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Clinical Trials List

Protocol NumberONO-4538-24/ BMS CA209473
NCT Number(ClinicalTrials.gov Identfier)NCT02569242
Completed

2015-09-15 - 2019-09-30

Phase III

Terminated11

ICD-10C15

Malignant neoplasm of esophagus

A Multicenter, Randomized, Open-label Study in Patients with esophageal Cancer refractory or intolerant to Combination Therapy with Fluoropyrimidine and Platinum-based Drugs

  • Trial Applicant

    Linical

  • Sponsor

    Ono Pharmaceutical Co., Ltd.

  • Trial scale

    Multi-Regional Multi-Center

  • Update

    2026/02/01

Investigators and Locations

Principal Investigator Chih-Hung Hsu Division of Hematology & Oncology
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Audit

None

Principal Investigator Chen-Yuan Lin Division of Hematology & Oncology
China Medical University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Principal Investigator Chueh-Chuan Yen Division of Hematology & Oncology
Taipei Veterans General Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

10 Terminated

Audit

None

Principal Investigator 王全正 Division of Hematology & Oncology
CHANGHUA CHRISTIAN HOSPITAL

Co-Principal Investigator

  • 賴冠銘 Division of Hematology & Oncology

The Actual Total Number of Participants Enrolled

0 Terminated

Principal Investigator Chia-Jui Yen Division of Hematology & Oncology
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Audit

None

Principal Investigator Shau-Hsuan Li Division of Hematology & Oncology
Kaoshiung Chang Gung Memorial Hospital of the C.G.M.F.

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Principal Investigator 李和昇 Division of Thoracic Medicine
E-DA Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Principal Investigator 王正旭 Division of Hematology & Oncology
Chang Gung Medical Foundation Chang Gung Memorial Hospital, Keelung

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Principal Investigator 呂長賢 Division of Hematology & Oncology
Chiayi Chang Gung Memorial Hospital of the C.G.M.F.

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Principal Investigator Chen-Yuan Lin 未分科
China Medical University Hospital-Taipei

Co-Principal Investigator

Audit

CRO

Principal Investigator Hsien-Kun Chang Division of Hematology & Oncology
Linkou Chang Gung Medical Foundation

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Audit

None

Principal Investigator I-CHEN WU 未分科
Kaohsiung Municipal Gangshan Hospital

Co-Principal Investigator

Audit

CRO

Principal Investigator I-CHEN WU Digestive System Department
Kaohsiung Medical Univeristy Chung-Ho Memorial Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Terminated

Condition/Disease

Esophageal cancer

Objectives

This is a multicenter, randomized, open-Iabel, 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.

Test Drug

ONO-4538 (Nivolumab)

Active Ingredient

Nivolumab (ONO-4538)

Dosage Form

Injection

Dosage

100mg/10ml/vial

Endpoints

1. Efficacy Endpoints - Primary Endpoint
Overall survival (OS)

2. Efficacy Endpoints - Secondary Endpoints
Objective response rate (ORR)
Disease control rate (DCR)
Progression free survival (PFS)
Duration of response
Time to response
Best overall response (BOR)
Maximum percent change from baseline in the sum of diameters of the target lesion

3. Safety Endpoints
Adverse events
Clinical laboratory tests
Vital signs
12-lead ECG
Chest X-ray
Performance Status (ECOG)

4. Pharmacokinetic Endpoint
Serum ONO-4538 concentrations (for the ONO-4538 group only)

5. Anti-drug Antibody Endpoint
Anti-ONO-4538 antibody (for the ONO-4538 group only)

6. Exploratory Biomarkers
Blood cell subset analysis (optional)
Blood cytokines
HLA analysis
Serum microRNA expression analysis
Genetic testing (optional)
Tumor tissue examination (PD-L1 expression analysis, essential; otherparameters, optional)

7. Other Test Variables
Tumor markers
Patient reported outcomes (PROs)
Healthcare Resource Utilization

Inclution Criteria

Main 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.”
• 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
• 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 ormore 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.


Inclusion Criteria for Entering the ONO-4538 Extension Phase :
Among the eligible subjects randomized to the control group, those who have +ended the docetaxel or paclitaxel treatment before 28 days prior to the first ONO-4538 dose and meet all of the following criteria will be included in the ONO-4538 extension phase
1. Patients who have at least 1 measurable or non-measurable lesion per the RECIST Guideline Ver. 1.1. 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.
2. ECOG Performance Status Score 0 or 1
3. Patients with a life expectancy of at least 3 months
4. Patients whose latest laboratory data meet the below criteria within 7 days before the first ONO-4538 dose in the ONO-4538 extension phase. 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
• 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
5. 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.
6. 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.

Exclusion Criteria

Main 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.
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
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 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 (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 sub investigator to be inappropriate as subjects of this study


Exclusion Criteria for Entering the ONO-4538 Extension Phase :
Subjects meet any of the following criteria will be excluded from entering the ONO-4538 extension phase.
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 the first ONO-4538 dose may enter the ONO-4538 extension phase.
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 (patients with 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 may enter the ONO-4538 extension phase)
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 sub investigator. Subjects whose toxicity excluding peripheral nerve disorder, resulting from the control group therapy has not resolved to baseline before the first ONO-4538 dose will also be excluded.
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
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 enter the ONO-4538 extension phase 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 enter the ONO-4538 extension phase 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 the first ONO-4538 dose.
13. Patients with a history of uncontrollable or significant cardiovascular disease meeting any of the following criteria:
・ Myocardial infarction within 180 days before the first ONO-4538 dose
・ Uncontrollable angina pectoris within 180 days before the first ONO-4538 dose
・ 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 enter the ONO-4538 extension phase.
15. Patients with uncontrollable diabetes mellitus
16. Patients with systemic infections requiring treatment
17. 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 the first ONO-4538 dose
18. Patients who have received antineoplastic drugs (e.g., chemotherapy agents, molecular-targeted therapy agents, or immunotherapy agents) within 28 days before the first ONO-4538 dose
19. Patients who have undergone surgical adhesion of the pleura or pericardium within 28 days before the first ONO-4538 dose
20. Patients who have undergone surgery under general anesthesia within 28 days before the first ONO-4538 dose
21. Patients who have undergone surgery involving local or topical anesthesia within 14 days before the first ONO-4538 dose
22. Patients who have received radiotherapy within 28 days before the first ONO-4538 dose, or radiotherapy to bone metastases within 14 days before the first ONO-4538 dose
23. Patients who have received any radiopharmaceuticals (except for examination or diagnostic use of radiopharmaceuticals) within 56 days before the first ONO-4538 dose
24. Women who are pregnant or breastfeeding, or possibly pregnant
25. 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 the first ONO-4538 dose
26. 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
27. Patients judged to be incapable of providing consent for reasons such as concurrent dementia
28. Other patients judged by the investigator or sub investigator to be inappropriate as subjects of this study

The Estimated Number of Participants

  • Taiwan

    72 participants

  • Global

    390 participants

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