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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

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.

Condition or disease Intervention/treatment Phase
Acral Lentiginous Melanoma Mucosal Melanoma Drug: Nivolumab Drug: Ipilimumab Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : December 2016
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2020


Arm Intervention/treatment
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.
Drug: Nivolumab
Other Names:
  • BMS-936558
  • Opdivo

Drug: Ipilimumab
Other Names:
  • BMS-734016
  • Yervoy




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. Progression-free survival (PFS) [ Time Frame: 36 months ]
    PFS will be assessed for each cohort

  3. Overall survival (OS) [ Time Frame: 36 months ]
    OS will be assessed for each cohort



Information from the National Library of Medicine

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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

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.

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): NCT02978443


Locations
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United States, District of Columbia
Lombardi Comprehensive Cancer Center Recruiting
Washington, District of Columbia, United States, 20007
Contact: Paveen Keshtmand, RN    202-687-6871    pnk6@georgetown.edu   
Sub-Investigator: Michael B Atkins, MD         
Sub-Investigator: Geoffrey Gibney, MD         
Principal Investigator: Suthee Rapisuwon, MD         
Washington Cancer Institute at MedStar Washington Hospital Center Recruiting
Washington, District of Columbia, United States, 20010
Contact: Okelue Okobi    202-877-3061    okelue.e.okobi@medstar.net   
Principal Investigator: Suthee Rapisuwon, MD         
United States, Florida
H. Lee Moffitt Cancer Center and Research Institute Recruiting
Tampa, Florida, United States, 33612
Contact: Valerie Moberg    813-745-5170    valerie.moberg@moffitt.org   
Principal Investigator: Zeynep Eroglu, MD         
United States, New Jersey
John Theurer Cacner Center at Hackensack University Medical Center Recruiting
Hackensack, New Jersey, United States, 07601
Contact: Danielle Blair, RN    551-996-5809    danielle.blair@hackensackmeridian.org   
Principal Investigator: Andrew Pecora, MD         
Sponsors and Collaborators
Georgetown University
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
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Study Chair: Suthee Rapisuwon, MD Lombardi Comprehensive Cancer Center

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Responsible Party: Georgetown University
ClinicalTrials.gov Identifier: NCT02978443     History of Changes
Other Study ID Numbers: 2016-0420
CA209-763 ( Other Identifier: Bristol-Myer Squibb (BMS) )
First Posted: December 1, 2016    Key Record Dates
Last Update Posted: May 21, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Georgetown University:
Melanoma
Mucosal
Acral Lentiginous
Ipilimumab
Nivolumab
Anti-tumor
Potential Predictors
Opdivo
Yervoy
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