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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01621490
Recruitment Status : Completed
First Posted : June 18, 2012
Results First Posted : December 3, 2019
Last Update Posted : December 3, 2019
Sponsor:
Information provided by (Responsible Party):
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)

Condition or disease Intervention/treatment Phase
Advanced Melanoma Metastatic Melanoma Biological: Nivolumab Drug: Ipilimumab Phase 1

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 227 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: 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)
Actual Study Start Date : September 27, 2012
Actual Primary Completion Date : September 12, 2017
Actual Study Completion Date : October 25, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

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 Name: 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
Biological: Nivolumab
Other Name: BMS-936558 (MDX1106)

Drug: Ipilimumab
Other Names:
  • BMS734016
  • Yervoy

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
Biological: Nivolumab
Other Name: BMS-936558 (MDX1106)

Drug: Ipilimumab
Other Names:
  • BMS734016
  • Yervoy

Experimental: Part 3-Arm B: Nivolumab
Nivolumab 3 mg/kg solution intravenously as specified
Biological: Nivolumab
Other Name: 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
Biological: Nivolumab
Other Name: BMS-936558 (MDX1106)

Drug: Ipilimumab
Other Names:
  • BMS734016
  • Yervoy

Experimental: Part 4-Arm E: Nivolumab
Nivolumab 3 mg/kg solution intravenously as specified
Biological: Nivolumab
Other Name: BMS-936558 (MDX1106)




Primary Outcome Measures :
  1. Median Change From Baseline to Week 7, of Interferon (IFN) and Interferon Gamma (IFN-gamma) Inducible Factors [ Time Frame: 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

  2. 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 [ Time Frame: 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 :
  1. Safety and Tolerability of Nivolumab, Ipilimumab and Nivolumab in Combination With Ipilimumab as Measured by the Number of Deaths and AEs [ Time Frame: Includes events reported between first dose and up to 100 days after last dose of study medication. ]
    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.

  2. Safety and Tolerability of Nivolumab, Ipilimumab and Nivolumab in Combination With Ipilimumab as Measured by SAEs and AEs Leading to Discontinuation of Study Drug. [ Time Frame: From enrollment to 100 days after the last dose date ]
    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.

  3. Number of Laboratory Abnormalities in Specific Liver Tests [ Time Frame: 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)

  4. Number of Laboratory Abnormalities in Specific Thyroid Tests [ Time Frame: 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)

  5. Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Objective Response Rate (ORR) [ Time Frame: Approximately every 8 weeks until disease progression and in follow-up if no progression ]
    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.

  6. Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Median Duration of Response (mDOR) [ Time Frame: 2 years from the first dose of treatment ]
    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.

  7. Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Median Time to Response (mTTR) [ Time Frame: 2 years from the first dose of treatment ]
    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).

  8. Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Progression Free Survival Rate (PFSR) [ Time Frame: 2 years from the first dose of treatment ]
    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.

  9. 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: 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)

  10. Association Between Programmed Cell Death Ligand 1 (PD-L1) and Clinical Efficacy Measures Such as Objective Response Rate (PD-L1 ORR) [ Time Frame: 2 years from first dose of treatment; Assessed up to September 2017 ]
    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).

  11. Association Between Programmed Cell Death Ligand 1 (PD-L1) and Clinical Efficacy Measures Such as the Duration of Response (PD-L1 DOR) [ Time Frame: 2 years from first dose of treatment; Assessed up to September 2017 ]
    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.

  12. Association Between Programmed Cell Death Ligand 1 (PD-L1) and Clinical Efficacy Measures Such as Progression Free Survival (PD-L1 PFS) [ Time Frame: 2 years from first dose of treatment; Assessed up to September 2017 ]
    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.

  13. Association Between Programmed Cell Death Ligand 1 (PD-L1) and Clinical Efficacy Measures Such as Overall Survival Rate (PD-L1 OSR) [ Time Frame: 2 years from first dose of treatment; Assessed up to September 2017 ]
    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

  14. Antitumor Activity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Overall Survival Rate (OSR) [ Time Frame: 2 years from first dose of treatment; Assessed up to September 2017 ]
    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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01621490


Locations
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United States, California
Ucla
Los Angeles, California, United States, 90095
United States, Illinois
University Of Chicago
Chicago, Illinois, United States, 60637
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center At Johns Hopkins
Lutherville, Maryland, United States, 21093
United States, Massachusetts
Beth Israel Deaconess Medical Center (BIDMC)
Boston, Massachusetts, United States, 02215
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02215
Massachusetts General Hospital
Boston, Massachusetts, United States, 02215
United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
United States, Oregon
Providence Portland Medical Center
Portland, Oregon, United States, 97213
United States, Tennessee
Vanderbilt-Ingram Cancer Ctr
Nashville, Tennessee, United States, 37232
United States, Texas
The University Of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
United States, Virginia
University Of Virginia
Charlottesville, Virginia, United States, 22908
United States, Washington
Seattle Cancer Care Alliance
Seattle, Washington, United States, 98109
Netherlands
Local Institution
Amsterdam, Netherlands, 1066 CX
Spain
Local Institution
Pamplona, Spain, 31192
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
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Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  Study Documents (Full-Text)

Documents provided by Bristol-Myers Squibb:
Study Protocol  [PDF] October 25, 2016
Statistical Analysis Plan  [PDF] March 27, 2016


Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT01621490    
Other Study ID Numbers: CA209-038
2012-001840-23 ( EudraCT Number )
First Posted: June 18, 2012    Key Record Dates
Results First Posted: December 3, 2019
Last Update Posted: December 3, 2019
Last Verified: November 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Nivolumab
Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents