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Study of Nivolumab (BMS-936558) vs. Everolimus in Pre-Treated Advanced or Metastatic Clear-cell Renal Cell Carcinoma (CheckMate 025)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01668784
Recruitment Status : Active, not recruiting
First Posted : August 20, 2012
Results First Posted : April 29, 2016
Last Update Posted : January 24, 2018
Ono Pharmaceutical Co. Ltd
Information provided by (Responsible Party):
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

Condition or disease Intervention/treatment Phase
Advanced or Metastatic (Medically or Surgically Unresectable) Clear-cell Renal Cell Carcinoma Biological: Nivolumab Drug: Everolimus Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1068 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Open-Label, Phase 3 Study of Nivolumab (BMS-936558) vs. Everolimus in Subjects With Advanced or Metastatic Clear-Cell Renal Cell Carcinoma Who Have Received Prior Anti-Angiogenic Therapy
Actual Study Start Date : September 27, 2012
Primary Completion Date : May 6, 2015
Estimated Study Completion Date : September 28, 2018

Arm Intervention/treatment
Experimental: Arm 1: 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
Biological: Nivolumab
Other Name: BMS-936558
Active Comparator: Arm 2: Everolimus
Everolimus 10 mg tablets by mouth daily until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends
Drug: Everolimus
Other Name: Afinitor

Primary Outcome Measures :
  1. Overall Survival (OS) at Primary Endpoint [ Time Frame: 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 :
  1. Investigator-assessed Objective Response Rate (ORR) at Primary Endpoint [ Time Frame: At 8 weeks post randomization, every 8 weeks for 12 months, and every 12 weeks until date of disease progression or death, up to May 2015 (approximately 30 months) ]
    ORR=number 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.

  2. Investigator-assessed Duration of Objective Response at Primary Endpoint [ Time Frame: From date of first response to date of disease progression or death or censoring if no progression or death occurred, up to May 2015 (approximately 30 months) ]
    Duration of objective response is defined as the time from first response (complete 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.

  3. Investigator-assessed Time to Objective Response at Primary Endpoint [ Time Frame: Randomization to date of first response, up to May 2015 (approximately 30 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.

  4. Investigator-assessed Time of Progression-free Survival (PFS) at Primary Endpoint [ Time Frame: Randomization until 398 deaths, up to May 2015 (approximately 30 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.

  5. Overall Survival (OS) by Programmed Death-Ligand 1 (PD-L1) Expression Level at Primary Endpoint [ Time Frame: 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.

  6. Number of Participants With Serious Adverse Events, Death, Discontinuation Due to Adverse Events at Primary Endpoint [ Time Frame: Day of first dose to 30 days post final dose, up to May 2015 (approximately 30 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.

  7. Percentage of Participants With Disease-related Symptom Progression (DRSP) at Primary Endpoint [ Time Frame: Randomization until 398 deaths, up to May 2015 (approximately 30 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.

  8. Number of Participants Meeting Marked Laboratory Abnormality Criteria in Specific Liver and Thyroid Tests at Primary Endpoint [ Time Frame: Day 1 to 30 days post last dose, up to May 2015 (approximately 30 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).

  9. Number of Participants With Abnormal Hematology and Serum Chemistry Laboratory Parameters by Worse CTC Grade - SI Units [ Time Frame: Day 1 to 30 days post last dose, up to May 2015 (approximately 30 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).

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

  • 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%

Exclusion Criteria:

  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01668784

  Hide Study Locations
United States, Arkansas
Highland Oncology Group
Fayetteville, Arkansas, United States, 72703
United States, California
UCSD Moores Cancer Center
La Jolla, California, United States, 92093-0698
University Of Southern California
Los Angeles, California, United States, 90033
Cedars Sinai Medical Center
Los Angeles, California, United States, 90048
Ucsf Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States, 94115
Stanford Cancer Institute
Stanford, California, United States, 94305
United States, Colorado
University Of Colorado
Aurora, Colorado, United States, 80045
United States, District of Columbia
Georgetown University Medical Center
Washington, District of Columbia, United States, 20007
United States, Florida
H. Lee Moffitt Cancer Center & Research Institute
Tampa, Florida, United States, 33612-9497
United States, Georgia
Winship Cancer Institute.
Atlanta, Georgia, United States, 30322
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
Loyola University Chicago
Maywood, Illinois, United States, 60153
United States, Indiana
Indiana University Simon Cancer Center
Indianapolis, Indiana, United States, 46202
United States, Iowa
University Of Iowa Hospitals And Clinics
Iowa City, Iowa, United States, 52242
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center At Johns Hopkins
Baltimore, Maryland, United States, 21231-1000
United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
United States, Michigan
University Of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States, 48109-5946
Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
United States, New Hampshire
Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire, United States, 03756
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
Weill Cornell Medical College
New York, New York, United States, 10065
United States, North Carolina
Levine Cancer Institute
Charlotte, North Carolina, United States, 28204
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Ohio
The Ohio State University
Columbus, Ohio, United States, 43210
United States, Pennsylvania
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States, 19111
Temple University Hospital
Philadelphia, Pennsylvania, United States, 19140
United States, South Carolina
Medical University Of South Carolina
Charleston, South Carolina, United States, 29425
St Francis Hospital
Greenville, South Carolina, United States, 29601
United States, Tennessee
Tennessee Oncology, PLLC
Nashville, Tennessee, United States, 37203
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
United States, Texas
UT Southwestern Medical Center
Dallas, Texas, United States, 75390-9133
The University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030-4009
CTRC at UTHSC San Antonio
San Antonio, Texas, United States, 78229
United States, Virginia
Virginia Cancer Institute
Richmond, Virginia, United States, 23230
United States, Washington
University Of Washington
Seattle, Washington, United States, 98109
Berazategui, Buenos Aires, Argentina, 1880
Local Institution
Capital Federal, Buenos Aires, Argentina, 1431
Centro Para La Atencion Integral Del Paciente Oncologico
San Miguel De Tucuman, Tucuman, Argentina, 4000
Local Institution
Buenos Aires, Argentina, C1280AEB
Local Institution
Buenos Aires, Argentina, C1426ANZ
Instituto Oncologico De Cordoba
Cordoba, Argentina, X5006HBF
Australia, New South Wales
Local Institution
Westmead, New South Wales, Australia, 2145
Australia, South Australia
Local Institution
Woodville South, South Australia, Australia, 5011
Australia, Victoria
Local Institution
Box Hill, Victoria, Australia, 3128
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Clayton, Victoria, Australia, 3168
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Melbourne, Australia, 3000
Local Institution
Linz, Austria, 4010
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Vienna, Austria, 1090
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Wien, Austria, 1130
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Brussels, Belgium, 1090
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Bruxelles, Belgium, 1200
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Gent, Belgium, 9000
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Leuven, Belgium, 3000
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Ijui, RIO Grande DO SUL, Brazil, 98700000
Local Institution
Sao Paulo, Brazil, 01246-000
Local Institution
Sao Paulo, Brazil, 01321-001
Canada, Alberta
Tom Baker Cancer Centre
Calgary, Alberta, Canada, T2N 4N2
Cross Cancer Institute
Edmonton, Alberta, Canada, T6G 1Z2
Canada, British Columbia
BC Cancer Agency - Vancouver Centre
Vancouver, British Columbia, Canada, V5Z 4E6
Canada, New Brunswick
Centre D'Oncologie Dr-Leon-Richard
Moncton, New Brunswick, Canada, E1C 8X3
Canada, Nova Scotia
QEII Health Sciences Centre
Halfax, Nova Scotia, Canada, B3H 2Y9
Canada, Ontario
Lakeridge Health Oshawa-Durham Regional Cancer Centre
