Study of Nivolumab (BMS-936558) vs. Everolimus in Pre-Treated Advanced or Metastatic Clear-cell Renal Cell Carcinoma (CheckMate 025)
- Conditions
- Advanced or Metastatic (Medically or Surgically Unresectable) Clear-cell Renal Cell Carcinoma
- Interventions
- Biological: Nivolumab
- Registration Number
- NCT01668784
- Lead Sponsor
- Bristol-Myers Squibb
- Brief Summary
The purpose of the study is to compare the clinical benefit, as measured by duration of overall survival, of Nivolumab vs. Everolimus in subjects with advanced or metastatic clear-cell renal cell carcinoma who have received prior anti-angiogenic therapy
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 821
- Men & women ≥18 years of age
- Histologic confirmation of renal cell carcinoma (RCC) with clear-cell component
- Advanced/metastatic RCC
- Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
- Received 1 or 2 prior anti-angiogenic therapy regimens in advanced or metastatic setting
- No more than 3 total prior systemic treatment regimens in the advanced or metastatic setting, and evidence of progression on or after last treatment regimen received and within 6 months of enrollment
- Karnofsky Performance Score ≥70%
- Any Central Nervous System (CNS) metastases or history of CNS metastases
- Prior therapy with an Mammalian target of rapamycin (mTOR) inhibitor
- Any active known or suspected autoimmune disease
- Uncontrolled adrenal insufficiency
- Active chronic liver disease
- Prior malignancy active within past 3 years, except for locally curable cancers
Other protocol-defined inclusion/exclusion criteria apply
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm 1: Nivolumab Nivolumab Nivolumab 3 mg/kg solution intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends Arm 2: Everolimus Everolimus Everolimus 10 mg tablets by mouth daily until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends
- Primary Outcome Measures
Name Time Method Overall Survival (OS) at Primary Endpoint Randomization until 398 deaths, up to May 2015 (approximately 30 months) Overall Survival (OS) was defined as the time from randomization to the date of death. Participants that had not died were censored at last known date alive. Median OS time was calculated using Kaplan-Meier Estimates. Interim analysis for the Primary Endpoint occurred after 398 deaths (70% of the total OS events needed for final analysis). At that time the data monitoring committee noted that the pre-specified boundary for OS (nominal significance level p \< 0.0148) was crossed while no new safety signals that would affect continuation of the study were found. The study was stopped early by the Sponsor, Bristol-Myers Squibb (BMS) and the interim analysis became the final analysis. As a result, participants in the everolimus groups could be assessed for a crossover to nivolumab treatment if they met all inclusion criteria.
- Secondary Outcome Measures
Name Time Method Number of Participants With Serious Adverse Events, Death, Discontinuation Due to Adverse Events Day of first dose to 30 days post study completion (approximately 106 months) Adverse event (AE) defined: any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Serious adverse event (SAE) defined: a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.
Investigator-assessed Objective Response Rate (ORR) from randomization up to disease progression or death (approximately up to 105 Months) ORR is defined as Percentage of participants with a best response of complete response (CR) or partial response (PR) divided by number of randomized participants. CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm.; PR=At least a 30% decrease in the sum of diameters of target lesions, the baseline sum diameters used as reference. Tumor assessments began at 8 weeks following randomization and continued every 8 weeks for the first year, then every 12 weeks thereafter until disease progression or death. CIs used Clopper and Pearson.
Investigator-assessed Duration of Objective Response From randomization to date of disease progression or death or censoring if no progression or death occurred (approximately 105 months) Duration of objective response is defined as the time from study start date to response, CR or partial response, PR) to the date of the first documented tumor progression as determined by the investigator (per RECIST 1.1 criteria or clinical) or death due to any cause, whichever occurred first. For participants who neither progress nor die, the duration of objective response were censored at the same time they were censored for the primary definition. CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm.; PR=At least a 30% decrease in the sum of diameters of target lesions, the baseline sum diameters used as reference. Based on Kaplan-Meier Estimates.
Number of Participants Meeting Marked Laboratory Abnormality Criteria in Specific Liver and Thyroid Tests Day 1 to 30 days post study completion (approximately 106 months) Aspartate aminotransferase, AST. Alanine aminotransaminase, ALT. Total bilirubin, tBIL. Thyroid stimulating hormone, TSH. Upper limit of normal (ULN). Units per Liter (U/L). Results reported in International System of Units (SI).
