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A Biomarker Study in Advanced Mucosal or Acral Lentiginous Melanoma Receiving Nivolumab in Combination With Ipilimumab

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ClinicalTrials.gov Identifier: NCT02978443
Recruitment Status : Recruiting
First Posted : December 1, 2016
Last Update Posted : May 21, 2019
Sponsor:
Collaborators:
Melanoma Research Foundation Breakthrough Consortium
Bristol-Myers Squibb
University of Colorado, Denver
University of California, San Francisco
Vanderbilt University
Columbia University
University of Pittsburgh
Yale University
M.D. Anderson Cancer Center
H. Lee Moffitt Cancer Center and Research Institute
Memorial Sloan Kettering Cancer Center
Northwestern University
Dana-Farber Cancer Institute
Information provided by (Responsible Party):
Georgetown University

Tracking Information
First Submitted Date  ICMJE November 23, 2016
First Posted Date  ICMJE December 1, 2016
Last Update Posted Date May 21, 2019
Actual Study Start Date  ICMJE December 2016
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 28, 2016)
Objective response rate (ORR) with mucosal melanoma (MCM) [ Time Frame: 24 months ]
ORR, defined as complete response [CR] + partial response [PR] per RECIST 1.1 criteria and to compare this response rate to the response rate of patients with "good" molecular predictive features
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02978443 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 28, 2016)
  • Objective response rate with acral lentiginous melanoma (ALM) [ Time Frame: 24 months ]
    ORR, defined as complete response [CR] + partial response [PR] per RECIST 1.1 criteria and to compare this response rate to the response rate of patients with "good" molecular predictive features
  • Progression-free survival (PFS) [ Time Frame: 36 months ]
    PFS will be assessed for each cohort
  • Overall survival (OS) [ Time Frame: 36 months ]
    OS will be assessed for each cohort
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Biomarker Study in Advanced Mucosal or Acral Lentiginous Melanoma Receiving Nivolumab in Combination With Ipilimumab
Official Title  ICMJE A Study to Estimate the Anti-Tumor Activity and Identify Potential Predictors of Response in Patients With Advanced Mucosal or Acral Lentiginous Melanoma Receiving Standard Nivolumab in Combination With Ipilimumab Followed by Nivolumab Monotherapy
Brief Summary Participants with advanced or metastatic mucosal melanoma (cohort A) and acral lentiginous melanoma (cohort B) eligible for treatment with nivolumab in combination with ipilimumab followed by nivolumab therapy will submit tissue blocks from tumors of malignant melanoma for histopathology review and immunohistochemistry analysis at Georgetown University-Lombardi Comprehensive Cancer Center. Pretreatment blood will be drawn and stored in the Melanoma Research Foundation Breakthrough Consortium Virtual Repository at each participating institution. At the end of participation, samples will be sent to Georgetown University-Lombardi Comprehensive Cancer Center for processing and storage. An optional pretreatment biopsy of an accessible tumor lesion will be performed in a subset of enrolled patients. Patients will receive nivolumab in combination with ipilimumab according to the standard FDA approved treatment regimen.
Detailed Description

Immunotherapy with HD-IL-2 has produced durable benefit in 10% of patients with metastatic cutaneous melanoma. The antitumor activity of IL-2 has been limited at least in part by immunosuppressive and immune-regulatory forces within the tumor microenvironment. Antibodies against CTLA4 (e.g. ipilimumab), PD1 and its ligand (PD-L1) produced long-term benefit in approximately 20-40% of patients with advanced melanoma. In addition, the combination of ipilimumab with the anti-PD1 antibody, nivolumab, has shown tumor responses in up to 60% of patients with advanced melanoma. These findings have led to FDA approval of ipilimumab and nivolumab as an indication for treatment of patients with advanced melanoma and nivolumab for other cancers. While these data are exciting, only a few patients enrolled to the prior studies had metastatic MCM or ALM. There is no prospective immunotherapy studies conducted in MCM or ALM-specific population. Therefore the activity of the ipilimumab + nivolumab combination in these subsets or patients remains unknown

Reliable predictive biomarkers for the use of immune checkpoint inhibitors are needed to identify pretreatment those patients most likely to respond and early on in treatment assays could help identify mechanisms of tumor response and resistance necessary to improve therapy. Although tumor PD-L1 expression in tumor confers higher treatment response rate, responses to nivolumab or nivolumab + ipilimumab alone were noted in 55% and 41% of patients, respectively, with PD-L1- tumors. Therefore, more reliable predictive biomarkers are needed.

Recently, extensive studies on metastatic colorectal cancer have demonstrated that a new scoring system as well as density of immune cells infiltrates at the center of the tumor and its invasive margin, described as Immunoscore, could accurately separate a group of patients with high Immunoscore with improved DFS, and OS from those with low Immunoscore where the histopathological staging system cannot. A recent study has also demonstrated relationship between degree of pre-treatment CD8+ tumor infiltrating lymphocytes (TILs) infiltration and PD-L1 expression at the invasive margin of the advanced cutaneous melanoma and improved long-term clinical benefits in patients with advanced melanoma who received pembrolizumab monotherapy. Further, there appeared to be an association between tumor response and clonality of the immune infiltrate based on a next-generation sequencing method used to evaluate T-cell receptor rearrangement pre- and in response to checkpoint inhibitor therapy. Also, high mutational burden correlated with overall survival in patients with cutaneous melanoma treated with ipilimumab or lung cancer treated with anti-PD1. However, the biology of MCM and ALM are distinct from cutaneous melanoma at multiple levels. Consequently, the utility of predictive biomarkers developed for cutaneous melanoma remains unknown.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acral Lentiginous Melanoma
  • Mucosal Melanoma
Intervention  ICMJE
  • Drug: Nivolumab
    Other Names:
    • BMS-936558
    • Opdivo
  • Drug: Ipilimumab
    Other Names:
    • BMS-734016
    • Yervoy
Study Arms  ICMJE Experimental: Nivolumab-Ipilimumab Combination Therapy
All patients will receive nivolumab administered IV over 60 minutes at 1 mg/kg combined with ipilimumab administered IV over 90 minutes at 3 mg/kg every 3 weeks for 4 treatment cycles (Induction) then continue with nivolumab administered IV over 60 minutes at 3 mg/kg every 2 weeks until progression, intolerable toxicity, or a maximum of 48 weeks, whichever comes first (Maintenance). Patients exhibiting complete response (CR) should continue nivolumab monotherapy at least 12 weeks beyond documentation of CR, if possible.
Interventions:
  • Drug: Nivolumab
  • Drug: Ipilimumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 28, 2016)
72
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2020
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients must have histologically confirmed MCM or ALM that is metastatic or unresectable.
  • Patients must be eligible to receive nivolumab in combination with ipilimumab treatment per institutional guidelines.
  • Patients must have a tissue block (or 20 unstained slides) available with adequate tumor to perform multiplex immunohistochemistry and nucleic acids analyses ( i.e. whole exome sequencing) Patients with only a previous fine-needle aspirate are ineligible for enrollment.
  • Patients must be willing to donate a small amount of whole blood prior to treatment and during treatment for laboratory analysis.
  • Patients must give informed consent prior to initiation of therapy.
  • Patients must be ambulatory with good performance status (ECOG 0 or 1)

Exclusion Criteria:

  • Patients who do not have available tissue for immunohistochemistry and nucleic acids analyses.
  • Patients who have received prior immunotherapy for unresectable or metastatic disease.
  • Patients with untreated brain metastases, leptomeningeal disease, or seizure disorders are ineligible. Patients with a history of brain metastases must have completed treatment (i.e. surgery or radiation) 1 month prior to enrollment and have no evidence of disease or edema on brain CT or head MRI.
  • Patients with inadequate tissue for analysis.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02978443
Other Study ID Numbers  ICMJE 2016-0420
CA209-763 ( Other Identifier: Bristol-Myer Squibb (BMS) )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Georgetown University
Study Sponsor  ICMJE Georgetown University
Collaborators  ICMJE
  • Melanoma Research Foundation Breakthrough Consortium
  • Bristol-Myers Squibb
  • University of Colorado, Denver
  • University of California, San Francisco
  • Vanderbilt University
  • Columbia University
  • University of Pittsburgh
  • Yale University
  • M.D. Anderson Cancer Center
  • H. Lee Moffitt Cancer Center and Research Institute
  • Memorial Sloan Kettering Cancer Center
  • Northwestern University
  • Dana-Farber Cancer Institute
Investigators  ICMJE
Study Chair: Suthee Rapisuwon, MD Lombardi Comprehensive Cancer Center
PRS Account Georgetown University
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP