Treatment of Low-flow Vascular Malformations With Bleomycin Electrosclerotherapy (BEST) (BEST)

In biomedical applications, electroporation is used not only for cancer treatment but also for vaccinations, treatment of cardiac arrhythmias and, more recently, for the treatment of vascular malformations. Bleomycin is a frequently used sclerosing agent in the treatment of various vascular malformations. The use of electrical pulses in addition to bleomycin increases the effectiveness of the treatment, similar to electrochemotherapy. Bleomycin electrosclerotherapy (BEST) is a new treatment modality that is effective in the treatment of low-flow malformations (venous and lymphatic malformations) and potentially also high-flow malformations (arteriovenous malformations). Although a limited number of reports have been published to date, more and more centers are using BEST for the treatment of vascular malformations. As part of the International Network for Sharing Practices on Electrochemotherapy (InspECT) consortium, a dedicated working group has been set up to develop standard operating procedures for BEST. Current Operating Procedures have been prepared and will be used in this clinical trial.

Study Overview

• Status: Not yet recruiting
• Conditions: Vascular Malformations
• Intervention / Treatment: Drug: Bleomycin Sulfate

Detailed Description

Vascular malformations are rare conditions caused by abnormally developed blood vessels. They can occur anywhere in the body and range from simple and benign lesions to complex conditions.

The latest and most commonly used categorization is the International Society for the Study of Vascular Anomalies (ISSVA) classification. This classification divides vascular anomalies into two main categories: tumors, defined as true proliferative neoplasms, and malformations, defined as morphogenetic defects. These two categories are further subcategorized: tumors are divided into benign, locally aggressive/borderline, and malignant tumors, whereas malformations are subdivided into simple, combined, or associated with other anomalies. Clinically, vascular anomalies can also be divided into low-flow and high-flow malformations.

Current treatment of vascular malformations varies depending on the type and anatomical location of the vascular malformation. Treatment options include observation, sclerotherapy, laser therapy, embolization, and surgery. Sclerotherapy involves the injection of sclerosing agents, such as bleomycin, pingyangmycin, absolute ethanol, ethanolamine oleate, polidocanol, doxycycline, cyanoacrylate, sodium morrhuate, and sodium tetradecyl sulfate (STS).

Current treatment options for low-flow vascular malformations remain suboptimal. Current therapies demonstrate limited clinical efficacy. Ethanol is widely used as a sclerosing agent and can induce substantial lesion regression; however, its clinical utility is limited by considerable safety concerns. In particular, ethanol may induce extensive tissue necrosis and damage to surrounding healthy structures, which limits its therapeutic use.

Another agent frequently employed for sclerotherapy is bleomycin. However, when administered as monotherapy, without the use of electroporation, bleomycin often shows insufficient therapeutic effectiveness. In many cases, treatment results only in minor reduction of lesion volume and fails to adequately alleviate patient-reported symptoms, including pain and functional discomfort.

Electrochemotherapy is a local ablative treatment in which electroporation is used to enhance the delivery of cytotoxic molecules, such as bleomycin or cisplatin, to treat cancer. The cytotoxicity of the drug is increased only at the site of electrical pulse application. This approach is often used to treat both skin tumors and deep-seated tumors, such as liver and pancreatic tumors. Several types of electrodes have been designed to optimize the delivery of electrical pulses to specific anatomical sites. The efficacy of electrochemotherapy ranges from 70% to 80%. Electrochemotherapy is included in many national and international guidelines as a local ablative therapy and is practiced in more than 200 centers throughout Europe.

There are three underlying mechanisms of electrochemotherapy. The first is enhanced drug delivery to tumor cells, which die due to the cytotoxicity of the drugs, either by apoptosis or necrosis. This is predominantly related to the drug used and its mode of action. Bleomycin, for example, induces mitotic cell death, which leads to slow resolution of the tumor mass.

The second mechanism is the induction of an immune response due to immunogenic tumor cell death induced by the drug. It is well established that certain ablative therapies induce immunogenic cell death that can attract and enhance the immune response of the organism.

The third mechanism is the vascular disrupting effect of electrochemotherapy. In early preclinical research, it was established that the application of electrical pulses only temporarily abrogates blood flow within tumors. This phenomenon was termed vascular lock and lasts less than an hour. Furthermore, the effect is enhanced when the drug is present during the application of electrical pulses. Investigations have shown that this results in vascular disruption that occurs within hours in tumors. Endothelial cells start to die, blood flow is obstructed, and secondary tumor cell death is induced within days due to tumor hypoxia.

