Dose-escalation Study of Combination BMS-936558 (MDX-1106) and Ipilimumab in Subjects With Unresectable Stage III or Stage IV Malignant Melanoma

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and tolerability of treatment with BMS-936558 (MDX-1106) in combination with Ipilimumab (BMS-734016) when given at the same time or as a sequenced regimen in subjects with unresectable Stage III or Stage IV malignant melanoma (MEL)

Official Title
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A Phase 1b, Open-label, Multicenter, Multidose, Dose-escalation Study of BMS-936558 (MDX-1106) in Combination With Ipilimumab in Subjects With Unresectable Stage III or Stage IV Malignant Melanoma

Conditions
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Malignant Melanoma

Intervention / Treatment
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* Drug: BMS-936558 (MDX1106-04)
* Drug: 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: Histologic diagnosis of malignant melanoma (MEL) Measurable unresectable Stage III or IV MEL ECOG performance status score of 0 or 1 Life expectancy ≥4 months For those enrolled in amendment 5 and later, tumor tissue (archival or recent acquisition) must be available For Cohorts 1-5, subjects may have been treated with up to 3 prior systemic standard treatments for metastatic melanoma not including any post-incisional adjuvant therapy. Subjects may be treatment naïve. All metastatic melanoma regardless of primary site of disease will be allowed For Cohorts 6-7, subjects may have been treated with up to 3 prior systemic standard treatments for metastatic melanoma; this does not include any post-incisional adjuvant therapy. Specifically, subjects must have received ≥3 doses of Ipilimumab therapy and the last dose having been administered within 4-12 weeks of initiation of study treatment Exclusion Criteria: History of severe hypersensitivity reactions to other mAbs Prior malignancy active within the previous 2 years except for localized cancers that are considered to have been cured and in the opinion of the investigator present a low risk for recurrence Active autoimmune disease or a history of known or suspected autoimmune disease History of recently active diverticulitis or symptomatic peptic ulcer disease and history of adrenal insufficiency Regular narcotic analgesia Active, untreated central nervous system metastasis For subjects enrolled in Cohorts 1-5, prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 or anti-CTLA-4 antibody For subjects enrolled in Cohorts 6-7, prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CD137 antibodies Any non-oncology vaccine therapy used for prevention of infectious disease Concomitant therapy with any other anti-cancer therapy, concurrent medical conditions requiring use of immunosuppressive medications or use of other investigational drugs Positive tests for human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS), hepatitis B, hepatitis C Subjects weighing ≥125 kg are excluded from Cohort 5 Subjects in Cohorts 6 and 7 must have received Ipilimumab monotherapy immediately prior to study entry, but must not have received that Ipilimumab as part of a clinical trial Subjects with ocular melanoma are excluded from Cohort 8

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: BMS-936558 (0.3 mg/kg)+Ipilimumab (3 mg/kg)<br>BMS-936558 (MDX1106-04) 0.3 mg/kg solution, 60 minutes intravenous infusion every 3 (q3) weeks for 21 weeks in induction and every 12 (q12) weeks for 84 weeks in maintenance Ipilimumab (BMS-734016) 3 mg/kg solution, 90 minutes intravenous infusion q3 weeks for 9 weeks in induction and q12 weeks for 84 weeks in maintenance | Drug: BMS-936558 (MDX1106-04)<br> <br> * Other names: Nivolumab;Drug: Ipilimumab<br> <br> * Other names: BMS-734016;|
| Experimental: Cohort 2: BMS-936558 (1 mg/kg)+Ipilimumab (3 mg/kg)<br>Ipilimumab (BMS-734016) 3 mg/kg solution, 90 minutes intravenous infusion, q3 weeks for 9 weeks in induction and q12 weeks for 84 weeks in maintenance BMS-936558 (MDX1106-04) 1 mg/kg solution, 60 minutes intravenous infusion, q3 weeks for 21 weeks in induction and q12 weeks for 84 weeks in maintenance | Drug: BMS-936558 (MDX1106-04)<br> <br> * Other names: Nivolumab;Drug: Ipilimumab<br> <br> * Other names: BMS-734016;|
| Experimental: Cohort 3: BMS-936558 (3 mg/kg)+Ipilimumab (3 mg/kg)<br>Ipilimumab (BMS-734016) 3 mg/kg solution, 90 minutes intravenous infusion, q3 weeks for 9 weeks in induction and q12 weeks for 84 weeks in maintenance BMS-936558 (MDX1106-04) 3 mg/kg solution, 60 minutes intravenous infusion, q3 weeks for 21 weeks in induction and q12 weeks for 84 weeks in maintenance | Drug: BMS-936558 (MDX1106-04)<br> <br> * Other names: Nivolumab;Drug: Ipilimumab<br> <br> * Other names: BMS-734016;|
| Experimental: Cohort 4: BMS-936558 (10 mg/kg)+Ipilimumab (3 mg/kg)<br>BMS-936558 (MDX1106-04) 10 mg/kg solution, 60 minutes intravenous infusion, q3 weeks for 21 weeks in induction and q12 weeks for 84 weeks in maintenance Ipilimumab (BMS-734016) 3 mg/kg solution, 90 minutes intravenous infusion, q3 weeks for 9 weeks in induction and q12 weeks for 84 weeks in maintenance | Drug: BMS-936558 (MDX1106-04)<br> <br> * Other names: Nivolumab;Drug: Ipilimumab<br> <br> * Other names: BMS-734016;|
| Experimental: Cohort 5: BMS-936558 (10 mg/kg)+Ipilimumab (10 mg/kg)<br>BMS-936558 (MDX1106-04) 10 mg/kg solution, 60 minutes intravenous infusion, q3 weeks for 21 weeks in induction and q12 weeks for 84 weeks in maintenance Ipilimumab (BMS-734016) 10 mg/kg solution, 90 minutes intravenous infusion, q3 weeks for 9 weeks in induction and q12 weeks for 84 weeks in maintenance | Drug: BMS-936558 (MDX1106-04)<br> <br> * Other names: Nivolumab;Drug: Ipilimumab<br> <br> * Other names: BMS-734016;|
| Experimental: Cohort 6: BMS-936558 (1 mg/kg)<br>BMS-936558 (MDX1106-04) 1 mg/kg solution, 60 minutes intravenous infusion, once q2 weeks for a total maximal duration of 96 weeks | Drug: BMS-936558 (MDX1106-04)<br> <br> * Other names: Nivolumab;|
| Experimental: Cohort 7: BMS-936558 (3 mg/kg)<br>BMS-936558 (MDX1106-04) 3 mg/kg solution, 60 minutes intravenous infusion, once q2 weeks for a total maximal duration of 96 weeks | Drug: BMS-936558 (MDX1106-04)<br> <br> * Other names: Nivolumab;|
| Experimental: Cohort 8: Nivolumab+Ipilimumab<br>Nivolumab 1 mg/kg and Ipilimumab 3 mg/kg solution intravenously q3 weeks, 4 doses for 12 weeks Followed by Nivolumab 3 mg/kg solution alone intravenously q2 weeks, 48 doses for a maximum of 96 weeks | Drug: BMS-936558 (MDX1106-04)<br> <br> * Other names: Nivolumab;Drug: Ipilimumab<br> <br> * Other names: BMS-734016;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With an Adverse Event (AE) | incidence of all cause and treatment related adverse events | Up to 3 years | 
| Number of Participants With a Serious Adverse Event (AE) | incidence of all cause and treatment related serious adverse events | Up to 3 years | 
| Number of Participants With an Adverse Event (AE) Which Lead to Discontinuation | incidence of all cause and treatment related adverse events which lead to discontinuation | Up to 3 years | 
| Number of Deaths | incidence of all cause and treatment related deaths | Up to 3 years | 
| Number of Participants With Select AEs | incidence of all cause and treatment related Adverse events in certain organ systems | Up to 3 years | 
| Laboratory Abnormalities: Specific Liver Tests | Number of Participants with On-Treatment Laboratory Abnormalities in Specific Liver Tests Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Upper Limit of Normal (ULN) | Up to 3 years | 
| Laboratory Abnormalities: Specific Thyroid Tests | Number of Participants with On-Treatment Laboratory Abnormalities in Specific Thyroid Tests Free T3 (FT3) Free T4 (FT4) Lower Limit of Normal (LLN) | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | the total number of participants whose best overall response (BOR) is either irCR or irPR divided by the total number of response-evaluable participants. | Up to 3 years | 
| Time to Response | the time from the first dose of study drug until the first documentation of irCR or irPR, as related to current database lock date or most current tumor measurement | Up to 3 Years | 
| Duration of Response | the time from the first documented response (irCR or irPR) until progression or death, whichever occurs first. For participants who did not progress or die, duration of response will be censored on the date of the last tumor assessment. | from the first documented response (irCR or irPR) until progression or death | 
| Progression Free Survival | the time from the first dose to the first observation of disease progression or death due to any cause. If a participant has not progressed or died at the time of analysis, PFS will be censored on the date of the last disease assessment. Participants who did not have any on-study tumor assessments and did not die will be censored on the date of the first dose of study medication. | 156 weeks | 
| Number of Participants With an Anti-Drug Antibody (ADA) Response for Nivolumab (Nivo) and Ipilimumab (Ipi) | Serum samples will be collected to evaluate the development of antibodies to BMS-936558 and to ipilimumab. | Up to 3 years | 
| Peak and Trough Concentrations | The peak and trough concentrations of BMS-936558 (MDX-1106) and ipilimumab in participants with quantifiable data | Up to 64 Weeks |