In addition, it should be reported to the sponsor as in a 
timely manner as possible. Imaging examinations to assess tumor response should be performed as per 
the schedule specified in the protocol, irrespective of the administration of docetaxel. When docetaxel 
administration is resumed after the dose delay, the criteria for dose reduction should be referred. 
Switching to paclitaxel during the study period (after informed consent and until completion of the 
final examination stipulated by the protocol [with the exception of the outcome investigation]) is not 
permitted. 
 


 
 
62 
 
1. No Grade ≥3 adverse events (i.e., adverse drug reactions) for which a causal relationship to 
docetaxel cannot be ruled out. Patients with controllable hypertension may continue docetaxel 
2. Neutrophils ≥1500/mm3 
3. None of the following adverse events (i.e., adverse drug reactions) for which a causal relationship 
to docetaxel cannot be ruled out: 
• 
AST (GOT) or ALT (GPT) >3.0-fold ULN of the study site (or >5.0-fold the ULN of the 
study site in patients with liver metastases)  
• 
Total bilirubin >1.5-fold ULN of the study site 
4. The investigator or subinvestigator judges that the dose of docetaxel may be administered to the 
subject. 
 
7.1.2.3 
Criteria for Administration of Paclitaxel 
Before the start of each infusion, the subject must fulfill the following criteria to receive the dose on 
the basis of the latest data available at that time. 
At the start of the treatment cycles, if the subject does not meet any of the following criteria, the 
planned dose of paclitaxel should be delayed. In the same cycle, if the subject does not meet any of the 
following criteria, the planned dose of paclitaxel will be skipped. If no worsening of clinical 
symptoms determined due to disease progression is observed, and continuation of study treatment is 
expected to lead clinical benefits, and the dose of paclitaxel can be continued safely without 
contraindications, treatment with paclitaxel may be continued. In this case, the subject’s willingness to 
continue with paclitaxel treatment must be confirmed prior to continuation and must be documented in 
the medical record. In addition, it should be reported to the Sponsor as in a timely manner as possible. 
Imaging examinations to assess tumor response should be performed as per the schedule specified in 
the protocol, irrespective of the administration of paclitaxel. When paclitaxel administration is 
resumed after the dose delay or skip, the criteria for dose reduction should be referred. Switching to 
docetaxel during the study period (after informed consent and until completion of the final 
examination stipulated by the protocol [with the exception of the outcome investigation]) is not 
permitted. 
 
1. No Grade ≥3 adverse events (i.e., adverse drug reactions) for which a causal relationship to 
paclitaxel cannot be ruled out. Patients with controllable hypertension may continue paclitaxel. 
2. Neutrophils ≥1500/mm3 (in the same cycle, neutrophils ≥1000/mm3) 


 
 
63 
 
3. None of the following adverse events (i.e., adverse drug reactions) for which a causal relationship 
to paclitaxel cannot be ruled out: 
• 
AST (GOT) or ALT (GPT) >3.0-fold ULN of the study site (or >5.0-fold the ULN of the 
study site in patients with liver metastases) 
• 
Total bilirubin >1.5-fold ULN of the study site 
4. 
The investigator or subinvestigator judges that the dose of paclitaxel may be administered to the 
subject. 
 
7.1.3 
Dosage Reduction Criteria 
7.1.3.1 
Dosage Reduction Criteria for ONO-4538 
The study has no dosage reduction criteria for ONO-4538. 
 
7.1.3.2 
Dose Reduction Criteria for Docetaxel 
The dose of docetaxel should be reduced in accordance with Table 7.1.3.2-1 based on the event listed 
in Table 7.1.3.2-2 and the other reasonable reason. After the dose reduction of docetaxel, safety 
measures such as frequent laboratory testing should be taken for the patient’s safety. Subsequent 
treatment cycles should be continued at the same dose or a further reduced dose; the dose should not 
be increased. 
 
Table 7.1.3.2-1 
Dose Criteria for Docetaxel 
Dose Level 
Dose of Docetaxel 
Initial dose 
75 mg/m2 
Level 1 Reduction 
60 mg/m2 
Level 2 Reduction 
45 mg/m2 
Level 3 Reduction 
To be discontinued 
 
Table 7.1.3.2-2 
Dose Reduction Criteria for Docetaxel 
Adverse Event (related to docetaxel) 
Docetaxel 
Grade 4 neutropenia (<500/mm3) 
Reduce by 1 dose level 
Grade ≥3 febrile neutropenia 
Reduce by 1 dose level 
Grade 4 thrombocytopenia (<25000/mm3) 
Reduce by 1 dose level 
Grade ≥2 peripheral neuropathy 
Reduce by 1 dose level 
Grade ≥3 non-hematological toxicity other than the above  
(except for controllable hypertension) 
Reduce by 1 dose level 


 
 
64 
 
7.1.3.3 
Dose Reduction Criteria for Paclitaxel 
The dose of paclitaxel should be reduced in accordance with Table 7.1.3.3-1 based on the event listed 
in Table 7.1.3.3-2 and the other reasonable reason. If the administration of paclitaxel is skipped for ≥2 
consecutive times, the dose should be reduced by 1 dose level. Dose reduction by 1 dose level should 
also be considered if the administration is skipped for 1 time. After the dose reduction of paclitaxel, 
safety measures such as frequent laboratory testing should be taken for patient’s safety. Subsequent 
cycles should be continued at the same dose or a further reduced dose; the dose should not be 
increased. 
 
Table 7.1.3.3-1 
Dose Criteria for Paclitaxel 
Dose Level 
Dose of Paclitaxel 
Initial dose 
100 mg/m2 
Level 1 Reduction  
80 mg/m2 
Level 2 Reduction 
60 mg/m2 
Level 3 Reduction 
To be discontinued 
 
Table 7.1.3.3-2 
Dose Reduction Criteria for Paclitaxel  
Adverse Event (related to paclitaxel) 
Paclitaxel 
Grade 4 neutropenia (<500/mm3) 
Reduce by 1 dose level 
Grade ≥3 febrile neutropenia 
Reduce by 1 dose level 
Grade 4 thrombocytopenia (<25,000/mm3) 
Reduce by 1 dose level 
Grade ≥2 peripheral neuropathy 
Reduce by 1 dose level 
Grade ≥3 non-hematological toxicity other than the above  
(except for controllable hypertension) 
Reduce by 1 dose level 
 
7.1.4 
Discontinuation Criteria 
If any of the following criteria are met during the treatment phase, the study treatment will be 
discontinued for the subject. The subject will undergo end-of-treatment examinations (at 
completion/discontinuation) and proceed to the follow-up phase. 
 
7.1.4.1 
Criteria for Discontinuation of ONO-4538 
1. Has an overall response of PD as assessed by the investigator or subinvestigator according to the 
RECIST Guideline Ver. 1.1. 


 
 
65 
 
2. Apparent worsening of clinical symptoms determined to be due to disease progression. 
3. Onset of Grade ≥2 interstitial lung disease with or without a causal relationship to ONO-4538. 
4. Onset of Grade ≥2 eye disorder (eye pain or reduced visual acuity) which does not improve to 
Grade ≤1 with topical treatment and for which a causal relationship to ONO-4538 cannot be ruled 
out. 
5. Onset of Grade ≥3 bronchospasm, diarrhea, colitis, neurologic toxicity, hypersensitivity reaction, 
infusion reaction (e.g., fever, chills, nausea, pain, headache, cough, itching, or rash) or uveitis for 
which a causal relationship to ONO-4538 cannot be ruled out. 
6. Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation. 
7. Any drug-related liver function test (LFT) abnormality that meets the following criteria require 
discontinuation: 
・ AST or ALT > 5-10x ULN for > 2 weeks 
・ AST or ALT >10x ULN 
・ Total bilirubin > 5x ULN 
・ Concurrent AST or ALT > 3x ULN and total bilirubin > 2x ULN 
8. Not received a dose of ONO-4538 within the past 6 weeks for specific reasons, such as the onset of 
an adverse event, unless study treatment is withheld for >6 weeks for steroid tapering, for which a 
consultation with the Sponsor is required prior to resuming study treatment. 
9. The investigator or subinvestigator judges that the continuation of study treatment for the subject is 
inappropriate for other reasons from the viewpoint of efficacy or safety. 
 
However, for subjects who meet either the above criterion 1 or 8 and who fulfill all of the following 
criteria in the opinion of the investigator or subinvestigator, treatment with ONO-4538 may be 
continued after consultation with the Sponsor. However, if continuing the study treatment is expected 
to be beneficial and ONO-4538 is promptly required, an after-the-fact report to the Sponsor is allowed. 
Per criterion 1 above, the subject’s willingness to continue with the study treatment must be confirmed 
and a written re-consent must be obtained using the subject information and an informed consent form 
separately prepared for the re-consent. 
If further PD is assessed in accordance with the RECIST Guideline Ver. 1.1 following the decision to 
continue treatment after the first PD, no additional continuation will be allowed and the study 
treatment must be discontinued. 


 
 
66 
 
1. No rapid disease progression and the continuation of study treatment is expected to lead to 
clinical benefits 
2. ONO-4538 was tolerated 
3. A stable ECOG Performance Status Score 
4. Continuation of study treatment will not cause a delay of any prophylactic intervention for 
serious complications associated with disease progression (e.g., brain metastasis) 
 
7.1.4.2 
Discontinuation Criteria for Docetaxel or Paclitaxel 
1. Despite dose reductions of docetaxel or paclitaxel being performed twice, a third round of dose 
reduction is required due to the onset of an adverse event 
2. Has an overall response of PD as assessed by the investigator or subinvestigator according to the 
RECIST Guideline Ver. 1.1 
3. Apparent worsening of clinical symptoms determined to be due to disease progression. 
4. Onset of Grade ≥3 peripheral neuropathy with or without a causal relationship to docetaxel or 
paclitaxel 
5. Onset of Grade ≥2 interstitial lung disease with or without a causal relationship to docetaxel or 
paclitaxel 
6. Onset of the following adverse events (adverse drug reactions) for which a causal relationship to 
docetaxel or paclitaxel cannot be ruled out: 
• 
Grade ≥3 thrombocytopenia with hemorrhage 
• 
Increase in AST (GOT) or ALT (GPT) >5.0- to 10.0-fold ULN of the study site persisting for 
more than 2 weeks  
• 
Increase in AST (GOT) or ALT (GPT) >10.0-fold ULN of the study site 
• 
Increase in Total bilirubin >5.0-fold ULN of the study site 
• 
Increase in AST (GOT) or ALT (GPT) >3.0-fold ULN of the study site and an increase in 
total bilirubin >2.0-fold ULN of the study site 
7. Not received docetaxel or paclitaxel within the past 6 weeks for specific reasons, such as the onset 
of an adverse event, unless study treatment is withheld for >6 weeks for steroid tapering, for which 
a consultation with the Sponsor is required prior to resuming study treatment 
8. The investigator or subinvestigator judges that continuation of study treatment for the subject is 
inappropriate for other reasons from the viewpoint of efficacy and safety. 
 


 
 
67 
 
However, for subjects who meet the above criterion 7 and who fulfill all of the following criteria in 
the opinion of the investigator or subinvestigator, treatment with docetaxel or paclitaxel may be 
continued after consultation with the Sponsor. However, if continuing the study treatment is expected 
to be beneficial and docetaxel or paclitaxel is promptly required, an after-the-fact report to the 
Sponsor is allowed. 
 
1. No rapid disease progression and the continuation of study treatment is expected to lead to 
clinical benefits  
2. Docetaxel or paclitaxel were tolerated 
3. A stable ECOG Performance Status Score 
4. Continuation of the study treatment will not cause a delay of any prophylactic intervention for 
serious complications associated with disease progression (e.g., brain metastases) 
 
7.2 
Prior and Concomitant Therapies 
7.2.1 
Prohibited Therapies During the Study Period 
7.2.1.1 
Prohibited Therapies During the Study Period (ONO-4538 Group) 
The following treatments are prohibited throughout the study period (i.e., after informed consent and 
until completion of the final examination stipulated by the protocol [with the exception of the outcome 
investigation]), unless absolutely necessary for medical reasons even after the examination at the end 
of the treatment phase (at discontinuation) has been completed. 
 
1. 
Immunosuppressants and corticosteroids1, 5 
2. 
Any 
antitumor 
therapies5 
(including 
chemotherapy, 
molecular 
target 
therapy, 
and 
immunotherapy2) 
3. 
Surgical treatment for malignant tumors5 
4. 
(Chemo) radiotherapy5 
5. 
Radiopharmaceuticals3, 5 
6. 
Bisphosphonates and anti-RANKL antibody products4 
7. 
Transplantation 
8. 
Other unapproved drugs5 (e.g., investigational use of drugs, unapproved combined formulations, 
and unapproved dosage forms) 
 


 
 
68 
 
1 Corticosteroids may only be used topically (e.g., external, intra-articular, intranasal, ophthalmic, or 
inhalational use) or temporarily (e.g., for the treatment or prophylaxis of contrast medium allergy or 
AEs). 
2 These include local therapeutic agents such as picibanil. 
3 Use for examination or diagnostic use of radiopharmaceuticals is allowed. 
4 Treatment with bisphosphonates or anti-RANKL antibody products that has been ongoing since 
before the subject’s first dose of the study treatment may be continued only if there are no changes 
made to the dosage and mode of administration. 
5  Before randomization, these therapies may be used unless they are performed in the respective 
periods specified in the exclusion criteria #18～24, 28. 
 
<Rationale for Selection of the Prohibited Therapies> 
The above mentioned therapies have been selected as prohibited therapies during the study period 
because they are likely to have a potential impact on the evaluation of safety and efficacy of the study. 
 
7.2.1.2 
Prohibited Therapies During the Study Period (Control Group) 
The following treatments are prohibited throughout the study period (i.e., after informed consent and 
until completion of the final examination stipulated by the protocol [with the exception of the outcome 
investigation]), unless absolutely necessary for medical reasons even after the examination at the end 
of the treatment phase (at discontinuation) has been completed. 
 
1. 
Immunosuppressants and corticosteroids1, 5 
2. 
Any antitumor therapies5 (including chemotherapy, molecular target therapy, and immunotherapy 
2) 
3. 
Surgical treatment for malignant tumors5 
4. 
(Chemo) radiotherapy5 
5. 
Radiopharmaceuticals3, 5 
6. 
Bisphosphonates and anti-RANKL antibody products4 
7. 
Transplantation 
8. 
Disulfiram, cyanamide, carmofur, and procarbazine hydrochloride (for the paclitaxel group only) 
9. 
Other unapproved drugs5 (e.g., investigational use of drugs, unapproved combined formulations,  
and unapproved dosage forms) 
 


 
 
69 
 
1 Corticosteroids may only be used topically (e.g., external, intra-articular, intranasal, ophthalmic, or 
inhalational use) or temporarily (e.g., for the treatment or prophylaxis of contrast medium allergy or 
adverse events). 
2 These include local therapeutic agents such as picibanil. 
3 Use for examination or diagnostic use of radiopharmaceuticals is allowed. 
4 Treatment with bisphosphonates or anti-RANKL antibody products that has been ongoing since 
before the subject’s first dose of the study treatment may be continued only if there are no changes 
made to the dosage and mode of administration. 
5  Before randomization, these therapies may be used unless they are performed in the respective 
periods specified in the exclusion criteria #18～24, 28. 
 
<Rationale for Selection of the Prohibited Therapies> 
The above mentioned therapies have been selected as prohibited therapies during the study period 
because they are likely to have a potential impact on the evaluation of safety and efficacy of the study. 
 
7.2.2 
Prophylactic Premedication 
7.2.2.1 
ONO-4538 Group 
In subjects who may experience infusion-related reactions to ONO-4538, prophylactic premedication 
with acetaminophen or diphenhydramine is recommended before administration of ONO-4538 for 
subjects who have experienced infusion reaction previously. 
 
7.2.2.2 
Docetaxel Group 
Follow recommendations per local SmPC/Package Insert. 
 
7.2.2.3 
Paclitaxel Group 
The following pretreatments are recommended to prevent the occurrence of serious hypersensitivity 
symptoms caused by paclitaxel. 
The following premedication should be completed approximately ≥30 minutes prior to administration 
of paclitaxel: intravenous doses of dexamethasone sodium phosphate injection (dexamethasone 8 mg), 
either ranitidine hydrochloride injection (ranitidine 50 mg) or famotidine injection (famotidine 20 mg), 
and oral diphenhydramine hydrochloride tablet (diphenhydramine hydrochloride 50 mg). 
The initial dose of dexamethasone is 8 mg. If hypersensitivity symptoms do not occur until the next 
administration or are not clinically significant, the dexamethasone dose may be reduced to half the 


 
 
70 
 
initial dose (4 mg) from Week 2. If hypersensitivity symptoms are absent or clinically insignificant in 
the subsequent weeks of administration, the dexamethasone dose may be further reduced by half, 
down to 1 mg. 
 
7.3 
Discontinuation of the Supply of the Investigational Product 
Subjects will be supplied with the investigational product until they meet the criteria in Section 7.1.4 
“Discontinuation Criteria” or in Section 13.1 “Rules or Criteria for Withdrawing Individual Subjects 
from the Study.” However, the sponsor will discontinue the supply of the investigational product in 
the following instances. 
 
1. When the regulatory authority of each country has rejected the approval application for ONO-
4538 for the indication of unresectable advanced or recurrent esophageal cancer 
2. When the entire study is discontinued 
3. When the subject is able to receive ONO-4538 for the same indication as this study under 
public or private health insurance coverage 
4. When the subject has become able to receive alternative treatment 
 
7.4 
Post-Study Access to Therapy 
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be eligible 
for sponsor supplied study drug. Study drug will be provided via an extension of the study, a rollover 
study requiring approval by responsible health authority and ethics committee or through another 
mechanism at the discretion of sponsor as per local health authority requirements. 
 
8 
Study schedule and Observation Items 
8.1 
Study Schedule 
The entire study period will consist of three phases: screening phase, treatment phase, and follow-up 
phase. A schema of this study is shown in Figure 2-1 in the protocol synopsis section. 
 
8.1.1 
Screening Phase 
The screening phase will start when the subject has signed the informed consent form. Subjects who 
have provided consent will be enrolled in the study. Among the enrolled subjects, the investigator or 
subinvestigator will proceed with randomization of those fulfilling the criteria in Section 4.2 
“Inclusion Criteria” and not meeting any of the criteria in Section 4.3 “Exclusion Criteria” judged to 


 
 
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be appropriate as subjects in this study. Protocol-specified evaluations and their schedule during this 
phase are specified in Table 6-1, Table 6-2, and Table 6-3 (ONO-4538, docetaxel, and paclitaxel 
groups, respectively) in the protocol synopsis section. 
 
8.1.2 
Treatment Phase 
8.1.2.1 
ONO-4538 Group 
During the treatment phase, ONO-4538 will be administered every 2 weeks up to 3 doses. These 6 
weeks will count as one cycle. Study treatment may be repeated in subjects fulfilling the criteria in 
Section 7.1.2.1 “Criteria for Administration of ONO-4538” and not meeting any of the criteria in 
Section 7.1.4.1 “Criteria for Discontinuation of ONO-4538.” Protocol-specified evaluations and their 
schedule during this phase are specified in Table 6-1 in the protocol synopsis section. 
 
8.1.2.2 
Docetaxel Group 
During the treatment phase, docetaxel will be administered every 3 weeks. This is defined as 1 cycle. 
Study treatment may be repeated in subjects fulfilling the criteria in Section 7.1.2.2 “Criteria for 
Administration of Docetaxel” and not meeting any of the criteria in Section 7.1.4.2 “Discontinuation 
Criteria for Docetaxel or Paclitaxel.” Protocol-specified evaluations and their schedule during this 
phase are specified in Table 6-2 in the protocol synopsis section. 
 
8.1.2.3 
Paclitaxel Group 
During the treatment phase, paclitaxel will be administered every 1 week up to 6 doses, followed by a 
2-week rest period. This is defined as 1 cycle. Study treatment may be repeated in subjects fulfilling 
the criteria in Section 7.1.2.3 “Criteria for Administration of Paclitaxel” and not meeting any of the 
criteria in Section 7.1.4.2 “Discontinuation Criteria for Docetaxel or Paclitaxel.” Protocol-specified 
evaluations and their schedule during this phase are specified in Table 6-3 in the protocol synopsis 
section. 
 
8.1.3 
Follow-up Phase 
All subjects meeting any of the criteria in Section 7.1.4 “Discontinuation Criteria” after administration 
of the investigational product will undergo end-of-treatment examination (at discontinuation) and 
proceed to the follow-up phase. Protocol-specified evaluations and their schedule during the follow-up 
phase are specified in Table 6-1, Table 6-2, and Table 6-3 (ONO-4538 group, docetaxel group, and 
paclitaxel group, respectively) in the protocol synopsis section. 


 
 
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8.2 
Observation Items 
8.2.1 
Patient Demographics and Other Background Characteristics 
During the screening phase, the investigator or designee will collect and enter the following data into 
the eCRF. The TNM Classification of Malignant Tumours, Seventh Edition, published by the Union 
for International Cancer Control (UICC) (hereinafter referred to as “the TNM classification”) will be 
used for determination of the lesion sites (anatomical subsites), clinical classification, and disease 
stage (see Appendix 1). 
 
• 
Subject identification code (ID) 
• 
Date of written informed consent 
• 
Sex 
• 
Date of birth 
• 
Race 
• 
Ethnicity 
• 
Height 
• 
Weight 
• 
Medical history (i.e., medical history within 1 year before randomization and other clinically 
relevant medical history) 
• 
Concurrent diseases 
• 
History of alcohol consumption 
• 
History of smoking 
• 
Performance Status Score (ECOG) 
• 
Date of diagnosis of the primary disease 
• 
Lesion sites (anatomical subsites according to the TNM classification) Note) 
• 
Clinical classification (TNM clinical classification) Note) 
• 
Disease stage (Stage grouping: TNM classification) Note) 
• 
Histological classification Note) 
• 
Number of organs with metastases Note) 
• 
Date of surgery (including EMR or ESD) for the primary lesion (for subjects with recurrent 
esophageal cancer) 
• 
Residual tumor (R) classification (for subjects with recurrent esophageal cancer) 
• 
Site of recurrence (for subjects with recurrent esophageal cancer) 
• 
Diameter of the target lesions Note) 


 
 
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• 
Past treatments for cancer (e.g., surgery, radiotherapy, pharmacotherapy) 
Note): Based on the results at randomization 
 
8.2.2 
Details of Study Treatment and Concomitant Treatments 
8.2.2.1 
Details of administration of the investigational product 
The investigator or designee will enter details of study treatment (i.e., dose, infusion start time, 
infusion end time) into the eCRF. 
 
8.2.2.2 
Details of Administration of Other Drugs and Concomitant Therapies 
For any drugs and therapies used after the start of study treatment and before completion of the final 
examination stipulated by the protocol (with the exception of the outcome investigation), the 
investigator or designee will enter details of administration (i.e., name of treatment, therapy dates, 
route of administration, reason for use and, if required, dosage and mode of administration) into the 
eCRF.  
During the follow-up investigation, an outcome investigation will be performed, and an investigation 
will also be performed on any post-study treatment for esophageal cancer, with its starting date and 
details.  
In subjects who, at the time of initiation of the follow-up investigation, have any adverse event for 
which a causal relationship to the investigational product cannot be ruled out or which led to 
discontinuation, treatment for the adverse event will be continued at appropriate intervals until the 
event resolves, improves, or stabilizes and thus is judged not to require further follow-up.  
Data from investigation of the details of any post-study treatment for esophageal cancer and 
concomitant therapies will be entered into the eCRF. 
Details of follow-up investigation are described in Section 8.2.10 “Follow-up Investigation.” 
 
8.2.3 
Items related to Efficacy 
The investigator or designee will perform the following measurements, examinations, and 
investigations at predetermined time points. For subjects who have discontinued study treatment, the 
subject’s safety will be prioritized, and measurements, examinations, and investigations will be 
performed as far as possible. 
 


 
 
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8.2.3.1 
Imaging Examination (with Measurements of Tumor Diameters and 
Assessment of Tumor Response) 
Neck-thoraco-abdomino-pelvic CT or other imaging examinations will be performed and the tumor 
response will be assessed. For the assessment of tumor response, in principle, the same method should 
be used throughout the study. If brain or bone metastasis is clinically suspected during the screening 
phase, a head CT/MRI or FDG-PET (or bone scintigraphy) must be performed to determine the 
presence of the brain or bone metastasis. Also after the start of study treatment, whenever brain or 
bone metastasis is suggested by clinical symptoms, an imaging examination should be performed to 
determine the presence or absence of brain or bone metastasis.  
In accordance with the RECIST Guideline Ver. 1.1 (see Appendix 2), the diameters of target lesions 
will be measured and the tumor response will be assessed, and the results of both the measurement 
and assessment will be entered into the eCRF. If previous data were obtained within the allowable 
window for the end-of-treatment examination (at completion/discontinuation) or the examination 28 
days after the end of the treatment phase, the previous data may be used as an alternative, unless new 
data are medically required. However, data will be newly obtained if 15 days have passed for imaging 
examination. Tests will be performed whenever medically indicated. 
Imaging examinations (with measurements of tumor diameters and assessment of tumor response) will 
be performed at the time points specified below. The decision to continue the study treatment will be 
made by the investigator or subinvestigator based on the imaging assessment in accordance with the 
RECIST Guideline Ver. 1.1. 
 
Time points of evaluation  
Screening phase 
Treatment phase: Every 6 weeks starting from the start of Cycle 1, every 12 weeks after a period of 1 
year from the start of Cycle 1, and at the end (discontinuation) of the treatment 
phaseNote 1) 
Follow-up phase: Day 28 post-treatmentNote 1) and during the follow-up investigation (subjects who 
have a response assessment other than PD in accordance with the RECIST 
Guideline Ver. 1.1 [see Appendix 2] and have discontinued the treatment phase for 
safety reasons should undergo imaging examinations as far as possible until either 
initiation of post-study treatment for esophageal cancer, or a diagnosis of PD or 
recurrence.) 
 


 
 
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Note 1): The previous data may be used as an alternative, unless new data are medically required. 
However, data will be newly obtained if 15 days have passed for imaging examination.  
Tests will be performed whenever medically indicated. 
 
8.2.4 
Items related to Safety 
For the items specified in the following subsections 8.2.4.1 to 8.2.4.7, the investigator or designee will 
perform measurements, examinations, and investigations at predetermined time points. For subjects 
who have discontinued study treatment, the subject’s safety will be prioritized, and measurements, 
examinations, and investigations will be performed as far as possible. 
 
8.2.4.1 
Vital Signs, Body Weight, and 12-lead ECG 
8.2.4.1.1 
Vital Signs (Systolic and Diastolic Blood Pressure, Pulse Rate, and Body 
Temperature), and Body Weight 
Vital signs and body weight will be measured at the time points specified below. Resting systolic and 
diastolic blood pressure and pulse rate will be measured in principle using the same body position 
throughout the study period. 
 
Time points of evaluation 
Screening phase (the allowance window starts from the day of the first dose, ranging between -7 and 
-1.) 
Treatment phase: [ONO-4538 group]: Before dosing on Day 1 of each cycleNote 1), after dosing on 
Day 1 (measured in Cycle 1 only, except for body weight), Day 8 (measured in 
Cycle 1 only, except for body weight), before dosing on Day 15 (except for 
body weight), before dosing on Day 29 (except for body weight), Day 43, and at 
the end (or discontinuation) of the treatment phaseNote 2) 
[Docetaxel group]: Before dosing on Day 1 in each cycleNote 1), after dosing on 
Day 1 (measured in Cycle 1 only, except for body weight), Day 8 (measured in 
Cycle 1 only, except for body weight), Day 22, and at the end (or discontinuation) 
of the treatment phaseNote 2) 
[Paclitaxel group]: Before dosing on Day 1 in each CycleNote 1), after dosing on 
Day 1 (measured in Cycle 1 only, except for body weight), before dosing on Day 
8 (except for body weight and pulse rate measurement [Cycle 2 and beyond for 
pulse rate]), before dosing on Days 15, 22, 29, and 36 (except for body weight and 


 
 
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pulse rate measurement), Day 50, and at the end (or discontinuation) of the 
treatment phaseNote 2) 
Follow-up phase: At the examination 28 days after the end of the treatment phase Note 2) 
 
Note 1): If a dose of the investigational product is administered within the allowed window for the 
last day of the previous cycle (Day 43 in the ONO-4538 group, Day 22 in the docetaxel 
group, and Day 50 in the paclitaxel group), the measurements obtained on the last day of 
the previous cycle (screening phase for Cycle 1) may be used unless a new test is deemed 
medically indicated. However, vital signs will be newly measured if ≥2 days have passed 
since the previous measurement, and body weight will be newly measured if ≥8 days have 
passed since the previous measurement. Measurements will be performed whenever 
medically indicated. 
Note 2): The previous measurements may be used as an alternative, unless new measurements are 
medically required. However, vital signs will be newly measured if ≥2 days have passed 
since the previous measurement, and body weight will be newly measured if ≥8 days have 
passed since the previous measurement. Measurements will be performed whenever 
medically indicated. 
 
8.2.4.1.2 
12-lead ECG (Heart Rate [HR], PR Interval, RR Interval, QRS Width and 
QT Interval) 
At the time point specified below, resting 12-lead ECG will be performed using the electrocardiograph 
lent by the Sponsor, with measurements of HR, PR interval, RR interval, QRS width, and QT interval. 
The ECG data will be forwarded to the core ECG analysis laboratory. The written procedure prepared 
separately will be followed for measurements of 12-lead ECG parameters and data transmission to the 
core ECG analysis laboratory. After a period of one year from the start of Cycle 1, resting ECG will 
be performed using the electrocardiograph at the study site, with measurements of HR, PR interval, 
RR interval, QRS width, and QT interval. Data transmission to the core ECG analysis laboratory is not 
necessary. Immediately after measurements of 12-lead ECG parameters and after receipt of ECG 
analysis results from the core ECG analysis laboratory, the investigator or subinvestigator will check 
the results for any abnormal findings.  
 
Time points of evaluation 
Screening phase Note 1) (or before dosing on Day 1 in Cycle 1) 


 
 
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Treatment phase: [ONO-4538 group]: After dosing on Day 1 and Day 43 in Cycle 1, before dosing 
on Day 1 and Day 43 in Cycle 4, and at the end (or discontinuation) of the 
treatment phaseNote 2) 
[Docetaxel group]: After dosing on Day 1 and Day 22 in Cycle 1, before 
dosing on Day 1 and Day 22 in Cycle 7, and at the end (or discontinuation) of 
the treatment phaseNote 2) 
[Paclitaxel group]: After dosing on Day 1 and Day 50 in Cycle 1, before 
dosing on Day 1 and Day 50 in Cycle 3, and at the end (or discontinuation) of 
the treatment phaseNote 2) 
Follow-up phase: At the examination 28 days after the end of the treatment phase Note 2) 
 
Note 1): The allowance window starts from the day of the first dose, ranging between -7 and -1. 
Note 2): The previous ECG data may be used as an alternative unless new ECG data are medically 
required. However, an ECG will be newly performed if ≥8 days have passed since the 
previous ECG. ECGs will be performed whenever medically indicated. 
 
8.2.4.2 
Chest X-ray 
Chest X-ray will be performed at the time points specified below. The investigator or subinvestigator 
will check if there are any abnormal findings. As necessary, unscheduled X-rays should be performed 
whenever onset of respiratory disease is suspected based on clinical symptoms or findings, or 
laboratory findings during the study period (i.e., after informed consent and until completion of the 
final examination stipulated by the protocol [with the exception of the outcome investigation]). 
 
Time points of evaluation 
Screening phase Note 1) 
Treatment phase: The last day of each cycle (Day 43 in the ONO-4538 group, Day 22 in the docetaxel 
group, Day 50 in the paclitaxel group), and at the end (or discontinuation) of the treatment phaseNote 2) 
Follow-up phase: At the examination 28 days after the end of the treatment phase Note 2) 
 
Note 1): The allowance window starts from the day of the first dose, ranging between -7 and -1. 
Note 2): The previous chest X-ray may be used as an alternative unless a new chest X-ray is medically 
required. However, chest X-ray will be newly performed if ≥8 days have passed since the 
previous chest X-ray. Chest X-rays will be performed whenever medically indicated. 


 
 
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8.2.4.3 
Laboratory Tests 
During the treatment phase and the follow-up phase, the investigator or subinvestigator will perform 
hematology tests, biochemistry tests, urinalysis, immunological tests and hormone tests as specified in 
the following subsections 8.2.4.3.1 and 8.2.4.3.2, and assess each test result to determine whether it is 
normal or abnormal. 
 
8.2.4.3.1 
Hematology Tests, Biochemistry Tests, and Urinalysis 
Hematology tests, biochemistry tests, and urinalysis will be performed at the time points specified 
below. In principle, these tests will be performed locally at individual study sites. 
 
Time points of evaluation 
Screening phase (the allowance window starts from the day of the first dose, ranging between -7 
and -1.) 
Treatment phase: [ONO-4538 group]: Day 8, before dosing on Day 15, before dosing on Day 29 
and Day 43 in Cycle 1; before dosing on Day 1 Note 1) and Day 43 in Cycle 2 
and beyond, and at the end (or discontinuation) of the treatment phaseNote 2) 
[Docetaxel group]: On Days 8 and 22 in Cycle 1; before dosing on Day 1Note 1) 
and Day 22 in and after Cycle 2, and at the end (or discontinuation) of the 
treatment phaseNote 2) 
[Paclitaxel group]: Before dosing on Days 8, 15, 22, 29, and 36 Note 3), and Day 
50 in Cycle 1; before dosing on Days 1 Note 1), 8, 15, 22, 29, and 36 Note 3, and 
Day 50 in and after Cycle 2, and at the end (or discontinuation) of the 
treatment phaseNote 2) 
Follow-up phase: At the examination 28 days after the end of the treatment phase Note 2) 
 
Note 1): If the investigational product is administered within the allowed window for the last day of 
the previous cycle (Day 43 in the ONO-4538 group, Day 22 in the docetaxel group, Day 
50 in the paclitaxel group), the measurements obtained on the last day of the previous 
cycle may be used unless a new test is deemed medically indicated. However, tests will be 
newly performed if ≥8 days have passed since the previous tests. Tests will be performed 
whenever medically indicated. 


 
 
79 
 
Note 2): The previous results may be used as an alternative, unless new results are medically 
required. However, tests will be newly performed if ≥8 days have passed since the 
previous tests. Tests will be performed whenever medically indicated. 
Note 3): For the paclitaxel group, the criteria for administration, dose reduction and discontinuation 
should be confirmed with the results of hemoglobin, white blood cells, neutrophils, and 
platelets of hematological parameters and albumin, AST, ALT, ALP, total bilirubin, Na, K, 
Ca, creatinine, and CRP of biochemical parameters.  
 
Test parameters  
Hematology: 
Red blood cell count, MCV, MCH, MCHC, hemoglobin, hematocrit, 
white blood cell count, white blood cell differential count (neutrophils, 
lymphocytes, eosinophils, basophils, monocytes), platelet count 
Biochemistry: 
Albumin, ALP, AST (GOT), ALT (GPT), total bilirubin, direct 
bilirubin, gamma-GTP, total protein, creatinine, blood glucose, LDH, 
BUN, uric acid, CK (CPK), P, Ca, Na, K, Cl, C-reactive protein (CRP) 
Urinalysis: 
Specific gravity, protein, glucose, occult blood, sediment (white blood 
cells, red blood cells) 
 
8.2.4.3.2 
Immunological and Hormone Tests 
Immunological and hormone tests will be performed at the time points specified below. Blood 
specimens will be collected in the morning as far as possible, and the time of blood collection will be 
recorded for each day of testing. These tests will be performed at the designated central laboratory. 
Measurements of SP-D and KL-6 at the time points specified below will be mandatory, but SP-D and 
KL-6 may be measured as necessary at other time points than these specified below. 
 
Time points of evaluation 
Screening phaseNote 1) 
Treatment phase: The last day of each cycle (Day 43 in the ONO-4538 group, Day 22 in the 
docetaxel group, Day 50 in the paclitaxel group) and at the end (or discontinuation) of 
the treatment phaseNote 2 
Follow-up phase: At the examination 28 days after the end of the treatment phase Note 2) 
 
Note 1): Latest results obtained within 14 days before randomization may be used as an alternative.  


 
 
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Note 2): The previous results may be used as an alternative, unless new results are medically 
required. However, tests will be newly performed if ≥8 days have passed since the 
previous tests. Tests will be performed whenever medically indicated. 
 
Test parameters (volume of blood collection at a time: 9 mL) 
Immunological tests: Rheumatoid factor (RA), antinuclear antibody (ANA), surfactant protein D 
(SP-D), Krebs von den Lungen-6 (KL-6) 
Hormone tests: Thyroid-stimulating hormone (TSH), free triiodothyronine (free T3), free 
thyroxine (free T4)  
 
If a clinically meaningful change in RA, ANA, TSH, or free T4 is shown as a result of these 
measurements, the following “Additional test parameters” will be measured as soon as possible. Other 
additional test parameters, such as adrenocorticotropic hormone (ACTH; volume of blood collection 
at a time, 2 mL), should also be performed as appropriate.  
 
Additional test parameters (volume of blood collection at a time: 15 mL) 
Anti-DNA antibody, anti-SSA antibody (Ro), anti-SSB antibody (La), anti-thyroglobulin 
antibody, anti-LKM antibody, anti-phospholipid antibody, anti-GAD antibody, anti-neutrophil 
cytoplasmic antibody, beta-1C/beta-1A globulin (C3), beta-1E globulin (C4), 50% hemolytic 
complement (CH50) activity in serum, TSH stimulating receptor antibody, anti-thyroid 
peroxidase antibody 
 
8.2.4.4 
Pregnancy Testing (Only in Women of Childbearing Potential) 
Serum or urine pregnancy testing will be performed in women of childbearing potential (including 
women with chemical menopause or no menstruation for other medical reasons).Note) The same testing 
method should be used throughout the study as far as possible. In principle, pregnancy testing will be 
performed locally at individual study sites.  
 
Note): Women of childbearing potential are defined as all women after onset of menstruation who 
are not post-menopausal and have not been surgically sterilized (e.g., hysterectomy, bilateral 
tubal ligation, bilateral oophorectomy). Postmenopause is defined as amenorrhea for ≥12 
consecutive months without specific reasons. Women using contraceptive methods, i.e., oral 
contraceptives or other hormonal contraceptives (vaginal contraceptives, injectable 


 
 
81 
 
contraceptives, etc.) or mechanical contraception (intrauterine devices, contraceptive barriers), 
are regarded as having childbearing potential. 
 
Time points of evaluation 
Screening phase (the allowance window starts from the day of the first dose, ranging between -7 
and -1.) 
Treatment phase: Before dosing on Day 1 in each cycleNote 1) and at the end (or discontinuation) 
of the treatment phaseNote 2) 
Follow-up phase: At the examination 28 days after the end of the treatment phase Note 2)  
 
Note 1): For Cycle 2 and beyond, pregnancy testing may be performed within 7 days before 
administration of the investigational product.  
Note 2): The previous result may be used as an alternative, unless a new result is medically 
required. However, testing will be newly performed if ≥8 days have passed since the 
previous test. Pregnancy testing will be performed whenever medically indicated. 
 
8.2.4.5 
Viral Tests 
In the screening phase, viral tests will be performed on the following parameters. If these tests have 
been performed within 1 year before randomization, the available results may be used as an alternative, 
unless new results are medically required. HBV-DNA quantification assay will be additionally 
performed in subjects with a negative HBs antigen test but with a positive test result for either HBs 
antibody or HBc antibody. In principle, these tests will be performed locally at individual study sites.  
 
Test parameters 
HIV-1 antibody, HIV-2 antibody, HTLV-1 antibody, HBs antigen, HBs antibody, HBc antibody, 
HCV antibody 
 
8.2.4.6 
ECOG Performance Status Score 
ECOG Performance Status (PS) Score will be assessed at the time points specified below. 
 
Time points of evaluation 
Screening phase (the allowance window starts from the day of the first dose, ranging between -7 
and -1.) 


 
 
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Treatment phase: [ONO-4538 group]: Before dosing on Day 1 in each cycleNote 1) (Cycle 2 and 
beyond), on Day 8 (in Cycle 1 only), before dosing on Day 15, before dosing 
on Day 29, on Day 43, and at the end (or discontinuation) of the treatment 
phaseNote 2) 
[Docetaxel group]: Before dosing on Day 1 in each cycleNote 1) (Cycle 2 and 
beyond), Day 8 (in Cycle 1 only), Day 22, and at the end (or discontinuation) 
of the treatment phaseNote 2) 
[Paclitaxel group]: Before dosing on Day 1 in each cycleNote 1) (Cycle 2 and 
beyond), before dosing on Day 8 (in Cycle 1 only), Day 50, and at the end (or 
discontinuation) of the treatment phaseNote 2) 
Follow-up phase: At the examination 28 days after the end of the treatment phase Note 2) 
 
Note 1): If the investigational product is administered within the allowed window for the last day of 
the previous cycle (Day 43 in the ONO-4538 group, Day 22 in the docetaxel group, Day 
50 in the paclitaxel group), the measurements obtained on the last day of the previous 
cycle may be used unless a new test is deemed medically indicated. If more than 8 days 
have passed since the previous test, a new test should be performed. Also, the test should 
be performed whenever it is deemed medically indicated. 
Note 2): The previous PS score may be used as an alternative, unless a new assessment is medically 
required. However, PS will be newly assessed if ≥8 days have passed since the previous 
assessment. PS assessment will be performed whenever medically indicated. 
 
8.2.4.7 
Adverse Events 
All adverse events will be assessed according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE), Version 4.0. For signs or symptoms not listed in the 
CTCAE, the investigator or subinvestigator will use his/her judgment in determining whether a given 
sign/symptom should be handled as an adverse event. 
For each adverse event occurring after the start of the initial dosing of the investigational product up to 
the time of completion of the final examination stipulated by the protocol (with the exception of the 
outcome investigation), the following data will be entered into the eCRF: event term, date of onset, 
grade, decision made on whether to continue the investigational product, any treatment for the adverse 
event, seriousness, causal relationship to the investigational product, and event outcome at the time of 
final assessment (or time of resolution if the event resolved before the final assessment). Immune-


 
 
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mediated adverse events (IMAEs) and adverse events likely to be IMAEs (see Table 9.2-1) and any 
treatment for IMAEs are to be collected during the treatment period and for 100 days following the last 
dose of investigational product. For subjects proceeding to the follow-up phase, any adverse events for 
which a causal relationship to the investigational product cannot be ruled out (i.e., adverse drug 
reactions) or which led to termination of the treatment phase should be followed up and appropriately 
treated, with the observation/measurement of clinical symptoms, general laboratory tests, or other 
parameters, until no further follow-up is deemed necessary for reasons of recovery, improvement, 
stabilization, or for any other reason. Serious adverse events should be reported to the sponsor (or 
designee) according to Section 9.9 “Actions to be Taken Following Onset of Any Serious Adverse 
Event.” 
If the investigator or subinvestigator concludes that if an adverse event of subjective 
symptoms/objective findings is related to an abnormal change in a laboratory test value, the event is in 
principle to be reported as a single adverse event (adverse event of subjective symptoms/objective 
findings only). If these events are considered to be mutually unrelated events, the subjective 
symptom/objective finding and the abnormal laboratory change are to be reported as separate 
independent adverse events.  
 
8.2.5 
Serum Drug Concentration Measurements (ONO-4538 group only) 
Serum ONO-4538 concentrations will be measured using an electrochemiluminescence assay by 
Pharmaceutical Product Development, LLC (PPD). Detailed measurement methods will be specified 
in the assay protocol prepared by the person responsible for serum ONO-4538 concentration 
measurements. Results of measurements will be reported in the serum ONO-4538 concentration 
measurement report. The specimens will be retrieved and transported in accordance with a written 
procedure prepared separately. 
Blood specimens for serum drug concentration measurements will be collected at the time points 
specified below (volume of blood collection at a time: 2 mL). As far as possible, blood will also be 
collected 6-12 weeks after the last dose of the investigational product. 
For the purpose of technical exploration, ONO-4538 and anti-ONO-4538 antibody may be measured 
in an exploratory manner using specimens for measuring serum drug concentration, but the results will 
not be reported. 
 
 
 


 
 
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Time points of evaluation 
Treatment phase: Before dosing on Days 1 and 29 in Cycle 1; and before dosing on Day 1 in 
Cycles 4 and 9 
Follow-up phase: At the examination 28 days after the end of the treatment phase (only in 
subjects proceeding to the follow-up phase by the end of Cycle 9), and 6–12 weeks 
after the last dose of the investigational product (as far as possible) 
 
8.2.6 
Anti-drug Antibody Measurements (ONO-4538 group only) 
Anti-ONO-4538 antibody will be measured using an electrochemiluminescence assay by 
Pharmaceutical Product Development, LLC (PPD). As necessary, neutralizing activity of antibody 
will be assessed by BMS. Detailed measurement methods will be specified in the assay protocol 
prepared by the person responsible for anti-ONO-4538 antibody measurements. The specimens will be 
retrieved and transported in accordance with a separate written procedure.  
Blood specimens for anti-ONO-4538 antibody measurements will be collected at the time points 
specified below (volume of blood collection at a time: 2 mL). As far as possible, blood will also be 
collected 6–12 weeks after the last dose of ONO-4538.  
If the volume of the specimen for anti-ONO-4538 antibody measurement is insufficient, the specimen 
collected at the same time for serum drug concentration measurement may be used. For the purpose of 
technical exploration, serum ONO-4538 and anti-ONO-4538 antibodies may be measured in an 
exploratory manner using samples for measuring serum anti-ONO-4538 antibodies, but these results 
will not be reported. 
 
Time points of evaluation 
Treatment phase: Before dosing on Days 1 and 29 in Cycle 1; and before dosing on Day 1 in 
Cycles 4 and 9 
Follow-up phase: At the examination 28 days after the end of the treatment phase (only in 
subjects proceeding to the follow-up phase by the end of Cycle 9), and 6–12 weeks 
after the last dose of ONO-4538 (as far as possible) 
 
8.2.7 
Tumor Markers (As needed) 
In subjects with tumor marker levels above the upper limit of the normal range, measurements of the 
tumor marker will be continued as far as possible, and as frequently as needed. In principle, tumor 
marker measurements will be performed locally at individual study sites. 


 
 
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8.2.8 
Patient Reported Outcomes (PROs), Healthcare Resource Utilization 
The evaluation of health-related quality of life is an increasingly important aspect of a clinical efficacy 
in oncology trials. Quality of life data provide an understanding of the impact of treatment from a 
patient’s perspective and offer insights into the patient experience that may not be captured through 
physician reporting. 
General health status will be measured using the EQ-5D. The EQ-5D is a standardized instrument for 
use as a measure of self-reported health status. The EQ-5D comprises 5 dimensions (mobility, self-
care, usual activities, pain/discomfort, and anxiety/depression) and a visual analog rating scale (VAS). 
The utility data generated from the EQ-5D is recommended for and commonly used in cost 
effectiveness analysis. 
Healthcare resource utilization data will be collected for all randomized subjects, including 
information about medical care encounters such as hospital admissions and their duration, outpatient 
visits, diagnostic tests and procedures, concomitant medications, and reasons for encounters. Data will 
be used for subsequent cost-effectiveness analyses. 
 
Time points of evaluation  
Screening phase (the allowance window starts from the day of the first dose, ranging between -7 and 
-1.) 
Treatment phase: Every 6 weeks starting from the start of Cycle 1 and at the end (discontinuation) of 
the treatment phaseNote 1) 
Follow-up phase: Every 12 weeks 
 
Note 1): The previous data may be used as an alternative, unless new data are medically required. 
However, data will be newly obtained if 15 days have passed for the previous evaluation. 
Tests will be performed whenever medically indicated. 
 
8.2.9 
Exploratory Biomarkers 
 
 
 
 
 
 
 


 
 
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87 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
 
88 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
8.2.9.6 
Tumor Tissue Examinations (some are essential) 
Tumor tissues must be obtained from each subject for analysis of PD-L1 expression during the 
screening phase to ensure the selection of subjects who meet all of the eligibility criteria (specified 
inclusion criteria). The collected tumor tissue specimens should be sent to the central laboratory 
before randomization. Collection of tumor tissues for biomarker analysis (expression analysis of the 
exploratory biomarkers) during the screening phase and during the follow-up phase is optional. For 
subjects in whom sampling of tumor tissue during the screening phase is possible and safe in the 
investigator's opinion, newly collected specimens will be provided to the central laboratory. If subjects 
are unable to undergo another tissue biopsy, the stored specimens can be used. During the follow-up 
phase, tumor tissues will be collected after the end of efficacy evaluation. 
Biopsy specimens collected from bone lesions are not suitable for any of the analyses planned for this 
study because decalcification of specimens compromises some of the planned biomarker analyses. 
 
Details of collection of tumor specimens 
For evaluation of PD-L1 expression, at least one formalin-fixed paraffin-embedded (FFPE) tumor-
tissue block (recommended) or at least five FFPE unstained slides are required. Tissue specimens 


 
 
89 
 
must contain at least 100 evaluable cancerous cells. PD-L1-stained tissue specimens will be analyzed 
by a pathologist at the sponsor-designated central laboratory. Specimens with insufficient cancerous 
cells are not evaluable and such subjects will not be randomized in the study. The subject will test 
positive for PD-L1 when cancerous cells with stained cell membranes account for ≥1% of at least 100 
evaluable cancerous cells and will test negative for PD-L1 when such cells account for <1%. If 
specimens meet the evaluation criteria, but assessment of the staining state of the cell membranes is 
difficult due to the biological conditions of the specimens (not due to their inappropriate preparation 
or handling), the specimens are classified as Indeterminate. These reasons include, but are not 
limited to: (1) a high melanin content in cells and (2) intensely stained cytoplasm.  
 
 
 
 
 
 
Procedures for the handling, storage and analysis of the specimens and provision of the genetic test 
results to patients will be in accordance with a separate written procedural manual. 
 
8.2.10 
Follow-up Investigation 
For subjects who have an overall response assessment other than PD and have discontinued the 
treatment phase for safety reasons in accordance with the RECIST Guideline Ver. 1.1 (see Appendix 
2), imaging examinations will be continued as far as possible, until either initiation of the post-study 
treatment for esophageal cancer or assessment of PD or recurrence. The obtained imaging findings 
will be assessed to determine the tumor response status according to the RECIST Guideline Ver. 1.1 
(see Appendix 2) and the results will be entered into the eCRF. 
For subjects who, at the time of initiation of the follow-up investigation, develop an adverse event for 
which a causal relationship to the investigational product cannot be ruled out or that led to 
discontinuation, the investigation of the adverse event and treatment for the event will be continued at 
appropriate intervals until the event resolves, improves, or stabilizes, etc. and thus is judged not to 
require further follow-up. The results of the follow-up investigation will be entered into the eCRF.  
The outcome investigation will be part of the follow-up investigation and will be conducted for all 
subjects enrolled in this study who have completed the examination 28 days after the end of the 


 
 
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treatment phase (if the patient died, data on the date and cause of death will also be collected). The 
outcome investigation (with collection of data on the date and cause of death if the patient died) 
should be conducted by direct contact or other means of communication, such as telephone or letter, 
roughly every 6 to 8 weeks but as frequently as required by the occurrence of events. Updated 
information on the survival status will be entered into the eCRF, as appropriate. The follow-up 
investigation will also collect data on any post-study treatment for esophageal cancer, its start date, 
and its details as far as possible. 
 
8.2.11 
Lost to Follow-up 
All reasonable efforts must be made to locate subjects to determine and report their ongoing status. 
This includes follow-up with persons previously authorized by subject to provide this information. 
Lost to follow-up is defined by the inability to reach the subject after a minimum of three documented 
phone calls, faxes, or emails as well as lack of response by subject to one registered mail letter. All 
attempts should be documented in the subject’s medical records. If it is determined that the subject has 
died, the site will use permissible local methods to obtain the date and cause of death. 
If investigator’s use of third-party representative to assist in the follow-up portion of the study has 
been included in the subject’s informed consent, then the investigator may use a Sponsor-retained 
third-party representative to assist site staff with obtaining subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study. The site staff and 
representative will consult publicly available sources, such as public health registries and databases, in 
order to obtain updated contact information. If after all attempts, the subject remains lost to follow-up, 
then the last known alive date as determined by the investigator should be reported and documented in 
the subject’s medical records. 
 
9 
Adverse Events and Matters to Ensure the Safety of Subjects 
9.1 
Definition of Adverse Events 
An adverse event is any unfavorable or unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of the investigational product, regardless of 
whether the event is causally related to the investigational product. Worsening of the primary disease, 
of a symptom associated with the primary disease, or of a concurrent disease will be regarded as an 
adverse event if the worsening is medically judged to be beyond the predictable range of the natural 
course of the disease. Also, tumor enlargement or appearance of a new lesion (except for a malignant 
tumor histologically different from the primary lesion) after initiation of the study will be regarded as 


 
 
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an adverse event if the enlargement/appearance is medically judged to be beyond the predictable range 
of the natural course of the disease. 
 
9.2 
Definition of Immune-mediated Adverse Events 
IMAEs include events, regardless of causality, occurring within 100 days of the last dose. IMAEs are 
specific events that include pneumonitis, diarrhea/colitis, hepatitis, nephritis/renal dysfunction, rash, 
and endocrine abnormalities (adrenal insufficiency, hypothyroidism/thyroiditis, hyperthyroidism, 
diabetes mellitus, and hypophysitis) for which subjects received immunosuppressive medication for 
treatment of the event, with the exception of endocrine events (hypothyroidism/thyroiditis, 
hyperthyroidism, hypophysitis, diabetes mellitus, adrenal insufficiency) but any inflammation 
confirmed by Histopathology, positive autoantibodies, findings of endoscope or imaging may also 
support the diagnosis of IMAEs. 
Table 9.2-1 below provides a summary of the IMAEs category and their respective PTs. 
 
Table 9.2-1 Preferred Terms of IMAEs  
* Irrespective of being treated with immunosuppressive medications or not.  
IMAE Category 
PTs included under IMAE Category 
Pneumonitis 
Pneumonitis, Interstitial lung disease 
Diarrhoea/Colitis 
Diarrhoea, Colitis, Enterocolitis 
Hepatitis 
Hepatotoxicity, 
Hepatitis, 
Hepatitis 
acute, 
Autoimmune 
Hepatitis, AST Increased, ALT increased, Hyperbilirubinaemia, 
Blood Bilirubin Increased, Blood ALP increased 
Adrenal Insufficiency* 
Adrenal Insufficiency 
Hypothyroidism*/Thyroiditis* 
Hypothyroidism, Thyroiditis 
Thyroiditis acute (collapsed with thyroiditis for frequency), 
Autoimmune 
Thyroiditis 
(collapsed 
with 
thyroiditis 
for 
frequency) 
Hyperthyroidism* 
Hyperthyroidism 
Hypophysitis* 
Hypophysitis 
Diabetes Mellitus* 
Diabetes Mellitus, Diabetic ketoacidosis 
Nephritis and renal dysfunction 
Nephritis, Nephritis allergic, Tubulointerstitial nephritis, Acute 
renal failure, Renal Failure, Increased Creatinine 
Rash 
Rash, Rash maculo-papular 


 
 
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9.3 
Definition of Serious Adverse Events 
Among events meeting the definition of adverse events, an event will be assessed as “serious” when it 
involves any of the following: 
 
1. Results in death 
2. Is life-threatening 
3. Requires inpatient hospitalization or prolongation of existing hospitalization Note 1) 
4. Results in persistent or significant disability or incapacity 
5. Is a congenital anomaly 
6. Other medically important events Note 2) 
 
Note 1): This does not include hospitalization for this study or any of the following: 
• Hospitalization or prolongation of existing hospitalization for a procedure (e.g., surgery, 
examination) that had been planned since before the study  
• Hospitalization or prolongation of existing hospitalization for examination or education  
• Hospitalization or prolongation of existing hospitalization for treatment (e.g., surgery) of 
a concurrent disease or associated symptom because of a change in the treatment strategy 
despite no worsening of the concurrent disease or associated symptom  
• Hospitalization or prolongation of existing hospitalization for follow-up observation of 
an already healed or improved condition  
• Admission to a hospice facility, nursing care facility, or rehabilitation facility 
• Hospitalization or prolongation of existing hospitalization for post-study treatment or 
other treatments for the primary disease  
• Hospitalization or prolongation of existing hospitalization for social reasons (e.g., leave 
of a caregiver or temporary absence of a family member) 
 
Note 2): Other medically important events include events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes listed in definitions 1 to 5 above. 
For such events, medical and scientific judgment should be exercised in deciding whether 
expedited reporting is appropriate. In other situations, these should also usually be 
considered serious. Examples of such events are intensive treatment in an emergency room, 
etc. for bronchospasm; blood disorder or convulsions that do not result in hospitalization; 


 
 
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development of drug dependency or drug abuse; or onset of a malignant tumor that is 
histologically different from the primary lesion. If a spread of any infectious factor 
mediated by the investigational product is suspected, it must be reported as a medically 
significant event.  
 
