Clinical Trials List
Protocol NumberONO-4538-12
NCT Number(ClinicalTrials.gov Identfier)NCT02267343
2014-11-01 - 2019-03-31
Phase III
Terminated9
ICD-10I86.4
Gastric varices
ONO-4538 Phase III Study A Multicenter, Double-Blind, Randomized Study in Patients with Unresectable Advanced or Recurrent Gastric Cancer
-
Sponsor
ONO Pharmaceutical CO., LTD.
-
Trial scale
Multi-Regional Multi-Center
-
Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- Nai-Jung Chiang Division of Hematology & Oncology
- Chia-Jui Yen Division of Hematology & Oncology
- Yan-Shen Shan Division of General Surgery
- Wei-Pang Chung Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Ming-Yu Lien Division of Hematology & Oncology
- Chang-Fang Chiu Division of Hematology & Oncology
- Chen-Yuan Lin Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- I-CHEN WU Digestive System Department
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Yung-Chia Kao Division of Hematology & Oncology
- Tsai-Sheng Yang Division of Hematology & Oncology
- Wen-Chi Shen Division of Hematology & Oncology
- Ming-Mo Hou Division of Hematology & Oncology
- Hung-Chih Hsu Division of Hematology & Oncology
- Chia-Hsun Hsieh Division of Hematology & Oncology
- Wen-Chi Chou Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Rheun-Chuan Lee Division of Radiology
- Ming-Huang Chen Division of Hematology & Oncology
- Chung-Pin Li Digestive System Department
The Actual Total Number of Participants Enrolled
0 Terminated
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- 陳彥豪 Division of Hematology & Oncology
- Yu-Li Su Division of Hematology & Oncology
- Shau-Hsuan Li Division of Hematology & Oncology
- 饒坤銘 Division of Hematology & Oncology
- 吳佳哲 Division of Hematology & Oncology
- Meng-Jer Hsieh Division of Hematology & Oncology
- Tai-Jan Chiu Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Gi-Ming Lai Division of Hematology & Oncology
- Chia-Lun Chang Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Chih-Hung Hsu Division of Hematology & Oncology
- 林宗哲 Division of Hematology & Oncology
- TA-CHEN HUANG Division of Hematology & Oncology
- Chiun Hsu Division of Hematology & Oncology
- SUNG-HSIN KUO Division of Hematology & Oncology
- YU-YUN SHAO Division of Hematology & Oncology
- Ann-Lii Cheng Division of Hematology & Oncology
- 林育麟 Division of Hematology & Oncology
- 張端瑩 Division of Hematology & Oncology
- Chia-Chi Lin Division of Hematology & Oncology
- Hsiang-Fong Kao Division of Hematology & Oncology
- I-RUE LAI Division of Hematology & Oncology
- 呂理駿 Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Condition/Disease
Unresectable Advanced or Recurrent Gastric Cancer
Objectives
This is a multicenter, randomized study aimed to evaluate the efficacy and safety of ONO-4538 in
combination with chemotherapy using fluoropyrimidines and platinum agents (SOX therapy, tegafur–
gimeracil–oteracil potassium/oxaliplatin combination; CapeOX therapy, capecitabine/oxaliplatin
combination), in comparison with placebo in combination with SOX therapy and CapeOX therapy
(hereinafter, chemotherapies), in human epidermal growth factor receptor type-2 (HER2)-negative,
unresectable advanced or recurrent gastric cancer (including esophagogastric junction cancer) not
previously treated with the first-line therapy.
