Trial Title:
The Effect of Reduced Bleomycin in Electrochemotherapy Treatment
NCT ID:
NCT06647342
Condition:
Cutaneous Metastasis
Cutaneous Malignant Mixed Tumor
Bleomycin Adverse Reaction
Electrochemotherapy
Conditions: Official terms:
Mixed Tumor, Malignant
Bleomycin
Conditions: Keywords:
Deescalating study
Bleomycin
Electrochemotherapy
Cutaneous malignancies
Cutaneous tumors
Study type:
Interventional
Study phase:
Phase 4
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
Double-blinded randomized controlled study
Primary purpose:
Treatment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description:
Investigators analysing bleomycin concentrations using HPLC.
Intervention:
Intervention type:
Drug
Intervention name:
Bleomycin
Description:
In the standard arm, Bleomycin (Baxter, Germany) at a dose of 15.000 IU/m² is used. In
the dose reduction arm, a dose of 7500 IU/m² is used. Note that in Denmark bleomycin is
dosed by international units, whereas other countries may use respectively U (units) or
mg.
Arm group label:
Dose reduction
Arm group label:
Standard dose
Summary:
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.
Detailed description:
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].
Recently, it has been shown that the disaccharide moiety of bleomycin facilitates uptake
by cancer cells. It is suggested that the upregulation of receptors associated with
enhanced glycolysis in tumour cells could be the reason for bleomycin targeting tumour
cells selectively [51].
Bleomycin is degraded by an enzyme - bleomycin hydrolase -, found in various normal
tissues [11]. A lower concentration of this enzyme is found in the skin and lungs, which
can lead to increased harms in these organs [15, 16]. The Danish Medicines Agency (DMA)
states in its product summary that half of patients receiving bleomycin experience harms
related to the skin (erythema, hyperpigmentation, striae or soreness) and one tenth
experience pulmonary reactions with a minority (1%) dying from pulmonary fibrosis [15].
Some studies have observed that the risk of developing pulmonary toxicity from bleomycin
is increased with age, drug dose, and concomitant oxygen therapy and thoracic radiation
therapy [16].
Since harms are associated with accumulative bleomycin dose, it is desirable to
investigate if the dose can be reduced to minimize risk of harms and maintain the same
efficacy. This may also enable some ineligible fragile patients to become eligible for
ECT treatment, e.g., lung cancer patients with a higher risk of developing pulmonary
toxicity.
Cutaneous malignancies A significant proportion of cancer patients develop cutaneous
metastases (~10%) that often become exuding, bleeding or odorous [17, 18]. Thus, the
metastases may influence patients' quality of life [19, 49]. Cutaneous metastases
negatively affect patients, i.e., self-esteem, body image, and sexuality with feelings
tied to frustration and loss of power [21, 22]. Most cancer patients receive chemotherapy
or immunotherapy, but some cancers do not respond to these standard treatments [23]. ECT
may be used for such cancers enhancing palliation and quality of life [3, 24]. The most
frequently seen cutaneous metastases originate from breast cancer and occur in the chest
region, but may arise anywhere on the body and originate from most cancer types [20]. The
cutaneous malignancies may vary in size from a few millimetres to very large and may be
focal or extensive.
Clinical experience with electrochemotherapy In 1993, Belehradek and colleagues published
the first clinical trial of ECT using bleomycin in 8 patients indicating that the
treatment was well-tolerated by patients and with a clinical complete rumour response of
57% [25]. In 2003 Gothelf and colleagues reviewed the 11 clinical trials completed
between 1993 and 2001, involving a total of 96 patients with 411 tumours/metastases
treated with different approaches [26]. The overall response (OR) varied between 15% and
100%. For the 11 ECT studies investigating bleomycin and ECT treatment on cutaneous
malignancies the OR has been between 22% and 100%. Three studies stand out, with an OR of
22%, 28% and 45%, respectively [27-29]. The study by Domenge from 1996, was one of the
first studies conducted on ECT and included only seven patients [27]. In the studies by
Matthiessen and Kreuter larger tumours (>3 cm) were included. It is well-known that
the size of the tumour affects the response of the ECT treatment [29]. When excluding
these studies the OR varies from 58% to 100%. The largest ECT bleomycin study by Clover
and colleagues from 2020 included 987 patients with 2,483 tumours [30] and showed that
different tumours have different ORs; for example, basal cell carcinoma (BCC) and
Kaposi's sarcoma (KS) show the highest OR with 96% and 98%, respectively; while breast
cancer metastases, malignant melanoma (MM) and squamous cell carcinoma (SCC) have lower
responses of 77%, 82% and 80%, respectively. This study also observed an effect of tumour
size on the overall tumour response. The highest response rates were observed in small
tumours (<3 cm). In small skin metastases (<2 cm), no significant OR difference was
observed between intravenous vs. intratumoural administration of bleomycin, however, for
larger skin metastases (>2cm), the OR was significantly (p<0.05) higher with
intravenous administration (57% vs. 48%) [30]. Thus, our trial will be stratified
according to tumour/metastasis size.
