Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Acral Lentiginous Melanoma

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Ipilimumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

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.

nivolumab administered IV over 60 minutes at 1 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

ipilimumab administered IV over 90 minutes at 3 mg/kg every 3 weeks for 4 treatment cycles (Induction)

Suthee Rapisuwon, MD

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.

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.

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

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

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 is defined as the time from the date of treatment initiation until the date that disease progression criteria are met or the date death without progression, or is censored at the date of last disease assessment without evidence of progression.

OS is calculated from the date of treatment initiation to the date of death, or censored at date of last contact.

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

Georgetown University

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.

Nivolumab: nivolumab administered IV over 60 minutes at 1 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

Ipilimumab: ipilimumab administered IV over 90 minutes at 3 mg/kg every 3 weeks for 4 treatment cycles (Induction)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Biomarker Study in Advanced Mucosal or Acral Lentiginous Melanoma Receiving Nivolumab in Combination With Ipilimumab	NCT02978443	Acral Lentigino... Mucosal Melanom...	Nivolumab Ipilimumab	18 Years -	Georgetown University
A Biomarker Study in Advanced Mucosal or Acral Lentiginous Melanoma Receiving Nivolumab in Combination With Ipilimumab	NCT02978443	Acral Lentigino... Mucosal Melanom...	Nivolumab Ipilimumab	18 Years -	Georgetown University

Spots Global Cancer Trial Database for acral lentiginous