Biomarkers in Immunotherapy of Melanoma

Study Overview
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Brief Summary
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Background: Immunotherapy has been successful in treating advanced melanoma, but a large proportion of patients do not respond to the treatment with immune checkpoint inhibitors (ICIs). Preclinical and small cohort studies suggest biomarkers from the primary tumor, stool and body fluids as markers of response. This prospective study will evaluate gastrointestinal microbiome (bacterial spices and virome) composition and exosomal mRNA expression of PD-L1 and IFNγ correlation with radiological response rates to ICIs treatment of advanced melanoma patients. Methods: Patients treated with immune checkpoint inhibitors as a first line treatment for metastatic melanoma are recruted to the study. Stool samples are submitted before the start of treatment, at the 12 (+/-2) week and 28 (+/-4) week, and at the event ( such as, suspected disease progression/hyperprogressio, immune related adverse event (irAE), etc). Peripheral venous blood samples are taken additionaly at the same time points for cytologic and molecular tests. Histological material from the tumor tissue is obtained before the start of immunotherapy treatment. Primary objectives are to determine whether human gastrointestinal microbiome (bacterial and viral) and exosomal mRNA expression of PD-L1 and IFNγ predict response to treatment with PD-1 and CTLA-4 inhibitors and are associated with occurrence of irAE in patients with metastatic melanoma at different time points. Response is evaluated radiologically with imaging methods in accordance with the irRECIST criteria. Conclussion: Despite the great success of the treatment of metastatic melanoma with immunotherapy, there remains a significant proportion of patients who do not respond to treatment or who develop severe adverse events during treatment. Identification of novel predictive and prognostic biomarkers for immunotherapy treatment response is therefore necessary. This study is the first to combine and investigate multiple potential predictive and prognostic biomarkers and its dynamics. The results could serve for a better and multi-level understanding of the various factors influencing immunotherapy treatment.

Official Title
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Effectiveness of Immunotherapy in the First-line Treatment of Disseminated Melanoma and Recognition of Prognostic and Predictive Biomarkers From the Primary Tumor, Stool and Body Fluids: PROTOCOL TRIAL

Conditions
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Metastatic Melanoma, Immune Checkpoints Inhibitors, Gastrointestinal Microbiome (Bacterial and Viral), Exosomal mRNA Expression of PD-L1 and IFNγ

Intervention / Treatment
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* Drug: Immune checkpoint inhibitor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age over 18 years Cytologically or histologically verified malignant melanoma Stage IIID unresectable/IV according to AJCC classification (8th edition, 2018) Performance status according to WHO 0 - 2 (ECOG criteria) 1st line of systemic treatment with immunotherapy (nivolumab, ipi/nivo, pembrolizumab) Triple CT/PET CT done within 4 weeks before the first application Signed consent to participate in clinical research Exclusion Criteria: Previously treated melanoma with systemic therapy Capacity status according to WHO 3 - 4 (ECOG criteria) Contraindications for immunotherapy treatment (known deficiency of the immune system or active immunosuppressive treatment or active autoimmune disease requiring treatment) Other malignant diseases (except cured basal cell carcinoma and squamous cell carcinoma)

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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Immune checkpoint inhibitors<br> | Drug: Immune checkpoint inhibitor<br>* Identification of novel predictive and prognostic biomarkers for immunotherapy treatment response in metastatic melanoma<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| response prediction in first line immune checkpoint inhibitors treatment in metastatic melanoma assessed by human gastrointestinal microbiome (bacterial and viral) and exosomal mRNA expression of PD-L1 and IFNγ | Primary objectives are to determine whether human gastrointestinal microbiome (bacterial and viral) and exosomal mRNA expression of PD-L1 and IFNγ predicts response to treatment with PD-1 and CTLA-4 inhibitors and are associated with occurrence of irAE in patients with metastatic melanoma. | 3 years |