9.4 
Grading Criteria of Adverse Events 
Adverse events not listed in the CTCAE will be graded using the following 5-point scale from 1 to 5, 
using the grade whose definition most closely applies to the event. If the grade definition text includes 
specific treatment, the clinical requirement for the treatment will be considered in the grading.  
 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
Grade 2 
Moderate; minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL Note 1). 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADLNote 2). 
Grade 4 
Life-threatening consequences; urgent intervention indicated.  
Grade 5 
Death related to adverse events 
 
A semi-colon (;) indicates “or” within the description of the grade.  
 
Note 1): Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
Note 2):  Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not being bedridden 
 
9.5 
Assessment Criteria of Causal Relationship to the Investigational Product 
Causal relationship to the investigational product will be assessed using the following 2-point scale, in 
light of the subject’s condition, medical history, concomitant drugs, and temporal relationship with the 
event onset. For all adverse events for which a causal relationship to the investigational product 
cannot be ruled out, the basis for the assessment will be entered into the comment field of the eCRF. 
 


 
 
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1. Related: There is a reasonable causal relationship between the use of the investigational product 
and the adverse event.  
2. Not related: There is no reasonable causal relationship between the use of the investigational 
product and the adverse event.  
 
A reasonable causal relationship means that there is evidence to suggest a causal relationship between 
the adverse event and the investigational product. 
 
9.6 
Event Outcome 
The outcome of adverse events (i.e., symptoms and abnormal laboratory test values) will be assessed 
using the following criteria. The date of outcome will be the date of recovery from adverse events 
with an outcome of “Resolved,” or the date of final assessment of adverse events with other outcomes. 
 
Event outcome 
Assessment Criteria (reference) 
Resolved 
The symptom resolved, or the test value normalized or returned to the pre-
therapy level.  
Resolving  
The event improved in intensity, or the symptom showed an improving 
tendency.  
Not resolved 
The symptom or the test value has not improved.  
Resolved with 
sequelae  
The event resolved or was resolving, but with remaining symptoms of 
disability or other sequela  
Death 
The subject died.  
Unknown  
(Lost to follow-up)  
The subject was lost to follow-up.  
 
9.7 
Action Taken with the Investigational Product 
For each adverse event experienced, the investigator or subinvestigator will determine the action taken 
with the investigational product, and record the action using one of the following seven categories. 
Note that the action here refers to the action taken by the investigator/subinvestigator, not by the 
subject. 
 
Action taken by the 
investigator/ 
subinvestigator 
Assessment Criteria 
1. Does not changed 
As a result of the adverse event, the investigator or subinvestigator has 
judged that administration of the investigational product may be continued. 
2. Drug interrupted 
As a result of the adverse event, the investigator or subinvestigator has 
judged that administration of the investigational product needs to be 
interrupted. Investigational product has begun but has temporarily ceased or 
investigational product infusion was started and was prematurely stopped and 
is expected to be re-introduced.  


 
 
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Action taken by the 
investigator/ 
subinvestigator 
Assessment Criteria 
3. Drug delayed 
As a result of the adverse event, the investigator or subinvestigator has 
judged that administration of the investigational product needs to be delayed 
(or skipped). Administration of investigational product at the next scheduled 
time point has not started and has been delayed, but is expected to be re-
introduced. 
4. Dose reduced 
As a result of the adverse event, the investigator or subinvestigator has 
judged that administration of the investigational product needs to be dose 
reduced. 
5. Drug withdrawn 
As a result of the adverse event, the investigator or subinvestigator has 
judged that administration of the investigational product needs to be 
discontinued. 
6. Not applicable 
The adverse event developed after the end of administration of the 
investigational product. 
7. Other  
None of the above apply, but as a result of the adverse event the investigator 
or subinvestigator has changed the mode of administration of the 
investigational product. 
 
9.8 
Any Treatment for Adverse Events 
Any treatments given for the adverse event will be specified. 
 
9.9 
Actions to be Taken Following Onset of Any Serious Adverse Event 
Following the subject’s written consent to participate in the study, all serious adverse events that occur 
between the start of administration of the investigational product and 100 days after the last dose of 
investigational product, whether related or not related to the investigational product, must be noted, 
including those thought to be associated with protocol-specified procedures. If applicable, serious 
adverse events must be noted that relate to any later protocol-specified procedure (e.g., biopsy after 
the end of the treatment phase). 
The investigator should report any serious adverse event that occurs after these time periods and that 
is believed to be related to the investigational product or protocol-specified procedure. 
An SAE report should be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that a serious adverse event is not related to the investigational product, but 
is potentially related to the conditions of the study (such as withdrawal of previous therapy or a 
complication of a study procedure), the relationship should be specified in the narrative section of the 
SAE Report Form. 
Serious adverse events including overdose, whether related or not to the investigational product, and 
pregnancies must be reported to the sponsor (or designee) within 24 hours. Serious adverse events 
must be recorded on the SAE Report Form; pregnancies on the Pregnancy Report Form.  


 
 
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The report forms are to be transmitted via email or confirmed fax transmission to the following, and 
the original report forms are to remain on site:  
SAE Email Address: Refer to Contact Information list. 
SAE Fax Number: Refer to Contact Information list. 
SAE Telephone Contact (required for serious adverse event and pregnancy reporting): Refer to 
Contact Information list. 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE 
reports should include the same investigator term(s) reported initially.) 
If an ongoing serious adverse event changes in its intensity or causal relationship to the investigational 
product or if new information becomes available, a follow-up SAE report should be sent within 24 
hours to the sponsor (or designee) using the same procedure used for transmitting the initial SAE 
report. 
All serious adverse events should be followed until resolution, resolving, or stabilization. 
 
9.10 
Actions to be Taken Following Pregnancy 
Between the start of administration of the investigational product and 28 days after the end (i.e., 
completion/discontinuation) of the treatment phase, if it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, the 
investigational product will be permanently discontinued in an appropriate manner (e.g., dose tapering 
if necessary for subject safety). 
The investigator will immediately notify the sponsor (or designee) of this event and complete and 
forward the Pregnancy Report Form to the sponsor (or designee) within 24 hours and in accordance 
with SAE reporting procedures described in Section 9.9. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy Report Form. 
Any pregnancy that occurs in a female partner of a male study participant should be reported to the 
sponsor. Information on this pregnancy will be collected on the Pregnancy Report Form. 
 
9.11 
Actions to be Taken Following Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product that is 
considered both excessive and medically important. All occurrences of overdose must be reported as a 
serious adverse event (see Section 9.9 for reporting details). 


 
 
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9.12 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
chest X-ray, and any other potential safety assessment required or not by the protocol should also be 
recorded as a non-serious or serious adverse event, as appropriate, and reported accordingly. 
 
9.13 
Provision of New Information 
The sponsor, upon obtaining any information that might adversely affect the safety of the subject, 
impact the study conduct, or require a change in the approval of the IRB regarding study continuation, 
or information on serious unpredictable adverse drug reactions, will report the information promptly 
to all investigators engaged in the study and to the head of each study site. If it is deemed necessary to 
revise the informed consent form and written subject information, these will be revised promptly. Also, 
the sponsor will revise the clinical study protocol and investigator's brochure as appropriate. 
 
10 
Statistical Analysis 
Ono Pharmaceutical Co., Ltd. will perform the statistical analysis. The analysis principles are outlined 
below, while details of the analytical methods are described in the statistical analysis plan prepared by 
the person responsible for statistical analysis and the statistical analysis personnel. 
The statistical analysis plan Version 1.0 will be finalized before randomization for the first subject. 
The statistical analysis plan will be amended after Version 1.0 of it was fixed, as needed. 
Additional analyses not stated in the statistical analysis plan may be performed, and will be reported in 
the clinical study report. 
 
10.1 
Description of Statistical Analysis Methods including the Interim Analysis 
Stopping criteria from statistical viewpoint is not set because formal interim analysis is not planned in 
this study. 
 
10.2 
Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will be established to independently monitor 
safety data as well as operation of the study. The IDMC will have periodic meetings to ensure careful 
monitoring of subject safety. Ad hoc meetings may also be held as required. After each meeting, the 
IDMC will provide advice on whether the study should be continued, modified, or discontinued on the 
basis of the toxicities observed. Detailed tasks of the IDMC will be described in a written procedure 
prepared separately.  


 
 
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10.3 
Significance Level to be Used 
10.3.1 
Efficacy 
Two-sided test will be performed with 5% significance level. If superiority in OS is determined, a 
hierarchical hypothesis testing approach for the key secondary endpoints will be used to preserve a 
study-wise type I error rate at 5%. The key secondary endpoints will be tested in the following 
hierarchical order: 
1. ORR 
2. PFS 
Interactions will be tested with two-sided 15% significance level. 
 
10.3.2 
Safety 
Not applicable because no statistical tests will be performed on safety.  
 
10.4 
Determination of Subjects included in Analysis 
10.4.1 
Definitions of Analysis Sets  
For efficacy endpoints, the Intention-to-Treat (ITT) population will be the analysis set. 
For safety endpoints, the Safety Set (SAF) will be the analysis set. 
For anti-drug antibody endpoint, the Anti-Drug Antibody Set (ADA) will be the analysis set. 
Individual sets of subjects are defined below.  
 
10.4.1.1 
Enrolled Set（ENR） 
The Enrolled Set (ENR) will consist of all subjects enrolled (enrollment) in this study via IWRS.  
 
10.4.1.2 
Randomized Set（RND）／ITT 
The Randomized Set (RND) and ITT will consist of all randomized (randomization) subjects.  
 
10.4.1.3 
SAF 
The SAF will consist of all subjects given at least one dose of the investigational product.  
 
10.4.1.4 
ADA 
The ADA will consist of all subjects which meet all of the following items in the SAF population. 
1. It is not GCP noncompliant subject defined in 10.4.2 “Criteria for Handling of Subjects.” 


 
 
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2. It has measurements of anti-ONO-4538-antibody (the sample which screening result is potential 
positive but confirmatory result is not available will be excluded) at both baseline and at least 
one post-baseline anti-drug antibody assessment. 
 
10.4.2 
Criteria for Handling of Subjects 
Criteria for handling of subjects are specified below. 
10.4.2.1 
Disqualified Subjects 
Disqualified subjects are defined as those who failed to fulfill 4.2 “Inclusion Criteria” and conflict 
with 4.3 “Exclusion Criteria.” 
 
10.4.2.2 
GCP Noncompiant Subjects 
GCP noncompliant subjects are defined as those who were enrolled based on materials not reviewed 
by the IRB/IEC, who were enrolled at a medical institution where no study contract had been signed, 
or who did not provide informed consent appropriately.  
 
10.4.2.3 
Untreated Subjects 
Untreated subjects are defined as those who received no dose of the investigational product. 
 
10.4.2.4 
Incomlete Anti-Drug Antibody Subjects 
Incomplete anti-drug antibody subjects are defined as those who were without baseline anti-ONO-
4538-antibody measurements, and/or all post-baseline anti-ONO-4538-antibody measurements. 
For any other subject with unexpected problems, the handling in the analysis will be determined by 
the sponsor before fixing the data for the interim analysis, on the basis of discussion with the medical 
officer and the biostatistical advisor. 
 
10.4.3 
Criteria for Handling of Time Points of Evaluation 
If the actual date of examination is not the protocol-specified date, analysis by the time point of 
evaluation will be performed with inclusion of only the data obtained within the respective allowable 
windows, as shown in Table 6-1, Table 6-2 and Table 6-3. Of note, Day 1 of each cycle of treatment 
during the treatment period is defined as the first day of each cycle. 
 


 
 
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10.5 
Analysis Methods 
10.5.1 
Reliability of the Study 
10.5.1.1 
Inclusion and Exclusion for Analyses 
For each analysis set, the frequency of inclusion and exclusion for analysis as well as the frequency by 
reason for exclusion will be summarized by treatment group.  
 
10.5.1.2 
Withdrawals and Dropouts 
The number of subjects withdrawn from the study will be summarized by treatment group.  
10.5.2 
Details of Treatment with the Investigational Product 
Details of treatment with the investigational product will be summarized by treatment group.  
 
10.5.3 
Distribution of Patient Background Factors 
In each treatment group, frequency distributions and summary statistics will be calculated for the 
following variables, and comparability between the two treatment groups will be assessed.  
 
10.5.3.1 
Demographic Variables 
Categorical variables such as sex, age, race, and ethnicity will be summarized in terms of frequency 
and continuous variables such as height, weight, and BMI will be summarized using summary 
statistics ( mean, standard deviation, median, minimum and maximum value ) by treatment group. 
 
10.5.3.2 
Patient Background Characteristics 
Medical history, concurrent diseases, history of alcohol consumption, history of smoking, 
performance status score（ECOG）, date of diagnosis of the primary disease，lesion sites 
(anatomical subsites according to the TNM classification), clinical classification (TNM clinical 
classification), disease stage (stage grouping: TNM classification), histological classification, number 
of organs with metastases, date of surgery (including EMR or ESD) for the primary lesion (for 
subjects with recurrent esophageal cancer), residual tumor (R) classification (for subjects with 
recurrent esophageal cancer), site of recurrence (for subjects with recurrent esophageal cancer), and 
past treatments for cancer (e.g., surgery, radiotherapy, pharmacotherapy) will be summarized by 
treatment group. 
 


 
 
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10.5.3.3 
Baseline Values of Observation 
Diameters of the target lesions will be summarized using summary statistics (mean, standard 
deviation, median, minimum and maximum value) by treatment group.  
 
10.5.3.4 
Concomitant drugs and therapies 
The presence or absence of analgesics will be summarized in terms of frequency by treatment group. 
 
10.5.4 
Primary Efficacy Endpoint 
10.5.4.1 
Purpose of Analysis  
To assess the efficacy of the ONO-4538 group compared to the control group (docetaxel or paclitaxel) 
on basis of overall survival (OS) as the primary endpoint in patients with esophageal cancer refractory 
to or intolerant of combination therapy with fluoropyrimidine and platinum-based drug .  
 
10.5.4.2 
Hypothesis  
The ONO-4538 group is superior to the control group in terms of OS. 
 
10.5.4.3 
Analytical Item and Data Handling 
1. 
Analytical Item 
OS 
2. 
Handling of data 
OS will be calculated from the following equation:  
OS (Months) = (“Date of death from any cause” - “Date of randomization” + 1) / 30.4375 
 
For subjects lost to follow-up and subjects who are alive at the time of data cutoff date, data will be 
censored at the time the subject was last confirmed to be alive. 
 
10.5.4.4 
Analytical Methods 
The following analyses will be performed on OS:  
1. 
Primary analytical method 
Data will be compared between the two treatment groups using the stratified log-rank test with 
the location (Japan vs rest of the world), the number of organs with metastases (≤1 vs. ≥2), and 
PD-L1 expression (≥1% vs. <1% or indeterminate) which are the randomization factors as the 
stratification factors. 


 
 
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2. 
Secondary analytical method 
1） The hazard ratio and the corresponding two-sided 95% confidence interval (CI) for the ONO-
4538 group relative to the control group will be estimated using a stratified Cox proportional 
hazards model with the randomization factors as the stratification factors. 
2） The Kaplan-Meier curve will be plotted for each treatment group. Using the Kaplan-Meier 
method, the median OS and the corresponding two-sided 95% CI will be estimated for each 
treatment group. CI for median OS will be calculated using the Brookmeyer and Crowley method 
based on a log-log transformed CI for the survivor function. 
3） For each treatment group, the survival rates at months 6, 9, and 12 will be derived from the 
Kaplan-Meier method and corresponding two-sided 95% confidence interval will be calculated 
based on Greenwood formula for variance derivation and on log-log transformation applied on 
the survivor function. 
 
10.5.5 
Secondary Efficacy Endpoints 
10.5.5.1 
Purpose of Analysis 
To assess the efficacy of ONO-4538 from various aspects by exploratory analysis on other endpoints 
than the primary endpoint  
 
10.5.5.2 
Analytical Items and Data Handling 
1. 
Analytical items 
1）Objective response rate 
2）Disease control rate 
3）Progression free survival 
4）Duration of response 
5）Time to response 
6）Best overall response 
7）Maximum percent change from baseline in the sum of diameters of target lesions 
 
2. 
Handling of data 
Overall response and best overall response will be determined solely by imaging assessment according 
to the RECIST Guideline Version 1.1, and will not take into account any clinical/symptomatic 
progression. Evaluable imaging data will be overall response without an overall response of “NE.”  


 
 
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For each analytical item, the handling of data will be as follows:  
 
1）Objective response rate is defined as the percentage of subjects whose best overall response is 
assessed as either CR or PR.  
2）Disease control rate is defined as the percentage of subjects whose best overall response is 
assessed as CR, PR or SD. 
3）Progression free survival will be calculated from the following equation:  
Progression free survival (Months) = (“Earlier date on which either the overall response was assessed 
as PD or the subject died of any cause” - “Date of randomization” + 1) / 30.4375 
 
For subjects who are alive without an overall response of PD, data will be censored on the day of last 
evaluable imaging. For subjects who are alive without evaluable imaging, data will be censored on the 
day of randomization. For subjects started on post-study esophageal cancer treatment before an overall 
response of PD or death, data will be censored on the day of last evaluable imaging before initiation of 
post-study esophageal cancer treatment.  
 
4）Duration of response will be calculated from the following equation: 
Duration of response (Months) = (“Earlier date on which either the overall response was assessed as 
PD for the first time after confirmed response or the subject died of any cause” - “Date of first 
assessment of confirmed CR or PR” + 1) / 30.4375 
This will be calculated in subjects who had confirmed CR or PR during the study. 
 
5）Time to response will be calculated from the following equation: 
Time to response (Months) = (“Date of first assessment of confirmed CR or PR” - “Date of 
randomization” + 1) / 30.4375 
For subjects without a response in individual treatment groups, the data on the time to response will be 
censored at the “longest time to response + 1 day among subjects with response in the treatment 
group”.  
 
6）Maximum percent change from baseline in the sum of diameters of target lesions 
In subjects with target lesions, on the basis of the diameters of target lesions as assessed according to 
the RECIST Guideline Version 1.1, the maximum percent change from baseline in the sum of 
diameters of target lesions will be calculated from the following equation. However, this calculation 


 
 
104 
 
will exclude the diameter data obtained after an overall response of PD and after new treatment for 
cancer. 
 
100
1
  
lesions
 target 
of
 
diameters
 
of
 
sum
 
Baseline
"
"
tment 
study trea
after 
 
lesions
 target 
of
 
diameters
 
of
 
sum
Smallest 
"
        
(%)
 
lesions
 target 
of
 
diameters
 
of
 
sum
 
in the
 
baseline
 
from
 
change
percent 
 
Maximum
×






−
＝
 
 
For progression free survival and duration of response, the details of judgment criteria of event and 
censor will be provided in the statistical analysis plan. 
 
10.5.5.3 
Analytical Methods, 
1． For the analytical item 1) and 2), the following analyses will be performed: 
（1）Data will be compared between the two treatment groups using the Cochran-Manten-
Haenszel test with the randomization factors as the stratification factors. The associated odds 
ratio and the corresponding two-sided 95% CI for the ONO-4538 group relative to the control 
group and the estimate of the difference in objective response rate and corresponding two-
sided 95% CI will be calculated using Cochran-Manten-Haenszel method and adjusted by the 
same stratification factors. 
（2）The proportions and the corresponding two-sided 95% CI will be estimated using the 
Clopper-Pearson method for each treatment group. 
2． For the analytical item 3), the following analyses will be performed:  
（1）Data will be compared between the two treatment groups using stratified log-rank test with 
the randomization factors as the stratification factors. The hazard ratio and the corresponding 
two-sided 95% CI for the ONO-4538 group relative to the control group will be estimated 
using a stratified Cox proportional hazards model with the randomization factors as the 
stratification factors. 
（2）The Kaplan-Meier curve will be plotted for each treatment group. Using the Kaplan-Meier 
method, the median OS and the corresponding two-sided 95% CI will be estimated for each 
treatment group. CI for median PFS will be calculated using the Brookmeyer and Crowley 
method based on a log-log transformed CI for the survivor function. 
（3）For each treatment group, the progression free survival rates at months 3, 6, 9, and 12 will be 
derived from the Kaplan-Meier estimates and the corresponding two-sided 95% confidence 
intervals will be derived based on Greenwood’s formula for variance derivation and on log-
log transformation applied on the survivor function. 


 
 
105 
 
3．For the analytical item 4), the following analyses will be performed: 
（1）The Kaplan-Meier curve will be plotted for each treatment group. Using the Kaplan-Meier 
method, the median OS and the corresponding two-sided 95% CI will be estimated for each 
treatment group. CI for median duration of response will be calculated using the Brookmeyer 
and Crowley method based on a log-log transformed CI for the survivor function.. 
4．For the analytical item 5), the following analyses will be performed: 
（1）Summary statistics will be calculated for subjects whose best overall response is CR or PR. 
（2）The Kaplan-Meier curve will be plotted for each treatment group. 
5．For the analytical item 6), the percentage of CR, PR, SD, PD and NE will be calculated for each 
treatment group. For the percentages of CR, PR and SD, the corresponding 95% CI will be 
estimated using the Clopper-Pearson method for each treatment group. 
6．For the analytical item 7), waterfall plot will be displayed. 
 
10.5.6 
Interaction Analysis 
For the primary efficacy endpoint, the interaction between treatment group and the each demographic 
variable will be assess using a stratified Cox proportional-hazards model with the randomization 
factors as the stratification factors. The demographic factors which will be used for interaction 
analysis will be provided in the statistical analysis plan. 
 
10.5.7 
Adjusted Analysis 
If any factors are found to be imbalanced between the two treatment groups or to affect evaluation in 
the study, adjusted analysis for the primary endpoint will be performed using a stratified Cox 
proportional-hazards model with the randomization factors as the stratification factors and those 
factors as adjustment factors . The adjustment factors for adjusted analysis will be provided in the 
statistical analysis plan. 
 
10.5.8 
Analysis of safety 
10.5.8.1 
Purpose of Analysis  
To assess the safety of ONO-4538.  
 
10.5.8.2 
Analytical methods 
1. Numbers of subjects with adverse events and adverse drug reactions in each treatment group 
will be summarized 


 
 
106 
 
2. Adverse events and adverse drug reactions in each treatment group will be summarized by 
System Organ Class (SOC), Preferred Term (PT), Grade, etc. 
3. For laboratory parameters whose Grade were defined in CTCAE v4.0, the baseline Grade and 
the worst CTC Grade after treatment in each treatment group will be evaluated in the shift table. 
4. Numbers of subjects with abnormal hepatic function and thyroid dusfunction in each treatment 
group will be summarized. 
 
10.5.9 
Data Reviews 
After data collection from this study, using the data before fixed, a preliminary analysis will be 
performed in terms of the distribution of background factors etc., to determine the appropriateness of 
planned analytical methods. 
 
10.5.10 
Other Issues 
Subgroup analyses will be performed on the efficacy and safety endpoints.  
Analysis for anti-ONO-4538 antibody will be performed. 
Analysis for Patient Reported Outcomes will be performed. 
Exploratory analyses may be additionally performed on the efficacy or safety of ONO-4538 and 
biomarkers as necessary. Pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) 
analyses may be performed as necessary. If these analyses are performed, reports will be separately 
prepared.  
 
11 
Ethical Conduct of the Study 
11.1 
Good Clinical Practice 
This study will be conducted in accordance with the ethical principles that are consistent with the 
Good Clinical Practice (GCP) guideline developed by the International Conference on Harmonization 
of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).  
This study will be conducted in compliance with the protocol. Prior to initiation of the study, the 
protocol and any amendments, and the subject information and informed consent form must have 
received approval/favorable opinion from the institutional review board or independent ethics 
committee (IRB/IEC).  
All potential serious breaches, if any, must be immediately reported to the sponsor. A serious breach is 
a breach of the conditions and principles of GCP in connection with the study or the protocol, which is 


 
 
107 
 
likely to affect, to a significant degree, the safety or physical or mental integrity of the subjects of the 
study or the scientific value of the study. 
Personnel involved in conducting this study will be qualified by education, training, and experience to 
perform their respective tasks.  
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). 
 
11.2 
Institutional Review Board or Independent Ethics Committee (IRB/IEC) 
Before study initiation, the investigator must have written and dated approval from the IRB/IEC for 
the protocol, subject information and informed consent form, subject recruitment materials or method 
of recruitment (e.g., advertisements), and any other written information to be provided to subjects. The 
investigator or sponsor should also provide the IRB/IEC with a copy of the Investigator’s Brochure or 
product labeling information to be provided to subjects and any updates.  
The investigator or sponsor should provide the IRB/IEC with reports, updates, and other information 
(e.g., expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures. 
 
11.3 
Privacy Protection for Subjects 
The utmost consideration should be given to the protection of subjects’ privacy. Subject Identification 
Codes will be used in place of subjects’ names to distinguish individuals on the eCRFs and in other 
data. Completed eCRFs will not be used for purposes other than this study. Any information made 
available to the sponsor via this study will never be released to a third party. 
 
12 
Subject Informed Consent 
12.1 
Informed Consent 
The investigator or subinvestigator must ensure that patients are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding the clinical study in which they volunteer to 
participate.  
In situations where consent cannot be given by patients, their legally acceptable representatives are 
clearly and fully informed about the purpose, potential risks, and other critical issues regarding the 
clinical study in which the subject volunteers to participate.  
The sponsor will provide the investigator with an appropriate (i.e., global or local) sample informed 
consent form, which will include all elements required by ICH-GCP and applicable regulatory 


 
 
108 
 
requirements. The sample informed consent form will adhere to the ethical principles that have their 
origin in the Declaration of Helsinki.  
The investigator or subinvestigator should: 
1. 
Provide a copy of the consent form and written information about the study in the language in 
which the patient is most proficient prior to clinical study participation. The language must be 
non-technical and easily understood.  
2. 
Allow time necessary for the patient or patient’s legally acceptable representative to inquire 
about the details of the study. 
3. 
Obtain an informed consent form signed and dated by the patient or the patient’s legally 
acceptable representative and by the person who conducted the informed consent discussion. 
4. 
Obtain the IRB/IEC’s written approval of the written informed consent form and any other 
information to be provided to the patients, prior to the beginning of the study and after any 
revisions are completed for new information.   
5. 
If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the subject. 
6. 
Revise the informed consent form whenever important new information becomes available that 
is relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject’s legally acceptable representative or legal 
guardian of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented.  
 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements and the subjects’ signed informed 
consent forms and subject information.  
The consent form and subject information must also include a statement that the sponsor and 
regulatory authorities have direct access to subject records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over the interests of science and society. 
 


 
 
109 
 
12.2 
Withdrawal of Consent 
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a subject 
specifically withdraws consent for any further contact with him/her or persons previously authorized 
by subject to provide this information. Subjects should notify the investigator of the decision to 
withdraw consent from future follow-up in writing, whenever possible. The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the withdrawal 
is from further treatment with study drug only or also from study procedures and/or post treatment 
study follow-up, and entered on the appropriate CRF page. In the event that vital status (whether the 
subject is alive or dead) is being measured, publicly available information should be used to determine 
vital status only as appropriately directed in accordance with local law. 
 
13 
Rules or Criteria for Withdrawing Individual Subjects from the Study or 
Discontinuing Parts of the Study or Entire Study 
13.1 
Rules or Criteria for Withdrawing Individual Subjects from the Study 
In any of the following instances, the subject will be immediately withdrawn from the treatment phase 
or the follow-up phase. The investigator or subinvestigator will provide appropriate treatment and also 
make observations and measurements of clinical symptoms and routine laboratory tests at the time of 
withdrawal as far as possible. Details of the withdrawal, including the date of withdrawal, reason for 
withdrawal, treatment after withdrawal, and clinical course will be entered into the eCRF, and the 
sponsor will be notified promptly. For a subject who do not make a scheduled visit and is thereby 
discontinued from study treatment, the investigator or subinvestigator will perform follow-up 
investigations by telephone, letter, or other means to determine the reason for not making the study 
visit, the subsequent course, and the patient’s current condition, and enter the results into the eCRF. 
 
1. When the subject requests to withdraw from the study 
2. When the subject is found not to fulfill the inclusion criteria 
3. When the subject is found to meet any of the exclusion criteria 
4. When the investigator or subinvestigator has judged it difficult to continue with further study 
procedures because of the occurrence of an adverse event, whether or not causally related to 
the investigational product 
5. When the investigator or subinvestigator has judged it inappropriate to continue with further 
study procedures because of progressive disease 


 
 
110 
 
6. When the subject has failed to return to the study site and thus no further study procedures can 
be performed 
7. When the investigator or subinvestigator has judged it inappropriate to continue with further 
study procedures for other reasons 
14 
Study Management 
14.1 
Compliance with the Protocol and Protocol Amendments 
This study will be conducted as described in this approved protocol. The investigator or 
subinvestigator should not implement any deviation or change to the protocol without prior review 
and documented approval/favorable opinion from the IRB/IEC of an amendment, except where 
necessary to protect study subjects from an immediate hazard.  
If a deviation or change to the protocol is implemented to eliminate an immediate hazard prior to 
obtaining IRB/IEC approval/favorable opinion, the deviation or change will be submitted as soon as 
possible to:  
 IRB/IEC for review and approval/favorable opinion 
 Sponsor  
 Regulatory Authority(ies), if required by local regulations 
 
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be sent to 
the sponsor.  
If an amendment substantially alters the study design or increases the potential risk to the subject: (1) 
the consent form and subject information must be revised and submitted to the IRB(s)/IEC(s) for 
review and approval/favorable opinion; (2) the revised documents must be used to obtain consent 
from subjects currently enrolled in the study if they are affected by the amendment; and (3) the new 
documents must be used to obtain consent from new subjects prior to enrollment.  
If the revision is made via an administrative letter, investigators must inform their IRB(s)/IEC(s). 
 
15 
Completion of Electronic Case Report Forms (eCRFs) 
15.1 
eCRF 
For all subjects who provide written consent, the investigator or designee will enter data into the eCRF 
promptly after completion of each assessment procedure, as stipulated by the protocol, for each 
subject. Clinical research coordinators will only be allowed to transcribe data from source documents 
to the eCRF. All data in the eCRF must be consistent with source documents, and any discrepancy 
should be explained by the investigator. The investigator will confirm that all entries in the eCRF 


 
 
111 
 
(including audit trails and query responses) are accurate and complete and ensure the accuracy and 
completeness by electronically signing the eCRF. An electronic signature is the legally binding 
equivalent of the signatory’s handwritten signature. Electronically signed entries cannot be modified. 
Procedures for eCRF data entries, changes and corrections, and electronic signatures will follow a 
written procedure prepared separately.  
The investigator or designee should meet the sponsor’s training requirements and access the sponsor’s 
electronic data capture (EDC) system using the unique user account provided by the sponsor. User 
accounts are not to be shared or reassigned to other individuals. 
 
16 
Monitoring 
Representatives of the sponsor must be allowed to visit all study site locations periodically to assess 
the data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator or subinvestigator, and 
verify that the facilities remain acceptable. 
In addition, the study may be evaluated by the sponsor’s internal auditors and government inspectors, 
who must be allowed access to the eCRFs, source documents, other study files, and study facilities. 
The sponsor’s audit reports will be kept confidential. 
The investigator shall notify the sponsor promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to the sponsor. 
 
17 
Procedures to Ensure Compliance of Subject Medication and Other Stipulations 
The investigator or subinvestigator will ensure treatment compliance and specimens such as blood and 
urine are collected appropriately at the study site. 
 
18 
Retention of Essential Documents 
18.1 
Record Retention 
Essential documents should be retained for up to 2 years after the last approval of the marketing 
application in an ICH region or until there are no pending or contemplated marketing applications in 
an ICH region, whichever is later, or until 2 years have elapsed since the formal discontinuation of 
clinical development for the investigational product. However, these essential documents should be 
retained for the period required by the applicable regulatory requirements or by agreement with the 
sponsor, whichever is longer. These essential documents must not be destroyed or transferred to 


 
 
112 
 
another location without prior written notification of the sponsor. The sponsor is responsible for 
informing the investigator or institution when these documents no longer need to be retained. 
 
19 
Publication of Study Results 
Results from the study conducted in accordance with this protocol are the property of the sponsor and 
study sites. Any publication of the study results requires prior approval of the sponsor. Issues related 
to publication will be resolved by discussion between the sponsor and the coordinating investigator. 
 


 
 
113 
 
20 
Literature references 
1) 
World Health Organization, World Cancer Report 2014 
2) 
Statistics and Information Department, Minister’s Secretariat, Ministry of Health, Labour and 
Welfare. Reports on Vital Statistics, published on September 11, 2014 
3) 
Center for Cancer Control and Information Services, National Cancer Center. Monitoring of 
Cancer Incidence in Japan: Cancer Incidence and Incidence Rates in Japan in 2011 (MCIJ2011) 
(2015) 
4) 
Ozawa S, Tachimori Y, Baba H, Fujishiro M, Matsubara H, Numasaki H, et al. Comprehensive 
Registry of Esophageal Cancer in Japan, 2004. Esophagus. 2012;9:75-98. 
5) 
Center for Cancer Control and Information Services, National Cancer Center. White book on 
cancer statistics 2012: toward evidence-based care for cancer 
6) 
Health Insurance Review Agency (HIRA). Disease statistics of 2013 
7) 
Department of Health, Executive Yuan. Cancer Registry Annual Report, 2010 TAIWAN 
8) 
Keio Igaku 2009;85 (2) 127-135 
9) 
Steevens J, Schouten LJ, Goldbohm RA, van den Brandt PA. Alcohol consumption, cigarette 
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Epidemiol. 2005;15 Suppl 2:S212-9. 
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Agency for Research on Cancer Monograph Working Group. A review of human carcinogens--
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14) Center for Cancer Control and Information Services, National Cancer Center. Monitoring of 
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(2-weekly DCF) with cisplatin plus fluorouracil (CF) in patients with metastatic or recurrent 
esophageal cancer: rationale, design and methods of Japan Clinical Oncology Group study 
JCOG1314 (MIRACLE study). Jpn J Clin Oncol. 2015; 1-5. 
24) Hironaka S, Tsubosa Y, Mizusawa J, Kii T, Kato K, Tsushima T, et al. Phase I/II trial of 2-
weekly docetaxel combined with cisplatin plus fluorouracil in metastatic esophageal cancer 
(JCOG0807). CancerSci. 2014; 105: 1189-95. 
25) Mizota A, Shitara K, Kondo C, Nomura M, Yokota T, Takahara D, et al. A Retrospective 
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Cancer Who Previously Received Platinum-Based Chemotherapy. Oncology 2011;81:237-242 
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active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an 
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Appendix 1 
Criteria and Definitions Used in This Study 
 
In this study, the TNM Classification of Malignant Tumours, Seventh Edition, published by the Union 
for International Cancer Control (UICC) (hereinafter referred to as “the TNM classification”) will be 
used to determine the lesion sites (anatomical subsites), clinical classification, and disease stage. 
 
1. Lesion site (anatomical subsites: the TNM classification) 
1) Cervical esophagus (Ce) 
From the lower border of the cricoid cartilage to the thoracic inlet (superior margin of the 
sternum), i.e., the range up to approximately 18 cm below the upper incisor teeth 
2) Thoracic esophagus (Te) 
(i) Upper thorax (Ut) 
From the thoracic inlet to the tracheal bifurcation, i.e., the range up to approximately 24 cm 
below the upper incisor teeth. 
(ii) Middle thorax (Mt) 
The proximal half of the two equal portions between the tracheal bifurcation and the 
esophagogastric junction. The lower border is approximately 32 cm from the upper incisor teeth. 
(iii) Lower thorax (Lt) (including the esophagogastric junction)   
A length of approximately 8 cm including the abdominal esophagus, consisting of the distal 
half of the two equal portions between the tracheal bifurcation and the esophagogastric junction. 
The lower border is approximately 40 cm from the upper incisor teeth. 
 
2. Clinical classification (the TNM classification) 
T： Primary tumor 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
Intraepithelial carcinoma/ high grade dysplasia 
T1 
Tumor invades lamina propria, muscularis mucosae, or submucosa 
  
T1a: Tumor invades lamina propria or muscularis mucosae 
  
T1b: Tumor invades submucosa 
T2 
Tumor invades muscularis propria 
T3 
Tumor invades adventitia 


 
 
117 
 
T4 
Tumor invades adjacent structures 
  
T4a: Tumor invades pleura, pericardium, or diaphragm 
  
T4b: Tumor invades other adjacent structures, such as the aorta, vertebral body, and trachea 
 
N: Regional lymph nodes 
NX 
Regional lymph node(s) cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Metastasis in 1-2 regional lymph nodes 
N2 
Metastasis in 3-6 regional lymph nodes 
N3 
Metastasis in 7 or more regional lymph nodes 
 
M：Distant metastasis 
M0 
No distant metastasis 
M1 
Distant metastasis 
 
Residual tumor (R) classification 
RX 
Presence of residual tumor cannot be assessed 
R0 
No residual tumor 
R1 
Microscopic residual tumor 
R2 
Macroscopic residual tumor 
 
Definition of regional lymph nodes: 
Regional lymph nodes are those along the lymph flow of the esophagus, including the celiac lymph 
nodes and the cervical para-esophageal lymph nodes (regardless of the primary site), but do not 
include the supraclavicular lymph nodes. 
 
 


 
 
118 
 
3. 
Disease stage (stage grouping, the TNM classification) 
Stage 
T 
N 
M 
0 
Tis 
N0 
M0 
IA 
T1 
N0 
M0 
IB 
T2 
N0 
M0 
IIA 
T3 
N0 
M0 
IIB 
T1, T2 
N1 
M0 
IIIA 
T4a 
N0 
M0 
T3 
N1 
M0 
T1, T2 
N2 
M0 
IIIB 
T3 
N2 
M0 
IIIC 
T4a 
N1, N2 
M0 
T4b 
Any N 
M0 
Any T 
N3 
M0 
IV 
Any T 
Any N 
M1 
 
 
4． Definition of terms used in this study 
Primary lesion: In the present study, a primary lesion is defined as follows.  
• Main lesion in isolated lesion 
• Main lesion and all secondary lesions in multiple lesions 
 
Main lesion/secondary lesion: In case of multiple lesions, the lesion with the greatest depth of 
invasion in clinical diagnosis is regarded as the main lesions, and 
others as secondary lesions. Both include intraepithelial spreadNote). 
 
• Main lesion = main focus + intraepithelial spread 
• Secondary lesion = secondary focus + intraepithelial spread 
 
Note): In this study, intraepithelial spread refers to the intraepithelial lesion 
that continuously spreads from the primary focus. 


 
 
119 
 
Appendix 2 
Tumor Response Assessment Criteria Used in This Study  
 
In this study, the RECIST Guideline Ver. 1.1Note 1) will be used for the assessment of tumor response 
by CT or other imaging examinations. 
 
Note 1 ): 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST Guideline Ver. 1.1. Eur J 
Cancer. 2009 Jan;45(2):228-47. 
 
 
A.  Imaging-based assessment according to the RECIST Guideline Ver. 1.1  
A-1  Examinations used for the response assessment  
 
CT of the neck to abdomen (recommended slice thickness, 5 mm) (or MRI if necessary)  
 
Tumor markers  
 
A-2  Measurability of tumors at baseline 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable 
according to criteria A-3 and A-4. 
Tumor diameters should be measured in the axial plane of CT. Tumors should not be measured in the 
sagittal or coronal plane of three-dimensional imaging. 
Baseline imaging will be the last imaging performed within 28 days before randomization. However, 
if other imaging is performed between randomization and the first dose of the investigational product, 
the later imaging will be used as the baseline. 
 
A-3  Definition of measurable lesions 
Non-lymph node lesions (Tumor lesions) 
On CT or MRI, a lesion will be considered measurable if the dimension (longest diameter) of the 
lesion in the plane of measurement is at least twice the slice thickness and at least 10 mm.  
 
Lymph node lesions  
To be considered pathologically enlarged and measurable, a lymph node must be ≥15 mm in short axis 
when assessed by CT scan (with CT slice thickness no greater than 5 mm).  


 
 
120 
 
A-4  Definition of non-measurable lesions  
All lesions other than measurable lesions will be considered non-measurable. The following lesions 
will also be considered non-measurable irrespective of the imaging technique and lesion size.  
 
Esophageal primary lesion 
 
Bone lesions (lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as CT or MRI can 
be considered as measurable lesions if the soft tissue component meets the definition of 
measurable lesions) (Blastic bone lesions are non-measurable.)  
 
Cystic lesions (“cystic lesions” thought to represent cystic metastases can be considered as 
measurable lesions if they meet the definition of measurable lesions; however, if noncystic 
lesions are present in the same patient, these are preferred for selection as target lesions.)  
 
Lesions with prior local treatment such as radiotherapy (with the exception of lesions showing 
progression on imaging after radiotherapy)  
 
Leptomeningeal disease   
 
Ascites, pleural, or pericardial effusion 
 
Inflammatory breast disease 
 
Lymphangitic involvement of skin or lung 
 
Abdominal masses/abdominal organomegaly identified by physical exam that is not measurable 
by reproducible imaging techniques  
 
A-5  Target lesions  
Among measurable lesions, up to a maximum of the five largest lesions (and a maximum of two 
lesions per organ) representative of all involved organs should be identified as target lesions. Target 
lesions should be selected on the basis of their size (longest axis for non-nodal lesions, short axis for 
nodal lesions) and be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. (If the largest lesion does not lend itself to 
reproducible measurement, the next largest lesion which can be measured reproducibly should be 
selected.) 
The sum of the diameters (longest axis for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and recorded as the baseline sum diameter. 
 
 
 


 
 
121 
 
A-6  Non-target lesions  
All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-
target lesions and should also be recorded at baseline. It is possible to record multiple nontarget 
lesions involving the same organ as a single item on the case record form (e.g. ‘multiple enlarged 
pelvic lymph nodes’ or ‘multiple liver metastases’).  
 
A-7  Response Criteria  
Evaluation of target lesions  
Complete Response (CR): 
Disappearance of all (non-lymph node) target lesions. Any pathological lymph nodes (whether 
target or non-target) must have reduction in the short axis to <10 mm. 
Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline 
sum diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest 
sum on study (this includes the baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.  
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum diameter while on study.  
Not Evaluable (NE): 
No imaging/measurement is done at all at the time points, or CR, PR, PD and SD are not 
applicable.  
 
Percent decrease in the sum of diameters = 
Baseline sum – Sum at the evaluation 
× 100% 
Baseline sum 
 
Percent increase in the sum of diameters = 
Sum at the evaluation − Smallest sum 
× 100% 
Smallest sum 
 
∗ 
All lesions recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g., <5 mm). However, when target lesions are 
“too small to measure,” and if the lesion has likely disappeared, the measurement should be 


 
 
122 
 
recorded as 0 mm, irrespective of CT slice thickness. If the lesion is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be assigned.  
∗ 
If the percent decrease meets PR and at the same time the percent increase meets PD, then PD 
should be selected.  
∗ 
When lesions fragment, the longest diameters of the fragmented portions should be added 
together to calculate the target lesion sum.  
∗ 
When lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced 
such that they are no longer separable, the vector of the longest diameter in this instance 
should be the maximal longest diameter for the coalesced lesion. 
 
Evaluation of non-target lesions  
Complete Response (CR): 
Disappearance of all non-lymph node, non-target lesions and normalization of tumor marker 
level (i.e., ≤ upper normal limit of the study site). All lymph nodes must be non-pathological in 
size (< 10mm short axis).  
Non-CR/Non-PD:  
Persistence of one or more non-lymph node, non-target lesions and/or maintenance of the tumor 
marker level above the normal limits of the study site. 
Progressive Disease (PD): 
“Unequivocal progression” of existing non-target lesions (including recurrence).  
To achieve “unequivocal progression”, there must be an overall level of substantial worsening in 
non-target lesions such that the overall tumor burden has increased sufficiently to merit 
discontinuation of study treatment. In the presence of SD or PR in target lesions, “unequivocal 
progression” will be selected if there is substantial worsening in non-target lesions beyond the 
extent of reduction in target lesion burden. If not, “Non-CR/Non-PD” should be selected.    
When the patient has no target lesions, “unequivocal progression” will be selected if, as a rough 
guide, the increase in overall non-target lesion burden is apparently greater than a 20% increase 
in diameter or a 73% increase in volume. 
Not Evaluable (NE):  
No imaging/measurement is done at all at the time points, or CR, PR, PD and SD are not 
applicable.  
 


 
 
123 
 
New lesions 
A lesion that was not present at baseline but identified after the start of study treatment is regarded as 
a “new lesion.” 
The finding of a “new lesion” should be unequivocal: i.e. not attributable to differences in scanning 
technique or changes in imaging modality between baseline and later evaluation, or findings thought 
to represent something other than a tumor. A lesion identified in an anatomical location that was not 
scanned at baseline is considered a new lesion. 
If a lesion disappears and reappears at a subsequent time point, it should continue to be measured. 
However, the patient’s response at the time point when the lesion reappears will depend upon the 
status of his/her other lesions. If the patient’s tumor has reached CR and the lesion reappears, then the 
patient should be considered PD at the time of reappearance. In contrast, if the tumor status is PD or 
SD and a lesion which had disappeared then reappears, its maximal diameter should be added to the 
sum of the remaining lesions for a calculated response: in other words, the reappearance of an 
apparently “disappeared” single lesion amongst many which remain is not in itself enough to qualify 
for PD: that requires the sum of all lesions to meet the PD criteria. The rationale for such a 
categorization is based upon the realization that most lesions do not actually “disappear” but are not 
visualized because they are beyond the resolving power of the imaging modality employed. 
When a lesion might be a new lesion but this is unclear, repeat imaging will be performed after a 
clinically appropriate interval. If the repeat imaging confirms that there is definitely a new lesion, the 
date of appearance of the new lesion will be the date of the repeat imaging that confirmed the 
appearance of a new lesion.  
 
A-8  Overall response  
Overall response will be assessed on the basis of the response by target lesions and non-target lesions 
as well as any appearance of new lesions. Table A below provides the criteria for the overall response 
status determination at each time point for patients who have target lesions at baseline. If the patient 
has no non-target lesions, the overall response will be determined based on the response by target 
lesions and any appearance of new lesions. For patients without target lesions at baseline, the overall 
response will be determined according to Table B, on the basis of the response by non-target lesions 
and any appearance of new lesions.  
 
 


 
 
124 
 
Table A: Overall Response Criteria (in patients with target lesions) 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
No 
SD 
NE 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Table B: Overall Response Criteria (in patients without target lesions) 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
NE  
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
A-9  Best overall response  
Best overall response will be determined on the basis of the overall response up to the end of the study, 
but in this study it will require confirmation of CR and PR, and will be assessed according to the 
criteria in Table C. The following will not be taken into account when assessing the best overall 
response: overall response after initiation of post-study treatment for esophageal cancer, overall 
response after the end of the follow-up investigation, and overall response after determination of PD. 
In this study, the best overall response will be assessed as SD in subjects without an overall response 
of PD until after Week 6 from the start of Cycle 1 and with SD or a better response at least once after 
Week 6 from the start of Cycle 1. In order for the best overall response to be rated as CR, 2 or more 
successive CR ratings should be obtained with intervals of not less than 4 weeks (28 days). In order 
for the best overall response to be rated as PR, 2 or more successive PR or better ratings (CR of PR) 
should be obtained with intervals of not less than 4 weeks (28 days). If the imaging assessment prior 
to the start of study treatment showed no target lesion, best overall response of the subject should be 
assessed as “NE”. 
 
 


125 
Table C: Best Overall Response Criteria 
Overall response 
First time point 
Overall response 
Subsequent 
time 
point  
Best overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR# 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE  
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD  
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
NE 
NE 
NE 
#:  If CR is truly obtained at the first time point, then any disease seen at a subsequent time point, even a 
disease meeting PR criteria relative to baseline, makes the disease PD at that point (since the disease 
must have reappeared after CR). The best response would depend on whether the minimum duration 
for SD was met. However, sometimes CR may be claimed when subsequent scans suggest that small 
lesions were likely still present and in fact the patient had PR, not CR at the first time point. Under 
these circumstances, the original CR should be changed to PR and the best response would be PR. 


 
 
126 
 
Appendix 3 Performance Status Score (ECOG) 
PS 0 
Fully active, able to continue all pre-disease activities without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light housework, office work 
PS 2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
PS 3 
Capable of only limited selfcare, confined to bed or a chair more than 50% of waking 
hours 
PS 4 
Completely disabled. Cannot carry out any selfcare. Totally confined to bed or a chair 
PS 5 
Dead 
 
As published in Am J. Clin. Oncol.: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, 
McFadden ET, Carbone PP. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982 Dec;5(6):649-55. 
 


127 
Appendix 4 
List of Autoimmune Diseases 
Patients will be excluded from the study in principle if they concurrently have any of the autoimmune 
diseases listed below or have a history of chronic or recurrent episodes thereof. For patients with 
autoimmune diseases other than those listed below, their eligibility should be carefully assessed. 
Patients with safety concerns posed by the presence of an autoimmune disease should not be included 
in the study. 
●Acute disseminated
encephalomyelitis
●IgA nephropathy
●Addison’s disease
●Inflammatory bowel disease
●Alopecia universalis
●Cystitis interstitial
●Ankylosing spondylitis
●Lambert-Eaton myasthenic
syndrome
●Antiphospholipid syndrome
●Erythematosus
●Aplastic anemia
●Lyme disease (chronic)
●Asthma
●Meniere’s syndrome
●Autoimmune hemolytic anemia
●Mooren ulcer
●Autoimmune hepatitis
●Morphoea
●Autoimmune hypophysitis
●Multiple sclerosis
●Autoimmune
hypoparathyroidism
●Myasthenia gravis
●Autoimmune myocarditis
●Neuromyotonia
●Autoimmune oophoritis
●Opsoclonus myoclonus syndrome ●Autoimmune orchitis
●Optic neuritis
●Autoimmune thrombocytopenic 
purpura
●Ord’s thyroiditis
●Behcet’s disease
●Pemphigus
●Bullous pemphigoid
●Pernicious anemia
●Celiac disease
●Polyarteritis nodosa
●Chronic fatigue syndrome
●Polyarthritis
●Chronic inflammatory
demyelinating
polyradiculoneuropathy
●Autoimmune polyglandular
syndrome
●Churg Strauss syndrome
●Primary biliary cirrhosis
●Crohn’s disease
(gastrointestinal ulcers)
●Psoriasis
●Dermatomyositis
●Reiter’s syndrome
●Type 1 diabetes mellitus
●Rheumatoid arthritis
●Dysautonomia
●Sarcoidosis
●Eczema
●Scleroderma
●Sjogren’s syndrome
●Acquired epidermolysis bullosa
●Stiff-man syndrome
●Pemphigoid gestationis
●Takayasu’s arteritis
●Giant cell arteritis
●Ulcerative colitis
●Goodpasture’s syndrome
●Graves’ disease
●Vogt-Koyanagi-Harada
syndrome
●Guillain-Barre syndrome
●Vulvodynia
●Hashimoto’s disease
●Wegener’s granulomatosis
●Kawasaki’s disease




 
 
 
 
1 
 
 
 
ONO-4538 PHASE III STUDY 
 
 
A MULTICENTER, RANDOMIZED, OPEN-LABEL 
STUDY IN PATIENTS WITH ESOPHAGEAL CANCER 
REFRACTORY OR INTOLERANT TO COMBINATION 
THERAPY WITH FLUOROPYRIMIDINE AND 
PLATINUM-BASED DRUGS  
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
ONO PHARMACEUTICAL CO., LTD. 
 
