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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1 Study of Nivolumab (BMS-936558) Plus Sunitinib, Pazopanib or Ipilimumab in Subjects With Metastatic Renal Cell Carcinoma

Conditions
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Renal Cell Carcinoma, Clear-cell Metastatic Renal Cell Carcinoma

Intervention / Treatment
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* Biological: Nivolumab
* Biological: Pazopanib
* Drug: Sunitinib
* Biological: Ipilimumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm S: Nivolumab + Sunitinib<br>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 | Biological: Nivolumab<br> <br> * Other names: BMS-936558 (MDX-1106);Drug: Sunitinib<br> <br> * Other names: Sunitinib Malate;|
| Experimental: Arm P: Nivolumab + Pazopanib<br>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 | Biological: Nivolumab<br> <br> * Other names: BMS-936558 (MDX-1106);Biological: Pazopanib<br> <br> * Other names: Votrient (Pazopanib hydrochloride);|
| Experimental: Arm I-1: Nivolumab + Ipilimumab<br>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 | Biological: Nivolumab<br> <br> * Other names: BMS-936558 (MDX-1106);Biological: Ipilimumab<br> <br> * Other names: YERVOY™;|
| Experimental: Arm I-3: Nivolumab + Ipilimumab<br>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 | Biological: Nivolumab<br> <br> * Other names: BMS-936558 (MDX-1106);Biological: Ipilimumab<br> <br> * Other names: YERVOY™;|
| Experimental: Arm IN-3: Nivolumab+Ipilimumab<br>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 | Biological: Nivolumab<br> <br> * Other names: BMS-936558 (MDX-1106);Biological: Ipilimumab<br> <br> * Other names: YERVOY™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From date of first dose to date of last dose plus 100 days (assessed up to March 2016, approximately 49 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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) | 
| 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. | From date of first dose to interim analysis (Assessed up to March 2016, approximately 49 months) | 
| 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). | From date of first dose to date of disease progression or death, whichever occurred first (assessed up to March 2016, approximately 49 months) | 
| 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. | 24 weeks | 
| 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. | From date of first dose to date of disease progression or death, whichever occurred first (assessed up to March 2016, approximately 49 months) |