The phenomenon is predominantly confined to the tumor vasculature, sparing the normal vasculature around the tumors. This is because of the high proliferation rate of endothelial cells in tumors compared with the vasculature in normal tissues, where the endothelial proliferation rate is very slow. The vascular disrupting effect of electrochemotherapy is not fully understood. To date, the proportion by which this vascular disrupting effect contributes to the overall effectiveness of electrochemotherapy in specific tumor types is not fully understood. The effect appears to depend on the distribution and extent of tumor vascularization, with better vascularized tumors generally responding better to electrochemotherapy.

• Study Type: Interventional
• Enrollment (Estimated): 140
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Neža Gros; Phone Number: 031860131; Email: ngros@onko-i.si

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• age ≥ 18
• patients with low-flow vascular malformations (venous, lymphatic, capillary or mixed type malformations),
• patients with a low-flow vascular malformation poorly responding or recurring after previous treatment(s),
• longer lesion diameter not exceeding 25 cm.
• more than one lesion can be treated. The limiting factor is the maximal dose per patient per treatment session; 10 000 IU in adults,
• skin or mucosal, superficial or deep-seated lesions can be treated,
• technical feasibility of the BEST procedure, i.e.: injection of bleomycin and safe placement of electrodes into the vascular malformation are technically feasible.

Exclusion Criteria:

• pregnancy and lactation,
• women of childbearing potential and men not using reliable contraception,
• in adults, previous bleomycin exposure with a cumulative dose greater than 100 000 IU. In case of abnormal respiratory results/chest pathology (including previous severe or long COVID) in consultation with a pulmonologist, special care is required, and bleomycin exposure may be contraindicated,
• known allergy or hypersensitivity to bleomycin,
• presence of significant central venous drainage precluding sclerotherapy,
• acute lung infection or severely reduced lung function,
• bleomycin-related lung toxicity or reduced lung function which can indicate bleomycin-related lung toxicity,
• ataxia telangiectasia,
• chronic renal dysfunction.

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
Experimental: Bleomycin electrosclerotherapy; Participants with low-flow vascular malformations will receive intralesional bleomycin combined with local application of electrical pulses according to the BEST procedure.	Drug: Bleomycin Sulfate; Bleomycin will be administered by local intralesional injection into the vascular malformation, followed by application of electrical pulses.; Other Names: Bleomycin Electrosclerotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRI-measured mean change in lesion volume from baseline to 3 months after BEST treatment	Lesion volume will be assessed by magnetic resonance imaging at baseline and 3 months after treatment. Lesion volume will be calculated from MRI images using the ellipsoid formula: a x b x c x π/6. The outcome measure will report the mean change in lesion volume from baseline to 3 months after BEST treatment.	Baseline and 3 months after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRI-measured mean change in lesion volume from baseline to 12 months after BEST treatment	Lesion volume will be assessed by magnetic resonance imaging at baseline and 12 months after treatment. Lesion volume will be calculated from MRI images using the ellipsoid formula: a x b x c x π/6. The outcome measure will report the mean change in lesion volume from baseline to 12 months after BEST treatment.	Baseline and 12 months after treatment
Number of participants who complete protocol-defined BEST treatment and follow-up visits	Feasibility will be assessed by the number of participants who complete the protocol-defined BEST treatment and scheduled follow-up visits at 3 months and 12 months after treatment.	Up to 12 months after treatment
Number of participants with treatment-emergent adverse events as assessed by CTCAE version 5.0	Treatment-emergent adverse events will be recorded, classified according to MedDRA terminology, graded using CTCAE version 5.0, and assessed for relationship to the investigational medicinal product or procedure.	Up to 12 months after treatment
Change in quality of life from baseline to 3 and 12 months after BEST treatment as assessed by the OVAMA questionnaire	Quality of life will be assessed using the OVAMA questionnaire at baseline, 3 months, and 12 months after treatment. The outcome measure will report the change in OVAMA questionnaire results from baseline to 3 and 12 months after BEST treatment.	Baseline, 3 months, and 12 months after treatment

Collaborators and Investigators

• Sponsor: Institute of Oncology Ljubljana
• Collaborators: University Medical Centre Ljubljana
• Investigators: Study Chair: Gregor Serša, Institute of Oncology Ljubljana

Study record dates

Study Major Dates

• Study Start (Estimated): June 30, 2026
• Primary Completion (Estimated): June 30, 2031
• Study Completion (Estimated): June 30, 2032

Study Registration Dates

• First Submitted: April 22, 2026
• First Submitted That Met QC Criteria: May 5, 2026
• First Posted (Actual): May 12, 2026

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 20, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: electroporation; vascular malformations; bleomycin; electrosclerotherapy; low flow vascular malformations
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Congenital Abnormalities; Cardiovascular Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Vascular Malformations; Peptides; Amino Acids, Peptides, and Proteins; Carbohydrates; Glycoconjugates; Glycopeptides; Bleomycin
• Other Study ID Numbers: ORI2025-46; 2025-524123-45-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No