Randomised Controlled Clinical Trial Investigating the Effect of Reduced Bleomycin in Elechtrochemotherapy Treatment on Patients With Cutaneous Malignancies (The BLESS Trial)
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 发起方
- 入组人数
- 55
- 试验地点
- 4
- 主要终点
- To evaluate the clinical overall response rate of electrochemotherapy treatment of cutaneous malignancies after three months
研究概览
简要总结
The objective of this trial is to determine if reducing the chemotherapy dose in electrochemotherapy is equally effective as using the standard dose for treating various types of skin tumors.
Electrochemotherapy involves administrating chemotherapy intravenously, followed shortly by a brief electrical pulse to the tumor. This pulses temporarily increases the tumor cells permeability, allowing the chemotherapy to enter more effectively.
Participants will undergo a single session of electrochemotherapy with either half the standard chemotherapy dose or the full standard dose. The size of the cutaneous tumors will be measured before treatment and again three months after the treatment to compare their response in both groups. To monitor the tumors, as well as assess the adverse events and quality of life, participants must attend follow-up visits at two weeks, three months and twelve months. Additional visits may be scheduled at one, two, four and six months, if necessary, as determined by the clinician or the patient. Concentration of chemotherapy will be measured in blood samples and in samples from the treated tumor and normal skin.
详细描述
Introduction
Electroporation Electroporation is a method in which the cell is exposed to an external electric field resulting in increased permeability of the cell membrane [1]. Electroporation is used to introduce drugs into cells, without affecting intracellular organelles or cell viability. By inducing this response, drugs that are normally non-permeant, e.g. hydrophilic chemotherapy such as bleomycin, will enter the cell by diffusion thus enhancing the cytotoxic effect [2, 3]. The combination of electroporation and chemotherapy is known as electrochemotherapy (ECT). The application of the electric pulses causes vasoconstriction, inducing drug entrapment due to reduced blood flow - this is termed the vascular lock [4, 5]. In addition, electroporation also has a vascular-disrupting effect, when combined with chemotherapy [4]. ECT damages tumour vasculature leading to an additional cascade of tumour cell death due to lack of oxygen, nutrients, and waste product accumulation [5]. These vascular changes are more prolonged in tumours than in normal tissue [6].
Electrochemotherapy ECT is the combination of chemotherapy and electroporation, in which electric pulses are administered to a tumour after intravenous or intratumoural injection of chemotherapy. ECT has been shown to be effective in the treatment of cutaneous malignancies and is established as standard treatment for cutaneous primary and secondary skin tumours and ulcerating malignant wounds [7, 8]. ECT is often used as a one time treatment, but can be repeated if necessary.
Bleomycin is the drug of choice for ECT; it has low toxicity to normal cells and the largest increase in efficacy after electroporation enhancing the cytotoxic effect with a factor 300 to 5.000 [9]. ECT is performed in general or local anaesthesia depending on tumour location and size. Patient preference and institutional practice is also taken into account [8].
Bleomycin is an antineoplastic drug derived from Streptomyces verticillus and is used in the treatment of a variety of malignancies, such as lymphoma and testicular cancer [11]. Bleomycin generates single- and double-strand DNA breaks, i.e., one molecule of bleomycin can cause 10-15 DNA strand breaks [12]. Due to its hydrophilic nature, the entry of bleomycin into cells is restricted and occurs via an endocytotic process [13]. Bleomycin causes cell death in two ways, depending on the doses used: 1) if a lower amount of bleomycin is used (thousands of bleomycin molecules) the cell arrests in the G2-M phase, enlarges and becomes polynucleated and dies slowly by necrosis; 2) if a larger amount is used (millions of bleomycin molecules), pseudo-apoptosis kills the cell within a few minutes [12, 14].
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Investigators analysing bleomycin concentrations using HPLC.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Trial subject > 18 years.
- •Trial subject must be able to understand the participant information.
- •Histologically verified cutaneous or subcutaneous, primary or secondary cancer of any histology.
- •Life expectancy > 3 months.
- •Trial subject can undergo simultaneous medical treatment (endocrine therapy, chemotherapy, immunotherapy, etc.) at any point during the study.
- •Trial subject may have received ECT treatment previously if selected tumours have not received ECT or if a minimum of 3 months after ECT treatment have passed.
- •Trial subject can undergo radiation therapy, provided that the treatment field does not involve the area intended to treat. If the trial subject has received radiation therapy in the area intended to treat, a minimum of 3 months should have passed.
- •A creatinine level within normal upper limit. If creatinine is above normal upper limit the subject needs to have a creatinine clearance > 50 ml/min.
- •Both men and women who are sexually active must use safe contraception. This includes the use of intrauterine device (IUD), oral contraceptives, male or female condom, vasectomy or female sterilization.
