Evaluation of Reduced-Dose Bleomycin in Electrochemotherapy for Cutaneous Malignancies: A Randomized Controlled Trial

The primary objective of this randomized controlled clinical trial, known as the BLESS Trial, is to evaluate whether the standard dose of **bleomycin** in electrochemotherapy can be reduced by 50% while maintaining the overall tumor response in patients with cutaneous malignancies. This investigation is clinically significant as it aims to optimize treatment efficacy while potentially reducing the adverse effects associated with higher doses of bleomycin, thereby improving patient outcomes and quality of life. No secondary objectives are specified for this study.

The clinical trial involves participants diagnosed with **cutaneous malignancies**, encompassing both primary and secondary cancers of any histology. The study population includes adults over the age of 18, with both male and female subjects eligible to participate. Participants must have a life expectancy greater than three months and be capable of understanding the participant information. The trial does not involve a vulnerable population. Participants may have previously received electrochemotherapy (ECT) or radiation therapy, provided specific conditions regarding treatment areas and time intervals are met. Additionally, participants can undergo simultaneous medical treatments such as endocrine therapy, chemotherapy, or immunotherapy during the study. All sexually active participants are required to use safe contraception methods. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the efficacy of a reduced dose of **bleomycin** in electrochemotherapy for patients with cutaneous malignancies. This is a randomized, controlled trial with a double-blind design to ensure unbiased results. The trial is expected to commence on July 2, 2024, and conclude by July 2, 2027, with an estimated duration of three years. Participants will be randomly assigned to either a standard dose group or a reduced dose group, with the primary endpoint being the clinical overall response rate after three months of treatment.

Study visits are structured to include an initial screening visit, where eligibility criteria are assessed, including age, informed consent, and medical history. Participants must be over 18 years old, have a life expectancy of more than three months, and meet specific medical criteria, such as normal creatinine levels. Follow-up visits will occur at regular intervals to monitor treatment response, side effects, and quality of life, using tools like the EORTC questionnaire and the Vancouver Scar Scale. The end-of-study visit will evaluate the long-term outcomes, including remission rates and mortality.

Participant involvement is expected to last up to 12 months, with conditions for early termination including significant adverse effects or withdrawal of consent. Secondary endpoints will assess treatment response using RECIST criteria, aesthetic outcomes, and pharmacokinetics. The trial will also explore the relationship between tumour histology and response rates, as well as the impact of tumour size on treatment efficacy. Data collection will include digital photography, ruler measurements, and optional biopsies for histological examination. The study aims to provide comprehensive insights into the potential for dose reduction in electrochemotherapy while maintaining therapeutic efficacy.

The clinical trial involves the administration of **bleomycin**, an antineoplastic agent classified under the ATC code L01DC01. Bleomycin is utilized in this study to evaluate its efficacy in electrochemotherapy for patients with cutaneous malignancies. The pharmaceutical form of bleomycin is designated as PHF00231MIG. The medication is administered intravenously, with a maximum daily dose of 30,000 IU and a cumulative maximum dose of 400,000 IU over the treatment period. The trial aims to assess whether a 50% reduction in the standard dose of bleomycin can maintain the overall tumor response.

In addition to the experimental treatment with bleomycin, the study protocol includes the use of standard chemotherapy as a non-experimental treatment. This serves as a comparator to evaluate the effectiveness of the reduced bleomycin dose in the context of electrochemotherapy. The trial does not involve the use of a placebo. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol. The maximum treatment period is set at one time unit, as defined in the study parameters.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the evaluation of the clinical overall response rate of electrochemotherapy (ECT) treatment in patients with cutaneous malignancies after three months. Secondary endpoints include treatment response for both normal and reduced dose groups, as well as for all treated tumors, using RECIST criteria, digital photography, and ruler measurements. Aesthetic outcomes will be evaluated using the Vancouver Scar Scale and the Patient and Observer Scar Assessment Scale (POSAS) at time periods of 2 to 6 months and 6 to 12 months.

Additional secondary endpoints involve assessing complete and partial remissions at the patient level, with a focus on the number of patients experiencing objective responses on at least one treated tumor. Optional biopsy after 12 months will be conducted for histological examination of malignancy presence. Mortality rates, both all-cause and cancer-related, will be tracked within 12 months. Quality of life assessments will be conducted using the EORTC questionnaire C30, with data collected from both dose groups and the entire study population. The emergence of pain due to cutaneous malignancies will be assessed using the Numeric Rating Scale (NRS).

Pharmacokinetic analysis will be performed through blood samples collected at multiple time points post-bleomycin infusion, with factors such as age, treatment dose, Body Surface Area (BSA), and kidney function considered. Bleomycin concentration in tumor tissue will be analyzed using UHPLC-ESI-MS, with comparisons made between normal and reduced dose groups. The study will also examine the relationship between tumor histology and response rates, as well as response duration according to tumor size. Side effects will be evaluated according to CTCAE criteria, with data compared across different treatment doses.