 
 
Protocol No.: ONO-4538-24/BMS CA209473 
Version No.: 3.0 
Date of preparation: Dec 17, 2018 
 


 
 
 
 
2 
 
 
 
 
 
 
 


 
 
 
 
3 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1 
DEFINITIONS OF STATISTICAL ANALYSIS PLAN .............................................9 
2 
SAMPLE SIZE ...........................................................................................................10 
3 
DETERMINATION OF SUBJECTS INCLUDED IN ANALYSIS..........................12 
3.1 
Definitions of Analysis Sets .....................................................................................12 
3.2 
Criteria for Handling of Subjects .............................................................................13 
4 
SIGNIFICANCE LEVEL TO BE USED ...................................................................15 
5 
GENERAL METHODS .............................................................................................16 
6 
RELIABILITY OF THE STUDY ..............................................................................17 
6.1 
Analysis Set ..............................................................................................................17 
6.2 
Analytical Items and Data Handling ........................................................................17 
6.3 
Analytical Methods ..................................................................................................18 
7 
EXTENT OF EXPOSURE AND ADMINISTRATION OF STUDY 
TREATMENT ............................................................................................................19 
7.1 
Analysis Set ..............................................................................................................19 
7.2 
Analytical Items and Data Handlings ......................................................................19 
7.3 
Analytical Methods ..................................................................................................21 
8 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ...................22 
8.1 
Analysis Set ..............................................................................................................22 
8.2 
Analytical Items and Data Handlings ......................................................................22 
8.3 
Analytical Methods and Classification ....................................................................23 
9 
PRIMARY EFFICACY ANALYSIS .........................................................................29 
9.1 
Hypothesis ................................................................................................................29 
9.2 
Analysis Sets ............................................................................................................29 
9.3 
Analytical Item and Data Handling .........................................................................29 
9.4 
Analytical Methods ..................................................................................................29 
9.4.1 
Primary Analytical Method ...................................................................................29 
9.4.2 
Sensitivity Analysis for Primary Analytical Method ............................................30 
9.4.3 
Secondary Analytical Methods .............................................................................30 
9.4.4 
Exploratory Analytical Methods ...........................................................................31 
10 
SECONDARY EFFICACY ANALYSIS ...................................................................33 
10.1 
Analysis Set ..............................................................................................................33 


 
 
 
 
4 
 
10.2 
Analytical Items and Data Handlings ......................................................................33 
10.3 
Analytical Methods ..................................................................................................38 
10.4 
Subgroup analyses for the efficacy endpoints ..........................................................40 
10.5 
Interaction Analysis .................................................................................................43 
10.6 
Adjusted Analysis ....................................................................................................44 
10.7 
Relationship Between Endpoints .............................................................................44 
10.8 
Other Analysis ..........................................................................................................44 
11 
ANALYSIS OF SAFETY ..........................................................................................45 
11.1 
Analysis Sets ............................................................................................................45 
11.2 
Analytical Items and Data Handlings ......................................................................45 
11.3 
Analytical methods ..................................................................................................51 
11.4 
Subgroup analyses for the safety endpoints .............................................................60 
12 
PD-L1 EXPRESSION ANALYSIS ...........................................................................62 
12.1 
Analysis Sets ............................................................................................................62 
12.2 
Analytical Item and Data Handlings ........................................................................62 
12.3 
Analytical methods ..................................................................................................62 
13 
ANTI-DRUG ANTIBODY ANALYSIS ...................................................................64 
13.1 
Analysis Sets ............................................................................................................64 
13.2 
Analytical Item and Data Handlings ........................................................................64 
13.3 
Analytical methods ..................................................................................................66 
14 
PATIENT REPORTED OUTCOMES ANALYSIS ..................................................67 
14.1 
Analysis Sets ............................................................................................................67 
14.2 
Analytical Items and Data Handling ........................................................................67 
14.3 
Analytical methods ..................................................................................................68 
15 
INTERIM STATISTICAL ANALYSIS.....................................................................70 
16 
DATA REVIEWS ......................................................................................................71 
16.1 
Objectives .................................................................................................................71 
16.2 
Analysis Sets ............................................................................................................71 
16.3 
Analytical Items and Data Handling ........................................................................71 
16.4 
Analytical Methods ..................................................................................................72 
17 
TECHNICAL MATTERS ..........................................................................................73 
17.1 
Statistical Software ..................................................................................................73 
17.2 
SAS Programming in Analyses ................................................................................73 


 
 
 
 
5 
 
17.3 
Data Format ..............................................................................................................74 
18 
MAJOR CHANGES IN THE STATISTICAL ANALYSIS PLAN BASED 
ON THE STUDY-SPECIFIC PROTOCOL ...............................................................77 
19 
MAJOR CHANGES IN THE STATISTICAL ANALYSIS PLAN BASED 
ON THE STATISTICAL ANALYSIS PLAN VERSION 1.0 ...................................78 
19.1 
Reliability of the study .............................................................................................78 
19.2 
Demographics and other baseline characteristics ....................................................78 
19.3 
Primary efficacy analysis .........................................................................................78 
19.3.1 
Proportional hazards assumption ...........................................................................78 
19.3.2 
State of follow-up ..................................................................................................79 
19.3.3 
Exploratory analytical methods .............................................................................79 
19.4 
Secondary efficacy analysis .....................................................................................79 
19.5 
Analysis of safety .....................................................................................................79 
19.5.1 
Adverse event ........................................................................................................79 
19.6 
PD-L1 expression analysis .......................................................................................80 
19.7 
Patient reported outcomes analysis ..........................................................................80 
20 
MAJOR CHANGES IN THE STATISTICAL ANALYSIS PLAN BASED 
ON THE STATISTICAL ANALYSIS PLAN VERSION 2.0 ...................................81 
20.1 
Significance level to be used ....................................................................................81 
20.2 
Secondary efficacy analysis .....................................................................................81 
APPENDIX 1 .................................................................................................................................82 
Definition of Select Adverse Events ...........................................................................................82 
APPENDIX 2 .................................................................................................................................86 
Definition of Immune-Mediated Adverse Events .......................................................................86 
APPENDIX 3 .................................................................................................................................87 
Definition of Other Adverse Events of Special Interests ............................................................87 
 
LIST OF TABLES 
Table 10-2-1: 
Criteria for event/censored assessment in primary definition of PFS ................34 
Table 10-2-2: 
Criteria for event/censored assessment in secondary definition of PFS .............35 
Table 10-2-3: 
Criteria for event/censored in DOR ....................................................................36 
Table 14-2-1: 
Time windows for EQ-5D Assessments .............................................................68 
 


 
 
 
 
6 
 
LIST OF ABBREVIATIONS 
ADA  
: Anti-Drug Antibody Set 
AE 
 
: Adverse Event 
ALP  
: Alkaline Phosphatase 
ALT (GPT) 
: Alanine aminotransferase (glutamic pyruvic transaminase) 
AST (GOT) 
: Aspartate aminotransferase (glutamic oxaloacetic transaminase) 
BMI  
: Body Mass Index 
BOR  
: Best Overall Response 
BSA  
: Body Surface Area 
CI 
 
: Confidence Interval 
CR 
 
: Complete Response 
CTCAE 
: Common Terminology Criteria for Adverse Events 
DCR  
: Disease Control Rate 
DOR  
: Duration of Response 
ECG  
: Electrocardiogram 
ECOG 
: Eastern Cooperative Oncology Group 
eCRF  
: Electronic Case Report Form 
EMR  
: Endoscopic Mucosal Resection 
ENR  
: Enrolled Set 
EQ-5D 
: EuroQol 5 dimension 
EQ-VAS 
: EuroQol visual analogue scale 
ESD  
: Endoscopic Submucosal Dissection 
Free T3 
: Free Triiodothyronine 
Free T4 
: Free Thyroxine 


 
 
 
 
7 
 
GCP  
: Good Clinical Practice 
HR 
 
: Heart Rate 
IEC  
: Independent Ethics Committee 
IMAE 
: Immune-Mediated Adverse Event 
INF  
: Informed Consent Set 
IRB  
: Institutional Review Board 
ITT  
: Intention-to-Treat 
IWRS 
: Interactive Web Response System 
LLN  
: Lower Limit of Normal 
MedDRA 
: Medical Dictionary for Regulatory Activities 
NCI  
: National Cancer Institute 
NE 
 
: Not Evaluable 
ORR  
: Objective Response Rate 
OS 
 
: Overall Survival 
PD 
 
: Progressive Disease 
PD-L1 
: Programmed Cell Death-Ligand 1 
PFS  
: Progression-Free Survival 
PP 
 
: Persistent Positive 
PR 
 
: Partial Response 
PR Interval 
: PR interval on an electrocardiogram (atrioventricular conduction time) 
PT 
 
: Preferred Term 
QRS Width 
: QRS width on an electrocardiogram (ventricular activation time) 
QT Interval 
: QT interval on an electrocardiogram (duration of ventricular electrical  
systole) 
QTcF Interval : Corrected QT interval using the Fridericia’s formula 


 
 
 
 
8 
 
RECIST 
: Response Evaluation Criteria in Solid Tumors 
RES  
: Response Evaluable Set 
RR Interval 
: RR interval on an electrocardiogram (ventricular rate) 
SAF  
: Safety Set 
SAS  
: Statistical Analysis System software 
SD 
 
: Stable Disease 
SD 
 
: Standard Deviation 
SOC  
: System Organ Class 
TNM  
: Tumor Node Metastasis 
TSH  
: Thyroid-Stimulating Hormone 
TTR  
: Time To Response 
UK 
 
: United Kingdom 
ULN  
: Upper Limit Of Normal 


 
 
 
 
9 
 
1 
DEFINITIONS OF STATISTICAL ANALYSIS PLAN 
This statistical analysis plan refers to the definition of terminologies, valid analytical methods 
and the detailed contents of statistical analysis for ONO-4538 Phase III study. 
The statistical analysis plan will be developed in accordance with the protocol for ONO-4538 
Phase III study. The statistical analysis plan will be finalized before randomization for the first 
subject. The analysis principles are outlined in Section 10 “Statistical Analysis” in the 
study-specific protocol. 
If additional analysis not stated in the statistical analysis plan was performed, the result will be 
reported in the clinical study report with the purpose of analysis. 


 
 
 
 
10 
 
2 
SAMPLE SIZE 
195 subjects in each group, totaling 390 subjects 
 
Rationale for the Sample Size 
This study is intended to verify the superiority of ONO-4538 group over the control groups 
(docetaxel or paclitaxel) in terms of OS, the primary endpoint, in patients with esophageal cancer 
refractory or intolerant to fluoropyrimidine and platinum-based agents, the standard 
chemotherapy regimen for the treatment of esophageal cancer. Subjects will be randomized to 
either the ONO-4538 group or the control group in a 1:1 ratio and stratified by region (Japan vs. 
rest of world) and number of organs with metastases (≤1 vs. ≥2) and PD-L1 expression (≥1% vs. 
<1% or indeterminate). 
 
As for OS, assuming an exponential distribution for the control group (7.2 months median OS) 
and a piecewise mixture model for the ONO-4538 group with 5.0% long term survival rate (the 
ratio that long term survival is expected due to the effect of ONO-4538), the hazard ratio of the 
ONO-4538 group relative to the control group was assumed to be 1.0 for the first 3 months and 
0.65 for non-long term survival population thereafter (10.0 months overall median OS for the 
ONO-4538 group), the expected average hazard ratio of the ONO-4538 group to the control 
groups was assumed to be 0.70 in this study. The number of events required to detect superiority 
of the ONO-4538 group over the control groups with two-sided significance level of 5% and 
90% or more power by the log-rank test was calculated to be 331. 
Assuming the enrollment period to be 16 months and the follow-up period after the last patient’s 
enrollment to be 18 months, the number of subjects required to ensure the required 331 events 
was estimated to be 390. For the calculation of the required events and sample size at the time of 
planning the study, the statistical analysis software SAS (version 9.3) was used. 
 
Rationale for assuming the median OS in the control group to be 7.2 months 
The phase II single-arm study of docetaxel and the retrospective study of paclitaxel as 2nd-line 
treatment for patients with esophageal cancer reported that the median OS of docetaxel and 


 
 
 
 
11 
 
paclitaxel was 5.5-8.1 months and 6.1-10.4 months, respectively. Based on this information, the 
median OS in the control groups of this study is assumed to be 7.2 months. 
 
Rationale for assuming long term survival rate (the ratio that long term survival is expected due 
to the effect of ONO-4538) as 5.0% and the hazard ratio of the ONO-4538 group relative to the 
control groups was assumed to be 1.0 for the first 3 months 
We set long term survival rate and the hazard ratio referring to the results of a randomized phase 
3 clinical trial of nivolumab vs investigator’s choice in recurrent or metastatic 
platinum-refractory squamous cell carcinoma of the head and neck (CA209141) and a phase 2 
uncontrolled study of nivolumab in esophageal cancer refractory or intolerant to standard therapy 
(ONO-4538-07). 
 
Rationale for setting the hazard ratio of the ONO-4538 group relative to the control groups was 
assumed to be 0.65 after first 3 months in non-long term survival population  
In the global phase III study conducted in patients with stage IIIB/IV or recurrent squamous 
non-small cell lung cancer who received a prior platinum-containing chemotherapy regimen 
(CA209017) to verify the superiority of ONO-4538 over docetaxel, one of the controls in this 
study, the hazard ratio of ONO-4538 relative to docetaxel was 0.59 [96.85% confidence interval: 
0.43, 0.81]. 
If the same histological type of cancer and control are used in the present study, the efficacy on 
ONO-4538 is expected to be similar. However, this study includes paclitaxel as well as docetaxel 
as controls. Efficacy data on ONO-4538 vs. paclitaxel has not been obtained previously. Based 
on these reasons, the expected average hazard ratio of the ONO-4538 group to the control groups 
was assumed to be 0.70 in this study. 
In this study, since we assumed that 5.0% of long term survival rate and the hazard ratio of the 
ONO-4538 group relative to the control group was to be 1.0 for the first 3 months, the hazard 
ratio of the ONO-4538 group relative to the control groups after first 3 months in non-long term 
survival population was calculated as 0.65 to become the expected average hazard ratio of the 
ONO-4538 group relative to the control groups was 0.70.  


 
 
 
 
12 
 
3 
DETERMINATION OF SUBJECTS INCLUDED IN ANALYSIS 
For efficacy endpoints, the Intention-to-Treat (ITT) population will be the analysis set. The 
Response Evaluable Set (RES) will also be used for some secondary endpoints. 
For safety endpoints, the Safety Set (SAF) will be the analysis set. 
For anti-drug antibody endpoint, the Anti-Drug Antibody Set (ADA) will be the analysis set. 
Individual sets of subjects are defined below. 
 
3.1 
Definitions of Analysis Sets 
1) Informed Consent Set (INF) 
The INF will consist of all subjects who signed an informed consent. 
2) Enrolled Set (ENR) 
The Enrolled Set (ENR) will consist of all subjects enrolled (enrollment) in this study via IWRS. 
3) ITT 
ITT will consist of all randomized (randomization) subjects. 
4) SAF 
The SAF will consist of all subjects given at least one dose of the investigational product. 
5) RES 
The RES will consist of all subjects which meet all of the following items in the ITT population. 
(1) It is not GCP noncompliant subject defined in 3.2 Criteria for Handling of Subjects. 
(2) It has target lesion measurements at baseline. 
6) ADA 
The ADA will consist of all subjects which meet all of the following items in the SAF 
population. 
(1) It is not GCP noncompliant subject defined in 3.2 Criteria for Handling of Subjects. 


 
 
 
 
13 
 
(2) It has measurements of anti-ONO-4538-antibody (the sample which screening result is 
potential positive but confirmatory result is not available will be excluded) at both baseline 
and at least one post-baseline anti-drug antibody assessment. 
 
3.2 
Criteria for Handling of Subjects 
Criteria for handling of subjects are specified below. 
1) Disqualified Subjects 
Disqualified subjects are defined as those who fail to fulfill 4.2 Inclusion Criteria or conflict with 
4.3 Exclusion Criteria in the study-specific protocol. 
2) GCP Noncompliant Subjects 
GCP noncompliant subjects are defined as those who were enrolled based on materials not 
reviewed by the IRB/IEC, who were enrolled at a medical institution where no study contract 
had been signed, or who did not provide informed consent appropriately. 
3) Untreated Subjects 
Untreated subjects are defined as those who received no dose of the investigational product. 
4) Incomplete Target Lesion Measurements Subjects 
Incomplete target lesion measurements subjects are defined as those who were without baseline 
target lesion measurements. 
5) Non-enrolled Subjects 
Non-enrolled subjects are defined as those who signed an informed consent but not enrolled. 
6) Non-randomized Subjects 
Non-randomized subjects are defined as those who enrolled but not randomized. 
7) Incomplete Anti-Drug Antibody Subjects 
Incomplete anti-drug antibody subjects are defined as those who were without baseline anti 
ONO-4538 antibody measurements, and/or all post-baseline anti ONO-4538 antibody 
measurements. 
 


 
 
 
 
14 
 
For any other subject with unexpected problems, the handling in the analysis will be determined 
by the sponsor before database lock, on the basis of discussion with the medical officer. 


 
 
 
 
15 
 
4 
SIGNIFICANCE LEVEL TO BE USED 
1) Efficacy 
Two-sided test will be performed with 5% significance level. If superiority in OS is determined, 
a hierarchical hypothesis testing approach for the key secondary endpoints will be used to 
preserve a study-wise type I error rate at 5%. The key secondary endpoints will be tested in the 
following hierarchical order: 
1. ORR 
2. PFS 
The ITT will be the analysis set for OS and PFS, and the RES will be the analysis set for ORR. 
Interactions will be tested with two-sided 15% significance level. 
 
2) Safety 
Not applicable because no statistical tests will be performed on safety. 


 
 
 
 
16 
 
5 
GENERAL METHODS 
Unless otherwise noted, analysis will be conducted based on treatment group randomized by 
IWRS. 
In the following sections, treatment group will refer to ONO-4538 group and control group. 
Control regimen will refer to docetaxel and paclitaxel. Investigational product will refer to 
ONO-4538, docetaxel and paclitaxel drugs. 
The treatment group “As Randomized” will be retrieved from IWRS. The treatment group “As 
Treated” will be the same as the arm randomized by IWRS. However, if a subject received the 
incorrect treatment for the entire period of treatment, the subject’s treatment group will be 
defined as the incorrect treatment the subject actually received. 
Efficacy analysis will be conducted by “As Randomized” while safety analysis will be conducted 
by “As Treated”. 
A term of ONO-4538 will be replace with Nivolumab in tables, figures and listings. 
 


 
 
 
 
17 
 
6 
RELIABILITY OF THE STUDY 
 
6.1 
Analysis Set 
The INF will be the analysis set for the analytical Item (2). 
The ENR will be the analysis set for the analytical Item (3). 
The ITT will be the analysis set for the analytical Item (1), (4) and (6). 
The SAF will be the analysis set for the analytical Item (5). 
 
6.2 
Analytical Items and Data Handling 
1) Analytical Item 
(1) Relevant protocol deviations 
(2) Reason excluded from each analysis set 
(3) Reason for subjects enrolled but not randomized 
(4) Reason for subjects randomized but not treated 
(5) Reason of discontinuation of study treatment 
(6) The number of randomized subjects per study center 
 
2) Handling of data 
The following deviations will be considered as relevant protocol deviations. 
Eligibility: 
・ Subjects who failed to fulfill inclusion criteria #3 
・ Subjects who failed to fulfill inclusion criteria #4 
・ Subjects who failed to fulfill inclusion criteria #6 
On-study: 
・ Subjects receiving any concurrent anti-cancer therapy (ie. chemotherapy, hormonal therapy, 
immunotherapy, surgery, or radiation therapy) while on study therapy 


 
 
 
 
18 
 
・ Subjects treated differently as randomized (subjects who received the wrong treatment 
excluding the never treated.) 
 
6.3 
Analytical Methods 
1) The number of subjects with relevant protocol deviations will be summarized by treatment 
group and control regimen. 
2) For INF and ENR, the frequency of inclusion and exclusion for each analysis set as well as 
the frequency of the reason for exclusion will be summarized. For the others, those will be 
summarized by treatment group and control regimen. 
3) The number of subjects enrolled but not randomized as well as the frequency by its reason 
will be summarized. 
4) The number of subjects randomized but not treated as well as the frequency by its reason 
will be summarized. 
5) The number of subjects who continued the treatment period and discontinued study 
treatment as well as the frequency of the reason for discontinuation of study treatment will 
be summarized by treatment group and control regimen. 
6) For the number of subjects randomized per study center, frequency distribution and 
summary statistics will be summarized by treatment group and control regimen. 


 
 
 
 
19 
 
7 
EXTENT OF EXPOSURE AND ADMINISTRATION OF STUDY 
TREATMENT 
 
7.1 
Analysis Set 
The SAF will be the analysis set. 
 
7.2 
Analytical Items and Data Handlings 
1) Analytical Items 
(1) Number of dose received  
(2) Duration of Treatment 
(3) Number of cycle 
(4) Cumulative dose 
(5) Relative dose intensity 
 
2) Handlings of data 
(1) Duration of Treatment 
Duration of Treatment (Months)  
= (“Date of the last dose” − “Date of the first dose” + 1) / 30.4375 
(2) Number of cycle 
The number of cycle will be calculated for the cycle proceeding to the next cycle. The 
discontinued cycle or the cycle receiving no investigational product also will be calculated. 
(3) Cumulative dose 
Cumulative dose of ONO-4538 (mg) is the sum of the doses (mg) administrated to a subject 
during the treatment period. 
 


 
 
 
 
20 
 
Cumulative dose of Docetaxel (mg/m2) is the sum of the doses (mg/m2) administrated to a 
subject during the treatment period. 
Dose of Docetaxel (mg/m2) will be calculated by the following equation. 
Dose (mg/m2) = “Total Dose administrated of Docetaxel (mg)” / “Most recent BSA NOTE1)” 
 Cumulative dose of Paclitaxel (mg/m2) is the sum of the doses (mg/m2) administrated to a 
subject during the treatment period. 
Dose of Paclitaxel (mg/m2) will be calculated by the following equation. 
Dose (mg/ m2) = “Total Dose administrated of Paclitaxel (mg)” / “Most recent BSANOTE1)” 
NOTE1: Body Surface Area (BSA) (DuBois Formula) 
BSA=“[Weight (kg)]0.425” x “[Height (cm)]0.725 ”x 0.007184 
 
(4) Relative dose intensity 
Relative dose intensity of ONO-4538 (%) will be calculated by the following equation. 
Relative dose intensity (%) = “Cumulative dose (mg)” / “[Date of the last dose – Date of the 
first dose + 14] (days) x240(mg) / 14 (days)” x 100 
Relative dose intensity of Docetaxel (%) will be calculated by the following equation. 
Relative dose intensity (%) = “Cumulative dose (mg/m2)” / “[Date of the last dose – Date of the 
first dose + 21] (days) x 75 (mg/m2) / 21 (days)” x 100 
Relative dose intensity of Paclitaxel (%) will be calculated by the following equation. 
Relative dose intensity (%) = “Cumulative dose (mg/m2)” / “The sum of defined dose in each 
cycle (mg/m2)” x 100 
For a completed cycle, defined dose is defined as 6 x 100 (mg/m2) . For discontinued cycle, 
defined dose is defined as “{[Date of last dose – Start date of discontinued cycle + 7] (days) x 
100 (mg/m2)}/7 (days)”. 
 


 
 
 
 
21 
 
7.3 
Analytical Methods 
1) For number of dose received, summary statistics will be calculated by investigational 
product. 
2) For duration of treatment, summary statistics will be calculated by treatment group and 
control regimen. Additionally, frequency distribution of subjects on duration of treatment for 
> 6 months and > 12 months will be calculated by treatment group and control regimen. 
3) For number of cycle, frequency distributions and summary statistics will be calculated by 
treatment group and control regimen. 
4) For cumulative dose, summary statistics will be calculated by investigational product. 
5) For relative dose intensity, frequency distributions and summary statistics will be calculated 
by treatment group and control regimen. 


 
 
 
 
22 
 
8 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
8.1 
Analysis Set 
The ITT will be the analysis set. 
 
8.2 
Analytical Items and Data Handlings 
1) Analytical Items 
(1) Demographic Variables 
Sex, age, race, ethnicity, height, weight, BMI, BSA 
(2) Baseline Characteristics 
Performance status score (ECOG), time from the date of diagnosis of the primary disease，
lesion sites (anatomical subsites according to the TNM classification), clinical classification 
(TNM clinical classification), disease stage (stage grouping: TNM classification), 
histological classification, presence of multiple lesions (secondary lesions), sites of 
metastases, recurrent, time from the date of surgery for the primary lesion (including EMR 
or ESD) to randomization (for subjects with recurrent esophageal cancer), residual tumor (R) 
classification (for subjects with recurrent esophageal cancer), site of recurrence (for subjects 
with recurrent esophageal cancer), Medical history, concurrent diseases, past treatments for 
esophageal cancer (e.g., surgery, radiotherapy, pharmacotherapy), history of alcohol 
consumption, history of smoking, geographic location (IWRS and eCRF source), number of 
organs with metastases (IWRS and eCRF source), PD-L1 expression (IWRS and test result 
source) 
(3) Baseline Values of Observation 
Sum of reference diameters of target lesions 
(4) Concomitant drugs and therapies 
Analgesics, Immune modulating concomitant medication 
(5) Subsequent anti-cancer therapy 
Surgery, Radiotherapy, Pharmacotherapy by generic name 
 
2) Handlings of data 
(1) BMI 


 
 
 
 
23 
 
BMI (kg/m2) = “Weight (kg)” / “[Height (m)]2” 
(2) Body Surface Area (BSA) (DuBois Formula) 
BSA=“[Weight (kg)]0.425” x “[Height (cm)]0.725 ”x 0.007184 
(3) Time from the date of diagnosis of the primary disease to the date of randomization 
Time from the date of diagnosis of the primary disease to the date of randomization (Months)  
= (“Date of randomization” − “The most recent date of diagnosis of the primary disease” + 1) 
/ 30.4375 
(4) Time from the date of surgery for the primary lesion (including EMR or ESD) to the date of 
randomization 
Time from the date of surgery for the primary lesion to the date of randomization (Months)  
= (“Date of randomization” − “The most recent date of surgery for the primary lesion” + 1) / 
30.4375 
(5) Immune modulating concomitant medication 
When calculaing the number of subjects who received immune modulating concomitant 
medication for management of adverse event and drug-related select adverse event, adverse 
events and select adverse events to be analyzed will be the events occurring between the start 
date of the first administration of the investigational product and 28 days after the last dose or the 
start date of subsequence anti-cancer therapy after the last dose whichever comes first. 
When caclulaing the number of subjects who received immune modulating concomitant 
medication for management of IMAE, IMAE to be analyzed will be the events occurring 
between the start date of the first administration of the investigational product and 100 days after 
the last dose. 
 
8.3 
Analytical Methods and Classification 
Each analytical item displayed in 8.2 Analytical Items and Data Handling will be summarized 
according to the following classification by treatment group and control regimen. 
 


 
 
 
 
24 
 
<Method of classification > 
1) Classification for the ordinal scale or the continuous value will be determined based on 
clinical symptom or equipartition of the number of subjects (i.e., 1/3，1/4，1/5). 
Each classification of analytical item will be displayed in the following table. 
 
Analytical Item 
Stratum 
Analytical Method 
Sex 
Female, Male 
Frequency 
distributions 
AgeNote1) 
<65, 65 - <75, >=75，>=65 
Summary statistics,   
Frequency 
distributions 
Race 
American Indian or Alaska Native, 
Asian, Black or African American, 
Native Hawaiian or Other Pacific 
Islander, White, Other 
Frequency 
distributions 
Ethnicity 
Hispanic or Latino, Not Hispanic or 
Latino, Not Reported, Unknown 
Frequency 
distributions 
Height 
＜Will be revised under the 
planned Data Reviews＞ 
Summary statistics,   
Frequency 
distributions 
Weight 
＜Will be revised under the 
planned Data Reviews＞ 
Summary statistics,   
Frequency 
distributions 
BMI 
＜Will be revised under the 
planned Data Reviews＞ 
Summary statistics,   
Frequency 


 
 
 
 
25 
 
distributions 
BSA 
＜Will be revised under the 
planned Data Reviews＞ 
Summary statistics 
Frequency 
distributions 
Performance Status score 
(ECOG) 
0, 1 
Frequency 
distributions 
Time from the date of 
diagnosis of the primary 
disease to randomization 
<=12, >12 - 24, >24 
Summary statistics, 
Frequency 
distributions 
Lesion sites (TNM 
classification) 
Cervical Esophagus, Thoracic 
Esophagus (Upper Thorax, Middle 
Thorax, Lower Thorax), Unknown 
Frequency 
distributions 
Clinical classification 
(TNM classification) Note2) 
T: Primary tumor 
TX, T0, Tis, T1a, T1b, T2, T3, T4a, 
T4b, Unknown 
N: Regional lymph nodes 
NX, N0, N1, N2, N3, Unknown 
M: Distant metastasis 
M0, M1, Unknown 
Frequency 
distributions 
Disease stage (TNM 
classification) Note2) 
0, IA, IB, IIA, IIB, IIIA, IIIB, IIIC, 
IV, Unknown 
Frequency 
distributions 
Histological classification 
Squamous Cell Carcinoma, 
Adenosquamous Cell Carcinoma, 
Other, Unknown 
Frequency 
distributions 


 
 
 
 
26 
 
Presence of multiple 
lesions (secondary 
lesions) 
No, Yes 
Frequency 
distributions 
Sites of metastases 
Lymph Node, Peritoneum, Liver, 
Lung, Pleural Tissue, Adrenal 
Gland, Brain,  
Bone, Bone Marrow, Skin, 
Stomach, Other 
Frequency 
distributions 
Recurrent 
No, Yes 
Frequency 
distributions 
Time from the date of 
surgery for the primary 
lesion (including EMR or 
ESD) to 
randomizationNote3) 
<=12, >12 - 24, >24 
Summary statistics,   
Frequency 
distributions 
Residual tumor (R) 
classificationNote3) 
RX, R0, R1, R2, Unknown 
Frequency 
distributions 
Site of recurrenceNote3) 
Esophagogastric, Cervical 
Esophagogastric, Thoracic 
Esophagus (Upper Thorax, Middle 
Thorax, Lower Thorax, Unknown), 
Lymph Node, Stomach, 
Peritoneum, Liver, Lung, Pleural 
Tissue, Adrenal Gland, Brain, 
Bone, Bone Marrow, Skin, Other 
Frequency 
distributions 
Medical history 
No, Yes 
Frequency 
distributions 


 
 
 
 
27 
 
Concurrent diseases 
No, Yes 
Frequency 
distributions 
Past treatments for cancer 
(surgery) 
No, Yes 
Frequency 
distributions 
Past treatments for cancer 
(radiotherapy) 
No, Yes 
Frequency 
distributions 
Past treatments for cancer 
(pharmacotherapy) 
No, Yes 
Frequency 
distributions 
History of alcohol 
consumption 
Never, Former, Current 
Frequency 
distributions 
History of smoking 
Never, Former, Current 
Frequency 
distributions 
Sum of reference 
diameters of target lesions 
 
Summary statistics 
Analgesics 
No, Yes 
Frequency 
distributions 
Geographic location 
(IWRS source) 
Japan, Rest of the world 
Frequency 
distributions 
Geographic location 
(eCRF source) 
Japan, Rest of the world 
Frequency 
distributions 
Number of organs with 
metastases 
(IWRS source) 
<=1, >=2 
Summary statistics,   
Frequency 
distributions 


 
 
 
 
28 
 
PD-L1 (IWRS source) 
>=1%, <1% or Indeterminate 
Frequency 
distributions 
PD-L1 
(test results source) 
(1) >=1%, <1% 
(2) >=5%, <5% 
(3) >=10%, <10% 
(4) Not Quantifiable 
Frequency 
distributions 
Note1): Additional categories 75-<85 and >=85 will be reported if there are subjects >=85 years old 
Note2): Summarized for subjects with non-recurrent esophageal cancer. 
Note3): Summarized for subjects with recurrent esophageal cancer. 
 
1) Past pharmacotherapy for cancer will be summarized for each treatment group and control 
regimen by medication class and generic name. 
2) Details of subsequence anti-cancer therapy (surgery, radiotherapy, pharmacotherapy) will be 
summarized by treatment group and control regimen. 
3) For immune modulating concomitant medication, the number of subjects who received 
immune modulating concomitant medication for management of adverse event, management 
of concurrent disease, management of drug-related select adverse event (any grade, grade 
3-5), management of IMAEs (any grade, grade 3-5), prevention, other use, and any use will 
be calculated separately for each treatment group by medication class and generic name. 
4) Cross-tabulation between stratification factors (IWRS source) and stratification factors 
(eCRF source) will be provided by treatment group and control regimen. 
(1) Number of organs with metastases (IWRS source) vs Number of organs with metastases 
(eCRF source) 
(2) PD-L1 expression (IWRS source) vs PD-L1 expression (test result source) 


 
 
 
 
29 
 
9 
PRIMARY EFFICACY ANALYSIS 
 
9.1 
Hypothesis 
The ONO-4538 group is superior to the control group in terms of OS. 
 
9.2 
Analysis Sets 
The ITT will be the primary analysis set. The primary analytical method will be conducted for 
the SAF, if necessary. 
 
9.3 
Analytical Item and Data Handling 
1) Analytical Item 
OS 
 
2) Handling of data 
OS will be calculated from the following equation:  
OS (Months) = (“Date of death due to any cause” − “Date of randomization” + 1) / 30.4375 
 
For subjects lost to follow-up and subjects who are alive at the time of data cutoff date, data 
will be censored at the time the subject was last confirmed to be alive. 
 
9.4 
Analytical Methods 
9.4.1 
Primary Analytical Method 
Data will be compared between the two treatment groups using the stratified log-rank test with 
the location (Japan vs. Rest of the world), the number of organs with metastases (1 organ or less 
vs. 2 organs or more), and PD-L1 expression (≥1% vs. <1% or indeterminate) which are the 
randomization factors from IWRS as the stratification factors. 
 


 
 
 
 
30 
 
9.4.2 
Sensitivity Analysis for Primary Analytical Method 
1) The distribution of OS will be compared between the two treatment groups by using the 
unstratified log-rank test. 
2) The distribution of OS will be compared between the two treatment groups by using the 
stratified log-rank test adjusted by the three stratification factors (location and the number of 
organs with metastases from eCRF source and PD-L1 expression from test result source), if 
there exist more than 10% discrepancy between stratification factors (IWRS source) and 
stratification factors (eCRF source). 
 
9.4.3 
Secondary Analytical Methods 
1) 
The hazard ratio and the corresponding two-sided 95% confidence interval (CI) for the 
ONO-4538 group relative to the control group, docetaxel group and paclitaxel group will be 
estimated using a stratified Cox proportional hazards model with the randomization factors 
as the stratification factors. 
2) 
To examine the assumption of proportional hazards in the stratified Cox proportional 
hazards model described in 9.4.3 1), in addition to treatment, a time-dependent variable 
defined by treatment by time interaction will be added into the model. A two-sided Wald 
Chi-square p-value of less than 0.1 may indicate a potential nonconstant treatment effect. In 
that case, additional exploratory analyses may be performed. 
3) 
The Kaplan-Meier curve will be plotted for each treatment group and control regimen. Using 
the Kaplan-Meier method, the median OS and the corresponding two-sided 95% CI will be 
estimated for each treatment group and control regimen. CI for median OS will be calculated 
based on a log-log transformed CI for the survivor function. 
4) 
For each treatment group and control regimen, the survival rates at months 6, 9, 12, 15 and 
18 will be derived from the Kaplan-Meier method and corresponding two-sided 95% 
confidence interval will be calculated based on Greenwood’s formula for variance derivation 
and on log-log transformation applied on the survivor function. 
5) 
The number of events and censors will be tabulated by treatment group and control regimen. 
The status of subjects who are censored in the Kaplan-Meier analysis will also be tabulated 
by treatment groups and control regimens using the following categories: (1) on-study, (2) 
off-study． 


 
 
 
 
31 
 
6) Current status of follow-up (time from date of last contact to cutoff date) for OS will be 
summarized for each treatment group and control regimen by using following categories: 0, 
>0 - 3 months, >3 - 6 months, >6 - 9 months, >9 - 12 months, and >12 months. Subjects who 
died, or whose last known alive date is on or after data cutoff date, are classified as having 
current follow-up 0. 
7) 
Summary statistics (median, minimum and maximum) for duration of follow-up (time 
between randomization date and last known date alive (for subjects who are alive) or date of 
death) will be summarized by treatment group and control regimen.  
 
9.4.4 
Exploratory Analytical Methods 
1) Intended investigator’s choice therapy subset analysis 
Per IWRS procedure, investigators are to indicate their choice of therapy (docetaxel or 
paclitaxel) for each patient prior to randomization. To further examine the efficacy of ONO-4538 
compare to docetaxel and paclitaxel, following analysis will be performed on OS. 
(1) The Kaplan-Meier curve will be plotted for each intended investigator’s choice therapy 
subset. Using the Kaplan-Meier method, the median OS and the corresponding two-sided 
95% CI will be estimated for each subset. CI for median OS will be calculated based on a 
log-log transformed CI for the survivor function. 
(2) The hazard ratio and the corresponding two-sided 95% CI for the ONO-4538 group relative 
to the docetaxel group and paclitaxel group in each intended investigator’s choice subset 
will be estimated using a stratified Cox proportional hazards model with the randomization 
factors as the stratification factors. 
 
2) Examine influence of subsequence anti-cancer therapy 
To examine the influence of subsequence anti-cancer therapy on OS from various perspectives, 
following analysis will be performed on OS, if necessary. 
• 
Rank-preserving structural failure time model 
• 
Inverse probability of censoring weighted methods 


 
 
 
 
32 
 
• 
Stratified Cox proportional hazards model with the randomization factors from IWRS as 
the stratification factors and subsequence anti-cancer therapy as the time-dependent 
covariate 
 
 
 


 
 
 
 
33 
 
10 SECONDARY EFFICACY ANALYSIS 
 
10.1 Analysis Set 
The ITT will be the analysis set. With regard to the analytical item (7), the RES will be the 
analysis set. With regard to the analytical item (1), (2), (4), (5) and (6), the RES also will be the 
analysis set as well as ITT and the primary population for the analytical item (1), (2), (4), (5) and 
(6) will be RES. 
 
10.2 Analytical Items and Data Handlings 
1) Analytical Item 
(1) Objective response rate (ORR)  
(2) Disease control rate (DCR)  
(3) Progression-free survival (PFS)  
(4) Duration of response (DOR) 
(5) Time to response (TTR) 
(6) Best overall response (BOR)  
(7) Maximum percent change from baseline in the sum of diameters of target lesions 
 
2) Handlings of data 
Overall response and best overall response will be determined solely by imaging assessment 
according to the RECIST Guideline Version 1.1, and will not take into account any 
clinical/symptomatic progression. Evaluable imaging data will be those without an overall 
response of “NE.”  
For each analytical item, the handling of data will be as follows:  
(1) ORR 
ORR is defined as the percentage of subjects whose best overall response (BOR) is assessed as 
either confirmed CR or confirmed PR. 


 
 
 
 
34 
 
(2) DCR 
DCR is defined as the percentage of subjects whose BOR is assessed as confirmed CR, 
confirmed PR or SD. 
(3) PFS 
PFS will be calculated from the following equation:  
PFS (Months) = (“Earlier date on which either the overall response was assessed as PD or the 
patient died due to any cause” − “Date of randomization” + 1) / 30.4375 
Event / censored assessment in primary and secondary definition of PFS will be performed 
according to Table 10-2-1 and Table 10-2-2.  
In primary definition of the PFS, if the date on which the overall response is assessed as PD for 
the first time and the date of the start of subsequence anti-cancer therapy are the same, it will be 
handled as event on the date on which the overall response is assessed as PD. Additionally, if 
the date of tumor assessment which overall response is not PD or NE and the date of the start of 
subsequence anti-cancer therapy are the same, PFS will be censored at that date. 
When a subject corresponds to more than one situation, the shortest PFS will be handled as the 
PFS of the subject. 
 
Table 10-2-1: Criteria for event/censored assessment in primary definition of PFS 
Situation 
Date of Progression or 
Censoring 
Outcome 
No baseline tumor 
assessments 
Date of randomization 
Censored 
No death without an 
overall response of PD 
Date of the last evaluable tumor 
assessment 
Censored 
No death without an 
evaluable tumor 
assessment 
Date of randomization 
Censored 


 
 
 
 
35 
 
Death without an evaluable 
tumor assessment 
Date of death 
Event 
Subsequence anti-cancer 
therapy before an overall 
response of PD or death 
Date of the last evaluable tumor 
assessment before initiation of 
subsequence anti-cancer 
therapy 
Censored 
End of investigating 
subsequence anti-cancer 
therapy before an overall 
response of PD or death 
Date of the last evaluable tumor 
assessment before the end of 
investigating subsequence 
anti-cancer therapy 
Censored 
With an overall response of 
PD 
Date of the first overall 
response of PD 
Event 
Death  
Date of death 
Event 
 
Table 10-2-2: Criteria for event/censored assessment in secondary definition of PFS 
Situation 
Date of Progression or 
Censoring 
Outcome 
No baseline tumor 
assessments 
Date of randomization 
Censored 
No death without an 
overall response of PD 
Date of the last evaluable tumor 
assessment 
Censored 
No death without evaluable 
tumor assessment 
Date of randomization 
Censored 
Death without an evaluable 
tumor assessment 
Date of death 
Event 


 
 
 
 
36 
 
With an overall response of 
PD 
Date of the first overall 
response of PD 
Event 
Death  
Date of death 
Event 
 
(4) DOR 
DOR will be calculated from the following equation. 
DOR (Months) = (“Earlier date on which either the overall response was assessed as PD for the 
first time after confirmed response or the patient died due to any cause” − “Date of first 
assessment of confirmed CR or PR” + 1) / 30.4375 
Event / censored assessment in analysis of DOR will be performed according to Table 10-2-3. If 
the date on which the overall response is assessed as PD for the first time and the date of the 
start of subsequence anti-cancer therapy are the same, it will be handled as event on the date on 
which the overall response is assessed as PD. 
When a subject corresponds to more than one situation, the shortest DOR will be handled as the 
DRO of the subject. 
DOR will be calculated in subjects whose BOR was assessed as either confirmed CR or 
confirmed PR. 
 
Table 10-2-3: Criteria for event/censored in DOR 
Situation 
Date of Progression or 
Censoring 
Outcome 
Death without an evaluable 
diagnostic imaging after the 
confirmation of response 
Date of death 
Event 
Death before an overall 
response of PD 
Date of death 
Event 


 
 
 
 
37 
 
Overall response of PD 
Date of the first overall 
response of PD 
Event 
No death without an 
overall response of PD 
Date of the last evaluable 
diagnostic imaging 
Censored 
Subsequence anti-cancer 
therapy before an overall 
response of PD or death 
Date of the last evaluable 
diagnostic imaging before 
initiation of subsequence 
anti-cancer therapy 
Censored 
End of investigating 
subsequence anti-cancer 
therapy before an overall 
response of PD or death 
Date of the last evaluable 
diagnostic imaging before end of 
investigating subsequence 
anti-cancer therapy 
Censored 
 
(5) TTR 
TTR will be calculated from the following equation:  
TTR (Months) = (“Date of first assessment of confirmed CR or confirmed PR” − “Date of 
randomization” + 1) / 30.4375 
For subjects without a response in each treatment group, the data on the time to response will be 
censored as at “the longest time to response among subjects with response in the treatment 
group + 1 (day)”.  
 
(6) Maximum percent change from baseline in the sum of diameters of target lesions  
In subjects with target lesions, on the basis of the diameters of target lesions as measured 
according to the RECIST Guideline Version 1.1, the maximum percent change from 
baseline in the sum of diameters of target lesions will be calculated from the following 
equation. However, this calculation will exclude the diameter data obtained after an overall 


 
 
 
 
38 
 
response of PD, after start of subsequence anti-cancer therapy and after end of investigating 
subsequence anti-cancer therapy. 
 
100
1
  
lesions
 target 
of
 
diameters
 
of
 
sum
 
Baseline
"
" 
lesions
 target 
of
 
diameters
 
of
 
sum
Smallest 
"
(%)
 
lesions
 target 
of
 
diameters
 
of
 
sum
 
in the
 
baseline
 
from
 
change
percent 
 
Maximum
×






−
＝
 
10.3 Analytical Methods 
The following analyses will be performed on the analytical items specified in 10.2 Analytical 
Items and Data Handling. 
1) Analytical items for ORR 
(1) Data will be compared between the two treatment groups using the 
Cochran-Mantel-Haenszel (CMH) test with the randomization factors as the stratification 
factors (IWRS). The associated odds ratio and the corresponding two-sided 95% CI and the 
estimate of the difference and corresponding two-sided 95% CI for ONO-4538 group 
relative to control group, docetaxel group and paclitaxel group will be calculated using 
CMH methodology and adjusted by the same stratification factors. 
(2) The proportions and the corresponding two-sided 95% CI will be estimated using the 
Clopper-Pearson method for each treatment group and control regimen. 
 
2) Analytical items for DCR 
(1) Data will be compared between the two treatment groups using the CMH test with the 
randomization factors as the stratification factors. The associated odds ratio and the 
corresponding two-sided 95% CI, and the estimate of the difference and corresponding 
two-sided 95% CI for ONO-4538 group relative to control group, docetaxel group and 
paclitaxel group will be calculated using CMH methodology and adjusted by the same 
stratification factors. 
(2) The proportions and the corresponding two-sided 95% CI will be estimated using the 
Clopper-Pearson method for each treatment group. 


 
 
 
 
39 
 
3) Analytical item for PFS 
(1) Data will be compared between the two treatment groups using the stratified log-rank test 
with the randomization factors as the stratification factors. The hazard ratio and the 
corresponding two-sided 95% CI for the ONO-4538 group relative to the control group and 
docetaxel group and paclitaxel group will be estimated using a stratified Cox proportional 
hazards model with the randomization factors as the stratification factors.  
(2) The Kaplan-Meier curve will be plotted for each treatment group and control regimen. 
Using the Kaplan-Meier method, the median PFS and the corresponding two-sided 95% CI 
will be estimated for each treatment group and control regimen. CI for median PFS will be 
calculated using the Brookmeyer and Crowley method based on a log-log transformed CI 
for the survivor function. 
(3) For each treatment group and control regimen, the progression free survival rates at months 
3, 6, 9, 12, 15 and 18 will be derived from the Kaplan-Meier estimates and the 
corresponding two-sided 95% confidence intervals will be derived based on Greenwood’s 
formula for variance derivation and on log-log transformation applied on the survivor 
function. 
(4) The status of subjects who are censored in the Kaplan-Meier analysis will be tabulated for 
each treatment group and control regimen by using following categories: (a) on-study, (b) 
off-study, (c) received subsequence anti-cancer therapy, (d) never treated. 
 
4) Analytical item for DOR  
(1) The Kaplan-Meier curve will be plotted for each treatment group and control regimen. 
Using the Kaplan-Meier method, the median DOR and the corresponding two-sided 95% CI 
will be estimated for each treatment group and control regimen. CI for median DOR will be 
calculated using the Brookmeyer and Crowley method based on a log-log transformed CI 
for the survivor function. Additionally, summary statistics (minimum and maximum) will 
also be estimated for each treatment group and control regimen. This analysis will be 
performed on ITT/RES subjects whose best overall response is confirmed CR or confirmed 
PR 


 
 
 
 
40 
 
(2) The number of events and censors will be tabulated by treatment group and control regimen. 
The status of subjects who are censored in the Kaplan-Meier analysis will also be tabulated 
by treatment group and control regimen using following categories: (1) on-study, (2) 
off-study, (3) received subsequence anti-cancer therapy. 
 
5) Analytical item for TTR 
(1) Summary statistics will be calculated for ITT/RES subjects whose best overall response is 
confirmed CR or confirmed PR by treatment group and control regimen. 
(2) The Kaplan-Meier curve will be plotted for each treatment group and control regimen on 
RES subjects. 
 
6) Analytical item for BOR  
(1) The percentage of confirmed CR, confirmed PR, SD, PD and NE will be calculated for 
each treatment group and control regimen. For the percentages of CR, PR and SD, the 
corresponding 95% CI will be estimated using the Clopper-Pearson method for each 
treatment group. 
 
7) Analytical item for maximum percent change from baseline in the sum of diameters of target 
lesions 
(1) Waterfall plot will be displayed by treatment group and control regimen.  
 
10.4 Subgroup analyses for the efficacy endpoints 
Subgroup analyses will be performed on following analytical items by the subgroups presented 
below. With regard to the analytical item (1) and (3), the ITT will be the analysis set. With 
regard to the analytical item (2), (4) and (5), the RES also will be the analysis set as well as ITT. 
 
1) Analytical Items 


 
 
 
 
41 
 
(1) OS 
(2) ORR 
(3) PFS (Primary definition) 
(4) DOR 
(5) BOR 
2) Handling of data 
(1) Stratification factor and Method of classification  
The stratification factors will be classified as the following table. Unless otherwise noted, the 
following two factors will only be extracted from IWRS; location and the number of organs with 
metastases. The others except for PD-L1 expression will be extracted from eCRF. PD-L1 
expression will be extracted from both IWRS and test result. 
 
Factor 
Stratum 
PD-L1 Expression (IWRS) 
(1) >=1% 
(2) <1% or Indeterminate 
PD-L1 Expression (test results) 
(1) >=1%, <1% 
(2) >=5%, <5% 
(3) >=10%, <10% 
(4) Not Quantifiable 
Location (IWRS) 
Japan, Rest of world 
AgeNote1) 
(1) <65, 65 - <75, >=75 
(2) <65, >=65 
Sex 
Male, Female 
Race 
American Indian or Alaska Native, Asian, 
Black or African American, Native 
Hawaiian or Other Pacific Islander, White, 


 
 
 
 
42 
 
Other 
ECOG Performance Status score at 
baseline 
0, 1 
Recurrent 
No, Yes 
Lesion sites (TNM classification) 
Cervical Esophagus, Thoracic Esophagus 
(Upper Thorax, Middle Thorax, Lower 
Thorax), Unknown 
Histological classification  
Squamous Cell Carcinoma, 
Adenosquamous Cell Carcinoma, Other, 
Unknown 
Number of organs with metastases 
(IWRS) 
=<1, >=2 
Lymph Node metastasis 
No, Yes 
Liver metastasis 
No, Yes 
Lung metastasis 
No, Yes 
Bone metastasis 
No, Yes 
Target lesion 
No, Yes 
Past treatments for cancer 
(surgery) 
No, Yes 
Past treatments for cancer 
(radiotherapy) 
No, Yes 
History of smoking 
Never, Former, Current 
Note1): Additional categories 75-<85 and >=85 will be reported if there are subjects >=85 years old 


 
 
 
 
43 
 
 
3) Analytical Methods 
(1) For OS, PFS and DOR, the hazard ratio and the corresponding 95% CIs for the ONO-4538 
group relative to the treatment group will be calculated using the unstratified Cox 
proportional-hazards model in each subgroup. 
(2) For OS, PFS and DOR, the median for each endpoint and the corresponding two-sided 95% 
CI will be estimated for each treatment group and subgroup. CIs for each median will be 
calculated using the Brookmeyer and Crowley method based on a log-log transformed CI 
for the survivor function. 
(3) Forest plots of OS, PFS and DOR will be created using (1) and (2) to present the hazard 
ratio and the corresponding 95% CIs and the median and the corresponding 95% CIs. 
(4) For OS and PFS, the Kaplan-Meier curve will be plotted for each treatment group by PD-L1 
Expression (test results). 
(5) For ORR, the associated odds ratio and the corresponding two-sided 95% CI for ONO-4538 
group relative to control group will be calculated using the logistic regression model with 
the treatment group as the single covariate in each subgroup. Forest plots will also be created 
to present the odds ratio and the corresponding 95% confidence interval. 
(6) For ORR, the proportions and the corresponding two-sided 95% CI will be estimated using 
the Clopper-Pearson method for each treatment group and control regimen by PD-L1 
Expression (test results). 
(7) For BOR, the percentage of confirmed CR, confirmed PR, SD, PD and NE will be 
calculated for each treatment group by PD-L1 Expression (test results). For the percentages 
of CR, PR and SD, the corresponding 95% CI will be estimated using the Clopper-Pearson 
method for each treatment group. 
 
10.5 Interaction Analysis 
For the primary efficacy endpoint (i.e. OS), the interaction between treatment group and the 
demographic factors presented in 10.4 Subgroup analyses for the efficacy endpoints will be 
assessed using a Cox proportional-hazards model. For the analysis, each demographic factor, 


 
 
 
 
44 
 
treatment group and interaction between each demographic variable and treatment group will be 
used for the factors. 
 
10.6 Adjusted Analysis 
The adjusted analysis for primary endpoint (i.e. OS) will be performed using a demographic 
factors presented in 10.4 Subgroup analyses for the efficacy endpoints except for location, the 
number of organs with metastases and PD-L1 expression. The hazard ratio and the corresponding 
two-sided 95% CI of the ONO-4538 group relative to the control group will be calculated using 
the stratified Cox proportional hazard model with the stratification factors (IWRS source) 
presented in 9.4 Analytical Methods as the stratification factors, treatment groups and each 
demographic factor as the covariance factors. 
 
10.7 Relationship Between Endpoints 
Not planned in this study. 
 
10.8 Other Analysis 
1) Swimmer plot will be displayed by investigational product and BOR. Other exploratory 
analyses may be performed additionally as necessary. 
2) Summary statistics of observation period will be calculated by treatment group and control 
regimen for the following analysis populations. 
∙ ITT 
∙ ITT and subjects continuing the study (ongoing treatment period or post observation 
period) 
Observation period for subject who died and who alive or lost to follow-up will be 
calculated by the following equations. 
Observation period for subjects who died (Months) = (“Date of death due to any cause” − 
“Date of randomization” + 1) / 30.4375 
Observation period for subjects who alive or lost to follow-up (Months) = (“Date of last 
survive confirmed” − “Date of randomization” + 1) / 30.4375 


 
 
 
 
45 
 
11 ANALYSIS OF SAFETY 
11.1 Analysis Sets 
The SAF will be the analysis set. 
 
11.2 Analytical Items and Data Handlings 
1) Analytical Items 
(1) Adverse events, drug-related adverse events and deaths 
(2) Select adverse events and drug-related select adverse events 
(3) Immune-mediated adverse events (IMAEs) 
(4) Other adverse events of special interests (AEOSIs) 
(5) Laboratory tests  
a) Hematology Tests 
Hemoglobin, White blood cell count, Neutrophils count, Lymphocytes count, Platelet 
count 
b) Biochemistry Tests 
ALP, AST (GOT), ALT (GPT), Total bilirubin, Creatinine, Na, K, Ca 
(6) Hormone Tests 
Thyroid-stimulating hormone (TSH), Free triiodothyronine (free T3), Free thyroxine 
(free T4) 
(7) 12-lead ECG 
Heart Rate (HR), PR Interval, RR Interval, QRS Width, QT Interval, QTcF Interval 
 
2) Handling of data 
Unless otherwise noted, the items occurring between the start date of the first administration of 
the investigational product and 28 days after the last dose or the start date of subsequence 
anti-cancer therapy after the last dose whichever comes first will be tabulated by treatment 
group. 


 
 
 
 
46 
 
(1) Adverse events, drug-related adverse events and deaths 
An adverse event (AE) is any unfavorable or unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of the 
investigational product, regardless of whether the event is causally related to the 
investigational product. AEs occurring between the start date of the first administration of the 
investigational product and 28 days after the last dose or the start date of subsequence 
anti-cancer therapy after the last dose whichever comes first will be tabulated. In addition, the 
entire AEs occurring in the treatment period as well as the post-treatment observation period 
will be reported by listing. 
Drug-related AEs will be defined as any AEs for which a causal relationship to the 
investigational product is “Related” or missing. If the causal relationship to the investigational 
product is missing, the AE will be considered as “Related”. 
AEs will be coded by using the Medical Dictionary for Regulatory Activities (MedDRA), and 
classified by System Organ Class (SOC) and Preferred Term (PT). In the summary table, a 
subject will be counted as the only one subject in case of the multiple occurrence of the same 
AE within the same subject. AEs will be graded by using the NCI Common Terminology 
Criteria for Adverse Event (CTCAE), version 4.0, when preparing the tabulation by Grade. 
The worst CTCAE grade for each subject will be summarized in case of the multiple 
occurrence of the same AE within the same subject, when preparing the tabulation by CTCAE 
grade.  
When preparing the tabulation by period, the earliest AE occurrence time in each period will 
be counted as one time in case of the multiple occurrence of the same AE within the same 
subject. Of note, the analysis set will include the only subjects who will be monitored during 
each period. 
Deaths will be counted regarding the deceased subjects from the start date of the first 
administration of the investigational product through the earlier date on which either 28 days 
after the last dose or the start date of subsequence anti-cancer therapy after the last dose. 
 
(2) Multiple events of adverse events 


 
 
 
 
47 
 
Analyses that take into account the multiple occurrences of a given adverse event will be 
conducted. This data will be presented as the rate per 100 person-years of exposure. The 
analyses will take into account all on-treatment events (allowing more than 1 event per 
subject) and the total exposure time. The person-year exposure will be computed as the sum 
over the subjects’ exposure expressed in years where the exposure time is defined as  
“Min (28 days after last dose of study treatment or Start date of subsequence anti-cancer 
therapy after the last dose of study treatment or Date of death or Last known date alive or cut 
off date – date of first dose of study treatment) / 365.25 ” 
 
(3) Select AEs and drug-related select AEs 
Select AEs will be defined as any AEs which are described in Appendix 1. Select AEs occurring 
between the start date of the first administration of the investigational product and 28 days 
after the last dose or the start date of subsequence anti-cancer therapy after the last dose 
whichever comes first will be tabulated. 
 
Time to onset of select AEs (any grade) in each category (Weeks) = (“The onset date of the 
earliest select AE in each category” – “The day of first dose of study treatment” + 1 ) / 7 
The time to onset of select AEs of a subject who does not have select AEs in each category will be 
censored at the maximum time of the period of the time to onset of select AEs in each category 
and each treatment group. 
Time to onset of select AEs (CTCAE grade 3-5) for a specific category is defined similarly but 
restricted to CTCAE grade 3-5 select AEs. 
Time to onset of drug-related select AEs (CTCAE grade 3-5 or any grade) for a specific 
category is defined similarly but restricted to drug-related select AEs. 
Time to onset for a specific subcategory is defined similarly but restricted to event of this 
subcategory. 
 
