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Bone Density Conservation Agents

Calcium

Calcium, Dietary

Hormones

Experimental treatment with calcium electroporation for malignant cutaneous and subcutaneous tumours

Patients with cutaneous or subcutaneous malignant tumours will be treated with calcium electroporation, i.e. intratumoral injection of calcium followed by electroporation by electric pulses applied directly to the tumor.

Calcium electroporation

Julie Gehl, MD

Phase II Investigation of Calcium Electroporation as a Treatment for Cutaneous and Subcutaneous Malignant Tumours.

This will be a non-randomized phase II trial with the objective of evaluating the clinical response rate of calcium electroporation treatment of malignant tumours of the skin and assessing treatment impact on quality of life. This study will investigate the response rate of calcium electroporation treatment of skin metastases and malignant wounds in a real-world setting, in three different cancer centres in Northern Europe. The centres aim to treat a total of 30 patients with cancer in the skin of any histology. The patients will be treated once and followed with regular examinations for 12 months, starting from first treatment day. All patients will have been offered the standard of care and all available alternatives before entering the protocol. Calcium electroporation will not be compared to other means of treatment.

The primary endpoint of this study is to evaluate the clinical overall response rate of calcium electroporation treatment of malignant tumours of the skin after two months. A subset of patients will undergo MR scans after treatment and another subset of patients will be interviewed regarding treatment impact on quality of life.

Calcium Electroporation as a Treatment for Cutaneous and Subcutaneous Malignant Tumours

Phase II Investigation of Calcium Electroporation as a Treatment for Cutaneous and Subcutaneous Malignant Tumours

Response rate will be defined as number of responding lesions (partial or complete response) relative to treated lesions evaluated by changes in size (mm) by clinical examination with caliper measurement. Tumor response will be further documented using clinical photography.

Evaluate treatment response at month 1, 3, 4, 6 and 12 in addition to evaluating treatment response after 2 months. Response rate will be defined as number of responding lesions (partial or complete response) relative to treated lesions evaluated by changes in size (mm) by clinical examination with caliper measurement. Tumor response will be further documented using clinical photography.

Assess tumour and surrounding tissue response to treatment from biopsies of the treated area after 1 year. Microscopy assessment of histopathological regressive changes (eg. % tumor cells and fibrosis).

Assess response after treatment on MRI scans on a subset of patients before and immediately after treatment, as well as after 2 months using diffusion-weighted magnetic resonance imaging (DW-MRI) as a method to monitor electroporated tissue, using the concept of the apparent diffusion coefficient (ADC).

Evaluate patient quality of life before treatment, after 2 months and after 1 year through EORTC QLQ-C15-PAL Core questionnaires evaluating cancer-related symptoms on a scale from 1-4 (not at all-very much) as well as overall quality of life on a scale from 1-7 (very poor-excellent).

Investigate any sign of systemic immunologic response from any routine scans (MRI, PET-CT etc.) before and after treatment in the inclusion period by tumor size and TNM stage.

To list response rates and response duration according to tumour histology.

To determine complete and partial remissions for all tumours treated. Response rate will be defined as number of responding lesions (partial or complete response) relative to treated lesions evaluated by changes in size (mm) by clinical examination with caliper measurement. Tumor response will be further documented using clinical photography.

To determine rate of response for each individual patient.

To investigate response (overall, as well as complete and partial) depending whether the treated tumour was in a previously irradiated area. Response rate will be defined as number of responding lesions (partial or complete response) relative to treated lesions evaluated by changes in size (mm) by clinical examination with caliper measurement. Tumor response will be further documented using clinical photography.

To measure current during treatment as measured by the pulse generator.

Analyses of qualitative interviews (in a subset of patients) performed before- and 2 months after treatment that include measures related to patient experience and impact on quality of life.

Vejle Hospital

University College Absalon

University Hospital Schleswig-Holstein

Zealand University Hospital

Neoplasms

Digestive System Diseases

All Conditions

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

Pembrolizumab

Immune Checkpoint Inhibitors

Immunomodulating Agents

Antineoplastic Agents, Immunological

Irreversible electroporation (IRE) and calcium electroporation (CaEP) on Day 1, followed by Pembrolizumab on Day 2 (+4 days) and then every 3 weeks (q3w) for up to 12 months in total.

Percutaneous ablation of a metastatic lesion.