Clinical experience with reduced bleomycin In 1996, one of the first clinical ECT
bleomycin studies with six patients used a bleomycin dose of 10.000 IU/m2 [31] (see Table
1), since medical and surgical oncologists believed that a dose of 22,700 IU/m2 - used in
the first clinical trials - was too high. This is the only study using this dose and from
1998 the standard dose of 15.000 IU/m2 was used in most studies.
In 2016, a case report of a patient receiving ECT with bleomycin with a 50% reduced dose
(7.500 IU/m2) due to renal dysfunction was published. In this case a complete tumour
response was observed [32].
From 2013 to 2016, Rotunno identified via the International Network for Sharing Practices
on Electrochemotherapy (InspECT) database 57 patients treated with ECT and reduced
bleomycin (7.500, 10.000 or 13.500 IU/m2) [33] due to e.g., reduced renal function and
high age. Reduced bleomycin showed similar tumour response to a standard bleomycin dose
(15.000 IU/m2), with an OR of 64% to 82 %. Thus, the authors of the study suggested that
reduced bleomycin doses could be as effective as the standard treatment - especially in
patients with impaired renal function or patients eligible to multiple ECT cycles. It was
concluded that further research in order to find a personalized bleomycin dose is needed
[33].
In 2018 and 2021, two studies concluded that a reduced dose of bleomycin is a feasible
treatment option for elderly patients, with equal efficacy to standard dose treatment (OR
87% to 100%) and should be considered as a treatment in patients with comorbidities [34,
35]. In addition, in a study by Groselj et al. from 2018 it was suggested that the
cosmetic outcome was improved with the use of a reduced dose of bleomycin compared to the
standard dose due to shorter healing and less development of fibrous scarring tissue
[36].
Rationale for 50% bleomycin reduction in this study:
Based on former literature [32-36] we find it realistic to reduce the bleomycin dose with
50% and still gain a sufficient overall tumour response after ECT treatment. For time
efficiency purposes, in this study we have decided to investigate a 50% reduced dose of
bleomycin only. Randomisation to several bleomycin dose levels would subsequently result
in the need of a significant increase in the number of included patients and/or referring
hospital departments, which would be time consuming and difficult to complete within a
manageable time frame.
Methods Trial design The study design as a non-inferiority study and is a parallel
two-armed double-blinded randomized clinical trial, where the patients are stratified due
to the size of their biggest cutaneous tumour (≤ 3 cm or > 3 cm) and afterwards
randomized (1:1) to receive a standard dose bleomycin or a 50% reduced dose bleomycin.
Blinding is performed by the pharmacy mixing the allotted dose regimen after
randomization, both patients and treating staff will be blinded to the bleomycin dose.
Unblinding will be performed according to procedure if need be. Unblinding of all results
will take place after last patients evaluation of primary endpoint.
The study will be conducted at two centers in Denmark: At the department of Clinical
Oncology and Palliative Care, Zealand University Hospital, Roskilde and at the Department
of Oncology, Copenhagen University Hospital, Herlev Gentofte Hospital. The three year
study period is expected to start in October 2024.
Study population Patients will be referred from oncologic departments and must be advised
about treatment alternatives. It must be evaluated whether the patient will benefit from
the treatment, given the localisation and size of the tumour/tumours, the patient's
general condition and expected survival. The purpose, possible risks and benefits should
be discussed in collaboration with the patient.
Indications for participating in this trial includes:
- Biopsy verified cutaneous malignancies of any histology, which are symptomatic due
to bleeding, ulceration, oozing, odour, or pain
- Primary skin cancers, including recurrent tumours, where other treatment modalities
have failed, are not possible or not appropriate
- Patients who are receiving systematic anti-neoplastic therapy, but where cutaneous
metastases are progressing or not responding despite satisfactory response to
systemic therapy in internal organs
- Patient preference for electrochemotherapy, after other treatment possibilities have
been thoroughly explained to the patient For eligibility criteria, please refer to
the section about eligibility criteria.
