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

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

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01472081

Enrollment

194

Registered

2011-11-16

Start date

2012-02-09

Completion date

2021-06-03

Last updated

2021-12-02

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Clear-cell Metastatic Renal Cell Carcinoma, Renal Cell Carcinoma

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.

Interventions

BIOLOGICALNivolumab

BIOLOGICALPazopanib

DRUGSunitinib

BIOLOGICALIpilimumab

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion 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: 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)

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With AEs, SAEs, and AEs Leading to Discontinuation	From date of first dose to date of last dose plus 100 days (assessed up to March 2016, approximately 49 months)	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

Measure	Time frame	Description
Best Overall Response Rate (BOR)	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)	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)	From date of first dose to interim analysis (Assessed up to March 2016, approximately 49 months)	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)	From date of first dose to date of disease progression or death, whichever occurred first (assessed up to March 2016, approximately 49 months)	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	24 weeks	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)	From date of first dose to date of disease progression or death, whichever occurred first (assessed up to March 2016, approximately 49 months)	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.

Countries

Canada, United States

Participant flow

Pre-assignment details

194 participants were enrolled; 153 were treated. Participants were enrolled but not treated due to the following reasons: withdrawal of consent (n=5), no longer met study criteria (n=32), administrative reason by sponsor (n=1), or other reasons (n=3)

Participants by arm

Arm	Count
Arm S: SUN + NIV2 Nivolumab 2 mg/kg administered on Day 1 and 22 of each 6 week (42 day) cycle as a 1-hour IV infusion followed 60 minutes later with Sunitinib 50 mg orally on Day 1 - 28 of each 42 day cycle until Progressive Disease (PD), toxicity or discontinuation for other reasons.	7
Arm S: SUN + NIV5 Nivolumab 5 mg/kg administered on Day 1 and 22 of each 6 week (42 day) cycle as a 1-hour IV infusion followed 60 minutes later with Sunitinib 50 mg orally on Day 1 - 28 of each 42 day cycle until Progressive Disease (PD), toxicity or discontinuation for other reasons.	26
Arm P: PAZ + NIV2 Nivolumab 2 mg/kg administered on Day 1 and 22 of each 6 week (42 day) cycle as a 1-hour IV infusion followed 60 minutes later with Pazopanib 800 mg orally on Day 1 - 42 of each 42 day cycle until Progressive Disease (PD), toxicity or discontinuation for other reasons.	20
Arm I-1: IPI1 + NIV3 Induction: Nivolumab 3 mg/kg was administered as a 1-hour IV infusion followed by Ipilimumab 1 mg/kg administered IV infusion over 90 minutes every 3 weeks for 4 doses. Maintenance: Nivolumab 3 mg/kg was administered as a 1-hour IV infusion every 2 weeks, starting 3 weeks after the 4th dose of induction therapy or after Day 113 if the 4th dose of induction therapy had not been administered due to treatment delays.	47
Arm I-3: IPI3 + NIV1 Induction: Nivolumab 1 mg/kg was administered as a 1-hour IV infusion followed by Ipilimumab 3 mg/kg administered IV infusion over 90 minutes every 3 weeks for 4 doses. Maintenance: Nivolumab 3 mg/kg was administered as a 1-hour IV infusion every 2 weeks, starting 3 weeks after the 4th dose of induction therapy or after Day 113 if the 4th dose of induction therapy had not been administered due to treatment delays.	47
Arm IN-3: IPI3 + NIV3 Induction: Nivolumab 3 mg/kg was administered as a 1-hour IV infusion followed by Ipilimumab 3 mg/kg administered IV infusion over 90 minutes every 3 weeks for 4 doses. Maintenance: Nivolumab 3 mg/kg was administered as a 1-hour IV infusion every 2 weeks, starting 3 weeks after the 4th dose of induction therapy or after Day 113 if the 4th dose of induction therapy had not been administered due to treatment delays.	6
Total	153

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005
Overall Study	Adverse Event unrelated to study drug	0	0	0	0	1	0
Overall Study	Continuing treatment at time of analysis	1	4	1	8	9	0
Overall Study	Death	0	0	0	0	1	0
Overall Study	Disease Progression	4	10	12	31	22	3
Overall Study	No longer meets study criteria	0	0	1	0	0	0
Overall Study	Poor/non-compliance	0	0	1	0	1	0
Overall Study	Study drug toxicity	2	9	4	6	13	2
Overall Study	Subject request to discontinue treatment	0	3	1	1	0	0
Overall Study	Withdrawal by Subject	0	0	0	0	0	1

Baseline characteristics

Characteristic	Arm S: SUN + NIV2	Arm S: SUN + NIV5	Arm P: PAZ + NIV2	Arm I-1: IPI1 + NIV3	Arm I-3: IPI3 + NIV1	Arm IN-3: IPI3 + NIV3	Total
Age, Continuous	56.9 years STANDARD_DEVIATION 11.36	58.3 years STANDARD_DEVIATION 8.62	56.3 years STANDARD_DEVIATION 8.52	53.0 years STANDARD_DEVIATION 8.97	55.6 years STANDARD_DEVIATION 11.58	54.8 years STANDARD_DEVIATION 2.71	55.4 years STANDARD_DEVIATION 9.71
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	2 Participants	0 Participants	1 Participants	2 Participants	1 Participants	6 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	7 Participants	22 Participants	18 Participants	42 Participants	40 Participants	5 Participants	134 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	2 Participants	2 Participants	4 Participants	5 Participants	0 Participants	13 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants
Race (NIH/OMB) Asian	0 Participants	1 Participants	0 Participants	2 Participants	0 Participants	0 Participants	3 Participants
Race (NIH/OMB) Black or African American	1 Participants	1 Participants	1 Participants	1 Participants	1 Participants	0 Participants	5 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	1 Participants	1 Participants	0 Participants	1 Participants	0 Participants	3 Participants
Race (NIH/OMB) White	6 Participants	22 Participants	18 Participants	44 Participants	45 Participants	6 Participants	141 Participants
Sex: Female, Male Female	0 Participants	7 Participants	2 Participants	14 Participants	9 Participants	1 Participants	33 Participants
Sex: Female, Male Male	7 Participants	19 Participants	18 Participants	33 Participants	38 Participants	5 Participants	120 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	33 / 33	20 / 20	47 / 47	46 / 47	6 / 6
serious Total, serious adverse events	19 / 33	13 / 20	29 / 47	30 / 47	4 / 6

Outcome results

Primary

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.

Time frame: From date of first dose to date of last dose plus 100 days (assessed up to March 2016, approximately 49 months)