PH 1 Biomarker Study of Nivolumab and Ipilimumab and Nivolumab in Combination With Ipilimumab in Advanced Melanoma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate pharmacodynamic changes of Nivolumab and Nivolumab in combination with Ipilimumab treatment on the biomarkers measured in the peripheral blood and tumor tissues of subjects with advanced melanoma (unresectable or advanced)

Detailed Description
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Allocation: Part 1 and 2: Single Arm study Part 3 and 4: Randomized Controlled Trial Intervention Model: Part 1 and 2: Single group: Single arm study Part 3 and 4: Parallel: Participants are assigned to one of two or more groups in parallel for the duration of the study Minimum Age: Part 1: 18 Part 2, 3 and 4: 16

Official Title
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An Exploratory Study of the Biologic Effects of Nivolumab and Ipilimumab Monotherapy and Nivolumab in Combination With Ipilimumab Treatment in Subjects With Advanced Melanoma (Unresectable or Metastatic)

Conditions
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Advanced Melanoma, Metastatic Melanoma

Intervention / Treatment
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* Biological: Nivolumab
* 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 Part 1: Inclusion Criteria: Men and women >18 years Eastern Cooperative Oncology Group (ECOG) status = 0 to 1 Subjects with unresectable Stage III or IV melanoma who are either refractory or intolerant to, or have refused standard therapy for treatment of metastatic melanoma Subject must have histologic or cytologic confirmation of advanced melanoma Subjects must have at least one measurable lesion at baseline by computed tomography (CT) or magnetic resonance imaging (MRI) as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria Subjects must have at least 1 tumor site that can be biopsied at acceptable clinical risk and must consent to pre- and post-treatment biopsies Exclusion Criteria: Active or progressing brain metastases Other concomitant malignancies (with some exceptions per protocol) Active or history of autoimmune disease Positive test for human immunodeficiency virus (HIV) 1&2 or known acquired immunodeficiency syndrome (AIDS) History of any hepatitis Prior therapy with any antibody/drug that targets the T cell coregulatory proteins, including but not limited to, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40,and anti-CD40 antibodies. However, half the patients must have progressed on anti Cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA4) monoclonal antibody therapy Part 2, 3 and 4: Inclusion Criteria Men and women >16 years Eastern Cooperative Oncology Group (ECOG) status = 0 to 1 Subjects with unresectable Stage III or IV melanoma who are either refractory or intolerant to, or have refused standard therapy for treatment of metastatic melanoma Subjects must never received anti-CTLA4 therapy Subjects must have histologic or cytologic confirmation of advanced melanoma Subjects must have at least two measurable lesions at baseline by CT or MRI as per RECIST 1.1 criteria Subjects must have at least 1 tumor site that can be biopsied at acceptable clinical risk and must consent to pre- and post-treatment biopsies Subjects in Part 4 must have brain metastases Exclusion Criteria Active or progressing brain metastases (except for Part 4 subjects) Other concomitant malignancies (with some exceptions per protocol) Active or history of autoimmune disease Positive test for HIV 1&2 or known AIDS History of any hepatitis Prior therapy with any antibody/drug that targets the T cell coregulatory proteins, including but not limited to, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40,and anti-CD40 antibodies

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: Basic Science
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1-Cohort 1 and 2: Nivolumab<br>Nivolumab 3 mg/kg solution intravenously Every 2 weeks, Up to 2 years depending on response | Biological: Nivolumab<br> <br> * Other names: BMS-936558 (MDX1106);|
| Experimental: Part 2-Arm A: Nivolumab + Ipilimumab<br>Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified | Biological: Nivolumab<br> <br> * Other names: BMS-936558 (MDX1106);Drug: Ipilimumab<br> <br> * Other names: Yervoy;|
| Experimental: Part 3-Arm A: Nivolumab + Ipilimumab<br>Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified | Biological: Nivolumab<br> <br> * Other names: BMS-936558 (MDX1106);Drug: Ipilimumab<br> <br> * Other names: Yervoy;|
| Experimental: Part 3-Arm B: Nivolumab<br>Nivolumab 3 mg/kg solution intravenously as specified | Biological: Nivolumab<br> <br> * Other names: BMS-936558 (MDX1106);|
| Experimental: Part 4-Arm D: Nivolumab + Ipilimumab<br>Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified | Biological: Nivolumab<br> <br> * Other names: BMS-936558 (MDX1106);Drug: Ipilimumab<br> <br> * Other names: Yervoy;|
| Experimental: Part 4-Arm E: Nivolumab<br>Nivolumab 3 mg/kg solution intravenously as specified | Biological: Nivolumab<br> <br> * Other names: BMS-936558 (MDX1106);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Change From Baseline to Week 7, of Interferon (IFN) and Interferon Gamma (IFN-gamma) Inducible Factors | Baseline and post-treatment modulation of serum levels of chemokines, cytokines and other immune mediators were assessed by techniques that included ELISA or other multiplex-based assay methods. Primary analysis included IFN-gamma and IFN-gamma inducible factors, including chemokine [C-X-C motif] ligand 9 (CXCL9) and CXCL10 | From last non-missing value prior to first dose to week 7 day 1 | 
| Tumor Infiltrating Lymphocytes (TILs) as Measured by Medians in Percent Positive CD8 and Positive CD4 at Baseline and On-treatment Biopsy, Both Using the Mosaic Singleplex IHC Assay | Biomarkers examined were percent positive CD8 and percent positive CD4, both using the Mosaic Singleplex IHC assay. Analyses are presented with the medians at baseline and on-treatment, rather than the median change because the baseline values differed across groups. Baseline was defined as the last non-missing value on or prior to the first dose of study therapy. Biopsies were also collected on treatment. | From last non-missing value prior to first dose to week 4 day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of Nivolumab, Ipilimumab and Nivolumab in Combination With Ipilimumab as Measured by the Number of Deaths and AEs | The assessment of safety was based on frequency of deaths, AEs, SAEs, AEs leading to discontinuation of study drug, and abnormalities in specific clinical laboratory assessments. AEs were coded using the MedDRA Version 20.1 AEs and laboratory values were graded for severity according to the NCI CTCAE version 4.0. | Includes events reported between first dose and up to 100 days after last dose of study medication. | 
| Safety and Tolerability of Nivolumab, Ipilimumab and Nivolumab in Combination With Ipilimumab as Measured by SAEs and AEs Leading to Discontinuation of Study Drug. | The assessment of safety was based on frequency of SAEs and AEs leading to discontinuation of study drug. AEs were coded using the MedDRA Version 20.1 AEs and laboratory values were graded for severity according to the NCI CTCAE version 4.0. | From enrollment to 100 days after the last dose date | 
| Number of Laboratory Abnormalities in Specific Liver Tests | Abnormalities in hepatic parameters measured included those in aspartate aminotransferase (AST), alanine aminotransferase (ALT)and total bilirubin, with respect to upper limit of normal (ULN) | 101-120 days after last dose. | 
| Number of Laboratory Abnormalities in Specific Thyroid Tests | Abnormalities in thyroid parameters measured included those in thyroid stimulating hormone (TSH) levels with respect to upper limit of normal (ULN) and lower limit of normal (LLN) | 101-120 days after last dose. | 
| Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Objective Response Rate (ORR) | The objective response rate (ORR) was defined as the number of subjects with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized subjects in the population of interest (eg, all treated subjects or response-evaluable subjects). The BOR was defined as the subject's best response designation, over the study as a whole, recorded between the date of first study drug administration and the date of objectively documented progression per RECIST 1.1, with subsequent confirmation, or date of subsequent anti-cancer therapy, whichever occurred first in the study. | Approximately every 8 weeks until disease progression and in follow-up if no progression | 
| Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Median Duration of Response (mDOR) | Median duration of response (mDOR) was calculated for subjects with BOR of CR or PR only, and is defined as time between the date of first documented objective response and the date of the first subsequent disease progression or death, whichever occurred first, if death occurred within 100 days after last dose of study medication. | 2 years from the first dose of treatment | 
| Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Median Time to Response (mTTR) | Median time to response (mTTR) for a participant with a BOR of CR or PR is defined as the time from the first dosing date to the date of the first documented objective response (CR or PR). | 2 years from the first dose of treatment | 
| Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Progression Free Survival Rate (PFSR) | The progression free survival rate (PFSR) for a subject was defined as the time from the date of first dose of study medication to the date of the first documented disease progression, or death due to any cause, whichever occurred first, if death occurred within 100 days after last dose of study medication. | 2 years from the first dose of treatment | 
| Immunogenicity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Number of Serum Anti-drug Antibody (ADA) Positive Participants and the Number of Neutralizing ADA Positive Participants | Time Frame: Part 1: Day 1, Day 15, Day 43 of cycle 1, Day 1 of cycle 2, Day 15 of cycle 3, every 16 weeks after cycle 3 up to 2 years, follow-up visit 1 (40-60 days after last treatment), and follow-up visit 2 (101-120 days since last treatment) Part 2, 3 and 4: Weeks 1, 3, 4, 7, 9, 10, 13, 25, 53, 79, 95 follow-up visit 1 (40-60 days after last treatment), and follow-up visit 2 (101-120 days since last treatment) | Up to follow-up visit 2 (101-120 days since last treatment) | 
| Association Between Programmed Cell Death Ligand 1 (PD-L1) and Clinical Efficacy Measures Such as Objective Response Rate (PD-L1 ORR) | For immunohistochemistry (IHC) measurements, to explore the PD-L1 expression as a potential predictive marker of clinical activity, PD-L1 expression status were derived from percent of tumor cells exhibiting cell surface staining for PD-L1 at baseline and/or in archived biopsy samples using verified and/or validated assays. In the case of multiple specimens, a subject would be identified as PD-L1 expression levels >= x%, where x% can be 10%, 5%, and/or 1% in any of the baseline and/or archived specimens. The association between PD-L1 expression status and/or level and clinical efficacy measures was assessed. The objective response rate (ORR) was defined as the number of subjects with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized subjects in the population of interest (all response-evaluable participants). | 2 years from first dose of treatment; Assessed up to September 2017 | 
| Association Between Programmed Cell Death Ligand 1 (PD-L1) and Clinical Efficacy Measures Such as the Duration of Response (PD-L1 DOR) | For immunohistochemistry (IHC) measurements, to explore the PD-L1 expression as a potential predictive marker of clinical activity, PD-L1 expression status were derived from percent of tumor cells exhibiting cell surface staining for PD-L1 at baseline and/or in archived biopsy samples using verified and/or validated assays. In the case of multiple specimens, a subject would be identified as PD-L1 expression levels >= x%, where x% can be 10%, 5%, and/or 1% in any of the baseline and/or archived specimens. The association between PD-L1 expression status and/or level and clinical efficacy measures was assessed. Median duration of response (mDOR) was calculated for all response-evaluable participants with best overall response of CR or PR only, and is defined as time between the date of first documented objective response and the date of the first subsequent disease progression or death, whichever occurred first, if death occurred within 100 days after last dose of study medication. | 2 years from first dose of treatment; Assessed up to September 2017 | 
| Association Between Programmed Cell Death Ligand 1 (PD-L1) and Clinical Efficacy Measures Such as Progression Free Survival (PD-L1 PFS) | For immunohistochemistry (IHC) measurements, to explore the PD-L1 expression as a potential predictive marker of clinical activity, PD-L1 expression status were derived from percent of tumor cells exhibiting cell surface staining for PD-L1 at baseline and/or in archived biopsy samples using verified and/or validated assays. In the case of multiple specimens, a subject would be identified as PD-L1 expression levels >= x%, where x% can be 10%, 5%, and/or 1% in any of the baseline and/or archived specimens. The association between PD-L1 expression status and/or level and clinical efficacy measures was assessed. The progression free survival rate (PFSR) for a subject was defined as the time from the date of first dose of study medication to the date of the first documented disease progression, or death due to any cause, whichever occurred first, if death occurred within 100 days after last dose of study medication. | 2 years from first dose of treatment; Assessed up to September 2017 | 
| Association Between Programmed Cell Death Ligand 1 (PD-L1) and Clinical Efficacy Measures Such as Overall Survival Rate (PD-L1 OSR) | For immunohistochemistry (IHC) measurements, to explore the PD-L1 expression as a potential predictive marker of clinical activity, PD-L1 expression status were derived from percent of tumor cells exhibiting cell surface staining for PD-L1 at baseline and/or in archived biopsy samples using verified and/or validated assays. In the case of multiple specimens, a subject would be identified as PD-L1 expression levels >= x%, where x% can be 10%, 5%, and/or 1% in any of the baseline and/or archived specimens. The association between PD-L1 expression status and/or level and clinical efficacy measures was assessed. The overall survival rate (OSR) for a subject was defined as the time from the date of first dose of study medication to the date of death for any cause. A subject who had not died was censored at last known date alive | 2 years from first dose of treatment; Assessed up to September 2017 | 
| Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Overall Survival Rate (OSR) | The proportion of subjects surviving to time t, where t is a specific length of time, eg, 12 months, which was determined by the available data for final analysis and was documented in the DPP. The proportion was calculated by the product-limit method (Kaplan-Meier estimate), which takes into account censored data. The overall survival rate (OSR) for a subject was defined as the time from the date of first dose of study medication to the date of death for any cause. A subject who had not died was censored at last known date alive | 2 years from first dose of treatment; Assessed up to September 2017 |