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

• 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: Bristol-Myers Squibb
• Information provided by (Responsible Party): Bristol-Myers Squibb

Tracking Information

• First Submitted Date: June 14, 2012
• First Posted Date: June 18, 2012
• Results First Submitted Date: September 12, 2018
• Results First Posted Date: December 3, 2019
• Last Update Posted Date: December 3, 2019
• Actual Study Start Date: September 27, 2012
• Actual Primary Completion Date: September 12, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 14, 2019)

• 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
• 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.

Original Primary Outcome Measures (submitted: June 15, 2012)

• Immunomodulatory effects of BMS-936558 as measured by changes from baseline in activated and memory T cells, interferon, interferon inducible factors, and CD4 and CD8 T cell infiltration [ Time Frame: Pre-dose day 1 ]
• Immunomodulatory effects of BMS-936558 as measured by changes from baseline in activated and memory T cells, interferon, interferon inducible factors, and CD4 and CD8 T cell infiltration [ Time Frame: Up to day 57 (Cycle 2 Day 1) ]

Current Secondary Outcome Measures (submitted: November 14, 2019)

• 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.
• 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.
• 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)
• 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)
• 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.
• 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.
• 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).
• 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.
• 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)
• 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).
• 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.
• 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.
• 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
• 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

Original Secondary Outcome Measures (submitted: June 15, 2012)

• Safety and tolerability of BMS-936558 as measured by the incidence of adverse events (AEs), serious AEs, death, and changes in vital signs [ Time Frame: Up to 14 weeks after last dose of study drug ]
• Safety and tolerability of BMS-936558 as measured by laboratory test abnormalities [ Time Frame: Every 2 weeks up to 14 weeks after last treatment ]
• Antitumor Activity of BMS-936558 as measured by the objective response rate (ORR), duration of response, and progression free survival (PFS) [ Time Frame: Every 8 weeks until confirmed disease progression and in follow-up if no progression ]
• Immunogenicity of BMS-936558 as measured by the frequency of subjects with at least one positive ADA assessment and the frequency of subjects who develop anti-drug antibodies (ADA) after a negative baseline assessment [ Time Frame: 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, and at Follow-up visits 1 (49±3 days after last treatment) and Follow-up visit 2 (90-120 days since last treatment) ]
• Association between Programmed cell death ligand 1 (PD-L1) and clinical efficacy will be measured by PDL1 expression levels clinical activity (ORR, PFS) [ Time Frame: Pre-dose Up to Day 1 (screening) and Day 29 of cycle 1 ]
  Screening (day -7 to day 1 predose)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: PH 1 Biomarker Study of Nivolumab and Ipilimumab and Nivolumab in Combination With Ipilimumab in Advanced Melanoma
• 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)
• 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

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Basic Science

Condition

• Advanced Melanoma
• Metastatic Melanoma

Intervention

• Biological: Nivolumab
  Other Name: BMS-936558 (MDX1106)
• Drug: Ipilimumab
  Other Names:

  • BMS734016
  • Yervoy

Study Arms

• Experimental: Part 1-Cohort 1 and 2: Nivolumab
  Nivolumab 3 mg/kg solution intravenously Every 2 weeks, Up to 2 years depending on response
  Intervention: Biological: Nivolumab
• 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
  Interventions:

  • Biological: Nivolumab
  • Drug: Ipilimumab
• 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
  Interventions:

  • Biological: Nivolumab
  • Drug: Ipilimumab
• Experimental: Part 3-Arm B: Nivolumab
  Nivolumab 3 mg/kg solution intravenously as specified
  Intervention: Biological: Nivolumab
• 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
  Interventions:

  • Biological: Nivolumab
  • Drug: Ipilimumab
• Experimental: Part 4-Arm E: Nivolumab
  Nivolumab 3 mg/kg solution intravenously as specified
  Intervention: Biological: Nivolumab

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 14, 2019): 227
• Original Estimated Enrollment (submitted: June 15, 2012): 80
• Actual Study Completion Date: October 25, 2018
• Actual Primary Completion Date: September 12, 2017 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Netherlands, Spain, United States

Administrative Information

• NCT Number: NCT01621490
• Other Study ID Numbers: CA209-038; 2012-001840-23 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Bristol-Myers Squibb
• Original Responsible Party: Same as current
• Current Study Sponsor: Bristol-Myers Squibb
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

• PRS Account: Bristol-Myers Squibb
• Verification Date: November 2019