RATIO: Rational Approach To Immuno-Oncology

Study Overview
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Brief Summary
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This trial will utilize a Molecular MicroscopeTM diagnostic system (MMDxTM) that combines the molecular and histopathological features of biopsies, plus clinical and laboratory parameters, to create the first Integrated Diagnostic System. This MMDxTM will be utilized to phenotype cutaneous melanoma biopsy samples to detect an immune responsive mRNA signature.

Detailed Description
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The trial treatment will consist of a pretreatment 18 gauge core biopsy of locally advanced or metastatic cutaneous or subcutaneous lesions. The biopsies will be stabilized on site in RNAlater and shipped to ATAGC by courier at ambient temperature. RNA will be extracted using Trizol-chloroform method and purified using RNAEasy micro kit (Qiagen). RNA samples passing the quality control test (Agilent Bioanalyzer) will be labeled, hybridized to PrimeView Affymetrix microarrays and scanned according to the manufacturer's protocol. Resulting .CEL files will be used for the analysis of the global gene expression. Pathogenesis Based Transcript (PBT) sets that represent molecular signatures of inflammation will be assessed in core biopsies from melanoma patients. Each PBT set gets a score - a summarized expression of all members of a set. PBT scores allow an estimate of pre and post-treatment immunological activity in each tumor e.g. TCMR activity or macrophage burden. PBT scores will be correlated with clinical outcome to determine the utility of this technology as a prognostic and predictive biomarker. Finally a molecular classifier predicting the response to therapy will be built.

Official Title
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Rational Approach To Immuno-Oncology Microarray Prediction of Response to Nivolumab, Ipilimumab, or Combined Therapy in Subjects With Previously Untreated, Locally Advanced or Metastatic Melanoma

Conditions
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Metastatic Melanoma

Intervention / Treatment
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* Procedure: Molecular Microscope Diagnostic system


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women, > 18 years of age Histologically confirmed locally advanced or metastatic melanoma with cutaneous or subcutaneous lesions Immunotherapy treatment naïve subjects (ie, no prior systemic anticancer therapy for unresectable or metastatic melanoma) Scheduled to receive ipilimumab, nivolumab, or combination treatment Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2 Not pregnant or lactating. Women who are of child-bearing potential must agree to use an effective means of birth control (i.e., latex condom, diaphragm, cervical cap, etc) to avoid pregnancy. Informed consent for microarray analysis of locally advanced lesion or skin metastasis retrieved by standard of care biopsy Exclusion Criteria: Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co- stimulation or immune checkpoint pathways Subjects with active, known, or suspected autoimmune disease If considered high-risk and tested for hepatitis: Any positive test result for hepatitis B virus or hepatitis C virus indicating acute or chronic infection Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) Any significant medical condition, laboratory abnormality, or psychiatric illness, that would prevent the subject from participating in the study, places the subject at unacceptable risk if he/she were to participate in the study, or any condition that confounds the ability to interpret data from the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cutaneous Biopsy for microarray analysis<br>To determine whether outcomes improve as a function of anti-tumor immunity which may enable the use of this technique as a predictive biomarker of treatment response. | Procedure: Molecular Microscope Diagnostic system<br>* Consented patients with locally advanced or metastatic melanoma with This trial will utilize a Molecular MicroscopeTM diagnostic system (MMDxTM) that combines the molecular and histopathological features of biopsies, plus clinical and laboratory parameters, to create the first Integrated Diagnostic System. This MMDxTM will be utilized to phenotype cutaneous melanoma biopsy samples to detect an immune responsive mRNA signature.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of the MMDx from pretreatment biopsy with overall response rate (ORR). |  | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) |  | 24 months | 
| Overall Survival (OS) |  | 24 months |