The time to resolution of select AEs in each category in each subject is the maximum time to 
resolution of select AEs in each subject calculated by the following equation. The time to 


 
 
 
 
48 
 
resolution of select AEs in each category will be defined only for a subject who has at least 
one select AE included in each category. 
Time to resolution of select AEs (any grade) in each category (Weeks) = (“The last complete 
resolution date of a select AEs appearing consecutively in each category” - “ The first onset 
date of a select AEs appearing consecutively in each category” + 1 ) / 7 
If a select AE is considered as unresolved, the resolution date will be censored on the last 
assessment date of outcome. 
The time to resolution of select AEs (CTCAE grade 3-5) for a specific category is defined 
similarly with an onset date corresponding to a CTCAE grade 3-5 select AE. 
Time to resolution of drug-related select AEs (CTCAE grade 3-5 or any grade) for a specific 
category is defined similarly but restricted to drug-related select AEs. 
 
(4) Immune-mediated AEs 
Immune-mediated AEs (IMAEs) will be defined as any AEs which are described in Appendix 
2. IMAEs occurring between the start date of the first administration of the investigational 
product and 100 days after the last dose will be tabulated. All IMAEs analyses will be 
performed using the 100 days window. Analyses for IMAEs will be limited to subjects who 
included in SAF and received immunosuppressive medication for treatment of the event, with 
the exception of endocrine events, which will be included in the analysis regardless of 
treatment since endocrine events are often managed without immunosuppression. 
Time to onset of IMAEs (any grade) in each category (Weeks) = (“The onset date of the 
earliest IMAE in each category” – “The day of first dose of study treatment” + 1 ) / 7 
The time to onset of IMAEs of a subject who does not have IMAEs in each category will be 
censored at the maximum time of the period of the time to onset of IMAEs in each category and 
each treatment group. 
Time to onset of IMAEs (CTCAE grade 3-5) for a specific category is defined similarly but 
restricted to CTCAE grade 3-5 IMAEs. 
The time to resolution of IMAEs (any grade) in each category in each subject is the maximum 
time to resolution of IMAEs in each subject calculated by the following equation. The time to 


 
 
 
 
49 
 
resolution of IMAEs in each category will be defined only for a subject who has at least one 
IMAE included in each category. 
Time to resolution of IMAEs (any grade) in each category (Weeks) = (“The last complete 
resolution date of IMAEs appearing consecutively in each category” – “ The first onset date of 
IMAEs appearing consecutively in each category” + 1 ) / 7 
Events which worsened into CTCAE grade 5 events (death) are considered unresolved. If 
IMAE is considered as unresolved, the resolution date will be censored to the last assessment 
date of outcome.  
The time to resolution of IMAEs (CTCAE grade 3-5) for a specific category is defined 
similarly with an onset date corresponding to a CTCAE grade 3-5 IMAEs. 
 
(5) Other adverse events of special interests (AEOSIs)  
AEOSIs will be defined as any AEs which are described in Appendix 3. AEOSIs occurring 
between the start date of the first administration of the investigational product and 28 days after 
the last dose or the start date of subsequence anti-cancer therapy after the last dose whichever 
comes first will be tabulated. 
Time to onset of AEOSIs (any grade) in each category (Weeks) = (“The onset date of the 
earliest AEOSIs in each category” – “The day of first dose of study treatment” + 1 ) / 7 
The time to onset of AEOSIs of a subject who does not have AEOSIs in each category will be 
censored at the maximum time of the period of the time to onset of AEOSIs in each category and 
each treatment group. 
Time to onset of AEOSIs (CTCAE grade 3-5) for a specific category is defined similarly but 
restricted to CTCAE grade 3-5 AEOSIs. 
Time to onset of drug-related AEOSIs (CTCAE grade 3-5 or any grade) for a specific category 
is defined similarly but restricted to drug-related AEOSIs. 
 
The time to resolution of AEOSIs (any grade) in each category in each subject is the maximum 
time to resolution of AEOSIs in each subject calculated by the following equation. The time to 


 
 
 
 
50 
 
resolution of AEOSIs in each category will be defined only for a subject who has at least one 
AEOSI included in each category. 
Time to resolution of AEOSIs (any grade) in each category (Weeks) = (“The last complete 
resolution date of AEOSIs appearing consecutively in each category” - “ The first onset date of 
AEOSIs appearing consecutively in each category” + 1 ) / 7 
Events which worsened into CTCAE grade 5 events (death) are considered unresolved. If 
AEOSI is considered as unresolved, the resolution date will be censored to the last assessment 
date of outcome. This measure is defined only for subjects who experienced at least one IMAE 
in the specific category. 
The time to resolution of AEOSIs (CTCAE grade 3-5) for a specific category is defined 
similarly with an onset date corresponding to a CTCAE grade 3-5 AEOSIs. 
Time to resolution of drug-related AEOSIs (CTCAE grade 3-5 or any grade) for a specific 
category is defined similarly but restricted to drug-related AEOSIs. 
 
(6) Laboratory tests 
Laboratory tests between the start date of the first administration of the investigational product 
and 28 days after the last dose or the start date of subsequence anti-cancer therapy after the last 
dose whichever comes first will be tabulated. 
Baseline data will be defined as the data in the screening period. If more than one data are 
collected in screening period then latest one is defined as the baseline data. 
If the measurement is lower than XX, upper than or equal to YY, and so on, the numerical 
value (i.e. XX, YY) will be used. 
Laboratory tests will be graded by using CTCAE version 4.0, when preparing the tabulation by 
Grade. 
Clinical laboratory data will be first analyzed using International System of Units (SI). 
Analyses will be repeated using US conventional units. 
 
 


 
 
 
 
51 
 
(7) Hormone tests 
Hormone tests between the start date of the first administration of the investigational product 
and 28 days after the last dose or the start date of subsequence anti-cancer therapy after the last 
dose whichever comes first will be tabulated. 
Baseline data will be defined as the data in the screening period. If more than one data are 
collected in screening period then latest one is defined as the baseline data. 
If the measurement is lower than XX, upper than or equal to YY, and so on, the numerical 
value (i.e. XX, YY) will be used. 
Hormone tests data will be first analyzed using International System of Units (SI). Analyses 
will be repeated using US conventional units. 
 
(8) 12-lead ECG 
12-lead ECG between the start date of the first administration of the investigational product and 
28 days after the last dose or the start date of subsequence anti-cancer therapy after the last dose 
whichever comes first will be tabulated. 
Baseline data will be defined as the data at Day 1 pre-dose in Cycle 1. Of note, in case of the 
missing data at Day 1 pre-dose in Cycle 1, the alternative baseline data will be defined as the 
data in the screening period. 
 
11.3 Analytical methods 
1) Adverse events, drug-related adverse events and deaths 
(1) Numbers of subjects with AEs and drug-related AEs, serious AEs (SAEs) and drug-related 
SAEs, AEs and drug-related AEs leading to discontinuation of study treatment, AEs and 
drug-related AEs leading to dose delay of study treatment, AEs and drug-related AEs 
leading to dose reduction of study treatment will be summarized by the worst CTCAE grade 
(any grade, grade 3-4, grade 5) in each treatment group and control regimen.  


 
 
 
 
52 
 
(2) Number of subjects who died within 28 days / 100 days after the last dose of the study 
treatment as well as the frequency by reason of death will be summarized by treatment 
group and control regimen. 
(3) Number of subjects who died within 28 days after the last dose of study treatment or the 
start date of subsequence anti-cancer therapy after the last dose of study treatment 
whichever comes first as well as the frequency by reason of death will be summarized by 
treatment group and control regimen. 
(4) Number of subjects who died as well as the frequency by reason of death will be 
summarized by treatment group and control regimen. 
(5) AEs and drug-related AEs with the incidence rate greater than or equal to 5% in any 
treatment group and control regimen will be summarized by PT as well as by period. 
(6) AEs and drug-related AEs by the worst CTCAE grade (grade 1, 2, 3, 4, and 5) in each 
treatment group and control regimen will be summarized by SOC and PT. 
(7) AEs and drug-related AEs by the worst CTCAE grade (grade 1, 2, 3, 4, and 5) with the 
incidence rate greater than or equal to 5% in any treatment group and control regimen will 
be summarized by SOC and PT. 
(8) AEs and drug-related AEs by the worst CTCAE grade (any grade, grade 3-4, grade 5) in 
each treatment group and control regimen will be summarized by SOC and PT.  
(9) AEs and drug-related AEs by the worst CTCAE grade (any grade, grade 3-4, grade 5) in 
each treatment group and control regimen with the incidence rate greater than or equal to 
5% in any treatment group and control regimen will be summarized by SOC and PT. 
(10) AEs and drug-related AEs leading to discontinuation of study treatment by the worst 
CTCAE grade (grade 1, 2, 3, 4, and 5) in each treatment group and control regimen will be 
summarized by SOC and PT. 
(11) AEs and drug-related AEs leading to discontinuation of study treatment by the worst 
CTCAE grade (any grade, grade 3-4, grade 5) in each treatment group and control regimen 
will be summarized by SOC and PT. 


 
 
 
 
53 
 
(12) AEs and drug-related AEs leading to dose delay of study treatment by the worst CTCAE 
grade (grade 1, 2, 3, 4, and 5) in each treatment group and control regimen will be 
summarized by SOC and PT. 
(13) AEs and drug-related AEs leading to dose delay of study treatment by the worst CTCAE 
grade (any grade, grade 3-4, grade 5) in each treatment group and control regimen will be 
summarized by SOC and PT. 
(14) AEs and drug-related AEs leading to dose reduction of study treatment by the worst 
CTCAE grade (grade 1, 2, 3, 4, and 5) in control group and control regimen will be 
summarized by SOC and PT. 
(15) AEs and drug-related AEs leading to dose reduction of study treatment by the worst 
CTCAE grade (any grade, grade 3-4, grade 5) in control group and control regimen will be 
summarized by SOC and PT. 
(16) AEs and drug-related AEs with any CTCAE grade 3 or 4 in each treatment group and 
control regimen will be summarized by SOC and PT. 
(17) SAEs and drug-related SAEs by the worst CTCAE grade (grade 1, 2, 3, 4, and 5) in each 
treatment group and control regimen will be summarized by SOC and PT. The same 
analysis will be performed for SAEs and drug-related SAEs occurring between the start date 
of the first administration of the investigational product and 100 days after the last dose. 
(18) SAEs and drug-related SAEs by the worst CTCAE grade (any grade, grade 3-4, grade 5) in 
each treatment group and control regimen will be summarized by SOC and PT. The same 
analysis will be performed for SAEs and drug-related SAEs occurring between the start date 
of the first administration of the investigational product and 100 days after the last dose. 
(19) AEs and drug-related AEs leading to death in each treatment group and control regimen 
will be summarized by SOC and PT. 
  
2) Multiple events of adverse events 
(1) The total number and rate (exposure adjusted) of occurrences for all AEs and drug-related 
AEs in each treatment group and control regimen will be summarized by SOC and PT. 


 
 
 
 
54 
 
(2) The number of subjects experiencing a select AEs once or multiple times in each treatment 
group and control regimen will be summarized by specific category, subcategory and PT. 
 
3) Select AEs and drug-related select AEs  
(1) Numbers of subjects with select AEs and drug-related select AEs, serious select AEs and 
drug-related serious select AEs, select AEs and drug-related select AEs leading to 
discontinuation of study treatment, select AEs and drug-related select AEs leading to dose 
delay of study treatment will be summarized by the worst CTCAE grade (any grade, grade 
3-4, grade 5) in each treatment group and specific category and subcategory. 
(2) Select AEs and drug-related select AEs by the worst CTCAE grade (grade 1, 2, 3, 4, and 5) 
in each treatment group will be summarized by specific category, subcategory and PT. 
(3) Select AEs and drug-related AEs by the worst CTCAE grade (any grade, grade 3-4, grade 5) 
in each treatment group will be summarized by specific category, subcategory and PT. 
(4) Select AEs and drug-related select AEs leading to discontinuation of study treatment by the 
worst CTCAE grade (grade 1, 2, 3, 4, and 5) in each treatment group will be summarized by 
specific category, subcategory and PT. 
(5) Select AEs and drug-related select AEs leading to discontinuation of study treatment by the 
worst CTCAE grade (any grade, grade 3-4, grade 5) in each treatment group will be 
summarized by specific category, subcategory and PT. 
(6) Select AEs and drug-related select AEs leading to dose delay of study treatment by the 
worst CTCAE grade (grade 1, 2, 3, 4, and 5) in each treatment group will be summarized by 
specific category, subcategory and PT. 
(7) Select AEs and drug-related AEs leading to dose delay of study treatment by worst CTCAE 
grade (any grade, grade 3-4, grade 5) in each treatment group will be summarized by 
specific category, subcategory and PT. 
(8) Serious select AEs and drug related serious select AEs by the worst CTCAE grade (grade 1, 
2, 3, 4, and 5) in each treatment group will be summarized by specific category, subcategory 
and PT. The same analysis will be performed for serious select AEs and drug-related serious 


 
 
 
 
55 
 
select AEs occurring between the start date of the first administration of the investigational 
product and 100 days after the last dose. 
(9) Serious select AEs and drug related serious select AEs by the worst CTCAE grade (any 
grade, grade 3-4, grade 5) in each treatment group will be summarized by specific category, 
subcategory and PT. The same analysis will be performed for serious select AEs and 
drug-related serious select AEs occurring between the start date of the first administration of 
the investigational product and 100 days after the last dose. 
(10) Select AEs and drug-related select AEs leading to death in each treatment group will be 
summarized by specific category, subcategory and PT. 
 
4) IMAEs 
(1) Numbers of subjects with IMAEs, serious IMAEs, IMAEs leading to discontinuation of 
study treatment, IMAEs leading to dose delay of study treatment will be summarized by the 
worst CTCAE grade (any grade, grade 3-4, grade 5) in each treatment group and specific 
category. 
(2) IMAEs by the worst CTCAE grade (grade 1, 2, 3, 4, and 5) in each treatment group will be 
summarized by specific category and PT. 
(3) IMAEs by the worst CTCAE grade (any grade, grade 3-4, grade 5) in each treatment group 
will be summarized by specific category and PT. 
(4) IMAEs leading to discontinuation of study treatment by worst CTCAE grade (grade 1, 2, 3, 
4, and 5) in each treatment group will be summarized by specific category and PT. 
(5) IMAEs leading to discontinuation of study treatment by worst CTCAE grade (any grade, 
grade 3-4, grade 5) in each treatment group will be summarized by specific category and 
PT. 
(6) IMAEs leading to dose delay of study treatment by worst CTCAE grade (grade 1, 2, 3, 4, 
and 5) in each treatment group will be summarized by specific category and PT. 
(7) IMAEs leading to dose delay of study treatment by worst CTCAE grade (any grade, grade 
3-4, grade 5) in each treatment group will be summarized by specific category and PT. 


 
 
 
 
56 
 
(8) Serious IMAEs by worst CTCAE grade (grade 1, 2, 3, 4, and 5) in each treatment group will 
be summarized by specific category and PT. 
(9) Serious IMAEs by the worst CTCAE grade (any grade, grade 3-4, grade 5) in each treatment 
group will be summarized by specific category and PT. 
(10) IMAEs leading to death in each treatment group will be summarized by specific category 
and PT. 
(11) AEs which are qualified for IMAE’s PT list by worst CTCAE grade (grade 1, 2, 3, 4, and 
5) in each treatment group will be summarized by specific category and PT. 
 
5) Total medication treatment duration (excluding overlaps) of immune-modulating 
concomitant medication 
(1) Percentage of subjects who received immune modulating concomitant medication for 
management of drug-related select AEs (any grade, grade 3-5) among subjects who 
experienced at least one drug-related select AEs in the category/subcategory will be 
calculated by treatment group. 
(2) Percentage of subjects who received immune modulating concomitant medication for 
management of IMAEs (any grade, grade 3-5) among subjects who experienced at least one 
drug-related select AEs in the category/subcategory will be calculated by treatment group. 
(3) For each category/subcategory of drug-related select AEs (any grade, grade 3-5) and IMAEs 
(any grade, grade 3-5), summary statistics (median, minimum and maximum) of total 
medication treatment duration (excluding overlaps) of immune-modulating concomitant 
medication will be calculated by treatment group. 
 
6) AEOSIs 
(1) AEOSIs and drug-related AEOSIs by the worst CTCAE grade (grade 1, 2, 3, 4, and 5) in 
each treatment group will be summarized by specific category and PT. 
(2) AEOSIs and drug-related AEOSIs by the worst CTCAE grade (any grade, grade 3-4, grade 
5) in each treatment group will be summarized by specific category and PT. 


 
 
 
 
57 
 
(3) Serious AEOSIs and drug-related serious AEOSIs of special interests by the worst CTCAE 
grade (grade 1, 2, 3, 4, and 5) in each treatment group will be summarized by specific 
category and PT. 
(4) AEOSIs and drug-related AEOSIs where immune modulating medication was initiated by 
the worst CTCAE grade (grade 1, 2, 3, 4, and 5) in each treatment group will be 
summarized by specific category and PT. 
 
7) Time to onset of select AEs, IMAEs and AEOSIs 
Summary statistics (median, minimum and maximum) of time to onset of the following specific 
events will be calculated by treatment group. 
(1) Time to onset of any grade IMAEs by treatment group 
(2) Time to onset of CTCAE grade 3 to 5 IMAEs by treatment group 
(3) Time to onset of any grade select AEs and drug-related select AEs by treatment group 
(4) Time to onset of CTCAE grade 3 to 5 select AEs and drug-related select AEs by treatment 
group 
(5) Time to onset of any grade AEOSIs and drug-related AEOSIs by treatment group 
(6) Time to onset of CTCAE grade 3 to 5 AEOSIs and drug-related AEOSIs by treatment group 
(7) Time to onset of any grade AEOSIs and drug-related AEOSIs where immune-modulating 
medication was initiated 
(8) Time to onset of CTCAE grade 3 to 5 AEOSIs and drug-related AEOSIs where immune 
modulating concomitant medication was initiated 
 
8) Time to resolution of select AEs, IMAEs and AEOSIs 
Using the Kaplan-Meier method, the median and the corresponding two-sided 95% CI for time 
to resolution and range of the following specific events will be estimated for each 
category/subcategory of select AEs, IMAEs (only for category) and AEOSIs (only for category). 
The CI will be calculated using the Brookmeyer and Crowley method based on a log-log 
transformed CI for the survivor function. 
(1) Time to resolution of any grade IMAEs by treatment group 


 
 
 
 
58 
 
(2) Time to resolution of CTCAE grade 3 to 5 IMAEs by treatment group 
(3) Time to resolution of any grade select AEs and drug-related select AEs by treatment group 
(4) Time to resolution of CTCAE grade 3 to 5 select AEs and drug-related select AEs by 
treatment group 
(5) Time to resolution of any grade select AEs and drug-related select AEs where immune 
modulating medication was initiated, by treatment group 
(6) Time to resolution of CTCAE grade 3 to 5 select AEs and drug-related select AEs where 
immune modulating concomitant medication was initiated, by treatment group 
(7) Time to resolution of any grade AEOSIs and drug-related AEOSIs by treatment group 
(8) Time to resolution of CTCAE grade 3 to 5 AEOSIs and drug-related AEOSIs by treatment 
group 
(9) Time to resolution of any grade AEOSIs and drug-related AEOSIs where immune 
modulating concomitant medication was initiated 
(10) Time to resolution of CTCAE grade 3 to 5 AEOSIs and drug-related AEOSIs where 
immune modulating concomitant medication was initiated 
 
9) Laboratory tests 
(1) The worst CTCAE Grade compared to the baseline grade will be evaluated by treatment 
group and control regimen in the shift table during the treatment period as to the following 
laboratory tests: Hematology (Hemoglobin, White blood cell count, Platelet count, 
Lymphocytes count, Neutrophils count), Liver (ALP, AST (GOT), ALT (GPT), Total 
bilirubin), Creatinine and Electrolyte (Na, K, Ca). 
(2) The worst CTCAE Grade (Grade 1-4 and Grade 3-4) in laboratory test that worsened 
relative to baseline will be evaluated by treatment group as to the following laboratory tests: 
Hematology (Hemoglobin, White blood cell count, Platelet count, Lymphocytes count, 
Neutrophils count), Liver (ALP, AST (GOT), ALT (GPT), Total bilirubin), Creatinine and 
Electrolyte (Na, K, Ca). 
(3) Focusing on the abnormal hepatic function, the frequency distributions of the appropriate 
subjects will be specified according to the following criteria by treatment group. 


 
 
 
 
59 
 
a) ALT or AST > 3xULN (Upper Limit of Normal), 5xULN, 10xULN, 20xULN 
b) Total bilirubin > 2xULN 
c) ALT or AST > 3xULN as well as total bilirubin collected 1 day before  
and after > 2xULN 
d) ALT or AST > 3xULN as well as total bilirubin collected 30 days before 
and after > 2xULN 
e) ALT or AST > 3xULN as well as total bilirubin collected 1 day before 
and after ≥ 2xULN, ALP < 2xULN 
 
10) Hormone tests 
(1) Focusing on the thyroid dysfunction, the frequency distributions of the appropriate subjects 
will be specified according to the following criteria by treatment group. Both free T3 and 
free T4 are targeted within a 2-week window after abnormal TSH test date. 
a) TSH > ULN (Upper limit of Normal) 
b) TSH > ULN as well as TSH ≤ ULN at the baseline 
c) TSH > ULN as well as either free T3 or free T4 < LLN (Lower Limit of Normal) 
at least one assessment time 
d) TSH > ULN as well as both free T3 and free T4 ≥ LLN at all assessment time 
e) TSH > ULN as well as either free T3 or free T4 is missing value. 
f) TSH < LLN 
g) TSH < LLN as well as TSH ≥ LLN at the baseline 
h) TSH < LLN as well as either free T3 or free T4 > ULN at least one assessment time 
i) TSH < LLN as well as both free T3 and free T4 ≤ ULN at all assessment time 
j) TSH < LLN as well as either free T3 or free T4 is missing value. 
 
11) 12-lead ECG 
(1)The maximal data of QRS Width, PR Interval, RR Interval, QT Interval, QTcF Interval, the 
change of QTcF Interval from baseline and HR will be summarized by treatment group using 
frequency distributions according to the following category. 
 


 
 
 
 
60 
 
ECG parameters (unit) 
Classification 
RR (ms) (actual value) 
<=600, >600 - 1200, >1200 
PR (ms) (actual value) 
<=120, >120 - 200, >200 
QRS (ms) (actual value) 
<=60, >60 - 109, >109 
HR (beats/min) (actual value) 
<=50, >50 - 100, >100 
QT (ms) (actual value) 
<=450, >450 - 480, >480 - 500, >500 
QTcF (ms) (actual value) 
<=450, >450 - 480, >480 - 500, >500 
QTcF (ms) (the change from baseline) 
<=30, >30 - 60, >60 
 
Focusing on the high incidence of adverse events, exploratory analyses may be performed 
additionally relating to the safety of ONO-4538 as necessary. 
 
11.4 Subgroup analyses for the safety endpoints 
AEs and drug-related AEs, serious AEs and drug-related serious AEs by the worst CTCAE grade 
(any grade, grade 3-4, grade 5) in each treatment group will be summarized by SOC and PT for 
the following factors. 
 
Factor 
Stratum 
PD-L1 Expression (test results) 
(1) >=1%, <1% 
(2) >=5%, <5% 
(3) >=10%, <10% 
(4) Not Quantifiable 
Location (IWRS) 
Japan, Rest of world 


 
 
 
 
61 
 
Age 
<65, >=65 
Sex 
Male, Female 
Race 
Asian, Other 
ECOG Performance Status score at 
baseline 
0, 1 
Recurrent 
No, Yes 
Past treatments for cancer 
(surgery) 
No, Yes 
Past treatments for cancer 
(radiotherapy) 
No, Yes 
History of smoking 
Never, Former, Current 


 
 
 
 
62 
 
12 PD-L1 EXPRESSION ANALYSIS 
 
12.1 Analysis Sets 
The ITT will be the analysis set 
 
12.2 Analytical Item and Data Handlings 
1) Analytical Item 
PD-L1 expression 
 
2) Handlings of data 
(1) Quantifiable 
Subjects with an available tissue specimens and number of available cancerous cells are ≥ 
100 and percentage of tumor PD-L1 expression is ≥ 0%. 
 
(2) PD-L1 expression at baseline 
If more than one tissue specimens are available, baseline PD-L1 expression will be determined 
from the most recently collected specimen (prior to first dose of study treatment or prior to 
randomization date for subjects randomized but never treated) with a quantifiable result. 
 
(3)PD-L1 status at baseline 
PD-L1 status at baseline is a categorical valuable by X% cutoff for quantifiable PD-L1 
baseline expression: 
• 
PD-L1 Positive at X% cutoff value: ≥ X% PD-L1 expression 
• 
PD-L1 Negative at X% cutoff value: < X% PD-L1 expression and ≥ 0% 
• 
PD-L1 Not Quantifiable: subjects with no quantifiable PD-L1 expression at baseline 
(includes subjects without tissue samples for PD-L1) 
where X denotes the PD-L1 expression cutoff of 1%, 5%, or 10%.  
 
12.3 Analytical methods 
1) Frequency of PD-L1 status at baseline will be summarized by treatment group and control 
regimen. 


 
 
 
 
63 
 
2) Cumulative distribution plot of baseline PD-L1 expression versus population percentile will 
be created by treatment group and control regimen on subjects with quantifiable PD-L1 
expression at baseline. 
 
 


 
 
 
 
64 
 
13 ANTI-DRUG ANTIBODY ANALYSIS 
 
13.1 Analysis Sets 
The ADA will be the analysis set. 
 
13.2 Analytical Item and Data Handlings 
1) Analytical Item 
Anti-ONO-4538 antibody up-regulated expression 
 
2) Handlings of data 
(1) Handling of each sample 
Each sample will be handled in the following manner; 
a) Baseline-positive sample 
Baseline-positive sample will be defined as the sample detected any anti-ONO-4538 antibody 
in the last sample prior to the first administration of the investigational product. 
b) Baseline-negative sample 
Baseline-negative sample will be defined as the sample not detected any anti-ONO-4538 
antibody in the last sample prior to the first administration of the investigational product. 
c) Anti-ONO-4538 antibody-positive sample 
Anti-ONO-4538 antibody-positive sample will be defined as the sample collected after the 
administration of the investigational product, meeting any conditions as follows; 
i) The sample detected no anti-ONO-4538 antibody prior to the first administration of the 
investigational product as well as detected any anti-ONO-4538 antibody after the first 
administration of the product. 
ii) For the sample detected any anti-ONO-4538 antibody in the last sample prior to the first 
administration of the investigational product, the sample detected greater than or equal to 
quadruple expression of the anti-ONO-4538 antibody relative to the baseline-sample 
expression after the first administration of the investigational product. 
d) Anti-ONO-4538 antibody-negative sample 


 
 
 
 
65 
 
Anti-ONO-4538 antibody-negative sample will be defined as the sample not positive relative 
to baseline after the first administration of the investigational product, excluding the missing 
data. 
 
(2) Handling of each subject 
Each subject will be handled in the following manner; 
a) Baseline-positive subject, Baseline neutralizing positive subject 
Baseline-positive subject will be defined as the subject who has the baseline-positive sample. 
Among the baseline-positive subjects, the subject who has greater than or equal to one 
baseline-positive sample detected the neutralizing antibody will be defined as the baseline 
neutralizing positive. 
b) Anti-ONO-4538 antibody-positive subject 
Anti-ONO-4538 antibody-positive subject will be defined as the subject who has at least one 
anti-ONO-4538 antibody-positive sample after the first administration of the investigational 
product. In addition, Anti-ONO-4538 antibody-positive subject will be classified according to 
the following definitions; 
i) Persistent Positive (PP) : 
The subject who has the anti-ONO-4538 antibody-positive samples on greater than or equal 
to two consecutive sampling time points after the first administration of the investigational 
product, provided that the time interval should leave at least 16 weeks (including 1 week as 
the defined allowable window). 
ii) Not PP – Last Sample Positive : 
The subject who is not PP with the anti-ONO-4538 antibody-positive sample at the last 
sampling time point. 
iii) Other positive : 
The subject who is not PP but some the anti-ONO-4538 antibody-positive samples after the 
first administration with last sample being negative. 
iv) Neutralizing positive : 
The subject who has greater than or equal to one anti-ONO-4538 antibody-positive sample 
detected the neutralizing antibody after the first administration of investigational product. 


 
 
 
 
66 
 
c) Anti-ONO-4538 antibody-negative subject  
Anti-ONO-4538 antibody-negative subject will be defined as the subject who has no 
anti-ONO-4538 antibody-positive sample. 
 
13.3 Analytical methods 
The percentage of the baseline-positive subject, baseline neutralizing positive subject, 
anti-ONO-4538 antibody-positive subject and anti-ONO-4538 antibody-negative subject will be 
calculated for each treatment group. For the anti-ONO-4538 antibody-positive subject, the 
percentage of the persistent positive (PP), not PP - last sample positive and the other positive will 
also be calculated. The percentage of the baseline neutralizing positive as well as neutralizing 
positive will be calculated as necessary. 


 
 
 
 
67 
 
14 PATIENT REPORTED OUTCOMES ANALYSIS 
 
14.1 Analysis Sets 
The ITT will be the analysis set. 
 
14.2 Analytical Items and Data Handling 
1) Analytical Items 
(1) Patient with questionnaire completion 
(2) EuroQol 5 Dimension (EQ-5D) 
(3) EQ-5D index scores (UK based scoring) 
(4) Change from baseline of EQ-5D index scores (UK based scoring) 
(5) EQ-5D index scores (Japan based scoring) 
(6) Change from baseline of EQ-5D index scores (Japan based scoring) 
(7) EuroQol visual analogue scale (EQ-VAS) scores 
(8) Change from baseline of EQ-VAS scores 
 
2) Handling of data 
(1) EQ-5D index scores (UK and Japan based scoring ) 
EQ-5D questionnaire asks the subjects to describe their current health state on 5 dimensions 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) with each 
dimension having 3 response choices (1 = no problem, 2 = some problem, and 3 = extreme 
problem). For example, if mobility = 2, self-care = 2, usual activities = 1, pain/discomfort = 
1, and anxiety/depression = 1, then “Health State” would be “22111”. 
(At least one 3 (N3), M2 (Mobility = 2), M3 (Mobility = 3), SC2 (Self Care = 2), SC3 (Self 
Care = 3), UA2 (Usual Activities = 2), UA3 (Usual Activities = 3), PD2 (Pain/Discomfort = 
2), PD3 (Pain/Discomfort = 3), AD2 (Anxiety/Depression = 2), AD3 (Anxiety/Depression = 
3)) 
If Full health “11111”, the value set is equal to 1. In other cases, the below mathematical 
representation is used. 
 


 
 
 
 
68 
 
UK Value Set: 1 - 0.081 - 0.269N3 - 0.069M2 - 0.314M3 - 0.104SC2 - 0.214SC3 - 0.036UA2 
- 0.094UA3 - 0.123PD2 - 0.386PD3 - 0.071AD2 - 0.236AD3 
Japan Value Set: 1 - 0.152 - 0.075MO2 - 0.418MO3 - 0.054SC2 - 0.102SC3 - 0.044UA2 - 
0.133UA3 - 0.080PD2 - 0.194PD3 - 0.063AD2 - 0.112AD3 
(2) Time window for EQ-5D assessments 
All questionnaires completed at baseline and on-study will be assigned to a time-point 
according to the windowing criteria in Table 14-2-1 and included in the analysis. In case a 
subject has two on-study assessments within the same window, the assessment closest to the 
time-point will be used. And, in the case of two assessments at a similar distance to the 
time-point, the latest one will be chosen. In the event where the subject has no assessment at 
all in a specific window, the observation will be treated as missing for that time-point. 
 
Table 14-2-1: Time windows for EQ-5D Assessments 
Nominal Time-Point 
Time Window 
Screening Phase (Baseline) 
Treatment phase (until last dose date) 
Week 6 (Day 43) 
Week 12 (Day 85) 
Week 18 (Day 127) 
…Every 6 weeks thereafter while on treatment 
Follow-up Phase (from last dose date) 
Follow-up 1 (Week 12 (Day 85) from last dose date) 
Follow up 2 (Week 24 (Day 169) from last dose date) 
…Every 12 weeks thereafter while on study 
< Date of the first dose of study treatment 
 
Day 1 - <=Day 64 
Day 65 - <=Day 106 
Day 107 - <= Day 148 
Nominal Day (+21 days / -20 days, inclusive) 
 
Last dose date to Last dose date + 127 days 
Last dose date + 128 days to Last dose date + 211 days 
Nominal Day(Range of previous follow-up +84 days) 
 
14.3 Analytical methods 
1) Patient with questionnaire completion 
The percentage of patients with questionnaire completion in each investigational product will be 
summarized at each time point. Percentage is defined as the proportion of questionnaires actually 


 
 
 
 
69 
 
received out of the expected number (i.e., the number of subjects still on treatment or in follow 
up at each time point). 
 
2) EQ-5D 
The percentages of patients with no health problems, moderate health problems and extreme 
health problems will be calculated for the each EQ-5D dimension at each time point by 
investigational product. Percentages will be calculated based on the number of patients assessed 
at each assessment time point for the each EQ-5D dimension. 
 
3) EQ-5D index scores (UK based scoring) and EQ-5D index score (Japan based scoring) 
(1) For EQ-5D index scores at each time point in each investigational product will be 
summarized using summary statistics. 95% CIs for mean scores of EQ-5D index scores at 
each time point in each investigational product will also be calculated. 
(2) For change from baseline of EQ-5D index scores at each time point in each investigational 
product will be summarized using summary statistics. 95% CIs for mean scores of change 
from baseline of EQ-5D index scores at each time point in each investigational product will 
also be calculated. 
 
4) EQ-VAS scores 
(1) For EQ-VAS scores at each time point in each investigational product will be summarized 
using summary statistics. 95% CIs for mean scores of EQ-VAS scores at each time point in 
each investigational product will also be calculated. 
(2) For change from baseline of EQ-VAS scores at each time point in each investigational 
product will be summarized using summary statistics. 95% CIs for mean scores of change 
from baseline of EQ-5D index scores at each time point in each investigational product will 
also be calculated. 
 


 
 
 
 
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15 INTERIM STATISTICAL ANALYSIS 
Formal interim analysis is not planned in this study. 


 
 
 
 
71 
 
16 DATA REVIEWS 
 
16.1 Objectives 
After data collection from this study, using the data before fixed, a preliminary analysis will be 
performed in terms of the distribution of background factors etc., to determine the 
appropriateness of planned analytical methods. 
 
16.2 Analysis Sets 
The ITT will be the analysis set. 
 
16.3 Analytical Items and Data Handling 
1) Analytical Items 
(1) Patient background factors 
(2) Subsequence anti-cancer therapy (surgery, radiotherapy, pharmacotherapy) 
(3) Efficacy endpoints 
a) OS 
b) PFS (Primary definition) 
c) ORR 
(4) Adverse events and drug-related adverse events 
 
2) Handling of data 
Each item will be analyzed according to the method defined above. 
 


 
 
 
 
72 
 
16.4 Analytical Methods 
1) Frequency distributions and summary statistics will be calculated for patient background 
factors, and the classification in 8.3 Analytical Methods and Classification will be 
determined. 
2) Details of subsequence anti-cancer therapy (surgery, radiotherapy, pharmacotherapy) will be 
summarized. 
3) The number of events and censors will be tabulated. The status of subjects who are censored 
in the Kaplan-Meier analysis will also be tabulated using the following categories: (1) 
on-study, (2) off-study． 
4) The median OS and the corresponding 95% confidence interval by using Kaplan-Meier 
method will be estimated. 95% confidence interval for the median OS will be calculated 
using the Brookmeyer and Crowley method based on a log-log transformed confidence 
interval for the survivor function. 
5) To examine the necessity of sensitive analysis for OS, cross-tabulation between stratification 
factors (IWRS source) and stratification factors (eCRF source) will be provided. 
6) The number of events and censors of PFS and reason for censored will be tabulated. 
Additionally, the median PFS and the corresponding 95% confidence interval by using 
Kaplan-Meier method will be estimated. 95% confidence interval for the median PFS will be 
calculated using the Brookmeyer and Crowley method based on a log-log transformed 
confidence interval for the survivor function. 
7) To verify the validity of the analysis method, ORR and the corresponding exact 
(Clopper-Pearson method) 95% confidence intervals will be calculated by using 
Clopper-Pearson method. As necessary, the missing condition will be verified. 
8) Numbers of patients with AEs and drug-related AEs will be summarized as a whole, or by 
System Organ Class (SOC), Preferred Term (PT) and Grade. 


 
 
 
 
73 
 
17 TECHNICAL MATTERS 
 
17.1 Statistical Software 
1) All statistical analyses will be carried out by using SAS (Statistical Analysis System 
software, SAS Institute, North Carolina, USA) version 9.3 or newer unless otherwise noted. 
2) Listings, tables and figures will be generated by using Microsoft Word or Microsoft Excel. 
Of note, Software version will be updated according to the situation. 
 
17.2 SAS Programming in Analyses 
The statistical analyses will be conducted in accordance with this statistical analysis plan. The 
contents of the SAS procedure for statistical analyses will be presented in this section. 
1) 95% confidence interval (Clopper-Pearson method) 
95% confidence interval (Clopper-Peason method) will be performed by using FREQ 
procedure in SAS programming. The following sample SAS programming will be applied for 
the calculation of 95% confidence interval (Clopper-Pearson method). 
 
PROC FREQ DATA = [Analysis data set]; 
TABLES [binary variable]; 
EXACT BINOMIAL; 
WEIGHT [frequency] / ZEROS; 
RUN; 
 
2) The median OS and corresponding two-sided 95% CI from the Kaplan-Meier estimate, 
stratified log-rank test 
The median OS and the corresponding two-sided 95% CI derived from the Kaplan-Meier 
estimate and stratified log-rank test will be performed by using LIFETEST procedure in 
SAS programming. 
 


 
 
 
 
74 
 
PROC LIFETEST DATA = [Analysis data set] ALPHA = 0.05 METHOD=KM 
CONFTYPE=LOGLOG; 
TIME [the survival time variable]* [the censoring variable](the value indicating 
censoring) ; 
STRATA [the stratification factor] / GROUP = [treatment group] test = logrank ; 
RUN; 
 
3) The hazard ratio and corresponding two-sided 95% CI from the stratified Cox 
proportional-hazards model 
The hazard ratio and corresponding two-sided 95% CI derived from the stratified Cox 
proportional-hazards model will be performed by using PHREG procedure in SAS 
programming. 
 
PROC PHREG DATA = [Analysis data set] ALPHA = 0.05; 
CLASS [treatment group]; 
STRATA [the stratification factor]; 
MODEL [the variables that define the survival time] * [the censoring variable](the value 
indicating censoring) = [treatment group] / RL TIES=EXACT; 
RUN; 
 
17.3 Data Format 
1) p-value 
The p-value will have fixed 4 decimal places, rounding off to 5 decimal places. Of note, 
p-value less than 0.0001 will be indicated as “p<0.0001”. 
2) Convert days to months or years 
1 month = 30.4375 days and 1 year = 365.25 days. 
3) Calculation of data 
In SAS programming, data will be evaluated complying with the double-precision operation in 
SAS system. Under the same condition, the calculation error will be removed from both the 
analysis data and the analysis result. 


 
 
 
 
75 
 
4) Definition of descriptive statistics and number of significant figures 
Unless otherwise noted, the descriptive statistics (N, mean, median, SD, maximum, and 
minimum) will be calculated in case the number of subjects is more than two. Each number of 
significant figures for individual data will be indicated below. Of note, the number of 
significant figures for the specific descriptive statistics (mean, median, and SD) will be 
indicated as the individual number of significant figures +1(i.e., in case the individual number 
of significant figures is first decimal place, the specific descriptive statistics (mean, median 
and SD) will be indicated as second decimal place). 
In addition, maximum and minimum will be indicated as the same decimal place as individual 
number of significant figures. 


 
 
 
 
76 
 
・Demographic variables and efficacy endpoints 
Integral number 
(No decimal places) 
Age(years) 
Number of organs with metastases (IWRS source and eCRF source) 
First decimal place 
Height(cm) 
Weight(kg) 
BMI(kg/m2) 
Time from the date of diagnosis of the primary disease to randomization 
(months) 
Time from the date of surgery (including EMR or ESD) for the primary 
lesion to randomization (months) 
Second decimal place 
Diameters of target lesions (mm) 
Third decimal place 
BSA (m2) 


 
 
 
 
77 
 
18 MAJOR CHANGES IN THE STATISTICAL ANALYSIS PLAN BASED 
ON THE STUDY-SPECIFIC PROTOCOL 
 
None 
 
 


 
 
 
 
78 
 
19 MAJOR CHANGES IN THE STATISTICAL ANALYSIS PLAN BASED 
ON THE STATISTICAL ANALYSIS PLAN VERSION 1.0 
 
Major analysis plan and data handlings wich were changed, added or deleted from statistical 
analysis plan version 1.0 are shown below. 
 
19.1 Reliability of the study 
<Additional items> 
Relevant protocol deviations, reason for subjects enrolled but not randomized and reason for 
subjects but not treated were added. 
<Deleted item> 
Reason of withdrawals and dropouts from the study was deleted. 
<Reason> 
To assess reliability of the study more appropriately 
 
19.2 Demographics and other baseline characteristics 
<Additional items> 
Analysis for past pharmacotherapy for cancer and details of immune modulating concomitant 
medication were added. 
<Reason> 
To assess imbalance of factors which may impact evaluation of efficacy and safety between the 
treatment groups 
 
19.3 Primay efficacy analysis 
19.3.1 
Proportional hazards assumption 
<Additional item> 
Test for examining the proportional hazards assumption for OS was added. 


 
 
 
 
79 
 
<Reason> 
To assess the proportional hazards assumption for OS 
 
19.3.2 
State of follow-up 
<Additional items> 
Analysis for current status of follow-up and duration of follow-up for OS were added. 
<Reason> 
To assess current status of follow-up for OS 
 
19.3.3 
Exploratory analytical methods 
<Additional items> 
Analyses using intented investigator’s choice therapy subset were added. 
<Reason> 
To evaluate an efficacy of ONO-4538 relative to control regimen from multilateral perspective 
 
19.4 Secondary efficacy analysis 
<Additional item> 
Secondary definition of PFS was added. 
<Reason> 
To evaluate robustness of analysis result using PFS 
 
19.5 Analysis of safety  
19.5.1 
Adverse event  
<Additional items> 


 
 
 
 
80 
 
Multiple events of adverse events and other adverse events of special interests (AEOSIs) were 
added. 
<Reason> 
To evaluate safety of ONO-4538 relative to control group from multilateral perspective 
 
19.6 PD-L1 expression analysis 
<Additional item> 
Section of PD-L1 expression analysis was added. 
<Reason> 
To evaluate expression level of PD-L1 in each treatment group 
 
19.7 Patient reported outcomes analysis 
<Additional items> 
Change from baseline of EQ-5D and EQ-VAS scores were added. 
<Additional items> 
To evaluate quality of life of ONO-4538 relative to control regimen from multilateral perspective 


 
 
 
 
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20 MAJOR CHANGES IN THE STATISTICAL ANALYSIS PLAN BASED 
ON THE STATISTICAL ANALYSIS PLAN VERSION 2.0 
 
Major analysis plan and data handlings which were changed, added or deleted from statistical 
analysis plan version 2.0 are shown below. 
 
20.1 
Significance level to be used 
<Additional item> 
Analysis population to be used for OS, ORR and PFS when performing the test using the 
Hierarchical hypothesis testing approach was added. 
<Reason> 
In this study, two analysis populations of ITT and RES (Response Evaluable Set) are defined as 
the analysis population for efficacy, and in order to clarify which analysis population will be 
tested for each endpoint. 
 
20.2 
Secondary efficacy analysis 
<Additional item> 
An analysis was added to calculate summary statistics of observation period of subjects for each 
treatment group. 
<Reason> 
To examine the observation period of subjects included in this study in more detail. 
 
 
 


 
 
 
 
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APPENDIX 1 
Definition of Select Adverse Events 
Category 
Subcategory 
PT 
Endocrine Adverse Event Adrenal Disorder 
Adrenal insufficiency 
 
 
Adrenal suppression 
 
 
Adrenocortical insufficiency acute 
 
 
Blood corticotrophin decreased 
 
 
Blood corticotrophin increased 
 
 
Hypothalamic pituitary adrenal axis suppression 
 
 
Primary adrenal insufficiency 
 
 
Secondary adrenocortical insufficiency 
 
Diabetes 
Diabetes mellitus 
 
 
Diabetic ketoacidosis 
 
 
Diabetic ketosis 
 
 
Fulminant type 1 diabetes mellitus 
 
 
Latent autoimmune diabetes in adults 
 
 
Type 1 diabetes mellitus 
 
Pituitary Disorder Hypophysitis 
 
 
Hypopituitarism 
 
 
Lymphocytic hypophysitis 
 
Thyroid Disorder 
Atrophic thyroiditis 
 
 
Autoimmune hypothyroidism 
 
 
Autoimmune thyroid disorder 
 
 
Autoimmune thyroiditis 
 
 
Basedow's disease 
 
 
Blood thyroid stimulating hormone decreased 
 
 
Blood thyroid stimulating hormone increased 
 
 
Hyperthyroidism 
 
 
Hypothyroidism 
 
 
Primary hyperthyroidism 
 
 
Primary hypothyroidism 
 
 
Silent thyroiditis 
 
 
Thyroid function test abnormal 
 
 
Thyroid hormones decreased 
 
 
Thyroid hormones increased 
 
 
Thyroiditis 
 
 
Thyroiditis acute 
 
 
Thyroxine decreased 
 
 
Thyroxine free decreased 
 
 
Thyroxine free increased 


 
 
 
 
83 
 
Category 
Subcategory 
PT 
 
 
Thyroxine increased 
 
 
Tri-iodothyronine uptake increased 
Gastrointestinal Adverse 
Event 
 
Autoimmune colitis 
Autoimmune enteropathy 
Colitis 
Colitis ulcerative 
Diarrhoea 
Duodenal perforation 
Enteritis 
Enterocolitis 
Enterocolitis haemorrhagic 
Frequent bowel movements 
Gastrointestinal perforation 
Lower gastrointestinal perforation 
Upper gastrointestinal perforation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatic Adverse Event 
 
Acute hepatic failure 
Acute on chronic liver failure 
Alanine aminotransferase increased 
Aspartate aminotransferase increased 
Autoimmune hepatitis 
Bilirubin conjugated increased 
Blood alkaline phosphatase increased 
Blood bilirubin increased 
Drug-induced liver injury 
Gamma-glutamyltransferase increased 
Hepatic enzyme increased 
Hepatic failure 
Hepatitis 
Hepatitis acute 
Hepatotoxicity 
Hyperbilirubinaemia 
Immune-mediated hepatitis 
Liver disorder 
Liver function test abnormal 
Liver function test increased 
Liver injury 
Transaminases increased 


 
 
 
 
84 
 
Category 
Subcategory 
PT 
Hypersensitivity/Infusion 
Reaction 
 
Anaphylactic reaction 
Anaphylactic shock 
Bronchospasm 
Hypersensitivity 
Infusion related reaction 
Pulmonary Adverse Event  
Acute respiratory distress syndrome 
Acute respiratory failure 
Idiopathic interstitial pneumonia 
Interstitial lung disease 
Lung infiltration 
Pneumonitis 
Renal Adverse Event 
 
Acute kidney injury 
Autoimmune nephritis 
Blood creatinine increased 
Blood urea increased 
Creatinine renal clearance decreased 
Hypercreatininaemia 
Nephritis 
Nephritis allergic 
Paraneoplastic glomerulonephritis 
Renal failure 
Renal tubular necrosis 
Tubulointerstitial nephritis 
Urine output decreased 


 
 
 
 
85 
 
Category 
Subcategory 
PT 
Skin Adverse Event 
 
Autoimmune dermatitis  
Blister  
Dermatitis  
Dermatitis allergic  
Dermatitis exfoliative  
Drug eruption  
Eczema  
Erythema  
Erythema multiforme  
Exfoliative rash  
Fixed eruption  
Nodular rash  
Palmar-plantar erythrodysaesthesia syndrome  
Pemphigoid  
Pemphigus  
Photosensitivity reaction  
Pruritus  
Pruritus allergic  
Pruritus generalised  
Psoriasis  
Rash  
Rash erythematous  
Rash generalised  
Rash macular  
Rash maculo-papular  
Rash morbilliform  
Rash papular  
Rash pruritic  
Rash vesicular  
Skin exfoliation  
Skin hypopigmentation  
Skin irritation  
Stevens-Johnson syndrome  
Toxic epidermal necrolysis  
Toxic skin eruption  
Urticaria  
Vitiligo 
MedDRA v21.1 


 
 
 
 
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APPENDIX 2 
Definition of Immune-Mediated Adverse Events 
Category 
Subcategory 
PT 
Endocrine 
Adrenal insufficiency 
Adrenal insufficiency 
 
Diabetes mellitus 
Diabetes mellitus 
 
 
Diabetic ketoacidosis 
 
Hyperthyroidism 
Hyperthyroidism 
 
Hypophysitis 
Hypophysitis 
 
Hypothyroidism/Thyroiditis Autoimmune thyroiditis 
 
 
Hypothyroidism 
 
 
Thyroiditis 
 
 
Thyroiditis acute 
Diarrhea/Colitis 
 
Colitis 
 
 
Diarrhoea 
 
 
Enterocolitis 
Hepatitis 
 
Alanine aminotransferase increased 
 
 
Aspartate aminotransferase increased 
 
 
Autoimmune hepatitis 
 
 
Blood alkaline phosphatase increased 
 
 
Blood bilirubin increased 
 
 
Hepatitis 
 
 
Hepatitis acute 
 
 
Hepatotoxicity 
 
 
Hyperbilirubinaemia 
Nephritis and renal 
dysfunction 
 
Nephritis 
Nephritis allergic 
 
 
Tubulointerstitial nephritis 
 
 
Acute kidney injury 
 
 
Renal failure 
 
 
Blood creatinine increased 
Pneumonitis 
 
Pneumonitis 
 
 
Interstitial lung disease 
Rash 
 
Rash 
 
 
Rash maculo-papular 
 
 


 
 
 
 
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APPENDIX 3 
Definition of Other Adverse Events of Special Interests 
Category 
PT 
Autoimmune Neuropathy Autoimmune neuropathy 
Demyelination Event 
Anti-myelin-associated glycoprotein associated polyneuropathy 
 
Autoimmune demyelinating disease 
 
Demyelination 
Encephalitis Event 
Acute encephalitis with refractory, repetitive partial seizures 
 
Bickerstaff's encephalitis 
 
Encephalitis 
 
Encephalitis allergic 
 
Encephalitis autoimmune 
 
Encephalitis brain stem 
 
Encephalitis haemorrhagic 
 
Encephalitis lethargica 
 
Encephalitis toxic 
 
Limbic encephalitis 
 
Lupus encephalitis 
 
Noninfective encephalitis 
 
Panencephalitis 
 
Rasmussen encephalitis 
 
Subacute sclerosing panencephalitis 
Graft Versus Host Disease Acute graft versus host disease 
 
Acute graft versus host disease in intestine 
 
Acute graft versus host disease in liver 
 
Acute graft versus host disease in skin 
 
Chronic graft versus host disease 
 
Chronic graft versus host disease in intestine 
 
Chronic graft versus host disease in liver 
 
Chronic graft versus host disease in skin 
 
Graft versus host disease 
 
Graft versus host disease in eye 
 
Graft versus host disease in gastrointestinal tract 
 
Graft versus host disease in liver 
 
Graft versus host disease in lung 
 
Graft versus host disease in skin 
Guillain-Barre Syndrome Guillain-Barre syndrome 
 
Miller Fisher syndrome 
Myasthenic Syndrome 
Myasthenia gravis 
 
Myasthenia gravis crisis 


 
 
 
 
88 
 
Category 
PT 
 
Myasthenic syndrome 
 
Ocular myasthenia 
Myocarditis Event 
Autoimmune myocarditis 
 
Eosinophilic myocarditis 
 
Hypersensitivity myocarditis 
 
Myocarditis 
Myositis Event 
Dermatomyositis 
 
Inclusion body myositis 
 
Myositis 
 
Necrotising myositis 
 
Paraneoplastic dermatomyositis 
 
Polymyositis 
Pancreatitis Event 
Autoimmune pancreatitis 
Haemorrhagic necrotic pancreatitis 
Pancreatitis 
Pancreatitis acute 
Pancreatitis necrotising 
Rhabdomyolysis Event 
Rhabdomyolysis 
Uveitis Event 
Autoimmune uveitis 
 
Chorioretinitis 
 
Cyclitis 
 
Iridocyclitis 
 
Iritis 
 
Keratouveitis 
 
Uveitis 
MedDRA v21.1 


SAP Amendments 
There were 2 SAP amendments during the study. 
Major Changes from the Statistical Analysis Plan 1.0 
Major analytical and data handling plans that were changed, added, or deleted from the statistical 
analysis plan 1.0 are shown below. 
Reliability of the Study 
<Additional items> 
Relevant protocol deviations, reason for subjects enrolled but not randomized and reason for 
subjects randomized but not treated were added. 
<Deleted item> 
Reason for withdrawals and dropouts from the study was deleted. 
<Reason> 
To assess the reliability of the study more appropriately. 
Demographic and Other Baseline Characteristics 
<Additional items> 
Analysis for past pharmacotherapy for cancer and details of immune-modulating concomitant 
medication were added. 
<Reason> 
To assess the imbalance of factors which could impact on the evaluation of efficacy and safety 
between treatment groups. 
Primary Efficacy Analysis 
Proportional hazards assumption 
<Additional items> 
Test for examining the proportional hazards assumption for OS was added. 
<Reason> 
To assess the proportional hazards assumption for OS. 
State of Follow-up 
<Additional items> 
Analyses for current status of follow-up and duration of follow-up for OS were added. 
<Reason> 
To assess the current status of follow-up for OS. 


Exploratory Analytical Methods 
<Additional items> 
Analyses using the intended investigator’s choice therapy subset were added. 
<Reason> 
To evaluate the efficacy of nivolumab relative to the control regimen from a multilateral 
perspective. 
Secondary Efficacy Analysis 
<Additional items> 
A secondary definition of PFS was added. 
<Reason> 
To evaluate the robustness of analysis result using PFS. 
Analysis of Safety 
Adverse Events 
<Additional items> 
Multiple occurrences of AEs and other AEOSIs were added. 
<Reason> 
To evaluate the safety of nivolumab relative to the control group from a multilateral perspective. 
PD-L1 Expression Analysis 
<Additional item> 
Section of PD-L1 expression analysis was added. 
<Reason> 
To evaluate the expression level of PD-L1 in each treatment group. 
Patient Reported Outcomes Analysis 
<Additional items>  
Change in EQ-5D and EQ-VAS scores from baseline were added. 
<Reason > 
To evaluate quality of life with nivolumab relative to the control regimen from a multilateral 
perspective. 
 


Major Changes from the Statistical Analysis Plan 2.0 
Major analytical and data handling plans that were changed, added, or deleted from the statistical 
analysis plan 2.0 are shown below. 
Significant Level to be Used 
<Additional items>  
Analysis population to be used for OS, ORR and PFS when performing the test using the 
Hierarchical hypothesis testing approach was added. 
<Reason > 
In this study, two analysis populations of ITT and RES were defined as the analysis population 
for efficacy, and in order to clarify which analysis population would be tested for each endpoint. 
Secondary Efficacy Analysis 
<Additional items>  
An analysis was added to calculate summary statistics of observation period of subjects for each 
treatment group. 
<Reason > 
To examine the observation period of subjects included in this study in more detail.