Neoplasms

Symptoms and General Pathology

All Conditions

Skin and Connective Tissue Diseases

Neoplasm Metastasis

Neoplasms, Second Primary

Skin Neoplasms

Neoplastic Processes

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Paclitaxel

Albumin-Bound Paclitaxel

Tubulin Modulators

Antimitotic Agents

0.15% SOR007 (Uncoated Nanoparticle Paclitaxel) Ointment applied topically twice daily for 28 days

1.0% SOR007 (Uncoated Nanoparticle Paclitaxel) Ointment applied topically twice daily for 28 days

2.0% SOR007 (Uncoated Nanoparticle Paclitaxel) Ointment applied topically twice daily for 28 days or up to 56 days

One (1) Finger Tip Unit (FTU), or approximately 0.5 g, of SOR007 ointment will be applied topically to a 50 cm2 treatment area.

SOR007 (Uncoated Nanoparticle Paclitaxel) Ointment

Rose Marie Cavanna-Mast

Julie E Lang, MD

This study evaluates a topical nanoparticle paclitaxel ointment (SOR007) for the treatment of cutaneous metastases from non-melanoma cancer in adults. Three concentrations of SOR007 will be evaluated in dose-rising cohorts of three. An expanded cohort will treat additional subjects at the maximum tolerated dose.

This is a Phase 1/2, open-label, dose-rising study evaluating the safety, tolerability and preliminary efficacy of three concentrations of SOR007 (Uncoated Nanoparticle Paclitaxel) Ointment (0.15%, 1.0%, and 2.0%) applied to non-melanoma cutaneous metastases. A treatment area of 50 cm2 will be selected by the Investigator. Using a gloved hand, subjects will apply one Finger Tip Unit (FTU) of SOR007 to the 50 cm2 treatment area twice daily at approximately the same time each day for 28 days, with the option of extending treatment an additional 28 days to total 56 days for subjects in the dose expansion phase. At each visit (Days 1, 8, 15, 29, and 43 for 28 treatment days; Days 8, 15, 29, 57, and 70 for 56 treatment days), at least two global and two close-up color photographs of the treatment area will be taken (with a ruler for scale). The photographs will be analyzed with ImageJ. Eligible lesions will be determined at baseline by the RECIST definition of measurable tumors (≥ 10mm in its longest diameter). The study will include a dose escalation phase and a dose expansion phase.

In the dose escalation phase, formal safety reviews will be conducted after the last subject in each cohort of three subjects completes 15 days of treatment. The next dose level will enroll upon a finding of safety and tolerability. The top dose or the maximum tolerated dose (if DLT occurs) will be taken into the dose expansion phase and additional subjects will be enrolled to reach a maximum of 16 subjects at that dose.

Phase 1/2, open-label, dose-rising trial of three concentrations of SOR007 (0.15%, 1.0%, 2.0%).

During the dose escalation phase, the study will follow a standard 3+3 dose-ascending design. If a single dose limiting toxicity (DLT) is identified in one of three subjects in the cohort, a further three subjects will be enrolled at the same dose level. If one or more DLT occur in the three additional subjects enrolled in the cohort, dose escalation will stop and the prior dose level will be regarded as the Maximum Tolerated Dose (MTD) and taken forward into the dose expansion phase. If no further DLT are identified, dose escalation will continue, until either a DLT is identified at a higher dose or the top dose of 2% is reached.

In the dose expansion phase, additional subjects will be enrolled up to a maximum of 12 subjects at the dose determined to be the MTD (or the top dose, 2.0% SOR007).

Study of Topical SOR007 Ointment for Cutaneous Metastases

Phase 1/2 Dose-Rising, Safety, Tolerability and Efficacy Study of Topical SOR007 for Cutaneous Metastases

Treatment emergent adverse events will include all reported adverse events, laboratory assessments, physical examination findings, and vital signs.

Objective Clinical Response (Complete Clinical Response (CR) + Partial Response (PR)) is defined as the percentage of study subjects who achieve complete clinical response or partial response 14 days after last treatment (Day 43 or Day 70).

Complete clinical response (CR) is defined as absence of any detectable residual disease in the treatment area; partial response (PR) as at least a 30% decrease in the sum of the diameters of eligible lesion(s) within the treatment area compared to baseline; progressive disease (PD) as at least a 20% increase in the sum of diameters of eligible lesion(s) within the treatment area, taking as reference the smallest sum on study (the sum must also demonstrate an absolute increase of at least 5 mm); and stable disease (SD) as between that defined as PR or PD. Eligible lesions will be determined at baseline by the RECIST definition of measurable tumors (≥ 10mm in its longest diameter).

Change in pain at the treatment area will be measured by the Numeric Rating Scale (NRS-11). The numerical scale ranges from 0 to 10, with 0 being "no pain" and 10 being "the worst pain imaginable." A lower score equates to less severe pain (better outcome) and a higher score equates to more severe pain (worse outcome).

Objective Tumor Response (OTR), defined as the difference in the lesion size within the treatment area between baseline and 14 days after the last dose in the dose group i.e. Day 43 for dose escalation Subjects, and dose expansion Group A Subjects; Day 70 for dose expansion Group B Subjects; or between baseline and last tumor assessment for early terminators. Four OTRs are calculated based on different definitions of "lesion size": 1) Area of the primary eligible lesion, 2) Sum of area of all eligible lesions, 3) Longest diameter of the primary eligible lesion, and 4) Sum of longest diameter of all eligible lesions.

US Biotest, Inc.

NanOlogy, LLC

AEs were collected at all study visits from the time of first study drug application. Study personnel were required to review the Subject's diary at each visit to confirm it was adequately completed and to address and document discrepancies, missing entries and errors. Study personnel also asked open-ended questions to obtain information about AEs at every visit.

0.15% SOR007 (Uncoated Nanoparticle Paclitaxel) Ointment applied topically twice daily for 28 days

SOR007 (Uncoated Nanoparticle Paclitaxel) Ointment: One (1) Finger Tip Unit (FTU), or approximately 0.5 g, of SOR007 ointment will be applied topically to a 50 cm2 treatment area.

SOR007 0.15%

1.0% SOR007 (Uncoated Nanoparticle Paclitaxel) Ointment applied topically twice daily for 28 days

SOR007 (Uncoated Nanoparticle Paclitaxel) Ointment: One (1) Finger Tip Unit (FTU), or approximately 0.5 g, of SOR007 ointment will be applied topically to a 50 cm2 treatment area.

SOR007 1.0%

2.0% SOR007 (Uncoated Nanoparticle Paclitaxel) Ointment applied topically twice daily for 28 days

SOR007 (Uncoated Nanoparticle Paclitaxel) Ointment: One (1) Finger Tip Unit (FTU), or approximately 0.5 g, of SOR007 ointment will be applied topically to a 50 cm2 treatment area.

SOR007 2.0% Group A

2.0% SOR007 (Uncoated Nanoparticle Paclitaxel) Ointment applied topically twice daily for 56 days

SOR007 (Uncoated Nanoparticle Paclitaxel) Ointment: One (1) Finger Tip Unit (FTU), or approximately 0.5 g, of SOR007 ointment will be applied topically to a 50 cm2 treatment area.

SOR007 2.0% Group B

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Body Mass Index

The ECOG performance status scale is a measurement that describes a patient's level of functioning in terms of their ability to care for themselves, daily activity, and physical ability. The scale ranges from 0 to 5, with a lower score indicating a more functional patient and a higher score indicating a patient with more negative impacts to their daily functions.

ECOG Performance Status

All enrolled subjects are included in the baseline analysis population.

Gere diZerega, MD

All subjects who received SOR007 were included in the analysis population.

Incidence of Treatment Emergent Adverse Events

Of the 23 Subjects enrolled, evaluable photography 14 days after the last dose of SOR007 was provided in 14 (60.9%) Subjects; two in the 0.15% treatment group, three in the 1.0% treatment group, four in 2.0% A treatment group, and five in 2.0% B treatment group.

Objective Clinical Response

Baseline (Day 1)

2 Weeks after Last Dose (Day 43 for 28-day treatment groups or Day 70 for 56-day treatment groups)

Change in Pain at the Treatment Area

Based on Area of the Primary Eligible Lesion

Based on Total Area of all Eligible Lesions

Based on Longest Diameter of the Primary Eligible Lesion

Based on Total Longest Diameter of all Eligible Lesions

2.0% SOR007 (Uncoated Nanoparticle Paclitaxel) Ointment applied topically twice daily for 28 days or up to 56 days

SOR007 (Uncoated Nanoparticle Paclitaxel) Ointment: One (1) Finger Tip Unit (FTU), or approximately 0.5 g, of SOR007 ointment will be applied topically to a 50 cm2 treatment area.

SOR007 2.0%

One subject in SOR007 2.0% Group A was not included in the analysis.

Objective Tumor Response (OTR)

Overall Study

Immunomodulating Agents

Adjuvants, Immunologic

Diphencyprone (DPCP)

Vicky K Wong, MS, CCRC

Nicholas Gulati

Nicholas Gulati, MD, PhD

Philip Friedlander, MD, PhD

This is a phase I, open label study employing diphencyprone (DPCP) to characterize gene expression changes of various immune cell and tumor markers in cutaneous metastases treated with topical DPCP twice weekly for 12 weeks in combination with PD-1 or PD-L1 immune checkpoint inhibition (ICI), compared to pre-treatment cutaneous metastases and to describe the adverse events associated with DPCP when administered topically twice weekly for 12 weeks in combination with PD-1 or PD-L1 ICI.

Diphencyprone Plus Immune Checkpoint Inhibition in the Treatment of Cutaneous Metastases

A Phase I, Open Label Study Employing the Topical Immunomodulator Diphencyprone to Improve Efficacy of PD-1 or PD-L1 Immune Checkpoint Inhibition in the Treatment of Advanced Cancer With Cutaneous Metastases

Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).

Safety and tolerability of dual-therapy DPCP plus immune checkpoint inhibition will be measured as the proportion of subjects with a grade 3 on the Common Terminology Criteria for Adverse Events (CTCAE) criteria for eczema, version 5.0.

Assistant Professor

Rare Diseases

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

Neuroendocrine Tumor

Neuroepithelioma

Central Nervous System Depressants

Bone Density Conservation Agents

Anti-Infective Agents

Bleomycin

Anesthetics

Calcium

Calcium, Dietary

Hormones

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.

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.

Calcium electroporation

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
Study of Topical SOR007 Ointment for Cutaneous Metastases	NCT03101358	Cutaneous Metas...	SOR007 (Uncoate...	18 Years -	NanOlogy, LLC
Study of Topical SOR007 Ointment for Cutaneous Metastases	NCT03101358	Cutaneous Metas...	SOR007 (Uncoate...	18 Years -	NanOlogy, LLC
Diphencyprone Plus Immune Checkpoint Inhibition in the Treatment of Cutaneous Metastases	NCT05481658	Cutaneous Metas...	Diphencyprone (...	18 Years -	Icahn School of Medicine at Mount Sinai
Diphencyprone Plus Immune Checkpoint Inhibition in the Treatment of Cutaneous Metastases	NCT05481658	Cutaneous Metas...	Diphencyprone (...	18 Years -	Icahn School of Medicine at Mount Sinai
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 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 cutaneous metastases