Test Drug
ONO-4538
Active Ingredient
antibody
Dosage Form
Injection
Dosage
100 mg/10 mL/Vial
Endpoints
Safety Endpoints (Part 1)
1. Adverse events
2. Laboratory tests
3. Vital signs
4. 12-Lead ECG
5. ECOG PS
Efficacy Endpoints (Part 1)
1. Objective response rate (ORR) (central assessment and assessment by the site investigator)
2. Overall survival (OS)
3. Progression-free survival (PFS) (central assessment and assessment by the site investigator)
4. Duration of response (central assessment)
5. Disease control rate (DCR) (central assessment and assessment by the site investigator)
6. Time to response (central assessment)
7. Best overall response (BOR) (central assessment and assessment by the site investigator)
8. Percent change in the sum of diameters of target lesions (assessment by the site investigator)
1. Adverse events
2. Laboratory tests
3. Vital signs
4. 12-Lead ECG
5. ECOG PS
Efficacy Endpoints (Part 1)
1. Objective response rate (ORR) (central assessment and assessment by the site investigator)
2. Overall survival (OS)
3. Progression-free survival (PFS) (central assessment and assessment by the site investigator)
4. Duration of response (central assessment)
5. Disease control rate (DCR) (central assessment and assessment by the site investigator)
6. Time to response (central assessment)
7. Best overall response (BOR) (central assessment and assessment by the site investigator)
8. Percent change in the sum of diameters of target lesions (assessment by the site investigator)
Inclution Criteria
1.Sex: Men and women
2.Age (at the time of informed consent): 20 years and older
3.Patients with unresectable advanced or recurrent gastric cancer (including esophagogastric junction cancer) that has been histologically confirmed to be adenocarcinoma and has not been treated with the first-line therapy with systemic antitumor agents for advanced or recurrent gastric cancer (including esophagogastric junction cancer) For patients who have received neoadjuvant or adjuvant chemotherapy (including
chemoradiotherapy) in combination with curative or endoscopic surgery (R0 resection confirmed), the chemotherapy in the last regimen must be completed by at least 180 days before the date of recurrence.
4.Have measurable lesions as defined in RECIST Guideline Version 1.1 on CT or MRI images within 14 days before randomization in the study
5.Able to provide tumor tissue specimens (archival or fresh biopsy specimens) for PD-L1 expression analysis (prior to randomization in Part 2). For patients who are unable to undergo another biopsy, archival specimens may be used as an alternative. If archival specimens are
provided for analysis, it is desirable that subjects do not receive systemic anticancer agents after collection of these specimens.
6.ECOG PS score 0 or 1
7.Have a life expectancy of at least 3 months
8.Have latest laboratory data meeting the criteria below within 7 days before randomization. If the date of the laboratory tests at randomization is not within 7 days before the first dose of the investigational products, testing should be repeated within 7 days before the first dose of the investigational products, and the latest laboratory data before the first dose of the investigational products must be confirmed to 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 3000/mm3 and neutrophils 1500/mm3
·Platelets 100000/mm3
·Hemoglobin 9.0 g/dL
·Aspartate aminotransferase (glutamic-oxaloacetic transaminase) (AST [GOT]) and alanine aminotransferase (glutamic-pyruvic transaminase) (ALT [GPT]) 3.0 upper limit of normal (ULN) of the study site (or 5.0 ULN in patients with liver metastases)
·Total bilirubin 2.0 ULN
·Creatinine 1.5#1 ULN or creatinine clearance (either measured value or estimated value using the Cockcroft-Gault equation) >60 mL/min
#1: It should be noted that if SOX therapy is chosen in Part 2, the criterion for starting SOX therapy is <= 1.2 x ULN
9.Women of childbearing potential (including women with chemical menopause or no menstruation for other medical reasons)#2 must agree to use contraception#3 from the time of informed consent until at least 5 months after the last dose of the investigational products or the combined chemotherapy, whichever comes later. Also, women must agree not to breastfeed from the time of informed consent until at least 5 months after the last dose of the investigational products or the combined chemotherapy, whichever comes later.
10. Men must agree to use contraception#3 from the start of the study treatment until at least 7 months after the last dose of the investigational products or the combined chemotherapy, whichever comes later.
#2: Women of childbearing potential are defined as all women after the onset of menstruation who are not post-menopausal and have not been surgically sterilized (e.g., hysterectomy, bilateral tubal ligation, bilateral oophorectomy). Post-menopause is defined as amenorrhea for 12
consecutive months without specific reasons. Women using oral contraceptives, or mechanical contraception such as intrauterine devices and contraceptive barriers are regarded as having childbearing potential.
#3: Patients must agree to use at least two of the following different contraceptive methods: vasectomy or condoms for male patients or male partners of female patients, and tubal ligation, pessary, intrauterine devices, and oral contraceptives for female patients or female partners of male patients.
