Clinical Trials /

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

NCT02978443

Description:

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.

Related Conditions:
  • Acral Lentiginous Melanoma
  • Mucosal Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Biomarker Study in Advanced Mucosal or Acral Lentiginous Melanoma Receiving Nivolumab in Combination With Ipilimumab
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 2016-0420
  • SECONDARY ID: CA209-763
  • NCT ID: NCT02978443

Conditions

  • Acral Lentiginous Melanoma
  • Mucosal Melanoma

Interventions

DrugSynonymsArms
NivolumabBMS-936558, OpdivoNivolumab-Ipilimumab Combination Therapy
IpilimumabBMS-734016, YervoyNivolumab-Ipilimumab Combination Therapy

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Nivolumab-Ipilimumab Combination TherapyAll 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.
  • Nivolumab
  • Ipilimumab

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR) with mucosal melanoma (MCM)
Time Frame:24 months
Safety Issue:
Description: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

Measure:Objective response rate with acral lentiginous melanoma (ALM)
Time Frame:24 months
Safety Issue:
Description: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
Measure:Progression-free survival (PFS)
Time Frame:36 months
Safety Issue:
Description:PFS will be assessed for each cohort
Measure:Overall survival (OS)
Time Frame:36 months
Safety Issue:
Description:OS will be assessed for each cohort

Details

Phase:N/A
Primary Purpose:Observational
Overall Status:Recruiting
Lead Sponsor:Georgetown University

Trial Keywords

  • Melanoma
  • Mucosal
  • Acral Lentiginous
  • Ipilimumab
  • Nivolumab
  • Anti-tumor
  • Potential Predictors
  • Opdivo
  • Yervoy

Last Updated

November 16, 2017