Irreversible electroporation is delivered through the NanoKnife system (AngioDynamics, New York, USA). The system is CE approved for medical use.

Irreversible electroporation

Just before the reversible electroporation, calcium chloride will be injected into the primary tumor. The electroporation will be delivered as at least four pulses and up to eight pulses. The device is repositioned after each pulse to ensure coverage of the entire surface area of the tumor.

The reversible electroporation regime will be delivered through the endoscopic device EndoVE®, while the ePORE® will be used for pulse generation, both CE approved.

Pembrolizumab 200 mg as an IV infusion every 3 weeks (+/- 3 days) for up to 12 months

Pembrolizumab is an immune checkpoint inhibitor (PD-1-inhibitor).

Ismail Gögenur

The trial is designed as an investigator initiated prospective phase 2 study in patients with metastatic pMMR colorectal cancer (CRC) to determine the safety and efficacy of calcium electroporation (CaEP) performed concurrently with irreversible electroporation (IRE) followed by a PD-1 inhibitor (pembrolizumab).

The investigators hypothesize that Ca-EP targeting the primary CRC tumor combined with IRE targeting a metastasis will be a promising, safe two target approach to ensure sufficient immune response both locally and systemic to potentiate the efficacy of immunotherapy in patients with pMMR metastatic CRC.

Electroporation and Immunotherapy in Metastatic Colorectal Cancer

Calcium Electroporation in Combination With Irreversible Electroporation and Immunotherapy in Patients With Proficient Mismatch Repair System (pMMR) Metastatic Colorectal Cancer - A Prospective, Phase 2 Study

Safety of electroporation and immunotherapy according to CTCAE v. 4.0

Based on CT chest/abdomen scans according to RECIST version 1.1

Based on contrast enhanced ultrasound (CEUS) utilizing the standardized and quantitative method Dynamic CEUS (DCEUS)

Professor

Symptoms and General Pathology

Skin and Connective Tissue Diseases

Rare Diseases

Neoplasm Metastasis

Melanoma

Melanoma, Cutaneous Malignant

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Central Nervous System Depressants

Anti-Infective Agents

Bleomycin

Anesthetics

Anti-Bacterial Agents

Antibiotics, Antitubercular

Calcium

Calcium chloride 220 mmol/L (9 mg/ml):

* Tumor \< 0.5 cm³ - 1 ml/cm³ tumor volume
* Tumor \> 0.5 cm³ - 0,5 ml/cm³ tumor volume Tumor volume = ab²π/6 (a = longest diameter, b = longest diameter perpendicular to "a")

Bleomycin

Bleomycin 1000 IU/ml:

* Tumor \< 0.5 cm³ - 1 ml/cm³ tumor volume
* Tumor \> 0.5 cm³ - 0,5 ml/cm³ tumor volume Tumor volume = ab²π/6 (a = longest diameter, b = longest diameter perpendicular to "a")

Maximum of injected bleomycin per tumor will be 1500 IU and total dose per treatment 7500 IU. Normal maximum limit for bleomycin is 15.000 IU/m² body surface area.

If the patient agrees biopsies will be performed from the tumor area before and after electroporation during local anaesthesia. Maximum of 8 biopsies will be done, depending on the patient's number of metastases.

All patient's regardless of the number of metastases will have one biopsy from area treated with calcium and one from area treated with bleomycin, after the randomization code is revealed at day 180.

Patients with more than 6 metastases: One to two biopsies before treatment, one to two biopsies one week after treatment from metastases treated with calcium and bleomycin respectively.

All biopsies will be handled according to current guidelines and analyzed by a pathologist for amount of tumor tissue, inflammation, fibrosis and necrosis.

Calcium Electroporation

Bleomycin based electrochemotherapy

Electroporation is a method that can facilitate transport of molecules across the cell membrane and into the cell by means of electrical pulses. The method can be used with molecules that normally have difficulty passing the cell membrane such as chemotherapy (electrochemotherapy). Electrochemotherapy (ECT) is used in cancer therapy, where chemotherapy is administered intratumoral or intravenous, then followed by electrical pulses applied directly on the tumor. The chemotherapy accumulates in the cancer cells which results in an increased cytotoxic effect. The most used chemotherapeutic drug used in electrochemotherapy is bleomycin. Electrochemotherapy is a well-documented local treatment form for especially cutaneous tumors. Today, the treatment is used mostly in palliative care in more than 140 centres around Europe.

In vitro and in vivo studies have shown that the combination of calcium and electroporation is an effective method in killing cancer cells without serious side effects.This new combination opens the possibility of replacing bleomycin with calcium in treatments with electroporation.

Calcium electroporation is a local treatment where calcium is administered intratumoral and followed by electrical pulses applied on the tumor.

The preclinical studies have shown that there is a difference in sensitivity in tumor cells and normal cells, as normal cells tolerate the treatment better than tumor cells (own data manuscript in preparation). The studies have also shown that there is no cell injury by calcium injection without electroporation, the investigators therefore expect that the treatment only will cause minor side effects.

Calcium electroporation would be possible to use on patients for whom chemotherapy is contradicted e.g. severe lung functions impairment, pregnant woman etc. Calcium electroporation is a simple and unexpensive cancer treatment that does not involve any administration of cytotoxic chemotherapy, and can be performed by surgeons, radiologists as well as oncologists. Both electroporation equipment and calcium are already being used in the clinic, so the treatment can easily be implemented.

Trial Design for Treatment of Cutaneous Metastases:

The current study is a randomized double blinded phase II study comparing the effect of calcium electroporation with ECT with bleomycin on patients with cutaneous metastases of any histology. As calcium and bleomycin are administered intratumoral, only small metastases from 0.5-3 cm will be treated. The treatments will be compared in tumor response and adverse events. Treatment will be done in a palliative purpose.

Cancer patients with cutaneous involvement have often several metastases. A maximum of ten metastases will be included per patient. One to six metastases (depending on the patient's number of metastases) will be numbered 1-6 and randomized into one of two treatment arms

1. Intratumoral calcium followed by electroporation
2. Intratumoral bleomycin followed by electroporation Randomization will be performed separately on each metastasis, so the patient may receive both treatments. Calcium and bleomycin will be mixed into syringes labeled with numbers according to the metastases and both treating doctor and patient will be blinded to the content of the syringes.

If the patient has more than six metastases, then one to four metastases will be used for biopsy. The treatment of these metastases will be known, and biopsies will be performed before and after treatment.

Biopsies will only be performed if the patient has more than six metastases. The metastases used for biopsy will not be evaluated on response.

The treatment will be performed in local or general anesthesia depending on location and number of metastases. Bleomycin/calcium will be administered intratumorally and immediately after the electrode will be placed on the metastasis. The electric pulses are generated using a cliniporator according to ESOPE (European Standard Operating Procedure of Electrochemotherapy). The therapy is a once only treatment and the patients will be followed up with regular clinical controls for six months. At follow up six months after treatment, the randomization code for the one patient will be revealed. If the patient agrees, biopsies will then be taken from an area treated with calcium and an area treated with bleomycin. Last visit will be one year after treatment.

To identify the metastases at follow up visits, the metastases will be marked with a pen, numbered and documented with clinical photos at baseline.

Randomization The metastases are randomized by block randomization and are done separately in each patient. The randomization is performed by an extern unit, using the computer program nQuery Adviser 7.0. The bleomycin and calcium are mixed and labeled by an extern unit, and since both calcium and bleomycin are transparent and identical in volume, it is possible to label the syringes in a manner to blind the treating doctor. The syringes are labeled with numbers according to the metastases so syringe number "1" goes to metastasis number "1" and so on. The randomization code is kept behind locked doors, and is not accessible to the treating doctor. The randomization code is revealed for each patient after follow up, 6 months after treatment.

The randomization code can be revealed before completion of the investigation, if the investigator believes that the treatment causes so serious unexpected events or reactions, that a continuation of treatment is unacceptable.

As the randomization is done separately in each patient, code-break is possible for the individual patient, without breaking the code of the other participants.

Dose In the preclinical study, the tumors were treated with isotonic calcium chloride solution 168 mmol/L and with a volume equivalent to 0.5 x tumor volume, and this with good effect. In another preclinical study the investigators have tested the effect of this dose in different tumor types and saw variable results of the response rate. Some tumor types showed slightly lower response at this dose (own data, manuscript in preparation). Because of this experience the investigators have decided to increase the dose of calcium chloride, in this trial, to 220 mmol/L.

Volume of calcium chloride is dependent on tumor volume. Smaller tumors should have bigger volume per cm³, as smaller tumors are expected to have a bigger loss of injected medicine into the surrounding tissue. The dose volume is calculated according to the "European Standard Operating Procedure of the Electrochemotherapy (ESOPE)".

Calcium

Calcium chloride 220 mmol/L (9 mg/ml):

* Tumor \< 0.5 cm³ - 1 ml/cm³ tumor volume
* Tumor \> 0.5 cm³ - 0.5 ml/cm³ tumor volume Tumor volume = ab2π/6 (a = longest diameter, b = longest diameter perpendicular to "a")

Bleomycin Both dose and volume of bleomycin is standard according to ESOPE

Bleomycin 1000 IU/ml:

* Tumor \< 0.5 cm³ - 1 ml/cm³ tumor volume
* Tumor \> 0.5 cm³ - 0,5 ml/cm³ tumor volume Tumor volume = ab²π/6 (a = longest diameter, b= longest diameter perpendicular to "a")

Maximum of injected bleomycin per tumor will be 1500 IU and total dose per treatment 7500 IU. Normal maximum limit for bleomycin is 15.000 IU/m² body surface area.

Bleomycin and calcium chloride are mixed and labeled according to current guidelines. The mixtures will be used in a maximum of 6 hours after mixing.

This randomized double blinded phase II study is comparing the effect of calcium electroporation with ECT with bleomycin on patients with cutaneous metastases of any histology where the metastases are randomized by block randomization and are done separately in each patient.

Confirmatory Trial in the Evaluation of Ca Electroporation for the Treatment of Cutaneous Metastases

Fázis II, randomizált, kettős Vak vizsgálat a bőr metasztázisok kezelésére kálcium elektroporációval

We measured the maximum electric current which was given to the metastases. The measurement was needed because the current is unknown during Ca-electroporation, and also we would like to determine wether there is a difference between bleomycin based electrochemotherapy and calcium electroporation in current.

Documentation was done with digital color photography, including a ruler to estimate tumor size. Primary evaluation of the response was based on criteria similar RECIST 1.1 guidelines and defined as complete response (CR) - disappearance of the lesion, partial response (PR) - at least 30% decrease in the largest diameter of the lesion, progressive disease - at least 20% increase in the largest diameter of the lesion and stable disease - neither 30% decrease nor 20% increase of the largest diameter of the lesion.

Change in the largest diameter:

* Adverse Event, AE: Any adverse events in a patient that occur or worsen during the trial and does not necessarily have a causal relationship to study treatment
* Adverse Reaction, AR: All noxious and unintended reactions to a trial drug at any dose (possible relation between the study drug and the adverse reaction cannot be excluded)
* Unexpected Adverse Reaction, UAR: An adverse reaction with a nature or severity that is not in accordance with the current product information (Investigator's Brochure)
* Serious Adverse Event, SAE: an event or side effect that at any dose:
* Results in death
* Is life threatening
* Leads to hospitalization or prolongation of hospital stay
* Results in persistent or significant disability or incapacity
* Leads to a congenital anomaly or birth defect
* Is a major medical event
* Suspected Unexpected Serious Adverse Reactions, SUSARs: adverse reactions that are not described in the product information for the experimental drug

Szeged University

Principal Investigator, Assistant Professor

Any adverse events in a patient that occur or worsen during the trial and does not necessarily have a causal relationship to study treatment

Experiences from treating small tumors with electrochemotherapy, show that the treated area initially can become erythmatose and swollen, but this fades quickly. The area can then become necrotic which heals within 6-10 weeks. In a few cases, infection may occur in the treatment area. With calcium electroporation we expect to see the same response to treatment.

At electrochemotherapy the most reported adverse events are pain after the procedure and flu-like symptoms. The latter is a reaction to bleomycin and is therefore not expected by calcium electroporation.

Bleomycin Based Electrochemotherapy

All participants receiving Calcium Electroporation and Bleomycin Based Electrochemotherapy.

All Study Participants

Age, Customized

Female

Male

Sex/Gender, Customized

Caucasian

Race/Ethnicity, Customized

Patients with MM cutaneous metastases

Patients with breast cc. cutaneous metastases

Patients with cutaneous metastases

The study has certain limitations, like the small number of enrolled metastases, and the use of different electrodes.

After reviewing existing data from electrochemotherapy with intratumoral bleomycin on small cutaneous metastases ≤3cm , we estimated the expected response rate for electrochemotherapy to 85%. We have no clinical results for the treatment of calcium electroporation, but on the basis of preclinical studies, we decided to accept a difference in response of 20%. All statistical analysis were done using IBM SPSS v24.

Volume of calcium chloride (220 mmol/L) was dependent on the tumor volume. Smaller tumors should have bigger volume per cm3, as smaller tumors were expected to have a bigger loss of injected medicine into the surrounding tissue. The dose volume was calculated according to the 'European Standard Operating Procedure of the Electrochemotherapi (ESOPE)'.

* Tumor \< 0.5 cm³ - 1 ml/cm³ tumor volume
* Tumor \> 0.5 cm³ - 0,5 ml/cm³ tumor volume Tumor volume = ab²π/6 (a = longest diameter, b = longest diameter perpendicular to "a")

All patient's regardless of the number of metastases have had one biopsy from area treated with calcium and one from area treated with bleomycin, after the randomization code is revealed at day 180.

All biopsies were handled according to current guidelines and analyzed by a pathologist for amount of tumor tissue, inflammation, fibrosis and necrosis.

Both dose and volume of bleomycin (1000 IU/ml) is standard according to ESOPE.

* Tumor \< 0.5 cm³ - 1 ml/cm³ tumor volume
* Tumor \> 0.5 cm³ - 0,5 ml/cm³ tumor volume Tumor volume = ab²π/6 (a = longest diameter, b = longest diameter perpendicular to "a")

Maximum of injected bleomycin per tumor was1500 IU and total dose per treatment 7500 IU. Normal maximum limit for bleomycin was 15.000 IU/m² body surface area.

All patient's regardless of the number of metastases have had one biopsy from area treated with calcium and one from area treated with bleomycin, after the randomization code is revealed at day 180.

All biopsies were handled according to current guidelines and analyzed by a pathologist for amount of tumor tissue, inflammation, fibrosis and necrosis.

There were 7 patients with a total of 44 cutaneous metastases which were randomized. We chose up to 10 tumours on each patient. At the first 6 tumours we examined the clinical response rate, and (if they had more) the rest 4 were used for biopsy. 33 from the 44 lesions were evaluated in clinical response, the rest were used for biopsy.

Response Rate (RECIST1.1) of Calcium Electroporation and Bleomycin Based Electrochemotherapy on Cutaneous Metastases at Day 180.

Ulceration

Hyperpigmentation

Flu-like symptoms

Itch

Adverse Events for Calcium Electroporation and Bleomycin Based Electrochemotherapy. The Adverse Reactions Are Classified According to CTCAE Version 4.0 (Common Terminology Criteria for Adverse Events).

Calcium electroporation is a local treatment where calcium is administered intratumoral and followed by electrical pulses applied on the tumor. Volume of calcium chloride (220 mmol/L) was dependent on tumor volume which was calculated according to the 'European Standard Operating Procedure of the Electrochemotherapy' (ESOPE).

Calcium chloride 220 mmol/L (9 mg/ml):

* Tumor \< 0,5 cm3 - 1 ml / cm3 tumor volume
* Tumor \>0,5 cm3 - 0,5 ml/ cm3 tumor volume Tumor volume = ab2π/6 (a=longest diameter, b= longest diameter perpendicular to a)

Electroporation is a method that can facilitate transport of molecules across the cell membrane and into the cell by means of electrical pulses. The method can be used with molecules that normally have difficulty passing the cell membrane such as chemotherapy (electrochemotherapy).The most used chemotherapeutic drug used in electrochemotherapy is bleomycin (1000 IU/ml). Both dose and volume of bleomycin is standard according to ESOPE.

Bleomycin 1000 IU/ml:

* Tumor \< 0.5 cm³ - 1 ml/cm³ tumor volume
* Tumor \> 0.5 cm³ - 0,5 ml/cm³ tumor volume Tumor volume = ab²π/6 (a = longest diameter, b = longest diameter perpendicular to "a")

Maximum of injected bleomycin per tumor was 1500 IU and total dose per treatment was 7500 IU.

The Tertiary Outcome is to Register if Calcium Affects the Current Strength in Electroporation Treatments.

Volume of calcium chloride (220 mmol/L) was dependent on tumor volume. Smaller tumors should have bigger volume per cm³, as smaller tumors were expected to have a bigger loss of injected medicine into the surrounding tissue.The dose volume was calculated according to the 'European Standard Operating Procedure of the Electrochemotherapy'.

* Tumor \< 0.5 cm³ - 1 ml/cm³ tumor volume
* Tumor \> 0.5 cm³ - 0,5 ml/cm³ tumor volume Tumor volume = ab²π/6 (a = longest diameter, b = longest diameter perpendicular to "a") Biopsies were performed from the tumor area before and after electroporation. Maximum of 8 biopsies were done, depending on the patient's number of metastases. All patient's regardless of the number of metastases had one biopsy from area treated with calcium and one from area treated with bleomycin, after the randomization code was revealed at day 180.

All biopsies were handled and analyzed by a pathologist for amount of tumor tissue, inflammation, fibrosis and necrosis.

Both dose and volume of bleomycin (1000 IU/ml) was standard according to ESOPE.

* Tumor \< 0.5 cm³ - 1 ml/cm³ tumor volume
* Tumor \> 0.5 cm³ - 0,5 ml/cm³ tumor volume Tumor volume = ab²π/6 (a = longest diameter, b = longest diameter perpendicular to "a") Maximum of injected bleomycin per tumor was 1500 IU and total dose per treatment was 7500 IU.

Biopsies were performed from the tumor area before and after electroporation. Maximum of 8 biopsies were done, depending on the patient's number of metastases. All patient's regardless of the number of metastases had one biopsy from area treated with bleomycin and one from area treated with calcium, after the randomization code was revealed at day 180.

All biopsies will be handled according to current guidelines and analyzed by a pathologist.

Overall Study

Calcium electroporation for colorectal cancer as a preoperative treatment before elective surgery.

Patients with potentially curable colorectal rectal cancer will be treated preoperatively

Malene Broholm Andersen, MD

Ismail Gögenur, DMSc

Malene Broholm, MD

This is an explorative, phase I clinical trial. The aim of this study is to establish the safety and efficacy of treating patients with early colorectal cancer with calcium electroporation prior to intended curative surgery.

This is an explorative, phase I clinical trial. The aim of this study is to establish the safety and efficacy of treating patients with early colorectal cancer with calcium electroporation as a down staging and immune-response enhancing treatment prior to intended curative surgery. The study involves recruitment of patients with histologically verified rectal and sigmoid colon cancer with no indication for neoadjuvant chemoradiotherapy (experimental or standard care based) prior to intended curative surgery. In total the study will involve 24 patients, of these, 12 patients with rectal cancer and 12 patients with sigmoid colon cancer.

In relation to the intervention, clinical examination, blood samples, biopsies and questionnaires will be collected to evaluate safety, tumor respons and immunologic response to the treatment.

Patients will be followed for one month after the elective surgery.

Calcium Electroporation for Early Colorectal Cancer

Safety will be evaluated through registration of adverse events related to the treatment. CTCAE will be used

ypTNM staging and tumor regression grade according to current standards

Specific immunohistochemical staining for PD-1/PD-L1, CD3 and CD8 will be performed on biopsies and the final surgical specimen.

Tumor infiltration on T-cells and subtypes will be characterized according to the immunoscore classification system.

Blood samples will be collected prior to calcium electroporation and again at follow-up. Multiplex cytokine analysis will be performed

Blood samples will be collected prior to calcium electroporation and again at follow-up. Flow cytometri will be performed to evaluate immunological changes to the treatment.

Cell adhesion assay will be performed on blood samples to evalutate the metastatic ability.

Cell proliferation analyses will be performed on blood samples to evaluate metastatic ability

Barrett Esophagus

Precancerous Conditions

Esophageal Diseases

Areas with Barrett's esophagus high-grade dysplasia will get an injection of calcium chloride in submucosa through an endoscopic system before getting electroporation

Michael Achiam, MD., Ph.D.

Laser Bazancir, Med. student

Michael Achiam, Md., Ph.D.

The aim of this first-in-man study is to evaluate the safety of calcium electroporation used in patients with Barrett's esophagus high-grade dysplasia through an endoscopic system.

After being informed about the study and potential risks, all patients give written informed consent. Thereafter, patient will get calcium electroporation with biopsies and digital photographs on day 0. We expect to discharge all patients same evening. Between day 3-7 an examination is followed by gastroscopy with biopsies and digital photographs. On day 14 the patients are followed in our outpatient clinic. 6 weeks after treatment the patients will undergo endoscopic mucosa resection (EMR) or endoscopic submucosa dissection (ESD) surgery and thereby the standard care of treatment for Barrett's esophagus high-grade dysplasia.

Patients with Barrett's esophagus high-grade dysplasia will get calcium electroporation

Calcium Electroporation in Patients With Cell Changes in the Esophagus

Calcium Electroporation in Patients With Barrett's Esophagus High-grade Dysplasia

This is part of a safety evaluation and will be registered by CTCAE into Adverse Events (AE) and Serious Adverse Events (SAE)

Second part of safety evaluation which will be registered by VAS score. The VAS score is a scale with values from 0-10, where 0 is no pain and 10 is the worst possible pain.

Danish Cancer Society

Michael Patrick Achiam

Consultant, MD, DMSci, Ph.D., FEBS-OG, Ass. Professor

Neoplastic Processes

The metastases will be treated with intratumoral injection of calcium chlorid followed by electrotransfer.

It is a once-only treatment. Calcium chlorid concentration: 9mg/ml. Total dose: 0,5ml/cm3 tumor volume.

The metastases will be treated with intratumoral injection of bleomycin followed by electrotransfer.

It is a once only treatment. bleomycin concentration: 1000 IU/ml. Total dose: o,5 ml/cm3 tumor volume.

Intratumoral injection, once only treatment.

Intratumoral injection, once only treatment

Electrochemotherapy with bleomycin

Julie Gehl

The purpose of this study is to evaluate the effect of calcium electroporation on cutaneous metastases, and compare calcium electroporation with standard treatment: electrochemotherapy.

Double-blinded phase II clinical study. We will compare the effect of calcium electroporation for the treatment of cutaneous metastases with standard treatment: electrochemotherapy with intratumoral injection of bleomycin. Separate randomisation will be performed and the lesions will be treated with either intratumoral injection of calcium or bleomycin. It is a once only treatment and the patients will be followed up for 6 months.

It is a non-inferiority study and we accept a difference in response on 15%.

Patients with cutanoues tumors of any cancer histology were included, and metastases were marked, numbered and photographed. Syringes with either calcium or bleomycin were prepared by a pharmacist, blinded for the treating clinician. After injection of study drug (calcium or bleomycin), electroporation was performed. Metastases were followed and at the 6 month follow-up response was recorded for treated metastases and the actual drug used for each metastasis was revealed.

The patient and treating doctor only knew the size of the treated tumor, and the injection volume, but not the content of the syringe (either calcium or bleomycin).

Calcium Electroporation for Treatment of Cutaneous Metastases

It is a non-inferiority study, and we accept a difference in response on 15%.

Response evaluated by "Response Evaluation Criteria in Solid Tumors" (RECIST) guidelines version 1.1.

Describe adverse events using Common Terminology for Adverse Events, version 4.0

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Calcium Electroporation as a Treatment for Cutaneous and Subcutaneous Malignant Tumours	NCT04225767	Cancer	Calcium electro...	18 Years -	Zealand University Hospital
Electroporation and Immunotherapy in Metastatic Colorectal Cancer	NCT05609656	Metastatic Colo...	Irreversible el... Calcium electro... Pembrolizumab	18 Years -	Zealand University Hospital
Confirmatory Trial in the Evaluation of Ca Electroporation for the Treatment of Cutaneous Metastases	NCT03628417	Cutaneous Melan...	Calcium Electro... Bleomycin based...	18 Years - 100 Years	Szeged University
Calcium Electroporation for Early Colorectal Cancer	NCT03694080	Colorectal Canc...	Calcium electro...	18 Years -	Zealand University Hospital
Calcium Electroporation in Patients With Cell Changes in the Esophagus	NCT04605419	Barretts Esopha...	Calcium electro...	18 Years -	Rigshospitalet, Denmark
Calcium Electroporation for Early Colorectal Cancer	NCT03694080	Colorectal Canc...	Calcium electro...	18 Years -	Zealand University Hospital
Calcium Electroporation for Treatment of Cutaneous Metastases	NCT01941901	Cutaneous Metas...	Calcium electro... Electrochemothe...	18 Years -	Herlev Hospital
Calcium Electroporation for Treatment of Cutaneous Metastases	NCT01941901	Cutaneous Metas...	Calcium electro... Electrochemothe...	18 Years -	Herlev Hospital

Spots Global Cancer Trial Database for calcium electroporation