PH 1 Biomarker Study of Nivolumab and Ipilimumab and Nivolumab in Combination With Ipilimumab in Advanced Melanoma (PD-1)

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)

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)

Study Overview

• Status: Completed
• Conditions: Metastatic Melanoma; Advanced Melanoma
• Intervention / Treatment: Drug: Ipilimumab; Biological: Nivolumab

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

• Study Type: Interventional
• Enrollment (Actual): 170
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Local Institution - 0016
• Spain
  • Pamplona, Spain, 31192
    • Local Institution - 0008
• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA
  • Illinois
    • Chicago, Illinois, United States, 60637-1443
      • University of Chicago
  • Maryland
    • Lutherville, Maryland, United States, 21093
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
    • Boston, Massachusetts, United States, 02215
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center (BIDMC)
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Portland Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Ctr
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia
  • Washington
    • Seattle, Washington, United States, 98109
      • University of Washington - Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1-Cohort 1 and 2: Nivolumab; Nivolumab 3 mg/kg solution intravenously Every 2 weeks, Up to 2 years depending on response	Biological: Nivolumab; Other Names: BMS-936558 (MDX1106)
Experimental: Part 2-Arm A: Nivolumab + Ipilimumab; Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified	Drug: Ipilimumab; Other Names: Yervoy; BMS734016; Biological: Nivolumab; Other Names: BMS-936558 (MDX1106)
Experimental: Part 3-Arm A: Nivolumab + Ipilimumab; Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified	Drug: Ipilimumab; Other Names: Yervoy; BMS734016; Biological: Nivolumab; Other Names: BMS-936558 (MDX1106)
Experimental: Part 3-Arm B: Nivolumab; Nivolumab 3 mg/kg solution intravenously as specified	Biological: Nivolumab; Other Names: BMS-936558 (MDX1106)
Experimental: Part 4-Arm D: Nivolumab + Ipilimumab; Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified	Drug: Ipilimumab; Other Names: Yervoy; BMS734016; Biological: Nivolumab; Other Names: BMS-936558 (MDX1106)
Experimental: Part 4-Arm E: Nivolumab; Nivolumab 3 mg/kg solution intravenously as specified	Biological: Nivolumab; Other Names: BMS-936558 (MDX1106)

What is the study measuring?

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
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.
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)
Frequency of Adverse Events or Death	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.	Includes events reported between first dose and up to 100 days after last dose of study medication (up to approximately 73 months).
Frequency of AEs Leading to Discontinuation of Study Drug and SAEs	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.	From enrollment to 100 days after the last dose date (up to approximately 73 months)
Objective Response Rate (ORR)	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.	Approximately every 8 weeks until disease progression and in follow-up if no progression (up to approximately 73 months)
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.	From date of first documented objective response to date of disease progression or death, up to approximately 27 months
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).	From the first dosing date to the date of the first documented objective response, up to approximately 15 months
Progression Free Survival (PFS)	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.	From first dose of study medication to the date of progression or death, whichever occurs first, up to approximately 29 months
Objective Response Rate (ORR) by PD-L1 Expression	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).	Approximately every 8 weeks until disease progression and in follow-up if no progression (up to approximately 73 months)
Duration of Response (DOR) by PD-L1 Expression	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.	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
Progression Free Survival (PFS) by PD-L1 Expression	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.	From first dose of study medication to the date of progression or death, whichever occurs first, up to approximately 29 months
Overall Survival Rate (OSR)	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.	From first dose of study medication to the date of death for any cause, up to approximately 73 months
Percent Probability for Progression Free Survival Rate (PFSR)	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.	From first dose up to the specified timepoints of 3, 6, 9, 12, and 24 months

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb
• Investigators: Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Publications and helpful links

General Publications

• Kim YJ, Sheu KM, Tsoi J, Abril-Rodriguez G, Medina E, Grasso CS, Torrejon DY, Champhekar AS, Litchfield K, Swanton C, Speiser DE, Scumpia PO, Hoffmann A, Graeber TG, Puig-Saus C, Ribas A. Melanoma dedifferentiation induced by IFN-gamma epigenetic remodeling in response to anti-PD-1 therapy. J Clin Invest. 2021 Jun 15;131(12):e145859. doi: 10.1172/JCI145859.
• Anagnostou V, Bruhm DC, Niknafs N, White JR, Shao XM, Sidhom JW, Stein J, Tsai HL, Wang H, Belcaid Z, Murray J, Balan A, Ferreira L, Ross-Macdonald P, Wind-Rotolo M, Baras AS, Taube J, Karchin R, Scharpf RB, Grasso C, Ribas A, Pardoll DM, Topalian SL, Velculescu VE. Integrative Tumor and Immune Cell Multi-omic Analyses Predict Response to Immune Checkpoint Blockade in Melanoma. Cell Rep Med. 2020 Nov 17;1(8):100139. doi: 10.1016/j.xcrm.2020.100139. eCollection 2020 Nov 17.
• Stein JE, Soni A, Danilova L, Cottrell TR, Gajewski TF, Hodi FS, Bhatia S, Urba WJ, Sharfman WH, Wind-Rotolo M, Edwards R, Lipson EJ, Taube JM. Major pathologic response on biopsy (MPRbx) in patients with advanced melanoma treated with anti-PD-1: evidence for an early, on-therapy biomarker of response. Ann Oncol. 2019 Apr 1;30(4):589-596. doi: 10.1093/annonc/mdz019.

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting
• FDA Safety Alerts and Recalls

Study record dates

Study Major Dates

• Study Start (Actual): September 27, 2012
• Primary Completion (Actual): September 12, 2017
• Study Completion (Actual): October 25, 2018

Study Registration Dates

• First Submitted: June 14, 2012
• First Submitted That Met QC Criteria: June 15, 2012
• First Posted (Estimated): June 18, 2012

Study Record Updates

• Last Update Posted (Actual): April 23, 2024
• Last Update Submitted That Met QC Criteria: April 19, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Melanoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab; Ipilimumab
• Other Study ID Numbers: CA209-038; 2012-001840-23 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No