Advanced or Metastatic (Medically or Surgically Unresectable) Clear-cell Renal Cell Carcinoma Clinical Trial
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
| Verified date | July 2022 |
| Source | Bristol-Myers Squibb |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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
| Status | Completed |
| Enrollment | 821 |
| Est. completion date | July 19, 2021 |
| Est. primary completion date | May 6, 2015 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years and older |
| Eligibility | 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 Other protocol-defined inclusion/exclusion criteria apply |
| Country | Name | City | State |
|---|---|---|---|
| Argentina | COIBA | Berazategui | Buenos Aires |
| Argentina | Local Institution | Buenos Aires | |
| Argentina | Local Institution | Buenos Aires | |
| Argentina | Local Institution | Capital Federal | Buenos Aires |
| Argentina | Instituto Oncologico De Cordoba | Cordoba | |
| Argentina | Centro Para La Atencion Integral Del Paciente Oncologico | San Miguel De Tucuman | Tucuman |
| Australia | Local Institution | Box Hill | Victoria |
| Australia | Local Institution | Clayton | Victoria |
| Australia | Local Institution | Melbourne | Victoria |
| Australia | Local Institution - 0095 | Westmead | New South Wales |
| Australia | Local Institution | Woodville South | South Australia |
| Austria | Local Institution | Linz | |
| Austria | Local Institution | Wien | |
| Austria | Local Institution | Wien | |
| Belgium | Local Institution | Brussels | |
| Belgium | Local Institution | Bruxelles | |
| Belgium | Local Institution | Gent | |
| Belgium | Local Institution | Leuven | |
| Brazil | Local Institution - 0125 | Ijui | RIO Grande DO SUL |
| Brazil | Local Institution | Sao Paulo | |
| Brazil | Local Institution - 0124 | Sao Paulo | |
| Canada | Tom Baker Cancer Centre | Calgary | Alberta |
| Canada | Cross Cancer Institute | Edmonton | Alberta |
| Canada | QEII Health Sciences Centre | Halfax | Nova Scotia |
| Canada | Centre D'Oncologie Dr-Leon-Richard | Moncton | New Brunswick |
| Canada | Chum, Hopital Notre-Dame | Montreal | Quebec |
| Canada | Local Institution - 0145 | Montreal | |
| Canada | Local Institution - 0143 | Oshawa | Ontario |
| Canada | Princess Margaret Hospital | Toronto | Ontario |
| Canada | BC Cancer Agency - Vancouver Centre | Vancouver | British Columbia |
| Czechia | Local Institution | Hradec Kralove | |
| Czechia | Local Institution | Olomouc | |
| Czechia | Local Institution | Prague 5 | |
| Denmark | Local Institution | Aarhus N | |
| Denmark | Local Institution | Herlev | |
| Denmark | Local Institution - 0137 | Odense | |
| Finland | Local Institution | Helsinki | |
| France | Local Institution | Bordeaux | |
| France | Local Institution - 0008 | Bordeaux | |
| France | Local Institution | Lyon Cedex | |
| France | Local Institution - 0007 | Lyon Cedex | |
| France | Local Institution | Marseille Cedex 9 | |
| France | Local Institution - 0004 | Marseille Cedex 9 | |
| France | Local Institution - 0118 | Paris | |
| France | Local Institution | Poitiers | |
| France | Local Institution - 0003 | Poitiers | |
| France | Local Institution | Saint Herblain Cedex | |
| France | Local Institution - 0005 | Saint Herblain Cedex | |
| France | Local Institution | Toulouse Cedex 9 | |
| France | Local Institution - 0012 | Toulouse Cedex 9 | |
| France | Local Institution | Vandoeuvre Les Nancy | |
| France | Local Institution - 0006 | Vandoeuvre-lès-Nancy | Lorraine |
| France | Local Institution | Villejuif Cedex | |
| France | Local Institution - 0002 | Villejuif Cedex | |
| Germany | Local Institution | Aachen | |
| Germany | Local Institution | Dresden | |
| Germany | Local Institution | Erlangen | |
| Germany | Local Institution | Essen | |
| Germany | Local Institution | Hannover | |
| Germany | Local Institution - 0126 | Heidelberg | |
| Germany | Local Institution | Munich | |
| Germany | Local Institution | Tuebingen | |
| Greece | Alexandra General Hospital Of Athens | Athens | |
| Greece | Euromedica General Clinic of Thessaloniki | Thessaloniki | |
| Ireland | Local Institution | Dublin | |
| Ireland | Local Institution - 0087 | Dublin | |
| Ireland | Local Institution | Tallaght | Dublin |
| Israel | Local Institution | Haifa | |