2.Age (at the time of informed consent): 20 years and older
3.Patients with unresectable advanced or recurrent gastric cancer (including esophagogastric junction cancer) that has been histologically confirmed to be adenocarcinoma and has not been treated with the first-line therapy with systemic antitumor agents for advanced or recurrent gastric cancer (including esophagogastric junction cancer) For patients who have received neoadjuvant or adjuvant chemotherapy (including
chemoradiotherapy) in combination with curative or endoscopic surgery (R0 resection confirmed), the chemotherapy in the last regimen must be completed by at least 180 days before the date of recurrence.
4.Have measurable lesions as defined in RECIST Guideline Version 1.1 on CT or MRI images within 14 days before randomization in the study
5.Able to provide tumor tissue specimens (archival or fresh biopsy specimens) for PD-L1 expression analysis (prior to randomization in Part 2). For patients who are unable to undergo another biopsy, archival specimens may be used as an alternative. If archival specimens are
provided for analysis, it is desirable that subjects do not receive systemic anticancer agents after collection of these specimens.
6.ECOG PS score 0 or 1
7.Have a life expectancy of at least 3 months
8.Have latest laboratory data meeting the criteria below within 7 days before randomization. If the date of the laboratory tests at randomization is not within 7 days before the first dose of the investigational products, testing should be repeated within 7 days before the first dose of the investigational products, and the latest laboratory data before the first dose of the investigational products must be confirmed to 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 3000/mm3 and neutrophils 1500/mm3
·Platelets 100000/mm3
·Hemoglobin 9.0 g/dL
·Aspartate aminotransferase (glutamic-oxaloacetic transaminase) (AST [GOT]) and alanine aminotransferase (glutamic-pyruvic transaminase) (ALT [GPT]) 3.0 upper limit of normal (ULN) of the study site (or 5.0 ULN in patients with liver metastases)
·Total bilirubin 2.0 ULN
·Creatinine 1.5#1 ULN or creatinine clearance (either measured value or estimated value using the Cockcroft-Gault equation) >60 mL/min
#1: It should be noted that if SOX therapy is chosen in Part 2, the criterion for starting SOX therapy is <= 1.2 x ULN
9.Women of childbearing potential (including women with chemical menopause or no menstruation for other medical reasons)#2 must agree to use contraception#3 from the time of informed consent until at least 5 months after the last dose of the investigational products or the combined chemotherapy, whichever comes later. Also, women must agree not to breastfeed from the time of informed consent until at least 5 months after the last dose of the investigational products or the combined chemotherapy, whichever comes later.
10. Men must agree to use contraception#3 from the start of the study treatment until at least 7 months after the last dose of the investigational products or the combined chemotherapy, whichever comes later.
#2: Women of childbearing potential are defined as all women after the onset of menstruation who are not post-menopausal and have not been surgically sterilized (e.g., hysterectomy, bilateral tubal ligation, bilateral oophorectomy). Post-menopause is defined as amenorrhea for 12
consecutive months without specific reasons. Women using oral contraceptives, or mechanical contraception such as intrauterine devices and contraceptive barriers are regarded as having childbearing potential.
#3: Patients must agree to use at least two of the following different contraceptive methods: vasectomy or condoms for male patients or male partners of female patients, and tubal ligation, pessary, intrauterine devices, and oral contraceptives for female patients or female partners of male patients.
Exclusion Criteria
1.Patients with HER2-positive or indeterminate gastric cancer (Determination for positive is made on the basis of the reference in each site. If there is no reference, rough indication for positive is 3+ by immunohistochemistry [IHC], or 2+ by IHC and positive by in situ hybridization [ISH]).
2.Have marked malnutrition. Patients will be excluded from the study if they are receiving enteral nutrition or intravenous hyperalimentation, or require continuous infusion therapy with hospitalization. Patients whose nutritional status is well controlled for at least 28 days before randomization may be enrolled in the study.
3.Unable to take oral medicines
4.Have multiple cancers (with the exception of completely resected basal cell carcinoma, stage I squamous cell carcinoma, carcinoma in situ, intramucosal carcinoma, and superficial bladder cancer, and any other cancers that have not recurred for at least 5 years)
5.Have a current or past history of severe hypersensitivity to any other antibody products
6.Have concurrent autoimmune disease or a history of chronic or recurrent autoimmune disease. Patients with Type 1 diabetes mellitus, hypothyroidism which is manageable by hormone replacement or skin disorders not requiring systemic treatment (such as vitiligo, psoriasis, or
alopecia) are permitted to be enrolled.
