Biomarkers in Immunotherapy of Melanoma

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

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.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Melanoma; Immune Checkpoints Inhibitors; Gastrointestinal Microbiome (Bacterial and Viral); Exosomal mRNA Expression of PD-L1 and IFNγ
• Intervention / Treatment: Drug: Immune checkpoint inhibitor

Detailed Description

The goal of this [type of study: observational study or clinical trial] is to [learn about, test, compare etc.] in [describe participant population/health conditions]. The main question[s] it aims to answer are:

• [question 1]
• [question 2] Participants will [describe the main tasks participants will be asked to do, treatments they'll be given and use bullets if it is more than 2 items].

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Tanja Mesti; Phone Number: 0038615879287; Email: tmesti@onko-i.si

Study Locations

• Slovenia
  • Ljubljana, Slovenia
    • Recruiting
    • Institute of Oncology Ljubljana
    • Contact: Tanja Mesti; Phone Number: +38615879287; Email: tmesti@onko-i.si

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Immune checkpoint inhibitors	Drug: Immune checkpoint inhibitor; Identification of novel predictive and prognostic biomarkers for immunotherapy treatment response in metastatic melanoma

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Institute of Oncology Ljubljana
• Collaborators: University Medical Centre Ljubljana; University of Ljubljana; Blood Transfusion Centre of Slovenia

Study record dates

Study Major Dates

• Study Start (Actual): October 5, 2022
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: April 19, 2023
• First Submitted That Met QC Criteria: May 17, 2023
• First Posted (Actual): May 30, 2023

Study Record Updates

• Last Update Posted (Actual): October 18, 2024
• Last Update Submitted That Met QC Criteria: October 16, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Melanoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors
• Other Study ID Numbers: ERIDNPVO-0034/2021

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No