Confirmatory Trial in the Evaluation of Ca Electroporation for the Treatment of Cutaneous Metastases
Condition: Cutaneous Melanoma
MeSH terms: Melanoma
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Calcium Electroporation; Bleomycin based electrochemotherapy
Intervention type(s): Procedure; Procedure
Intervention description(s): 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.; 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.
Intervention MeSH terms: Bleomycin; Calcium
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: 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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Supportive Care
Keywords: cutaneous metastases; calcium electroporation; bleomycin electroporation