- •Signed informed consent.
排除标准
- •Pregnancy or lactation. All fertile women will have to deliver a negative pregnancy test before ECT treatment.
- •Allergy or hypersensitivity to bleomycin.
- •Acute lung infection.
- •Severely impaired lung function or any lung condition the investigator deems severe.
- •Any other caution, clinical disease or previous treatments that make the investigator deem the trial subject unfit.
- •The cumulative bleomycin dose must not exceed the by the drug manufacturer recommended maximum dose.
研究组 & 干预措施
Standard dose
Patients in this arm will recieve the standard dose of bleomycin during treatment with electrochemotherapy
干预措施: Bleomycin (Drug)
Dose reduction
Patients in this arm will recieve half the standard dose of bleomycin during treatment with electrochemotherapy
干预措施: Bleomycin (Drug)
结局指标
主要结局
To evaluate the clinical overall response rate of electrochemotherapy treatment of cutaneous malignancies after three months
时间窗: The tumors will be meassured before electrochemotherapy (baseline) and three months after electrochemotherapy treatment.
The response to treatment will be evaluated according to the modified Response Evaluation Criteria in Solid Tumours (RECIST) criteria. Response rate will be defined as the number of responding tumours relative to the number of treated tumours (Intention to treat analysis, ITT), evaluated 3 months after treatment. The response will be evaluated by clinical examination with ruler measurements (in mm) and photographical documentation using rulers for scale.
次要结局
- Treatment response for normal dose group, reduced dose group, and for all treated tumors at optimnal time points using the mRECIST criteria.(The follow up is mandatory for the patients after 2 weeks, after 3 months and 12 months. Follow up is optional at 1 month, 2 moths, 4 moths and 6 months. At every visit the tumours size will be measured.)
- Aesthetic outcome for normal dose group, reduced dose group and for all tumours 3 months after treatment and 1 year after treatment, using the Vancouver Scar Scale.(Assessed 3 months after treatment and 1 year after treatment.)
- Aesthetic outcome for normal dose group, reduced dose group and for all tumors assessed at 3 month and 12 month, using Patient and Observer Scar Assessment Scale (POSAS).(3 months ater treatment and 1 year after treatment.)
- Complete and partial remissions for all patients treated (patient level)(Before treatment (baseline) compared to 3 months after treatment.)
- Biopsy at 12 months (optional) for histological examination of malignancy presence (HE stain, and staining for specific tumour markers can be included).(12 months)
- All-cause mortality and cancer related mortality within 12 months.(Study period of 12 months.)
- Quality of life before treatment and at approximately 3 months measured by EORTC-QLQ-C30(Questionaires will be performed before electrochemotherapy, and at 3 and 12 months after the treatment. .)
- Quality of life before treatment and 3 months post-treatment measured in 16 patients with semi-structured qualitative interviews.(Qualitative interviews will be performed before electrochemotherapy and 3 months post-treatment in the same patients.)
- Relation between tumour histology and tumor response rates at 3 months and 12 months.(Response rate will be calculated by comparing measurement at baseline and at respectively 3 months, and at 12 months.)
- Response rates in tumours according to size(Baseline measurement will be compared to measurements at respectively 3 months and 12 months.)
- Side effects according to CTCAE according to treatment dose - data from normal dose group, reduced dose group, and for the whole population will be registered and compared.(Will be meassured at every visit up to one year)
- The presence of pain (if any) associated with the cutaneous malignancies will be assessed using Numeric Rating Scale (NRS).(Will be meassured at every visit up to 12 months.)
- Bleomycin pharmakokinetics at electrochemotherapy procedure(Blood samples will be drawn before bleomycin infusion (time 0), and at 5, 10, 20, 30 and 40 minutes after bleomycin infusion.)
- Bleomycin pharmakokinetics related to dose group, age and body surface area(Samples will be drawn before bleomycin infusion (time 0), and at 5, 10, 20, 30 and 40 minutes after bleomycin infusion.)
- Bleomycin pharmakokinetics realted to kidney function.(Serum creatinine will be measured before treatment. Samples for bleomycin pharmakokinetics will be measured in blood drawn before bleomycin infusion (time 0), and at 5, 10, 20, 30 and 40 minutes after bleomycin infusion.)
- Bleomycin concentration in tumours over time(Biopsies from tumor will be obtained before bleomycin infusion (0 min), 2, 4, 6, and 8 min. after bleomycin infusion.)
- The fraction of tumour cells will be related to the bleomycin concentration in tumor.(Pretreatment biopsy from tumor, obtained on the day of treatment.)
研究者
Julie Gehl
Professor
Zealand University Hospital