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

Phase 1

Completed

Conditions: Advanced Melanoma
Metastatic Melanoma

Interventions: Biological: Nivolumab
Drug: Ipilimumab

Registration Number: NCT01621490

Lead Sponsor: Bristol-Myers Squibb

Brief Summary: 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: 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

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 170

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Part 1-Cohort 1 and 2: Nivolumab	Nivolumab	Nivolumab 3 mg/kg solution intravenously Every 2 weeks, Up to 2 years depending on response
Part 2-Arm A: Nivolumab + Ipilimumab	Nivolumab	Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified
Part 2-Arm A: Nivolumab + Ipilimumab	Ipilimumab	Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified
Part 3-Arm A: Nivolumab + Ipilimumab	Nivolumab	Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified
Part 3-Arm A: Nivolumab + Ipilimumab	Ipilimumab	Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified
Part 3-Arm B: Nivolumab	Nivolumab	Nivolumab 3 mg/kg solution intravenously as specified
Part 4-Arm D: Nivolumab + Ipilimumab	Nivolumab	Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified
Part 4-Arm E: Nivolumab	Nivolumab	Nivolumab 3 mg/kg solution intravenously as specified
Part 4-Arm D: Nivolumab + Ipilimumab	Ipilimumab	Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified

Primary Outcome Measures

Name	Time	Method
Median Change From Baseline to Week 7, of Interferon (IFN) and Interferon Gamma (IFN-gamma) Inducible Factors	From last non-missing value prior to first dose to week 7 day 1	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
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	From last non-missing value prior to first dose to week 4 day 1	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.

Secondary Outcome Measures

Name	Time	Method
Frequency of Adverse Events or Death	Includes events reported between first dose and up to 100 days after last dose of study medication (up to approximately 73 months).	The assessment of safety was based on frequency of deaths and adverse events (AEs). AEs were graded for severity according to the NCI CTCAE version 4.0.
Frequency of AEs Leading to Discontinuation of Study Drug and SAEs	From enrollment to 100 days after the last dose date (up to approximately 73 months)	The assessment of safety was based on frequency of serious adverse events (SAEs) and adverse events (AEs) leading to discontinuation of study drug. AEs were graded for severity according to the NCI CTCAE version 4.0.
Number of Laboratory Abnormalities in Specific Liver Tests	101-120 days after last dose.	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)
Number of Laboratory Abnormalities in Specific Thyroid Tests	101-120 days after last dose.	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)
Objective Response Rate (ORR)	Approximately every 8 weeks until disease progression and in follow-up if no progression (up to approximately 73 months)	The objective response rate (ORR) was defined as the percentage of participants with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized participants in the population of interest. The BOR was defined as the participant'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.
Median Duration of Response (mDOR)	From date of first documented objective response to date of disease progression or death, up to approximately 27 months	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.
Median Time to Response (mTTR)	From the first dosing date to the date of the first documented objective response, up to approximately 15 months	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).
Progression Free Survival (PFS)	From first dose of study medication to the date of progression or death, whichever occurs first, up to approximately 29 months	Progression free survival (PFS) for a participant 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.
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	Up to follow-up visit 2 (101-120 days since last treatment)	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)
Objective Response Rate (ORR) by PD-L1 Expression	Approximately every 8 weeks until disease progression and in follow-up if no progression (up to approximately 73 months)	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).
Duration of Response (DOR) by PD-L1 Expression	From the date of first documented objective response and the date of the first subsequent disease progression or death, whichever occurred first, up to approximately 73 months	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. 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.
Progression Free Survival (PFS) by PD-L1 Expression	From first dose of study medication to the date of progression or death, whichever occurs first, up to approximately 29 months	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.
Overall Survival Rate (OSR)	From first dose of study medication to the date of death for any cause, up to approximately 73 months	The percentage of participants 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 percentage was calculated by the product-limit method (Kaplan-Meier estimate), which takes into account censored data. The overall survival rate (OSR) for a participant was defined as the time from the date of first dose of study medication to the date of death for any cause. A participant who had not died was censored at last known date alive.
Percent Probability for Progression Free Survival Rate (PFSR)	From first dose up to the specified timepoints of 3, 6, 9, 12, and 24 months	The Progression Free Survival Rate (PFSR) is defined as the probability of a participant remaining progression free or survival to time t, where t is equal to the specified timepoints. This probability will be calculated by the product limit method (Kaplan-Meier estimates) which takes into account censored data. Medians and 95% confidence interval are estimated using the Kaplan-Meier method. If there is an insufficient number of events, the median and confidence intervals cannot be calculated.

Trial Locations

Locations (14): Dana Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Local Institution - 0016
🇳🇱
Amsterdam, Netherlands
University Of Chicago
🇺🇸
Chicago, Illinois, United States
Massachusetts General Hospital
🇺🇸
Boston, Massachusetts, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸
New York, New York, United States
Local Institution - 0008
🇪🇸
Pamplona, Spain
The University Of Texas MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
University of Washington - Seattle Cancer Care Alliance
🇺🇸
Seattle, Washington, United States
Providence Portland Medical Center
🇺🇸
Portland, Oregon, United States
Sidney kimmel comprehensive cancer center at johns hopkins
🇺🇸
Lutherville, Maryland, United States
Beth Israel Deaconess Medical Center (BIDMC)
🇺🇸
Boston, Massachusetts, United States
Vanderbilt-Ingram Cancer Ctr
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Nashville, Tennessee, United States
Ucla
🇺🇸
Los Angeles, California, United States
University Of Virginia
🇺🇸
Charlottesville, Virginia, United States