Oshawa, Ontario, Canada, L1G 2B9
Princess Margaret Hospital
Toronto, Ontario, Canada, M5G 2M9
Canada, Quebec
Chum, Hopital Notre-Dame
Montreal, Quebec, Canada, H2L 4M1
Smbd Jewish General Hospital
Montreal, Quebec, Canada, H3T 1E2
Local Institution
Hradec Kralove, Czechia, 500 05
Local Institution
Olomouc, Czechia, 775 20
Local Institution
Prague 5, Czechia, 150 06
Local Institution
Aarhus C, Denmark, 8000
Local Institution
Herlev, Denmark, 2730
Local Institution
Odense, Denmark, 5000
Local Institution
Helsinki, Finland, 00029
Local Institution
Bordeaux, France, 33075
Local Institution
Lyon Cedex, France, 69373
Local Institution
Marseille Cedex 9, France, 13009
Local Institution
Paris, France, 75908
Local Institution
Poitiers, France, 86000
Local Institution
Saint Herblain Cedex, France, 44805
Local Institution
Toulouse Cedex 9, France, 31059
Local Institution
Vandoeuvre Les Nancy, France, 54511
Local Institution
Villejuif Cedex, France, 94805
Local Institution
Aachen, Germany, 52074
Local Institution
Dresden, Germany, 01307
Local Institution
Erlangen, Germany, 91054
Local Institution
Essen, Germany, 45122
Local Institution
Hannover, Germany, 30625
Local Institution
Heidelberg, Germany, 69120
Local Institution
Munich, Germany, 81675
Local Institution
Tuebingen, Germany, 72076
Local Institution
Athens, Greece, 115 28
Local Institution
Thessaloniki, Greece, 54645
Local Institution
Tallaght, Dublin, Ireland, DUBLIN 24
Local Institution
Dublin, Ireland, Dublin 7
Local Institution
Dublin, Ireland
Local Institution
Haifa, Israel, 31096
Local Institution
Petah Tikva, Israel, 49100
Local Institution
Ramat-gan, Israel, 52621
Local Institution
Tel Aviv, Israel, 64239
Local Institution
Arezzo, Italy, 52100
Local Institution
Meldola (fc), Italy, 47014
Local Institution
Milano, Italy, 20133
Local Institution
Rimini, Italy, 47900
Local Institution
Roma, Italy, 00144
Local Institution
Roma, Italy, 00152
Local Institution
Rozzano, Italy, 20089
Local Institution
Siena, Italy, 53100
Local Institution
Terni, Italy, 05100
Local Institution
Akita-shi, Akita, Japan, 0108543
Local Institution
Chiba-shi, Chiba, Japan, 2608717
Local Institution
Higashi-ku, Fukuoka, Japan, 812-8582
Local Institution
Sapporo-shi, Hokai-do, Japan, 0608543
Local Institution
Sapporo-shi, Hokkaido, Japan, 0608648
Local Institution
Morioka-shi, Iwate, Japan, 0208505
Local Institution
Yokohama, Kangawa, Japan, 2360004
Local Institution
Kumamoto-shi, Kumamoto, Japan, 8608556
Local Institution
Kyoto-shi, Kyoto, Japan, 602-8566
Local Institution
Osaka-sayama-shi, Osaka, Japan, 5898511
Local Institution
Suita, Osaka, Japan, 5650871
Local Institution
Hamamatsu-shi, Shizuoka, Japan, 4313192
Local Institution
Tokushima-shi, Tokushima, Japan, 7708503
Local Institution
Yamagata-shi, Yamagata, Japan, 9909585
Local Institution
Kobe-city, Hyogo, Japan, 650-0017
Local Institution
Tokyo, Japan, 1138603
Local Institution
Tokyo, Japan, 1138655
Local Institution
Tokyo, Japan, 1358550
Local Institution
Tokyo, Japan, 1608582
Local Institution
Tokyo, Japan, 1628666
Local Institution
Tokyo, Japan, 1738606
Local Institution
Bergen, Norway, 5021
Local Institution
Lorenskog, Norway, 1478
Local Institution
Gdansk, Poland, 80-219
Local Institution
Lodz, Poland, 93-513
Local Institution
Poznan, Poland, 60-569
Local Institution
Rybnik, Poland, 44-200
Local Institution
Warszawa, Poland, 00-909
Local Institution
Wroclaw, Poland, 50-556
Local Institution
Bucharest, Romania, 022328
Local Institution
Craiova, Romania, 200385
Local Institution
Iasi, Romania, 700106
Local Institution
Timisoara, Romania, 300167
Russian Federation
Local Institution
Moscow, Russian Federation, 115 478
Local Institution
Moscow, Russian Federation, 115478
Local Institution
St Petersburg, Russian Federation, 198255
Local Institution
Hospitalet De Llobregat, Barcelona, Spain, 08907
Local Institution
Pamplona, Navarra, Spain, 31008
Local Institution
Barcelona, Spain, 08035
Local Institution
Madrid, Spain, 28007
Local Institution
Madrid, Spain, 28040
Local Institution
Madrid, Spain, 28041
Local Institution
Gothenberg, Sweden, 413 45
Local Institution
Solna, Sweden, 17176
United Kingdom
Local Institution
Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
Local Institution
Swansea, Carmarthenshire, United Kingdom, SA2 8QA
Local Institution
London, Greater London, United Kingdom, HA6 2RN
Local Institution
London, Greater London, United Kingdom, SW3 6JJ
Sponsors and Collaborators
Bristol-Myers Squibb
Ono Pharmaceutical Co. Ltd
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT01668784     History of Changes
Other Study ID Numbers: CA209-025
2011‐005132‐26 ( EudraCT Number )
First Posted: August 20, 2012    Key Record Dates
Results First Posted: April 29, 2016
Last Update Posted: January 24, 2018
Last Verified: January 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Carcinoma, Renal Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Antibodies, Monoclonal
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents