Trial Title:
Electrochemotherapy Induces Changes in the Tumor Microenvironment of Cutaneous and Subcutaneous Metastases in Patients With Cutaneous Melanoma
NCT ID:
NCT06388252
Condition:
Cutaneous Malignant Melanoma
Conditions: Official terms:
Melanoma
Neoplasm Metastasis
Melanoma, Cutaneous Malignant
Bleomycin
Conditions: Keywords:
In-transit melanoma metastases
Cutaneous and subcutaneous melanoma metastases
Electrochemotherapy
Bleomycin
Cysplatin
Study type:
Interventional
Study phase:
N/A
Overall status:
Enrolling by invitation
Study design:
Allocation:
Non-Randomized
Intervention model:
Factorial Assignment
Intervention model description:
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.
Primary purpose:
Basic Science
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Electrochemotherapy with Intratumoral Cysplatin
Description:
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.
Arm group label:
Electrochemotherapy with Intratumoral Cysplatin
Other name:
Electrochemotherapy with Intravenous Bleomycin
Intervention type:
Procedure
Intervention name:
Electrochemotherapy with Intravenous Bleomycin
Description:
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.
Arm group label:
Electrochemotherapy with Intravenous Bleomycin
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, we 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 we 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. We 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 us to 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.
Detailed description:
The study is prospective. The primary objective is to evaluate the changes in the tumor
microenvironment of cutaneous and subcutaneous melanoma metastases induced by
electrochemotherapy (ECT), 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.
In the study 10-15 patients will be enrolled and devided in two arms, ECT with bleomycin
and ECT with cysplatin.
ECT will be offered to patients with cuteaneous melanoma and at least 5 in-transit or
distant cutaneous and/or subcutaneous melanoma metastases regardless of previous
treatments. The decision will be made in a multidisciplinary tumor board. The choice of
chemotherapeuthic drug will depend on the size andnumber of lesions to be treated.
Inclusion in the study has no influence on the decision regarding the timing of treatment
with immunotherapy. Treatment with immunotherapy will later be included as a factor in
the statistical analysis.
ECT will be performed according to the standard operating procedures for the treatment of
cutaneous and subcutaneous tumors with ECT. ECT will be performed within 8 - 28 minutes
after intravenous bolus administration of bleomycin (15.000 IU/m2 BSA) or 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.
One cutaneous/subcutaneous metastasis will be excised before ECT. One treated
cutaneous/subcutaneous metastasis will be excised 2-4 and 9-13 days after the procedure.
An untreated cutaneous/subcutaneous metastasis will be excised on day 9-13. The excisions
will be performed under local anesthesia. All patients will be enrolled in the study
after the procedures and the study have been explained to them in detail and they have
signed an informed consent form. A venous blood sample will be taken at the same time
points (before ECT, 2-4 days and 9-13 days after ECT).
Histological examination, assessment of the degree of regression and the presence of
tumor infiltrating lymphocytes (TIL) will be performed according to standardized
procedures on 2-3 μm thick tissue sections, previously fixed in formalin and embedded in
paraffin (FFPE), stained with the hematoxylin-eosin (HE) staining method.
Immunohistochemical characterization of the tumor microenvironment will be performed on
2-4 μm thick tissue sections pre-fixed in formalin and embedded in paraffin. We will use
commercially available primary monoclonal antibodies to define the tumor inflammatory
infiltrate, stroma and vasculature. We will use the following antibodies: CD3, CD4, CD8,
CD56, CD163, FoxP3, ERG, PGM1, CD274 (PD-L1). The choice of antibodies used and the
method of pathohistologic analysis may change depending on the results. Specific binding
of primary antibodies will be visualized using the recommended three-step detection
system OptiView DAB IHC Detection Kit (Cat. No. 760-700; manufactured by Ventana ROCHE
inc., Tucson, AZ, USA) according to the manufacturer's instructions. The analysis will be
performed by two independent pathologists.
We will also collect the information about previous treatments for cutaneous melanoma and
photographic documentation of the effectiveness of ECT treatment. Patients will also fill
out internationally recognized, validated quality of life questionnaires (EORTC QLQ-C 30
and EQ-5D-5L) at entollment, after ECT, 3 months, 6 months and 12 months after ECT and
then once a year during the follow-up period.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- 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
Exclusion Criteria:
- 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
Gender:
All
Minimum age:
18 Years
Maximum age:
100 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Institute of Oncology Ljubljana
Address:
City:
Ljubljana
Zip:
1000
Country:
Slovenia
Start date:
November 10, 2023
Completion date:
November 30, 2025
Lead sponsor:
Agency:
Institute of Oncology Ljubljana
Agency class:
Other
Collaborator:
Agency:
Slovenian Research and Innovation Agency
Agency class:
Other
Source:
Institute of Oncology Ljubljana
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06388252