| Israel | Local Institution - 0148 | Petah Tikva | |
| Israel | Local Institution | Ramat-gan | |
| Israel | Local Institution | Tel Aviv | |
| Italy | Local Institution | Arezzo | |
| Italy | Local Institution | Meldola (fc) | |
| Italy | Local Institution - 0082 | Milano | |
| Italy | Local Institution | Rimini | |
| Italy | Local Institution | Roma | |
| Italy | Local Institution | Roma | |
| Italy | Local Institution - 0102 | Rozzano | |
| Italy | Local Institution | Siena | |
| Italy | Local Institution | Terni | |
| Japan | Local Institution | Akita-shi | Akita |
| Japan | Local Institution | Chiba-shi | Chiba |
| Japan | Local Institution - 0167 | Hamamatsu-shi | Shizuoka |
| Japan | Local Institution | Higashi-ku | Fukuoka |
| Japan | Local Institution | Kobe-city, Hyogo | |
| Japan | Local Institution | Kumamoto | |
| Japan | Local Institution | Kyoto-shi | Kyoto |
| Japan | Local Institution | Morioka-shi | Iwate |
| Japan | Local Institution | Osaka-sayama-shi | Osaka |
| Japan | Local Institution | Sapporo-city | Hokkaido |
| Japan | Local Institution | Sapporo-shi | Hokkaido |
| Japan | Local Institution - 0169 | Suita | Osaka |
| Japan | Local Institution | Tokushima-shi | Tokushima |
| Japan | Local Institution | Tokyo | |
| Japan | Local Institution | Tokyo | |
| Japan | Local Institution | Tokyo | |
| Japan | Local Institution | Tokyo | |
| Japan | Local Institution | Tokyo | |
| Japan | Local Institution | Tokyo | |
| Japan | Local Institution | Yamagata-shi | Yamagata |
| Japan | Local Institution | Yokohama | Kanagawa |
| Norway | Local Institution | Bergen | |
| Norway | Local Institution | Lorenskog | |
| Poland | Local Institution | Gdansk | |
| Poland | Local Institution | Lodz | |
| Poland | Local Institution | Poznan | |
| Poland | Local Institution | Rybnik | |
| Poland | Local Institution | Warszawa | |
| Poland | Local Institution | Wroclaw | |
| Romania | Local Institution | Bucharest | |
| Romania | Local Institution | Craiova | |
| Romania | Local Institution | Iasi | |
| Romania | Local Institution | Timisoara | |
| Russian Federation | Local Institution | Moscow | |
| Russian Federation | Local Institution | Moscow | |
| Russian Federation | Local Institution | St Petersburg | |
| Spain | Local Institution | Barcelona | |
| Spain | Local Institution - 0064 | Hospitalet De Llobregat | |
| Spain | Local Institution | Madrid | |
| Spain | Local Institution | Madrid | |
| Spain | Local Institution | Madrid | |
| Spain | Local Institution | Pamplona | Navarra |
| Sweden | Local Institution | Gothenberg | |
| Sweden | Local Institution | Solna | |
| United Kingdom | Local Institution | Cambridge | Cambridgeshire |
| United Kingdom | Local Institution | London | Greater London |
| United Kingdom | Local Institution | London | Greater London |
| United Kingdom | Local Institution | Swansea | Carmarthenshire |
| United Kingdom | Local Institution - 0048 | Swansea | Carmarthenshire |
| United States | University Of Michigan Comprehensive Cancer Center | Ann Arbor | Michigan |
| United States | Winship Cancer Institute. | Atlanta | Georgia |
| United States | University Of Colorado | Aurora | Colorado |
| United States | Sidney Kimmel Comprehensive Cancer Center At Johns Hopkins | Baltimore | Maryland |
| United States | Beth Israel Deaconess Medical Center | Boston | Massachusetts |
| United States | Roswell Park Cancer Institute | Buffalo | New York |
| United States | Medical University Of South Carolina | Charleston | South Carolina |
| United States | Levine Cancer Institute | Charlotte | North Carolina |
| United States | Northwestern University | Chicago | Illinois |
| United States | The Ohio State University | Columbus | Ohio |
| United States | Ut Southwestern Medical Center | Dallas | Texas |
| United States | Karmanos Cancer Institute | Detroit | Michigan |
| United States | Duke University Medical Center | Durham | North Carolina |
| United States | Local Institution - 0182 | Fayetteville | Arkansas |
| United States | St Francis Hospital | Greenville | South Carolina |
| United States | Local Institution - 0139 | Houston | Texas |
| United States | Indiana University Simon Cancer Center | Indianapolis | Indiana |
| United States | University Of Iowa Hospitals And Clinics | Iowa City | Iowa |
| United States | UCSD Moores Cancer Center | La Jolla | California |
| United States | Dartmouth-Hitchcock Medical Center | Lebanon | New Hampshire |
| United States | Cedars Sinai Medical Center | Los Angeles | California |
| United States | Local Institution - 0024 | Los Angeles | California |
| United States | University Of Southern California | Los Angeles | California |
| United States | Loyola University Chicago | Maywood | Illinois |
| United States | Tennessee Oncology, PLLC | Nashville | Tennessee |
| United States | Vanderbilt University Medical Center | Nashville | Tennessee |
| United States | Memorial Sloan Kettering Nassau | New York | New York |
| United States | Weill Cornell Medical College | New York | New York |
| United States | Fox Chase Cancer Center | Philadelphia | Pennsylvania |
| United States | Temple University Hospital | Philadelphia | Pennsylvania |
| United States | Local Institution - 0076 | Richmond | Virginia |
| United States | CTRC at UTHSC San Antonio | San Antonio | Texas |
| United States | Ucsf Helen Diller Family Comprehensive Cancer Center | San Francisco | California |
| United States | Local Institution - 0009 | Seattle | Washington |
| United States | University Of Washington | Seattle | Washington |
| United States | Stanford Cancer Institute | Stanford | California |
| United States | H. Lee Moffitt Cancer Center & Research Institute | Tampa | Florida |
| United States | Georgetown University Medical Center | Washington | District of Columbia |
| United States | Local Institution - 0027 | Washington | District of Columbia |
| Lead Sponsor | Collaborator |
|---|---|
| Bristol-Myers Squibb | Ono Pharmaceutical Co. Ltd |
United States, Argentina, Australia, Austria, Belgium, Brazil, Canada, Czechia, Denmark, Finland, France, Germany, Greece, Ireland, Israel, Italy, Japan, Norway, Poland, Romania, Russian Federation, Spain, Sweden, United Kingdom,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Overall Survival (OS) at Primary Endpoint | 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. | Randomization until 398 deaths, up to May 2015 (approximately 30 months) | |
| Secondary | Investigator-assessed Objective Response Rate (ORR) | 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. | from randomization up to disease progression or death (approximately up to 105 Months) | |
| Secondary | Investigator-assessed Duration of Objective Response | 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. | From randomization to date of disease progression or death or censoring if no progression or death occurred (approximately 105 months) | |
| Secondary | Investigator-assessed Time to Objective Response | 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. | Randomization to date of first response (approximately 105 months) | |
| Secondary | Investigator-assessed Time of Progression-free Survival (PFS) | 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. | from randomization up to disease progression or death (approximately up to 105 Months) | |
| Secondary | Overall Survival (OS) by Programmed Death-Ligand 1 (PD-L1) Expression Level | 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. | Randomization to date of death or date of last contact for patients without documentation of death, up to May 2015 (approximately 30 months) | |
| Secondary | Number of Participants With Serious Adverse Events, Death, Discontinuation Due to Adverse Events | 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. | Day of first dose to 30 days post study completion (approximately 106 months) | |
| Secondary | Percentage of Participants With Disease-related Symptom Progression (DRSP) | 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. | from randomization up to disease progression or death (approximately up to 105 Months) | |
| Secondary | Number of Participants Meeting Marked Laboratory Abnormality Criteria in Specific Liver and Thyroid Tests | 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). | Day 1 to 30 days post study completion (approximately 106 months) | |
| Secondary | Number of Participants With Abnormal Hematology and Serum Chemistry Laboratory Parameters by Worse CTC Grade - SI Units | 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). | Day 1 to 30 days post study completion (approximately 106 months) |