Number of Participants With Abnormal Hematology and Serum Chemistry Laboratory Parameters by Worse CTC Grade - SI Units Day 1 to 30 days post study completion (approximately 106 months) Common Terminology Criteria (CTC) version 4.0 in International System of Units (SI); Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling. Hematology parameters=Hemoglobin (Gr 3: \< 8.0 g/dL), Platelet Count (Gr 3: 25.0 -\< 50.0\*10\^9 c/L; Gr 4: \< 25.0\*10\^9 c/L), Leukocyte Count (Gr 3: 1.0 -\< 2.0\*10\^3 c/µL; Gr4: \< 1.0\*10\^3 c/µL), Absolute Lymphocyte Count (Gr 3: 0.2 -\< 0.5\*10\^3 c/µL; Gr 4: \< 0.2\*10\^3 c/µL), Absolute Neutrophil Count (Gr 3: 0.5 - \< 1.0\*10\^3 c/µL; Gr 4: \< 0.5\*10\^3 c/µL). Liver Function parameters=Alkaline Phosphatase (Gr 3: \> 5.0 - 20.0 U/L \* ULN; Gr 4: \> 20.0 U/L \* ULN), AST (Gr 3: \> 5.0 - 20.0 U/L \* ULN; Gr 4: \> 20.0 U/L \* ULN), ALT (Gr 3: \> 5.0 - 20.0 U/L \* ULN; Gr 4: \> 20.0 U/L \* ULN), tBIL (Gr 3: \> 3.0 - 10.0 mg/dL \* ULN; Gr 4: \> 10.0 mg/dL \* ULN). Renal parameter=Creatinine (Grade: Gr3: \> 3.0 - 6.0 mg/dL \*ULN; Gr4: \> 6.0 mg/dL \*ULN). Cells per microliter (c/µL). Cells per Liter (c/L). Grams per deciliter (g/dL). Milligrams per deciliter (mg/dL).
Investigator-assessed Time to Objective Response Randomization to date of first response (approximately 105 months) Time to objective response is defined as the time from randomization to first response (complete response, CR or partial response, PR). CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm.; PR=At least a 30% decrease in the sum of diameters of target lesions, the baseline sum diameters used as reference.
Percentage of Participants With Disease-related Symptom Progression (DRSP) from randomization up to disease progression or death (approximately up to 105 Months) Disease-related symptom progression rate (DRSPR)=a decrease of two points in the Functional Assessment of Cancer Therapy-Kidney Symptom Index - Disease Related Symptoms (FKSI-DRS) questionnaire relative to the participant's baseline FKSI-DRS score with no later increase above this threshold observed during the course of the study. The 9 items of the FKSI-DRS were summarized into a symptom scale ranging in score from 0 to 36, with 0 being the worst possible score and 36 being the best possible score. A single measure reporting a decrease of at least 2 units was considered disease-related symptom progression only if it was the last one available for the participant. In order to consider a questionnaire received as valid, over 50% of the items were to be completed. Calculated by the Clopper-Pearson method for each treatment group.
Investigator-assessed Time of Progression-free Survival (PFS) from randomization up to disease progression or death (approximately up to 105 Months) PFS=time from randomization to date of first documented tumor progression as determined by investigator (per RECIST 1.1 criteria or clinical) or death due to any cause, whichever occurred first. Participants who die without a reported prior progression and without subsequent anti-cancer therapy were considered to have progressed on the date of their death. Participants who did not progress or die were censored on the date of their last evaluable tumor assessment. Participants who did not have any on-study tumor assessments and did not die were censored on the date they were randomized. Participants who received any subsequent anti-cancer therapy without a prior reported progression were censored at the last evaluable tumor assessment prior to or on initiation date of the subsequent anti-cancer therapy. Progressive disease: \>=20% increase in sum of target lesion diameters and sum must show absolute increase of \>=5mm; smallest sum on study as reference. Based on Kaplan-Meier Estimates.
Overall Survival (OS) by Programmed Death-Ligand 1 (PD-L1) Expression Level Randomization to date of death or date of last contact for patients without documentation of death, up to May 2015 (approximately 30 months) Quantifiable PD-L1 expression=percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per Dako PD-L1 IHC assay. If the PD-L1 staining could not be quantified it was classified as: indeterminate=tumor cell membrane staining hampered for reasons attributed to biology of tumor biopsy specimen and not due to improper sample preparation or handling; not evaluable=tumor biopsy specimen was not optimally collected or prepared. Not evaluable determined from H\&E process before the tumor biopsy specimen was sent for evaluation or from H\&E process during PD-L1 evaluation; baseline PD-L1 expression=if more than one tumor biopsy specimen was available, the most recently collected specimen with a quantifiable result. If all specimens for a given participant are either indeterminate or not evaluable, then the PD-L1 expression was considered indeterminate as long as at least one specimen is indeterminate. Otherwise, PD-L1 expression was considered not evaluable.