7.Have a current or past history of interstitial lung disease or pulmonary fibrosis diagnosed based on imaging (preferably CT) or clinical findings
8.Have concurrent diverticulitis or symptomatic gastrointestinal ulcerative disease.
9.Have brain or meninx metastases. Patients may be randomized for the study if they are asymptomatic and require no treatment.
10.Have pericardial fluid, pleural effusion, or ascites requiring treatment#1
#1: Patients with a small amount of pericardial fluid, pleural effusion, or ascites that can be controlled with only oral medication may be permitted.
11.Have uncontrollable, tumor-related pain
12.Have experienced a transient ischemic attack, cerebrovascular accident, thrombosis or thromboembolism (pulmonary arterial embolism or deep vein thrombosis) within 180 days before randomization
13.Have a history of uncontrollable or significant cardiovascular disease meeting any of the following;
·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.Are receiving or require anticoagulant therapy (other than antiplatelet therapy including lowdose aspirin) for a disease
15.Have uncontrollable diabetes mellitus
16.Have systemic infection requiring treatment
17.Are contraindicated for oxaliplatin
18.Are contraindicated for a tegafur–gimeracil–oteracil potassium combination drug or capecitabine (Part 1 only)
19.Are contraindicated for all of tegafur–gimeracil–oteracil potassium combination drug and capecitabine) (Part 2 only)
20.Require or, within 28 days before randomization, have received systemic corticosteroids (except for temporary use, e.g., for examination, prophylaxis of allergic reactions, or reduction of radiotherapy-related edema) or immunosuppressants
21.Have undergone surgical adhesion of the pleura or pericardium within 28 days before randomization
22.Have undergone surgery (any surgery involving general anesthesia) within 28 days before randomization
23.Have undergone surgery (any surgery involving local or topical anesthesia) within 14 days before randomization
24.Have received radiotherapy for gastric cancer within 28 days before randomization or radiotherapy for bone metastases within 14 days before randomization
25.Have received any radiopharmaceuticals (except for examination or diagnostic use of radiopharmaceuticals) within 56 days before randomization
26.Have a positive test result for human immunodeficiency virus-1 (HIV-1) antibody, human immunodeficiency virus-2 (HIV-2) antibody, human T-lymphotropic virus-1 (HTLV-1) antibody, hepatitis B surface protein (HBs) antigen, or hepatitis C virus (HCV) antibody
27.Have a negative test result for HBs antigen, but have a positive test result for either HBs
antibody or HBc antibody with a detectable level of hepatitis B virus-deoxyribonucleic acid (HBVDNA)
28.Are pregnant or breastfeeding, or possibly pregnant
29.Have received any other unapproved drug (e.g.,marketed drugs unapproved for gastric cancer, investigational use of drugs, unapproved combined formulations, unapproved dosage forms) within 28 days (or within 90 days for antibody products) before randomization
30.With peripheral neuropathy of Grade 2
31.History of adverse reactions of Grade 3 in previous chemotherapy containing oxaliplatin, tegafur–gimeracil–oteracil–potassium combination drug, or capecitabine. Patients may be randomized for the study if protocol-specified initial dose of chemotherapy is tolerable for the relevant patients.
32.Have previously received ONO-4538 (MDX-1106 or BMS-936558), anti-programmed cell death1 (PD-1) antibody, anti-PD-L1 antibody, anti-programmed cell death-ligand 2 (PD-L2) antibody, anti-CD137 antibody, anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody, or other
therapeutic antibodies or pharmacotherapies for the regulation of T-cells
33.Are incapable of providing consent for specific reasons, such as concurrent dementia
34.Are otherwise inappropriate for this study in the investigator’s or subinvestigator’s opinion.
35. Have received a live/attenuated vaccine within 28 days before randomization
2.Have marked malnutrition. Patients will be excluded from the study if they are receiving enteral nutrition or intravenous hyperalimentation, or require continuous infusion therapy with hospitalization. Patients whose nutritional status is well controlled for at least 28 days before randomization may be enrolled in the study.
3.Unable to take oral medicines
4.Have multiple cancers (with the exception of completely resected basal cell carcinoma, stage I squamous cell carcinoma, carcinoma in situ, intramucosal carcinoma, and superficial bladder cancer, and any other cancers that have not recurred for at least 5 years)
5.Have a current or past history of severe hypersensitivity to any other antibody products
6.Have concurrent autoimmune disease or a history of chronic or recurrent autoimmune disease. Patients with Type 1 diabetes mellitus, hypothyroidism which is manageable by hormone replacement or skin disorders not requiring systemic treatment (such as vitiligo, psoriasis, or
alopecia) are permitted to be enrolled.
7.Have a current or past history of interstitial lung disease or pulmonary fibrosis diagnosed based on imaging (preferably CT) or clinical findings
8.Have concurrent diverticulitis or symptomatic gastrointestinal ulcerative disease.
9.Have brain or meninx metastases. Patients may be randomized for the study if they are asymptomatic and require no treatment.
10.Have pericardial fluid, pleural effusion, or ascites requiring treatment#1
#1: Patients with a small amount of pericardial fluid, pleural effusion, or ascites that can be controlled with only oral medication may be permitted.
11.Have uncontrollable, tumor-related pain
12.Have experienced a transient ischemic attack, cerebrovascular accident, thrombosis or thromboembolism (pulmonary arterial embolism or deep vein thrombosis) within 180 days before randomization
13.Have a history of uncontrollable or significant cardiovascular disease meeting any of the following;
·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.Are receiving or require anticoagulant therapy (other than antiplatelet therapy including lowdose aspirin) for a disease
15.Have uncontrollable diabetes mellitus
16.Have systemic infection requiring treatment
17.Are contraindicated for oxaliplatin
18.Are contraindicated for a tegafur–gimeracil–oteracil potassium combination drug or capecitabine (Part 1 only)
19.Are contraindicated for all of tegafur–gimeracil–oteracil potassium combination drug and capecitabine) (Part 2 only)
20.Require or, within 28 days before randomization, have received systemic corticosteroids (except for temporary use, e.g., for examination, prophylaxis of allergic reactions, or reduction of radiotherapy-related edema) or immunosuppressants
21.Have undergone surgical adhesion of the pleura or pericardium within 28 days before randomization
22.Have undergone surgery (any surgery involving general anesthesia) within 28 days before randomization
23.Have undergone surgery (any surgery involving local or topical anesthesia) within 14 days before randomization
24.Have received radiotherapy for gastric cancer within 28 days before randomization or radiotherapy for bone metastases within 14 days before randomization
25.Have received any radiopharmaceuticals (except for examination or diagnostic use of radiopharmaceuticals) within 56 days before randomization
26.Have a positive test result for human immunodeficiency virus-1 (HIV-1) antibody, human immunodeficiency virus-2 (HIV-2) antibody, human T-lymphotropic virus-1 (HTLV-1) antibody, hepatitis B surface protein (HBs) antigen, or hepatitis C virus (HCV) antibody
27.Have a negative test result for HBs antigen, but have a positive test result for either HBs
antibody or HBc antibody with a detectable level of hepatitis B virus-deoxyribonucleic acid (HBVDNA)
28.Are pregnant or breastfeeding, or possibly pregnant
29.Have received any other unapproved drug (e.g.,marketed drugs unapproved for gastric cancer, investigational use of drugs, unapproved combined formulations, unapproved dosage forms) within 28 days (or within 90 days for antibody products) before randomization
30.With peripheral neuropathy of Grade 2
31.History of adverse reactions of Grade 3 in previous chemotherapy containing oxaliplatin, tegafur–gimeracil–oteracil–potassium combination drug, or capecitabine. Patients may be randomized for the study if protocol-specified initial dose of chemotherapy is tolerable for the relevant patients.
32.Have previously received ONO-4538 (MDX-1106 or BMS-936558), anti-programmed cell death1 (PD-1) antibody, anti-PD-L1 antibody, anti-programmed cell death-ligand 2 (PD-L2) antibody, anti-CD137 antibody, anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody, or other
therapeutic antibodies or pharmacotherapies for the regulation of T-cells
33.Are incapable of providing consent for specific reasons, such as concurrent dementia
34.Are otherwise inappropriate for this study in the investigator’s or subinvestigator’s opinion.
35. Have received a live/attenuated vaccine within 28 days before randomization
The Estimated Number of Participants
-
Taiwan
48 participants
-
Global
290 participants
