Clinical trial NCT01621490: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Melanoma
Metastatic Melanoma
Lead sponsor: Bristol-Myers Squibb
Sponsor class: INDUSTRY
First posted: 2012-06-18
Enrollment: 170
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

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

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

Primary outcomes:
measure: Median Change From Baseline to Week 7, of Interferon (IFN) and Interferon Gamma (IFN-gamma) Inducible Factors
timeFrame: From last non-missing value prior to first dose to week 7 day 1
measure: 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
timeFrame: From last non-missing value prior to first dose to week 4 day 1
Secondary outcomes:
measure: Frequency of Adverse Events or Death
timeFrame: Includes events reported between first dose and up to 100 days after last dose of study medication (up to approximately 73 months).
measure: Frequency of AEs Leading to Discontinuation of Study Drug and SAEs
timeFrame: From enrollment to 100 days after the last dose date (up to approximately 73 months)
measure: Number of Laboratory Abnormalities in Specific Liver Tests
timeFrame: 101-120 days after last dose.
measure: Number of Laboratory Abnormalities in Specific Thyroid Tests
timeFrame: 101-120 days after last dose.
measure: Objective Response Rate (ORR)
timeFrame: Approximately every 8 weeks until disease progression and in follow-up if no progression (up to approximately 73 months)
measure: Median Duration of Response (mDOR)
timeFrame: From date of first documented objective response to date of disease progression or death, up to approximately 27 months
measure: Median Time to Response (mTTR)
timeFrame: From the first dosing date to the date of the first documented objective response, up to approximately 15 months
measure: Progression Free Survival (PFS)
timeFrame: From first dose of study medication to the date of progression or death, whichever occurs first, up to approximately 29 months
measure: 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
timeFrame: Up to follow-up visit 2 (101-120 days since last treatment)
measure: Objective Response Rate (ORR) by PD-L1 Expression
timeFrame: Approximately every 8 weeks until disease progression and in follow-up if no progression (up to approximately 73 months)
measure: Duration of Response (DOR) by PD-L1 Expression
timeFrame: 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
measure: Progression Free Survival (PFS) by PD-L1 Expression
timeFrame: From first dose of study medication to the date of progression or death, whichever occurs first, up to approximately 29 months
measure: Overall Survival Rate (OSR)
timeFrame: From first dose of study medication to the date of death for any cause, up to approximately 73 months
measure: Percent Probability for Progression Free Survival Rate (PFSR)
timeFrame: From first dose up to the specified timepoints of 3, 6, 9, 12, and 24 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Ucla
state: California
city: Chicago
country: United States
facility: University Of Chicago
state: Illinois
city: Lutherville
country: United States
facility: Sidney kimmel comprehensive cancer center at johns hopkins
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center (BIDMC)
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Ctr
state: Tennessee
city: Houston
country: United States
facility: The University Of Texas MD Anderson Cancer Center
state: Texas
city: Charlottesville
country: United States
facility: University Of Virginia
state: Virginia
city: Seattle
country: United States
facility: University of Washington - Seattle Cancer Care Alliance
state: Washington
city: Amsterdam
country: Netherlands
facility: Local Institution - 0016
city: Pamplona
country: Spain
facility: Local Institution - 0008
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.