Pre-treatment examination and pain management:
The pre-treatment examination will be performed up to one month prior to the procedure
and will include diagnosis of primary tumour, TNM (tumour, node, and metastasis)
classification, and previous anti-neoplastic treatments. Under previous treatments, it
must be noted which nodules have been treated with which treatment. Radiotherapy fields
or other local treatments must be listed if nodules were subjected to this. Additionally,
assessment of medical history, previous problems with anaesthesia, any other relevant
medical history, combination with other treatments, and presence of symptoms will be
noted. A physical examination with clinical assessment of the tumour, location and
availability of electroporation will be made. All the cutaneous tumours of the patient
will be treated, but a maximum of seven tumours per patient will be registered and
followed over time, and only one tumour will be selected for tissue biopsies.
Moreover assessment of performance status will be performed, and pre-existing pain
problems will be examined in order to create a pain management plan.
Treatment day Anaesthesia As this is a study including treatment with intravenous
bleomycin, participants will in most cases receive general anaesthesia, administered
according to institutional guidelines or standard operating procedures [52]. In cases
where local anaesthetics are preferable, this can also be utilized and administered
according to institutional guidelines.
Bleomycin dose Bleomycin is the approved chemotherapeutic drug for use in ECT and will be
used according to the marketing authorization in this trial.
In order to calculate the body surface area (BSA), the patients' height will be noted and
their weight measured. Patients will receive either a standard dose of bleomycin (15.000
IU/m2 BSA) or a dose reduced with 50% (7.500 IU/m2 BSA) intravenously. Bleomycin is
infused over a short time (2-5 min) and 8 min after completion of the infusion, the drug
has diffused into tumour tissues and hereafter the electric pulses can be applied.
Applied electric pulses The electric pulses will be administered 8 minutes after
bleomycin infusion. It is important that the entire tumour volume with surrounding tissue
is treated with electroporation, so a margin of 3 mm around the tumour is included in the
treatment.
For electroporation we use the Cliniporator (model EPS02, IGEA, Carpi, Italy), square
wave pulse generator, which delivers a series of eight consecutive pulses of 0.1 msec
each with an amplitude of 1 kV/cm and a frequency of 1 Hz. The electrodes will be chosen
according to the standard operating procedures [8], depending on size and anatomical
location of the tumour.
All tumours will be treated, but a maximum of seven tumours per patient will be followed,
and only one tumour will be selected for tissue biopsies.
Biological samples Two biopsies from normal skin surrounding the tumour will be
collected: one before bleomycin infusion and one 8 minutes after bleomycin infusion. Five
biopsies will be collected from each patient from one of the tumours, at the time points;
before bleomycin infusion, 2, 4, 6 and 8 minutes after bleomycin infusion. An additional
tumour biopsy will be collected before bleomycin infusion for histologic analysis, this
biopsy will (optional to the patient) be repeated after one year. The biopsies will
include 3 mm tissue per biopsy and a maximum of 0.75 ml.
Six blood samples will be collected at predetermined time points at treatment day (before
bleomycin infusion, 5, 10, 20, 30 and 40 min after bleomycin administration.
The blood and biopsies (except those made for histological analysis) will be analysed at
the Department of Science and Environment at Roskilde University according to the amount
of bleomycin. Here the HPLC machine will be used to detect the All blood samples will be
stored in a collective bio bank situated at Region Zealand Biobank approved by the Danish
Data Protection Agency.
Follow up Mandatory follow-ups occur at 2 weeks, 3 months and 12 months. Optional
follow-up consultations will be possible at 30, 60, 120 and 180 days after ECT treatment.
The necessity of these optional consultations will be decided by the physician and
patient.
Each target tumour size will be assessed with a ruler and documented with photography's
before treatment and at all the follow up consultations. At 3 months and 12 months
evaluation of wound healing and scar formation will be accessed by three independent
observers (1 plastic surgeon, 1 oncologist, and 1 research associate) using the Vancouver
Scar Scale and the Patient and Observer Scar Assessment Scale. Moreover quality of life
EORTC-questionnaires will be performed. At all follow-up consultations pain from the
tumours and adverse events will be measured.
For primary and secondary endpoints, please refer to the relevant sections.
Methods employed for evaluation of quality of life Patients will be asked to answer the
European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire
at month 0, 3 and 12. This questionnaire is developed to assess the quality of life of
cancer patients.
Additionally, 16 patients will participate in a qualitative interview at baseline and at
month 3 if they give separate consent. This is in order to learn about patient
experiences with treatment and to assess ECT treatment impact on quality of life. In this
study qualitative interviews may uncover concerns and priorities that distinguish cancer
patients with cutaneous malignancies from other patients and thereby help to sufficiently
capture the patient's experience [38]. To collect patient experiences, semi-structured
interview is chosen as it gives the researcher the freedom to probe the interviewee to
elaborate or to follow a new line of inquiry introduced by what the interviewee is
saying.
Sample size:
This is a non-inferiority study, where the primary endpoint is to compare overall
response at tumour level three months after ECT treatment with two different doses of
bleomycin. The appropriate sample size is calculated to determine the minimum number of
tumours that need to be treated in this study in order to have a sufficient statistical
power showing that halving the dose of bleomycin is non-inferior to the standard dose.
To calculate the sample size, we utilized the formula for non-inferiority study with
continuous data [37]. The standard deviation was derived from 55 studies from 1996 - 2021
exploring electrochometherapy with intravenous bleomycin in different tumour histologies
[38]. We assumed an acceptable response rate difference on 10%. The significance level
where set at 0.05 with 80% power. Based on the findings on five previous studies, where
there was observed a drop-out rate at 16% [30, 39-42], we conservatively estimated a
drop-out rate at 20%. This led to the conclusion that 110 tumours needed to be treated in
this study. Anticipating an average of approximately 2 tumours per patient to be
evaluated, as observed in previous literature [30], we plan to enroll 55 patients.
Recruitment Patients will be recruited from four departments: the Department of Clinical
Oncology and Palliative Care and the Department of Plastic and Breast Surgery at Zealand
University Hospital Roskilde, and Department of Oncology and Department of Plastic
Surgery at Herlev Hospital, respectively. Patients eligible for treatment might be
referred from other departments throughout Denmark.
End of Trial The trial will conclude when 55 patients have been enrolled, have received
ECT, and the last patient has completed their final scheduled follow-up (12 months after
ECT).
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Trial subject > 18 years.
2. Trial subject must be able to understand the participant information.
3. Histologically verified cutaneous or subcutaneous, primary or secondary cancer of
any histology.
4. Life expectancy > 3 months.
5. Trial subject can undergo simultaneous medical treatment (endocrine therapy,
chemotherapy, immunotherapy, etc.) at any point during the study.
6. 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.
7. 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.
8. 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.
9. 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.
10. Signed informed consent.
Exclusion Criteria:
1. Pregnancy or lactation. All fertile women will have to deliver a negative pregnancy
test before ECT treatment.
2. Allergy or hypersensitivity to bleomycin.
3. Acute lung infection.
4. Severely impaired lung function or any lung condition the investigator deems severe.
5. Any other caution, clinical disease or previous treatments that make the
investigator deem the trial subject unfit.
6. The cumulative bleomycin dose must not exceed the by the drug manufacturer
recommended maximum dose.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Copenhagen University Hospital Herlev-Gentofte
Address:
City:
Herlev
Zip:
2730
Country:
Denmark
Contact:
Last name:
Camilla Lønkvist, MD, Ph.D
Phone:
+45 38682982
Email:
camilla.kjaer.loenkvist@regionh.dk
Investigator:
Last name:
Camilla Kjær Lønkvist, MD, Ph.D
Email:
Principal Investigator
Facility:
Name:
Zealand University Hospital
Address:
City:
Roskilde
Zip:
4000
Country:
Denmark
Contact:
Last name:
Julie Gehl, MD Professor
Phone:
+45 93577626
Email:
kgeh@regionsjaelland.dk
Contact backup:
Last name:
Marie Tolstrup, Medical doctor
Phone:
+45 61548049
Email:
maato@regionsjaelland.dk
Investigator:
Last name:
Julie Gehl, Professor
Email:
Principal Investigator
Start date:
October 18, 2024
Completion date:
December 31, 2027
Lead sponsor:
Agency:
Julie Gehl
Agency class:
Other
Collaborator:
Agency:
Roskilde University
Agency class:
Other
Collaborator:
Agency:
Herlev Hospital
Agency class:
Other
Source:
Zealand University Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06647342