Trial Locations
- Locations (76)
Local Institution - 0006
🇫🇷Vandoeuvre-lès-Nancy, Lorraine, France
Local Institution - 0102
🇮🇹Rozzano, Italy
Local Institution - 0007
🇫🇷Lyon Cedex, France
Local Institution - 0124
🇧🇷Sao Paulo, Brazil
Local Institution - 0064
🇪🇸Hospitalet De Llobregat, Spain
Local Institution - 0095
🇦🇺Westmead, New South Wales, Australia
Local Institution - 0012
🇫🇷Toulouse Cedex 9, France
Local Institution - 0169
🇯🇵Suita, Osaka, Japan
Local Institution - 0004
🇫🇷Marseille Cedex 9, France
Local Institution - 0082
🇮🇹Milano, Italy
Local Institution - 0008
🇫🇷Bordeaux, France
Local Institution - 0126
🇩🇪Heidelberg, Germany
Local Institution - 0005
🇫🇷Saint Herblain Cedex, France
Local Institution - 0002
🇫🇷Villejuif Cedex, France
Local Institution
🇬🇧London, Greater London, United Kingdom
Local Institution - 0145
🇨🇦Montreal, Canada
Local Institution - 0118
🇫🇷Paris, France
Euromedica General Clinic of Thessaloniki
🇬🇷Thessaloniki, Greece
University Of Southern California
🇺🇸Los Angeles, California, United States
Winship Cancer Institute.
🇺🇸Atlanta, Georgia, United States
Sidney Kimmel Comprehensive Cancer Center At Johns Hopkins
🇺🇸Baltimore, Maryland, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
Loyola University Chicago
🇺🇸Maywood, Illinois, United States
Local Institution - 0143
🇨🇦Oshawa, Ontario, Canada
Indiana University Simon Cancer Center
🇺🇸Indianapolis, Indiana, United States
Temple University Hospital
🇺🇸Philadelphia, Pennsylvania, United States
Beth Israel Deaconess Medical Center
🇺🇸Boston, Massachusetts, United States
The Ohio State University
🇺🇸Columbus, Ohio, United States
Ut Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Local Institution - 0009
🇺🇸Seattle, Washington, United States
Local Institution - 0139
🇺🇸Houston, Texas, United States
Princess Margaret Hospital
🇨🇦Toronto, Ontario, Canada
Local Institution - 0024
🇺🇸Los Angeles, California, United States
UCSD Moores Cancer Center
🇺🇸La Jolla, California, United States
Stanford Cancer Institute
🇺🇸Stanford, California, United States
University Of Iowa Hospitals And Clinics
🇺🇸Iowa City, Iowa, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
Memorial Sloan Kettering Nassau
🇺🇸New York, New York, United States
Levine Cancer Institute
🇺🇸Charlotte, North Carolina, United States
Cross Cancer Institute
🇨🇦Edmonton, Alberta, Canada
Chum, Hopital Notre-Dame
🇨🇦Montreal, Quebec, Canada
Local Institution - 0003
🇫🇷Poitiers, France
Local Institution - 0125
🇧🇷Ijui, RIO Grande DO SUL, Brazil
Local Institution - 0137
🇩🇰Odense, Denmark
Dartmouth-Hitchcock Medical Center
🇺🇸Lebanon, New Hampshire, United States
St Francis Hospital
🇺🇸Greenville, South Carolina, United States
Centro Para La Atencion Integral Del Paciente Oncologico
🇦🇷San Miguel De Tucuman, Tucuman, Argentina
Fox Chase Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
COIBA
🇦🇷Berazategui, Buenos Aires, Argentina
Weill Cornell Medical College
🇺🇸New York, New York, United States
BC Cancer Agency - Vancouver Centre
🇨🇦Vancouver, British Columbia, Canada
Cedars Sinai Medical Center
🇺🇸Los Angeles, California, United States
Georgetown University Medical Center
🇺🇸Washington, District of Columbia, United States
Local Institution - 0182
🇺🇸Fayetteville, Arkansas, United States
Local Institution - 0027
🇺🇸Washington, District of Columbia, United States
University Of Washington
🇺🇸Seattle, Washington, United States
Instituto Oncologico De Cordoba
🇦🇷Cordoba, Argentina
Tom Baker Cancer Centre
🇨🇦Calgary, Alberta, Canada
Alexandra General Hospital Of Athens
🇬🇷Athens, Greece
Local Institution - 0087
🇮🇪Dublin, Ireland
Local Institution - 0167
🇯🇵Hamamatsu-shi, Shizuoka, Japan
Centre D'Oncologie Dr-Leon-Richard
🇨🇦Moncton, New Brunswick, Canada
QEII Health Sciences Centre
🇨🇦Halfax, Nova Scotia, Canada
Local Institution - 0148
🇮🇱Petah Tikva, Israel
Local Institution - 0048
🇬🇧Swansea, Carmarthenshire, United Kingdom
H. Lee Moffitt Cancer Center & Research Institute
🇺🇸Tampa, Florida, United States
Ucsf Helen Diller Family Comprehensive Cancer Center
🇺🇸San Francisco, California, United States
University Of Colorado
🇺🇸Aurora, Colorado, United States
Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
Tennessee Oncology, PLLC
🇺🇸Nashville, Tennessee, United States
CTRC at UTHSC San Antonio
🇺🇸San Antonio, Texas, United States
University Of Michigan Comprehensive Cancer Center
🇺🇸Ann Arbor, Michigan, United States
Medical University Of South Carolina
🇺🇸Charleston, South Carolina, United States
Local Institution - 0076
🇺🇸Richmond, Virginia, United States