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Nivolumab (BMS-936558; MDX-1106) in Combination With Sunitinib, Pazopanib, or Ipilimumab in Subjects With Metastatic Renal Cell Carcinoma (RCC) (CheckMate 016)

Primary Purpose

Renal Cell Carcinoma, Clear-cell Metastatic Renal Cell Carcinoma

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Nivolumab
Pazopanib
Sunitinib
Ipilimumab
Sponsored by
Bristol-Myers Squibb
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Renal Cell Carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Inclusion Criteria:

  • Subjects with histological confirmation of RCC
  • Advanced or metastatic disease
  • Measurable disease as defined by RECIST 1.1 criteria
  • Karnofsky Performance Status (KPS) ≥80%
  • Available tumor tissue (archival or recent acquisition)

  • Subjects enrolled in the I-1, I-3 expansion arms and IN-3 addition arms must not have received any prior systemic therapy for RCC with the following exceptions:

    1. One prior adjuvant or neoadjuvant therapy for localized or locally advanced RCC is allowed provided recurrence occurred ≥ 6 months after the last dose of the adjuvant or neoadjuvant therapy
    2. Only prior cytokine based treatment for metastatic RCC [eg, interferon-alpha (IFN-alpha) or interleukin 2 (IL-2)] as prior therapy is allowed

Exclusion Criteria:

  • Active central nervous system (CNS) metastases
  • Active or history of autoimmune disease
  • Ongoing symptomatic cardiac dysrhythmias or uncontrolled atrial fibrillation
  • History of cerebrovascular accident including transient ischemic attack within the past 12 months
  • History of pulmonary embolism or deep vein thrombosis (DVT) within the past 6 months
  • Chronic systemic steroids (>10 mg/day Prednisone equivalents) or any other immunosuppressive agents
  • White blood cell (WBC) <2,000/mm3
  • Neutrophiles <1,500/mm3
  • Platelets <100,000/mm3
  • Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) >3x upper limit of normal (ULN)
  • Total Bilirubin >1.5x ULN (except subjects with Gilbert syndrome, total bilirubin <3.0 mg/dL)
  • Cardiac ejection fraction <LLN (lower limit of normal)
  • Serum creatinine >1.5x ULN or creatinine clearance <40 mL/min (Cockroft-Gault formula)

Exclusion Criteria for Arm S and Arm P only:

  • For dose escalation cohorts - subjects who received prior Sunitinib or Pazopanib and required permanent discontinuation due to toxicity or required dose reduction or delay during the first 12 weeks of therapy due to toxicity, or received both prior Sunitinib and Pazopanib
  • Poorly controlled hypertension
  • Active bleeding or bleeding susceptibility

Sites / Locations

  • City Of Hope
  • Sidney Kimmel Comprehensive Cancer Center At Johns Hopkins
  • Beth Israel Deaconess Medical Center
  • Dartmouth-Hitchcock Medical Center
  • Memorial Sloan Kettering Nassau
  • Blumenthal Cancer Center
  • Cleveland Clinic
  • Fox Chase Cancer Center
  • Tennessee Oncology, PLLC
  • University Of Texas M.D. Anderson Cancer Center
  • Tom Baker Cancer Centre
  • Cross Cancer Institute
  • BC Cancer Agency - Vancouver Centre
  • Princess Margaret Cancer Centre

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Arm S: Nivolumab + Sunitinib

Arm P: Nivolumab + Pazopanib

Arm I-1: Nivolumab + Ipilimumab

Arm I-3: Nivolumab + Ipilimumab

Arm IN-3: Nivolumab+Ipilimumab

Arm Description

Nivolumab 0.3, 2.0 (starting dose), 5.0 mg/kg solution intravenously every 21 days until Progressive disease (PD), toxicity or discontinue for other reasons Sunitinib 50 mg capsule by mouth on Days 1-28 of 42 day cycle until Progressive disease (PD), toxicity or discontinue for other reasons

Nivolumab 0.3, 2.0 (starting dose), 5.0 mg/kg solution intravenously every 21 days until Progressive disease (PD), toxicity or discontinue for other reasons Pazopanib 800 mg tablet by mouth daily until Progressive disease (PD), toxicity or discontinue for other reasons

Nivolumab 3 mg/kg solution intravenously (IV) every 21 days during Induction phase and every 14 days during Maintenance phase until Progressive disease (PD), toxicity or discontinue for other reasons Ipilimumab 1mg/kg solution intravenously (IV) every 21 days during Induction phase (Ipilimumab will not be administered during Maintenance phase) until Progressive disease (PD), toxicity or discontinue for other reasons

