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

Metastatic Melanoma Clinical Trial

— PD-1  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01621490
• Other study ID #: CA209-038
• Secondary ID: 2012-001840-23
• Status: Completed
• Phase: Phase 1
• Start date: September 27, 2012
• Est. completion date: October 25, 2018

Study information

• Verified date: April 2024
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

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 information / eligibility

• Status: Completed
• Enrollment: 170
• Est. completion date: October 25, 2018
• Est. primary completion date: September 12, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Advanced Melanoma
• Melanoma
• Metastatic Melanoma

Intervention

Biological:
• Nivolumab

Drug:
• Ipilimumab

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Netherlands,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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).
Secondary	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)
Secondary	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.
Secondary	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.
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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

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