Clinical Trials List
Protocol NumberCA209-214
NCT Number(ClinicalTrials.gov Identfier)NCT02231749
2015-07-01 - 2023-10-27
Phase III
Terminated3
ICD-10C64
Malignant neoplasm of kidney, except renal pelvis
A Phase 3, Randomized, Open-Label Study of Nivolumab Combined with Ipilimumab Versus Sunitinib Monotherapy in Subjects with Previously Untreated, Advanced or Metastatic Renal Cell Carcinoma
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Trial Applicant
BRISTOL-MYERS SQUIBB (TAIWAN) LTD.
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Sponsor
Bristol-Myers Squibb
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Trial scale
Multi-Regional Multi-Center
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Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- Yen-Hwa Chang Division of Hematology & Oncology
- 沈書慧 Division of Hematology & Oncology
- Hsiao-Jen Chung Division of Hematology & Oncology
- Tzu-Ping Lin Division of Hematology & Oncology
- Mu-Hsin Chang Division of Hematology & Oncology
- Chueh-Chuan Yen Division of Hematology & Oncology
- 潘競成 Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
2 Stop recruiting
Audit
None
Co-Principal Investigator
- Rita cheng Division of Hematology & Oncology
- Yung-Chia Kao Division of Hematology & Oncology
- Po-Jung Su Division of Hematology & Oncology
- See-Tong Pang Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
1 Stop recruiting
Audit
None
Co-Principal Investigator
- Yeong-Shiau Pu Division of Hematology & Oncology
- - - Division of Hematology & Oncology
- Yu-Chieh Tsai Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Audit
None
Condition/Disease
Renal Cell Carcinoma
Objectives
Primary Objectives
• To compare the PFS of nivolumab combined with ipilimumab to sunitinib monotherapy in intermediate and poor-risk subjects with previously untreated mRCC, based on Independent Radiation Review Committee (IRRC) assessments
• To compare the OS of nivolumab combined with ipilimumab to sunitinib monotherapy in intermediate and poor-risk subjects with previously untreated mRCC
Key Secondary Objectives
• To compare the PFS of nivolumab combined with ipilimumab to sunitinib monotherapy in any-risk subjects with previously untreated mRCC, based on IRRC assessments
• To compare the OS of nivolumab combined with ipilimumab to sunitinib monotherapy in any-risk subjects with previously untreated mRCC
• To estimate the objective response rate (ORR) of nivolumab combined with ipilimumab and sunitinib monotherapy in subjects with previously untreated mRCC (intermediate/poor-risk and any-risk), based on IRRC assessments
• To estimate the incidence of AEs of nivolumab combined with ipilimumab and sunitinib monotherapy in all treated subjects with previously untreated mRCC
Test Drug
Nivolumab (BMS-936558)
Active Ingredient
Nivolumab
Dosage Form
Injection
Dosage
100mg/10ml
Endpoints
Overall Survival and Progression Free Survival are the co-primary endpoints of the study. Subjects will be assessed for response by CT or MRI beginning at 12 weeks ( 1 week) after randomization and continuing every 6 weeks ( 1 week) for the first 13 months and then every 12 weeks ( 1 week) until progression or treatment discontinuation, whichever occurs later. Overall survival is defined as the time from randomization to the date of death.
Inclution Criteria
Key Inclusion Criteria:
• Histological confirmation of RCC with a clear-cell component
• Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC Stage IV) RCC
• No prior systemic therapy for RCC with the following exception:
a) One prior adjuvant or neoadjuvant therapy for completely resectable RCC if such therapy did not include an agent that targets VEGF or VEGF receptors and if recurrence occurred at least 6 months after the last dose of adjuvant or neoadjuvant therapy.
• Karnofsky Performance Status (KPS) of at least 70%
• Measurable disease as per RECIST 1.1
• Tumor tissue (formalin-fixed paraffin-embedded (FFPE) archival or recent acquisition) must be received by the central vendor (block or unstained slides) in order to randomize a subject to study treatment. (Note: Fine Needle Aspiration [FNA] and bone metastases samples are not acceptable for submission).
• Patients with favorable, intermediate and poor risk categories will be eligible for the study. Patients must be categorized according to favorable versus intermediate/poor risk status at registration.
To be eligible for the Intermediate and Poor-Risk cohort, at least one of the following prognostic factors as per International Metastatic RCC Database Consortium (IMDC) must be present:
a) KPS equal to 70
b) Less than 1 year from diagnosis to randomization
c) Hemoglobin less than the LLN
d) Corrected calcium concentration greater than 10 mg/dL
e) Absolute neutrophil count greater than the ULN
f) Platelet count greater than the ULN
If none of the above factors are present, subjects are only eligible for the favorable-risk cohort. The favorable risk cohort may close to enrollment earlier than the intermediate- or poor-risk cohort.
• Histological confirmation of RCC with a clear-cell component
• Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC Stage IV) RCC
• No prior systemic therapy for RCC with the following exception:
a) One prior adjuvant or neoadjuvant therapy for completely resectable RCC if such therapy did not include an agent that targets VEGF or VEGF receptors and if recurrence occurred at least 6 months after the last dose of adjuvant or neoadjuvant therapy.
• Karnofsky Performance Status (KPS) of at least 70%
• Measurable disease as per RECIST 1.1
• Tumor tissue (formalin-fixed paraffin-embedded (FFPE) archival or recent acquisition) must be received by the central vendor (block or unstained slides) in order to randomize a subject to study treatment. (Note: Fine Needle Aspiration [FNA] and bone metastases samples are not acceptable for submission).
• Patients with favorable, intermediate and poor risk categories will be eligible for the study. Patients must be categorized according to favorable versus intermediate/poor risk status at registration.
To be eligible for the Intermediate and Poor-Risk cohort, at least one of the following prognostic factors as per International Metastatic RCC Database Consortium (IMDC) must be present:
a) KPS equal to 70
b) Less than 1 year from diagnosis to randomization
c) Hemoglobin less than the LLN
d) Corrected calcium concentration greater than 10 mg/dL
e) Absolute neutrophil count greater than the ULN
f) Platelet count greater than the ULN
If none of the above factors are present, subjects are only eligible for the favorable-risk cohort. The favorable risk cohort may close to enrollment earlier than the intermediate- or poor-risk cohort.
Exclusion Criteria
Key Exclusion Criteria:
• Any history of or current CNS metastases. Baseline imaging of the brain is required within 28 days prior to randomization.
• Prior systemic treatment with VEGF or VEGF receptor targeted therapy (including, but not limited to, sunitinib, pazopanib, axitinib, tivozanib, and bevacizumab).
• Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
• Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (> 10 mg daily prednisone equivalent) or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger. Subjects with vitiligo or type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll.
• Any condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Uncontrolled adrenal insufficiency.
• Ongoing symptomatic cardiac dysrhythmias, uncontrolled atrial fibrillation, or prolongation of the Fridericia corrected QT (QTcF) interval defined as > 450 msec for males and > 470 msec for females, where QTcF = QT / 3√RR
• Poorly controlled hypertension (defined as systolic blood pressure (SBP) of 150 mmHg or diastolic blood pressure (DBP) of 90 mmHg), despite antihypertensive therapy
• History of any of the following cardiovascular conditions within 12 months of enrollment: cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery by-pass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure, as defined by the New York Heart Association
• History of cerebrovascular accident including transient ischemic attack within the past 12 months
• History of deep vein thrombosis (DVT) unless adequately treated with low molecular weight heparin.
• History of pulmonary embolism within the past 6 months unless stable, asymptomatic, and treated with low molecular weight heparin for at least 6 weeks.
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months.
• Serious, non-healing wound or ulcer.
• Evidence of active bleeding or bleeding susceptibility; or medically significant hemorrhage within prior 30 days.
• Any requirement for anti-coagulation, except for low molecular weight heparin.
• Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
• Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection.
• Known medical condition (eg, a condition associated with diarrhea or acute diverticulitis) that, in the investigator’s opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results.
• Major surgery (eg, nephrectomy) less than 28 days prior to the first dose of study drug.
• Anti-cancer therapy less than 28 days prior to the first dose of study drug or palliative, focal radiation therapy less than 14 days prior to the first dose of study drug.
• Presence of any toxicities attributed to prior anti-cancer therapy, other than alopecia, that have not resolved to Grade 1 (NCI CTCAE v4) or baseline before administration of study drug.
• Receiving concomitant CYP3A4 inducers or strong CYP3A4 inhibitors (See Appendix 4).
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of sunitinib (eg, malabsorptive disorder, ulcerative disease, uncontrolled nausea, vomiting, diarrhea, or small bowel resection).
• Left ventricular ejection fraction (LVEF) less than the LLN as assessed by echocardiography or multigated acquisition (MUGA) scan.
• Any of the following laboratory test findings:
a) WBC < 2,000/mm3
b) Neutrophils < 1,500/mm3
c) Platelets < 100,000/mm3
d) AST or ALT > 3 x ULN (> 5 x ULN if liver metastases are present)
e) Total Bilirubin > 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
f) Serum creatinine > 1.5 x upper limit of normal (ULN) or creatinine clearance < 40 mL/min (measured or calculated by Cockroft-Gault formula)
• Any history of or current CNS metastases. Baseline imaging of the brain is required within 28 days prior to randomization.
• Prior systemic treatment with VEGF or VEGF receptor targeted therapy (including, but not limited to, sunitinib, pazopanib, axitinib, tivozanib, and bevacizumab).
• Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
• Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (> 10 mg daily prednisone equivalent) or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger. Subjects with vitiligo or type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll.
• Any condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Uncontrolled adrenal insufficiency.
• Ongoing symptomatic cardiac dysrhythmias, uncontrolled atrial fibrillation, or prolongation of the Fridericia corrected QT (QTcF) interval defined as > 450 msec for males and > 470 msec for females, where QTcF = QT / 3√RR
• Poorly controlled hypertension (defined as systolic blood pressure (SBP) of 150 mmHg or diastolic blood pressure (DBP) of 90 mmHg), despite antihypertensive therapy
• History of any of the following cardiovascular conditions within 12 months of enrollment: cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery by-pass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure, as defined by the New York Heart Association
• History of cerebrovascular accident including transient ischemic attack within the past 12 months
• History of deep vein thrombosis (DVT) unless adequately treated with low molecular weight heparin.
• History of pulmonary embolism within the past 6 months unless stable, asymptomatic, and treated with low molecular weight heparin for at least 6 weeks.
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months.
• Serious, non-healing wound or ulcer.
• Evidence of active bleeding or bleeding susceptibility; or medically significant hemorrhage within prior 30 days.
• Any requirement for anti-coagulation, except for low molecular weight heparin.
• Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
• Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection.
• Known medical condition (eg, a condition associated with diarrhea or acute diverticulitis) that, in the investigator’s opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results.
• Major surgery (eg, nephrectomy) less than 28 days prior to the first dose of study drug.
• Anti-cancer therapy less than 28 days prior to the first dose of study drug or palliative, focal radiation therapy less than 14 days prior to the first dose of study drug.
• Presence of any toxicities attributed to prior anti-cancer therapy, other than alopecia, that have not resolved to Grade 1 (NCI CTCAE v4) or baseline before administration of study drug.
• Receiving concomitant CYP3A4 inducers or strong CYP3A4 inhibitors (See Appendix 4).
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of sunitinib (eg, malabsorptive disorder, ulcerative disease, uncontrolled nausea, vomiting, diarrhea, or small bowel resection).
• Left ventricular ejection fraction (LVEF) less than the LLN as assessed by echocardiography or multigated acquisition (MUGA) scan.
• Any of the following laboratory test findings:
a) WBC < 2,000/mm3
b) Neutrophils < 1,500/mm3
c) Platelets < 100,000/mm3
d) AST or ALT > 3 x ULN (> 5 x ULN if liver metastases are present)
e) Total Bilirubin > 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
f) Serum creatinine > 1.5 x upper limit of normal (ULN) or creatinine clearance < 40 mL/min (measured or calculated by Cockroft-Gault formula)
The Estimated Number of Participants
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Taiwan
10 participants
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Global
1070 participants