Nivolumab 1mg/kg solution intravenously (IV) every 21 days during Induction phase and 3mg/kg solution intravenously (IV) every 14 days during Maintenance phase Ipilimumab 3mg/kg solution intravenously (IV) every 21 days during Induction phase. Ipilimumab will not be administered during Maintenance phase

Nivolumab 3mg/kg solution intravenously (IV) every 21 days during Induction phase and 3mg/kg solution intravenously (IV) every 14 days during Maintenance phase Ipilimumab 3mg/kg solution intravenously (IV) every 21 days during Induction phase. Ipilimumab will not be administered during Maintenance phase

Outcomes

Primary Outcome Measures

Number of Participants With AEs, SAEs, and AEs Leading to Discontinuation
Safety assessments by treatment arm and dose level were based on incidence of AEs, and the incidence of serious adverse events (SAEs). AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=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. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling.

Secondary Outcome Measures

Best Overall Response Rate (BOR)
BOR was defined as the best response designation over the study as a whole, recorded between the date of first dose of study medication and the date of objectively documented progression per RECIST 1.1 criteria or the date of subsequent anti-cancer therapy, whichever occurred first. CR = Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR = At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD = At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. SD = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Objective Response Rate (ORR)
ORR was defined as the proportion of participants who achieved a BOR of either complete response (CR) or partial response (PR) in the population of interest. 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, taking as reference the baseline sum diameters.
Duration of Response (DOR)
DOR was computed for participants with BOR of CR or PR only, and defined as the time between the date of first documented objective response and the date of the first subsequent disease progression or death. Participants who remained alive and had not progressed were censored on the last tumor assessment date (prior to subsequent cancer therapy).
Rate of Progression-free Survival (PFS) at Week 24
Rate of PFS at week 24 was defined as the proportion of participants remaining progression free or surviving at 24 weeks, calculated by the product-limit method (Kaplan-Meier estimate) which took into account censored data. Participants who did not have any on-study tumor assessment and did not die were censored on the date of first dose of study medication.
Progression-free Survival (PFS)
PFS was defined as the time from the date of first dose of study medication to the date of first disease progression or death. Participants who did not have any on-study tumor assessment and did not die were censored on the date of first dose of study medication.

Full Information

First Posted
October 26, 2011
Last Updated
November 30, 2021
Sponsor
Bristol-Myers Squibb
Collaborators
Ono Pharmaceutical Co. Ltd
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1. Study Identification

Unique Protocol Identification Number
NCT01472081
Brief Title
Nivolumab (BMS-936558; MDX-1106) in Combination With Sunitinib, Pazopanib, or Ipilimumab in Subjects With Metastatic Renal Cell Carcinoma (RCC) (CheckMate 016)
Official Title
A Phase 1 Study of Nivolumab (BMS-936558) Plus Sunitinib, Pazopanib or Ipilimumab in Subjects With Metastatic Renal Cell Carcinoma
Study Type
Interventional

2. Study Status

Record Verification Date
November 2021
Overall Recruitment Status
Completed
Study Start Date
February 9, 2012 (Actual)
Primary Completion Date
February 2, 2016 (Actual)
Study Completion Date
June 3, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bristol-Myers Squibb
Collaborators
Ono Pharmaceutical Co. Ltd

