Study Protocol Designed to Investigate Tumour Response to Calcium Electroporation in Cancers Affecting the Skin: a Non-randomised Phase II Clinical Trial

Overview

Journal BMJ Open

Specialty General Medicine

Date 2021 Jun 17

PMID 34135049

Citations 9

Authors

Mille Vissing

John Ploen

Mascha Pervan

Kitt Vestergaard

Mazen Schnefeldt

Stine Krog Frandsen

Soren Rafael Rafaelsen

Christina Louise Lindhardt

Lars Henrik Jensen

Achim Rody

Julie Gehl

Affiliations

Soon will be listed here.

Abstract

Introduction: Skin malignancy is a distressing problem for many patients, and clinical management is challenging. This article describes the protocol for the Calcium Electroporation Response Study (CaEP-R) designed to investigate tumour response to calcium electroporation and is a descriptive guide to calcium electroporation treatment of malignant tumours in the skin. Calcium electroporation is a local treatment that induces supraphysiological intracellular calcium levels by intratumoural calcium administration and application of electrical pulses. The pulses create transient membrane pores allowing diffusion of non-permeant calcium ions into target cells. High calcium levels can kill cancer cells, while normal cells can restore homeostasis. Prior trials with smaller cohorts have found calcium electroporation to be safe and efficient. This trial aims to include a larger multiregional cohort of patients with different cancer diagnoses and also to investigate treatment areas using MRI as well as assess impact on quality of life.

Methods And Analysis: This non-randomised phase II multicentre study will investigate response to calcium electroporation in 30 patients with cutaneous or subcutaneous malignancy. Enrolment of 10 patients is planned at three centres: Zealand University Hospital, University Hospital of Southern Denmark and University Hospital Schleswig-Holstein. Response after 2 months was chosen as the primary endpoint based on short-term response rates observed in a prior clinical study. Secondary endpoints include response to treatment using MRI and change in quality of life assessed by questionnaires and qualitative interviews.

Ethics And Dissemination: The trial is approved by the Danish Medicines Agency and The Danish Regional Committee on Health Research Ethics. All included patients will receive active treatment (calcium electroporation). Patients can continue systemic treatment during the study, and side effects are expected to be limited. Data will be published in a peer-reviewed journal and made available to the public.

Trial Registration Numbers: NCT04225767 and EudraCT no: 2019-004314-34.

Citing Articles

Immune cell populations in the tumour environment following calcium electropora-tion for cutaneous metastasis: a histopathological study.

Vissing M, Pouplier S, Munch Larsen L, Krog Frandsen S, Lodin A, Laenkholm A Acta Oncol. 2024; 63:398-410.

PMID: 38804839 PMC: 11332521. DOI: 10.2340/1651-226X.2024.19462.

Pulsed Electric Fields in Oncology: A Snapshot of Current Clinical Practices and Research Directions from the 4th World Congress of Electroporation.

Campana L, Daud A, Lancellotti F, Arroyo J, Davalos R, Di Prata C Cancers (Basel). 2023; 15(13).

PMID: 37444450 PMC: 10340685. DOI: 10.3390/cancers15133340.

The effectiveness of calcium electroporation combined with gene electrotransfer of a plasmid encoding IL-12 is tumor type-dependent.

Lisec B, Markelc B, Ursic Valentinuzzi K, Sersa G, Cemazar M Front Immunol. 2023; 14:1189960.

PMID: 37304301 PMC: 10247961. DOI: 10.3389/fimmu.2023.1189960.

Electric Fields Regulate In Vitro Surface Phosphatidylserine Exposure of Cancer Cells via a Calcium-Dependent Pathway.

Kaynak A, Nguessan K, Patel P, Lee J, Kogan A, Narmoneva D Biomedicines. 2023; 11(2).

PMID: 36831002 PMC: 9953458. DOI: 10.3390/biomedicines11020466.

Qualitative Investigation of Experience and Quality of Life in Patients Treated with Calcium Electroporation for Cutaneous Metastases.

Vestergaard K, Vissing M, Gehl J, Lindhardt C Cancers (Basel). 2023; 15(3).

PMID: 36765556 PMC: 9913084. DOI: 10.3390/cancers15030599.

References

Heller L, Pottinger C, Jaroszeski M, Gilbert R, Heller R . In vivo electroporation of plasmids encoding GM-CSF or interleukin-2 into existing B16 melanomas combined with electrochemotherapy induces long-term antitumour immunity. Melanoma Res. 2001; 10(6):577-83. DOI: 10.1097/00008390-200012000-00010. View

Frandsen S, Kruger M, Mangalanathan U, Tramm T, Mahmood F, Novak I . Normal and Malignant Cells Exhibit Differential Responses to Calcium Electroporation. Cancer Res. 2017; 77(16):4389-4401. DOI: 10.1158/0008-5472.CAN-16-1611. View

Bonora M, Bononi A, De Marchi E, Giorgi C, Lebiedzinska M, Marchi S . Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition. Cell Cycle. 2013; 12(4):674-83. PMC: 3594268. DOI: 10.4161/cc.23599. View

Krog Frandsen S, Gibot L, Madi M, Gehl J, Rols M . Calcium Electroporation: Evidence for Differential Effects in Normal and Malignant Cell Lines, Evaluated in a 3D Spheroid Model. PLoS One. 2015; 10(12):e0144028. PMC: 4669124. DOI: 10.1371/journal.pone.0144028. View

Krog Frandsen S, Gissel H, Hojman P, Eriksen J, Gehl J . Calcium electroporation in three cell lines: a comparison of bleomycin and calcium, calcium compounds, and pulsing conditions. Biochim Biophys Acta. 2013; 1840(3):1204-8. DOI: 10.1016/j.bbagen.2013.12.003. View

Agoston D, Baltas E, Ocsai H, Ratkai S, Lazar P, Korom I . Evaluation of Calcium Electroporation for the Treatment of Cutaneous Metastases: A Double Blinded Randomised Controlled Phase II Trial. Cancers (Basel). 2020; 12(1). PMC: 7017133. DOI: 10.3390/cancers12010179. View

Mahmood F, Hansen R, Agerholm-Larsen B, Gissel H, Ibsen P, Gehl J . Detection of electroporation-induced membrane permeabilization states in the brain using diffusion-weighted MRI. Acta Oncol. 2015; 54(3):289-97. PMC: 4438348. DOI: 10.3109/0284186X.2014.991045. View

Plaschke C, Gehl J, Johannesen H, Fischer B, Kjaer A, Lomholt A . Calcium electroporation for recurrent head and neck cancer: A clinical phase I study. Laryngoscope Investig Otolaryngol. 2019; 4(1):49-56. PMC: 6383303. DOI: 10.1002/lio2.233. View

Frandsen S, Vissing M, Gehl J . A Comprehensive Review of Calcium Electroporation -A Novel Cancer Treatment Modality. Cancers (Basel). 2020; 12(2). PMC: 7073222. DOI: 10.3390/cancers12020290. View

10.

Sersa G, Cemazar M, Miklavcic D . Antitumor effectiveness of electrochemotherapy with cis-diamminedichloroplatinum(II) in mice. Cancer Res. 1995; 55(15):3450-5. View

11.

Mir L, Banoun H, Paoletti C . Introduction of definite amounts of nonpermeant molecules into living cells after electropermeabilization: direct access to the cytosol. Exp Cell Res. 1988; 175(1):15-25. DOI: 10.1016/0014-4827(88)90251-0. View

12.

Clover A, Salwa S, Bourke M, McKiernan J, Forde P, OSullivan S . Electrochemotherapy for the treatment of primary basal cell carcinoma; A randomised control trial comparing electrochemotherapy and surgery with five year follow up. Eur J Surg Oncol. 2019; 46(5):847-854. DOI: 10.1016/j.ejso.2019.11.509. View

13.

Falk H, Lambaa S, Johannesen H, Wooler G, Venzo A, Gehl J . Electrochemotherapy and calcium electroporation inducing a systemic immune response with local and distant remission of tumors in a patient with malignant melanoma - a case report. Acta Oncol. 2017; 56(8):1126-1131. DOI: 10.1080/0284186X.2017.1290274. View

14.

Eisenhauer E, Therasse P, Bogaerts J, Schwartz L, Sargent D, Ford R . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2008; 45(2):228-47. DOI: 10.1016/j.ejca.2008.10.026. View

15.

Bhat T, Herbosa C, Rosenberg A, Sogade O, Jeffe D, Mehta-Shah N . Current measures are not sufficient: an interview-based qualitative assessment of quality of life in cutaneous T-cell lymphoma. Br J Dermatol. 2020; 184(2):310-318. PMC: 7722174. DOI: 10.1111/bjd.19298. View

16.

Sener R . Diffusion MRI: apparent diffusion coefficient (ADC) values in the normal brain and a classification of brain disorders based on ADC values. Comput Med Imaging Graph. 2001; 25(4):299-326. DOI: 10.1016/s0895-6111(00)00083-5. View

17.

Staresinic B, Jesenko T, Kamensek U, Krog Frandsen S, Sersa G, Gehl J . Effect of calcium electroporation on tumour vasculature. Sci Rep. 2018; 8(1):9412. PMC: 6010477. DOI: 10.1038/s41598-018-27728-z. View

18.

Gehl J, Sersa G, Matthiessen L, Muir T, Soden D, Occhini A . Updated standard operating procedures for electrochemotherapy of cutaneous tumours and skin metastases. Acta Oncol. 2018; 57(7):874-882. DOI: 10.1080/0284186X.2018.1454602. View

19.

Hansen E, Sozer E, Romeo S, Krog Frandsen S, Vernier P, Gehl J . Dose-dependent ATP depletion and cancer cell death following calcium electroporation, relative effect of calcium concentration and electric field strength. PLoS One. 2015; 10(4):e0122973. PMC: 4390219. DOI: 10.1371/journal.pone.0122973. View

20.

Szewczyk A, Gehl J, Daczewska M, Saczko J, Krog Frandsen S, Kulbacka J . Calcium electroporation for treatment of sarcoma in preclinical studies. Oncotarget. 2018; 9(14):11604-11618. PMC: 5837766. DOI: 10.18632/oncotarget.24352. View