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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Ono Pharmaceutical Co. Ltd
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT01668784
First received: August 16, 2012
Last updated: April 28, 2016
Last verified: April 2016
  Purpose
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 Intervention Phase
Advanced or Metastatic (Medically or Surgically Unresectable) Clear-cell Renal Cell Carcinoma
Biological: Nivolumab
Drug: Everolimus
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Overall Survival (OS) at Primary Endpoint [ Time Frame: Randomization until 398 deaths, up to May 2015 (approximately 30 months) ] [ Designated as safety issue: No ]

    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:
  • 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) ] [ Designated as safety issue: No ]
    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.

  • 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) ] [ Designated as safety issue: No ]
    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.

  • Investigator-assessed Time to Objective Response at Primary Endpoint [ Time Frame: Randomization to date of first response, up to May 2015 (approximately 30 months) ] [ Designated as safety issue: No ]
    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.

  • Investigator-assessed Time of Progression-free Survival (PFS) at Primary Endpoint [ Time Frame: Randomization until 398 deaths, up to May 2015 (approximately 30 months) ] [ Designated as safety issue: No ]
    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 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) ] [ Designated as safety issue: No ]
    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.

  • 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) ] [ Designated as safety issue: Yes ]
    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.

  • 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) ] [ Designated as safety issue: No ]
    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.

  • 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) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Day 1 to 30 days post last dose, up to May 2015 (approximately 30 months) ] [ Designated as safety issue: Yes ]
    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).


Enrollment: 1054
Study Start Date: September 2012
Estimated Study Completion Date: September 2017
Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01668784

  Show 158 Study Locations
Sponsors and Collaborators
Bristol-Myers Squibb
Ono Pharmaceutical Co. Ltd
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

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 
Study First Received: August 16, 2012
Results First Received: March 28, 2016
Last Updated: April 28, 2016
Health Authority: Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Australia: Department of Health and Ageing Therapeutic Goods Administration
Austria: Federal Office for Safety in Health Care
Belgium: The Federal Public Service (FPS) Health, Food Chain Safety and Environment
Brazil: National Health Surveillance Agency
Canada: Health Canada
Czech Republic: State Institute for Drug Control
Denmark: Danish Dataprotection Agency
Finland: Finnish Medicines Agency
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Greece: National Organization of Medicines
Ireland: Irish Medicines Board
Italy: Ministry of Health
Israel: Israeli Health Ministry Pharmaceutical Administration
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Norway: Data Protection Authority
Norway: Directorate of Health
Poland: National Institute of Medicines
Portugal: National Pharmacy and Medicines Institute
Russia: Ethics Committee
Russia: Ministry of Health of the Russian Federation
Spain: Spanish Agency of Medicines
Sweden: Medical Products Agency
United Kingdom: Medicines and Healthcare Products Regulatory Agency
United States: Food and Drug Administration
Japan: Pharmaceuticals and Medical Devices Agency

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

ClinicalTrials.gov processed this record on September 27, 2016