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose is to determine the safety, effectiveness and best dose to use when giving Nivolumab in combination with Sunitinib, Pazopanib, or Ipilimumab for the treatment of metastatic renal cell carcinoma.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Renal Cell Carcinoma, Clear-cell Metastatic Renal Cell Carcinoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
194 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm S: Nivolumab + Sunitinib
Arm Type
Experimental
Arm Description
Nivolumab 0.3, 2.0 (starting dose), 5.0 mg/kg solution intravenously every 21 days until Progressive disease (PD), toxicity or discontinue for other reasons Sunitinib 50 mg capsule by mouth on Days 1-28 of 42 day cycle until Progressive disease (PD), toxicity or discontinue for other reasons
Arm Title
Arm P: Nivolumab + Pazopanib
Arm Type
Experimental
Arm Description
Nivolumab 0.3, 2.0 (starting dose), 5.0 mg/kg solution intravenously every 21 days until Progressive disease (PD), toxicity or discontinue for other reasons Pazopanib 800 mg tablet by mouth daily until Progressive disease (PD), toxicity or discontinue for other reasons
Arm Title
Arm I-1: Nivolumab + Ipilimumab
Arm Type
Experimental
Arm Description
Nivolumab 3 mg/kg solution intravenously (IV) every 21 days during Induction phase and every 14 days during Maintenance phase until Progressive disease (PD), toxicity or discontinue for other reasons Ipilimumab 1mg/kg solution intravenously (IV) every 21 days during Induction phase (Ipilimumab will not be administered during Maintenance phase) until Progressive disease (PD), toxicity or discontinue for other reasons
Arm Title
Arm I-3: Nivolumab + Ipilimumab
Arm Type
Experimental
Arm Description
Nivolumab 1mg/kg solution intravenously (IV) every 21 days during Induction phase and 3mg/kg solution intravenously (IV) every 14 days during Maintenance phase Ipilimumab 3mg/kg solution intravenously (IV) every 21 days during Induction phase. Ipilimumab will not be administered during Maintenance phase
Arm Title
Arm IN-3: Nivolumab+Ipilimumab
Arm Type
Experimental
Arm Description
Nivolumab 3mg/kg solution intravenously (IV) every 21 days during Induction phase and 3mg/kg solution intravenously (IV) every 14 days during Maintenance phase Ipilimumab 3mg/kg solution intravenously (IV) every 21 days during Induction phase. Ipilimumab will not be administered during Maintenance phase
Intervention Type
Biological
Intervention Name(s)
Nivolumab
Other Intervention Name(s)
BMS-936558 (MDX-1106)
Intervention Type
Biological
Intervention Name(s)
Pazopanib
Other Intervention Name(s)
Votrient (Pazopanib hydrochloride)
Intervention Type
Drug
Intervention Name(s)
Sunitinib
Other Intervention Name(s)
Sutent®, Sunitinib Malate
Intervention Type
Biological
Intervention Name(s)
Ipilimumab
Other Intervention Name(s)
YERVOY™
Primary Outcome Measure Information:
Title
Number of Participants With AEs, SAEs, and AEs Leading to Discontinuation
Description
Safety assessments by treatment arm and dose level were based on incidence of AEs, and the incidence of serious adverse events (SAEs). AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=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. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling.
Time Frame
From date of first dose to date of last dose plus 100 days (assessed up to March 2016, approximately 49 months)
Secondary Outcome Measure Information:
Title
Best Overall Response Rate (BOR)
Description
BOR was defined as the best response designation over the study as a whole, recorded between the date of first dose of study medication and the date of objectively documented progression per RECIST 1.1 criteria or the date of subsequent anti-cancer therapy, whichever occurred first. CR = Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR = At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD = At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. SD = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time Frame
From date of first dose to date of disease progression or subsequent anti-cancer therapy, whichever occurred first (assessed up to March 2016, approximately 49 months)
Title
Objective Response Rate (ORR)
Description
ORR was defined as the proportion of participants who achieved a BOR of either complete response (CR) or partial response (PR) in the population of interest. 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, taking as reference the baseline sum diameters.
Time Frame
From date of first dose to interim analysis (Assessed up to March 2016, approximately 49 months)
Title
Duration of Response (DOR)
Description
DOR was computed for participants with BOR of CR or PR only, and defined as the time between the date of first documented objective response and the date of the first subsequent disease progression or death. Participants who remained alive and had not progressed were censored on the last tumor assessment date (prior to subsequent cancer therapy).
Time Frame
From date of first dose to date of disease progression or death, whichever occurred first (assessed up to March 2016, approximately 49 months)
Title
Rate of Progression-free Survival (PFS) at Week 24
Description
Rate of PFS at week 24 was defined as the proportion of participants remaining progression free or surviving at 24 weeks, calculated by the product-limit method (Kaplan-Meier estimate) which took into account censored data. Participants who did not have any on-study tumor assessment and did not die were censored on the date of first dose of study medication.
Time Frame
