Electrochemotherapy Changes in Tumor Microenvironment of Cutaneous and Subcutaneous Metastases in Melanoma Patients

NCT06388252 | Enrolling By Invitation

• 2 other identifiers: ERID-KSOPR-0049/20230120-297/2023/3
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

In the last 10 years, the treatment of metastatic cutaneous melanoma has changed dramatically. The new systemic treatment with immunotherapy has led to a dramatic improvement in quality of life and overall survival. Systemic treatment means that the patient receives the drug as an infusion into a vein. Unfortunately, investigators know that immunotherapy is not equally successful in all patients. Recent studies have shown that the success of the treatment is not only influenced by the cellular composition of the metastasis, but also by its surroundings. This is called tumor microenvironment. Depending on the differences in the composition of this microenvironment, some metastases can be described as immunologically hot and others as immunologically cold. Immunologically hot metastases respond better to immunotherapy than immunologically cold metastases. Studies have shown that with some interventions can change the tumor microenvironment from being immune-cold to being immune-hot. Electrochemotherapy is one of the interventions that might improve the efficacy of immunotherapy in cutaneous melanoma. Electrochemotherapy is an established method for the local treatment of tumors, in which only a certain tumor is treated with special electrodes, to which a weak electric current is applied. Investigators hypothesize that electrochemotherapy stimulates the body's own immune response and enables more effective treatment. Since immunotherapy also stimulates the body's own immune response to cutaneous melanoma cells, the interaction of the two drugs could be even more successful. Recent research results support this assumption. The primary objective is to evaluate the changes in the tumor microenvironment of cutaneous and subcutaneous melanoma metastases induced by electrochemotherapy, based on the histologic analysis of treated and untreated metastases before and after treatment. The secondary aim is to determine whether the changes in the tumor microenvironment differ depending on the chemotherapeutic agent used. The results will help Investigators better understand the synergistic effects of electrochemotherapy and immunotherapy on cutaneous melanoma metastases. The combination of systemic immunotherapy and electrochemotherapy could become an important treatment method for patients with metastatic melanoma.

Conditions

Cutaneous Malignant Melanoma

Keywords

In-transit melanoma metastases; Cutaneous and subcutaneous melanoma metastases; Electrochemotherapy; Bleomycin; Cysplatin

Outcome Measures

Primary Outcomes (3)

• Change in Tumor-Infiltrating Lymphocytes (TIL) Score Assessed by MIA Scoring System (Azimi et al.)

  Tumor-infiltrating lymphocytes (TILs) will be evaluated semi-quantitatively using the MIA scoring system (Azimi et al.) in tissue samples from treated and untreated cutaneous/subcutaneous melanoma metastases. Assessment will be performed independently by two experienced pathologists.

  Before electrochemotherapy (baseline), 2-4 days after electrochemotherapy, and 9-13 days after electrochemotherapy

• Lymphocyte and Macrophage Distribution Density in Tumor Microenvironment Assessed by Park CH Method

  Distribution densities of lymphocytes and macrophages in the tumor microenvironment will be estimated according to Park CH et al. in biopsies of treated and untreated melanoma metastases. Assessment will be performed independently by two experienced pathologists.

  Before electrochemotherapy (baseline), 2-4 days after electrochemotherapy, and 9-13 days after electrochemotherapy

• Number of Immune Marker-Positive Cells per mm² in Tumor Tissue Assessed by Immunohistochemistry (IHC)

  The number of CD3+, CD4+, CD8+, CD56+, CD163+, FoxP3+, PGM1+, and PD-L1 (CD274)+ cells per mm² will be quantified by immunohistochemistry (IHC) in tissue samples from treated and untreated melanoma metastases. Results will be evaluated independently by two experienced pathologists.

  Before electrochemotherapy (baseline), 2-4 days after electrochemotherapy, and 9-13 days after electrochemotherapy

Secondary Outcomes (2)

• Difference in Change of Tumor-Infiltrating Lymphocytes (TIL) Score (MIA Scoring) Between Bleomycin and Cisplatin Electrochemotherapy

  Before electrochemotherapy (baseline), 2-4 days after electrochemotherapy, and 9-13 days after electrochemotherapy

• Difference in Immune Cell Density and Immune Marker-Positive Cells per mm² Between Bleomycin and Cisplatin Electrochemotherapy

  Before electrochemotherapy (baseline), 2-4 days after electrochemotherapy, and 9-13 days after electrochemotherapy

Study Arms (2)

Electrochemotherapy with Intratumoral Cysplatin

ACTIVE COMPARATOR

ECT will be performed directly after the intratumorally administration of cysplatin (0,5-2 mg/cm3 tumor). CliniporatorTM (IGEA S.P.A., Carpi, Italy) will be used to apply the pulses (8 pulses, 1300 V/cm, 100 μs, 5 kHz). Triggering of the electrical pulses will be synchronized with ECG signals, through the ECG triggering device AccuSync to avoid delivery of pulses in vulnerable period of the heart. The type of electrode used will be selected according to the size and location of the tumors.

Procedure: Electrochemotherapy with Intratumoral Cysplatin

Electrochemotherapy with Intravenous Bleomycin

ACTIVE COMPARATOR

ECT will be performed within 8 - 28 minutes after intravenous bolus administration of bleomycin (15.000 IU/m2 BSA). CliniporatorTM (IGEA S.P.A., Carpi, Italy) will be used to apply the pulses (8 pulses, 1300 V/cm, 100 μs, 5 kHz). Triggering of the electrical pulses will be synchronized with ECG signals, through the ECG triggering device AccuSync to avoid delivery of pulses in vulnerable period of the heart. The type of electrode used will be selected according to the size and location of the tumors.

Procedure: Electrochemotherapy with Intravenous Bleomycin

Interventions

Electrochemotherapy with Intratumoral Cysplatin PROCEDURE

ECT will be performed directly after the intratumorally administration of cysplatin (0,5-2 mg/cm3 tumor). CliniporatorTM (IGEA S.P.A., Carpi, Italy) will be used to apply the pulses (8 pulses, 1300 V/cm, 100 μs, 5 kHz). Triggering of the electrical pulses will be synchronized with ECG signals, through the ECG triggering device AccuSync to avoid delivery of pulses in vulnerable period of the heart. The type of electrode used will be selected according to the size and location of the tumors.

Electrochemotherapy with Intratumoral Cysplatin

Electrochemotherapy with Intravenous Bleomycin PROCEDURE

ECT will be performed within 8 - 28 minutes after intravenous bolus administration of bleomycin (15.000 IU/m2 BSA). CliniporatorTM (IGEA S.P.A., Carpi, Italy) will be used to apply the pulses (8 pulses, 1300 V/cm, 100 μs, 5 kHz). Triggering of the electrical pulses will be synchronized with ECG signals, through the ECG triggering device AccuSync to avoid delivery of pulses in vulnerable period of the heart. The type of electrode used will be selected according to the size and location of the tumors.

Electrochemotherapy with Intravenous Bleomycin

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• more than 4 cytologically and/or histologically confirmed intransit or distant cutaneous/subcutaneous cutaneous melanoma metastases
• ECT should be proposed as a treatment in the multidisciplinary tumor board
• cutaneous/subcutaneous melanoma metastases, that can be excised under local anesthesia with primary wound closure, minimal morbidity of the procedure (risk of complications \< 5%) and nocosmetic or functional consequences of the procedure
• stage IIIB, IIIC or IV of the disease
• age over 18 years
• performance status World Health Organization more than 2
• patients must give informed consent

You may not qualify if:

• age less than 18 years
• polimorbidity
• performance status World Health Organization more than 2
• high risk for intervention under general anesthesia;
• wound closure would require coverage with a skin graft or local flap;
• undesirable cosmetic or functional consequences would be expected (face, extensor side of joints)
• patients incapable of understanding the aim of the study or disagree with the entering into the clinical study

Sponsors & Collaborators

• Institute of Oncology Ljubljana: lead
• Slovenian Research Agency: collaborator

Study Sites (1)

Institute of Oncology Ljubljana

Ljubljana, 1000, Slovenia

Location

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MeSH Terms

Conditions

Melanoma, Cutaneous Malignant

Interventions

Electrochemotherapy

Condition Hierarchy (Ancestors)

Melanoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Drug Therapy; Therapeutics; Electroporation Therapies; Electroporation; Cytological Techniques; Clinical Laboratory Techniques; Investigative Techniques; Electrochemical Techniques

Study Officials

• Barbara Perić

  Dep. of Surgical Oncology, Institute of Oncology Ljubljana

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Electrochemotherapy with intratumoural cysplatin is recommended for smaller (less than 3 cm) and fewer tumours (up to 10 lesions), while electrochemotherapy with intravenous bleomycin is preferable for multiple and larger tumours.

Study Record Dates

• First Submitted: April 24, 2024
• First Posted: April 29, 2024
• Study Start: November 10, 2023
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: February 19, 2026

Record last verified: 2026-02

Locations

SL (1)