Safety Study of IL-21/Ipilimumab Combination in the Treatment of Melanoma

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the combination of interleukin-21 (IL-21) and Ipilimumab in subjects with melanoma is safe, and provide preliminary information on the clinical benefits of the combination compared with Ipilimumab alone

Detailed Description
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Allocation: Part 1 Dose Escalation Phase: Non-randomized; Part 2 Cohort Expansion Phase: Randomized

Official Title
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A Phase I Dose Escalation Study of BMS-982470 (Recombinant Interleukin 21, rIL-21) in Combination With Ipilimumab in Subjects With Unresectable Stage III or Stage IV Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Biological: BMS-982470 (recombinant interleukin-21)
* Biological: BMS-982470 (recombinant interleukin-21)
* Biological: BMS-982470 (recombinant interleukin-21)
* Biological: BMS-982470 (recombinant interleukin-21)
* Biological: Ipilimumab
* Biological: Ipilimumab
* 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: Unresectable Stage III or Stage IV melanoma Part 1 Dose Escalation: Prior melanoma treatment allowed except for the following: ipilimumab, BMS-982470 (rIL-21), anti-Programmed Death-1 (anti-PD-1), anti-programmed death-ligand 1 (anti-PD-L1), anti-PD-L2 or anti-CD137 Part 2 Cohort expansion: Prior treatment for melanoma is not allowed, except for adjuvant therapy with interferon alpha or melanoma vaccines which are permitted Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) Normal liver function tests Exclusion Criteria: Part 1 Dose escalation: subjects with ≤ 2 brain metastases of stable size, ≥ 4 weeks post-radiation treatment, and off steroids are allowed Part 2 Cohort expansion: subjects with known or suspected brain metastases and uveal melanoma are excluded Autoimmune disease

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: Part 1 - Arm 1: BMS-982470 (Daily x 5) + Ipilimumab<br>Dose Escalation | Biological: BMS-982470 (recombinant interleukin-21)<br>* Solution, Intravenous, 10,30,50 μg/kg, daily for 5 days every 3 weeks (daily x 5), 16-20 weeks depending on response<br>Biological: Ipilimumab<br>* Solution, Intravenous, 1,3,10 mg/kg, every 3 weeks, 16-20 weeks depending on response<br>* Other names: Yervoy®;|
| Experimental: Part 1 - Arm 2: BMS-982470 (Weekly) + Ipilimumab<br>Dose Escalation | Biological: BMS-982470 (recombinant interleukin-21)<br>* Solution, Intravenous, 30,100,150 μg/kg, weekly, 16-20 weeks depending on response<br>Biological: Ipilimumab<br>* Solution, Intravenous, 1,3,10 mg/kg, every 3 weeks, 16-20 weeks depending on response<br>* Other names: Yervoy®;|
| Experimental: Part 2 - Arm 1: BMS-982470 (Daily x 5) + Ipilimumab<br>Cohort Expansion | Biological: BMS-982470 (recombinant interleukin-21)<br>* Solution, Intravenous, Maximum tolerated dose from Part 1, daily for 5 days every 3 weeks (daily x 5), 12-16 weeks depending on response<br>Biological: Ipilimumab<br>* Solution, Intravenous, Maximum tolerated dose from Part 1, every 3 weeks, 12-16 weeks depending on response<br>* Other names: Yervoy®;|
| Experimental: Part 2 - Arm 2: BMS-982470 (Weekly) + Ipilimumab<br>Cohort Expansion | Biological: BMS-982470 (recombinant interleukin-21)<br>* Solution, Intravenous, Maximum tolerated dose from Part 1, Weekly, 12-16 weeks depending on response<br>Biological: Ipilimumab<br>* Solution, Intravenous, Maximum tolerated dose from Part 1, every 3 weeks, 12-16 weeks depending on response<br>* Other names: Yervoy®;|
| Active Comparator: Part 2 - Arm 3: Ipilimumab monotherapy<br>Cohort Expansion | Biological: Ipilimumab<br>* Solution, Intravenous, 3mg/kg, Every 3 weeks, 12-16 weeks depending on response<br>* Other names: Yervoy®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part1 (Dose Escalation): The Maximum tolerated dose (MTD) of BMS-982470 using 2 distinct schedules when administered in combination with Ipilimumab | Based on the dose-limiting toxicity (DLT) rate | Within the first 63 days | 
| Part 2 (Cohort Escalation): Safety and tolerability of the MTD dose for each of the schedules | Based on medical review of AE reports and the results of vital sign measurements, physical examinations, medical history, and clinical laboratory tests | 84 days on treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of BMS-982470 in combination with Ipilimumab as measured by objective response |  | Baseline (Day 1), End of Treatment (EOT) [3 weeks after last dose of Ipilimumab], 3 and 6 months Follow-up | 
| Area under the serum concentration-time curve from time zero to the last quantifiable concentration [AUC(0-T)] of BMS-982470 and Ipilimumab |  | 20 time points during Lead-In Cycle; Up to 11 time points during Cycle 3 | 
| Area under the serum concentration-time curve in one dosing interval [AUC(TAU)] of BMS-982470 and Ipilimumab |  | 20 time points during Lead-In Cycle; Up to 11 time points during Cycle 3 | 
| Area under the serum concentration-time curve from time zero extrapolated to infinite time [AUC(INF)] of BMS-982470 and Ipilimumab |  | 20 time points during Lead-In Cycle; Up to 11 time points during Cycle 3 | 
| The maximum observed serum concentration (Cmax) of BMS-982470 and Ipilimumab |  | 20 time points during Lead-In Cycle; Up to 11 time points during Cycle 3 | 
| Trough observed serum concentration (Cmin) of BMS-982470 and Ipilimumab |  | 1 time point each 3-week Cycle | 
| The time of maximum observed serum concentration (Tmax) of BMS-982470 and Ipilimumab |  | 20 time points during Lead-In Cycle; Up to 11 time points during Cycle 3 | 
| Serum half-life (T-HALF) of BMS-982470 and Ipilimumab |  | 20 time points during Lead-In Cycle; Up to 11 time points during Cycle 3 | 
| Apparent total body clearance (CLT) of BMS-982470 and Ipilimumab |  | 20 time points during Lead-In Cycle; Up to 11 time points during Cycle 3 | 
| Apparent volume of distribution at steady state (Vss) of BMS-982470 and Ipilimumab |  | 20 time points during Lead-In Cycle; Up to 11 time points during Cycle 3 | 
| Incidence of BMS-984270 and Ipilimumab Anti-Drug Antibodies |  | Up to 6 months following last dose |