24 weeks
Title
Progression-free Survival (PFS)
Description
PFS was defined as the time from the date of first dose of study medication to the date of first disease progression or death. Participants who did not have any on-study tumor assessment and did not die were censored on the date of first dose of study medication.
Time Frame
From date of first dose to date of disease progression or death, whichever occurred first (assessed up to March 2016, approximately 49 months)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: Subjects with histological confirmation of RCC Advanced or metastatic disease Measurable disease as defined by RECIST 1.1 criteria Karnofsky Performance Status (KPS) ≥80% Available tumor tissue (archival or recent acquisition) Subjects enrolled in the I-1, I-3 expansion arms and IN-3 addition arms must not have received any prior systemic therapy for RCC with the following exceptions: One prior adjuvant or neoadjuvant therapy for localized or locally advanced RCC is allowed provided recurrence occurred ≥ 6 months after the last dose of the adjuvant or neoadjuvant therapy Only prior cytokine based treatment for metastatic RCC [eg, interferon-alpha (IFN-alpha) or interleukin 2 (IL-2)] as prior therapy is allowed Exclusion Criteria: Active central nervous system (CNS) metastases Active or history of autoimmune disease Ongoing symptomatic cardiac dysrhythmias or uncontrolled atrial fibrillation History of cerebrovascular accident including transient ischemic attack within the past 12 months History of pulmonary embolism or deep vein thrombosis (DVT) within the past 6 months Chronic systemic steroids (>10 mg/day Prednisone equivalents) or any other immunosuppressive agents White blood cell (WBC) <2,000/mm3 Neutrophiles <1,500/mm3 Platelets <100,000/mm3 Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) >3x upper limit of normal (ULN) Total Bilirubin >1.5x ULN (except subjects with Gilbert syndrome, total bilirubin <3.0 mg/dL) Cardiac ejection fraction <LLN (lower limit of normal) Serum creatinine >1.5x ULN or creatinine clearance <40 mL/min (Cockroft-Gault formula) Exclusion Criteria for Arm S and Arm P only: For dose escalation cohorts - subjects who received prior Sunitinib or Pazopanib and required permanent discontinuation due to toxicity or required dose reduction or delay during the first 12 weeks of therapy due to toxicity, or received both prior Sunitinib and Pazopanib Poorly controlled hypertension Active bleeding or bleeding susceptibility
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bristol-Myers Squibb
Organizational Affiliation
Bristol-Myers Squibb
Official's Role
Study Director
Facility Information:
Facility Name
City Of Hope
City
Duarte
State/Province
California
ZIP/Postal Code
91010-3000
Country
United States
Facility Name
Sidney Kimmel Comprehensive Cancer Center At Johns Hopkins
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Dartmouth-Hitchcock Medical Center
City
Lebanon
State/Province
New Hampshire
ZIP/Postal Code
03756
Country
United States
Facility Name
Memorial Sloan Kettering Nassau
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Blumenthal Cancer Center
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28204
Country
United States
Facility Name
Cleveland Clinic
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Fox Chase Cancer Center
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19111
Country
United States
Facility Name
Tennessee Oncology, PLLC
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States
Facility Name
University Of Texas M.D. Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030-4009
Country
United States
Facility Name
Tom Baker Cancer Centre
City
Calgary
State/Province
Alberta
ZIP/Postal Code
T2N 4N2
Country
Canada
Facility Name
Cross Cancer Institute
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T6G 1Z2
Country
Canada
Facility Name
BC Cancer Agency - Vancouver Centre
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V5Z 4E6
Country
Canada
Facility Name
Princess Margaret Cancer Centre
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1Z5
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
30348216
Citation
Amin A, Plimack ER, Ernstoff MS, Lewis LD, Bauer TM, McDermott DF, Carducci M, Kollmannsberger C, Rini BI, Heng DYC, Knox J, Voss MH, Spratlin J, Berghorn E, Yang L, Hammers HJ. Safety and efficacy of nivolumab in combination with sunitinib or pazopanib in advanced or metastatic renal cell carcinoma: the CheckMate 016 study. J Immunother Cancer. 2018 Oct 22;6(1):109. doi: 10.1186/s40425-018-0420-0. Erratum In: J Immunother Cancer. 2019 Mar 14;7(1):73.
Results Reference
derived
PubMed Identifier
24308791
Citation
Dorff TB, Pal SK, Quinn DI. Novel tyrosine kinase inhibitors for renal cell carcinoma. Expert Rev Clin Pharmacol. 2014 Jan;7(1):67-73. doi: 10.1586/17512433.2014.862496. Epub 2013 Dec 2.
Results Reference
derived
Links:
URL
https://www.bms.com/researchers-and-partners/clinical-trials-and-research.html
Description
BMS Clinical Trial Information
URL
https://www.bmsstudyconnect.com/s/US/English/USenHome
Description
BMS Clinical Trial Patient Recruiting
URL
https://www.bms.com/researchers-and-partners/clinical-trials-and-research.html
Description
Investigator Inquiry Form
URL
https://www.fda.gov/Safety/MedWatch/SafetyInformation/default.htm
Description
FDA Safety Alerts and Recalls

Learn more about this trial

Nivolumab (BMS-936558; MDX-1106) in Combination With Sunitinib, Pazopanib, or Ipilimumab in Subjects With Metastatic Renal Cell Carcinoma (RCC) (CheckMate 016)

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