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Treatment procedure: anesthesia, positioning of electrodes, intravenous in bolus administration of bleomycin, within 8-30 min after administration of bleomycin application of electric pulses, removal of electrodes.

Electrochemotherapy

Positioning of electrodes, within 8-30 min after administration of bleomycin application of electric pulses (8 pulses, duration 100 microseconds, frequency 4 Hz with amplitude adequate to cover the whole treated lesion with electric field necessary for reversible plasma membrane permeabilization), removal of electrodes.

Cliniporator Vitae®

Intravenous in bolus administration of bleomycin (15 mg/m2), 8 minutes before application of electric pulses

Bleomycin PHC 15 e. (United States Pharmacopeia - USP)

Gregor Sersa, PhD

Ibrahim Edhemovic, MD, PhD

The study is prospective, phase II study, The primary objective of the study is evaluation of the feasibility and safety of intraoperative electrochemotherapy of colorectal liver metastases. The secondary objective is to determine the efficacy of electrochemotherapy treatment, based on histological and radiological evaluation of treated metastases. The endpoints are: toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) ver. 4.0 and response rate measured by percentage of vital tumor cells and mRECIST criteria.

The study is an extension of previously concluded and published study on electrochemotherapy of colorectal liver metastases (Edhemovic et al. JSO 2014). In this extension 15 patients will be included. Four groups of patients will be included. The patients from groups 1 and 2 are patients with up to 3 unresectable liver metastases, demanding too excessive resection, or untreatable by standard thermal ablative methods due to the close proximity of major blood vessels. Electrochemotherapy will be offered to these patients as the only treatment option. In case of multiple, both resectable and non-resectable liver metastases, the latter will be treated with electrochemotherapy, whereas other metastases will be resected or treated by RFA. These groups of patients are:

1. Patients with one to three (1-3) metachronous liver metastases of colorectal cancer, not larger than 5 cm, that are positioned in unresectable liver area, near blood vessels, but in otherwise operable patients.
2. Recurrent liver metastases of colorectal cancer, not more than 3 and not larger than 5 cm in diameter, each. For those patients any other treatment could represent unacceptable risk due to possibility of insufficient liver residual after resection or less effective radiofrequency ablation due to the proximity of blood vessels.

   Groups 3 and 4 include patients with intent to cure within standard of care using two-stage surgical approach. This two-stage surgical approach will allow adding electrochemotherapy during the first operation and tissue collection for histological analysis during the second operation. Adding electrochemotherapy to these patients will not affect their treatment within standard of care recommended in the current guidelines. These groups of patients are:
3. Patients with synchronous metastases, but their general condition and extent of the disease will not allow simultaneous removal of the primary tumor and metastases. During the first operation, the primary tumor will be removed (colorectal resection) and some of the liver metastases will be treated by electrochemotherapy. About 6 weeks later, during the second operation for liver metastases, both treated and non-treated metastases will be removed with liver resection.
4. Patients with bilateral, multiple, metachronous metastases in whom standard treatment includ two-stage liver resection, due to the extent of the disease and/or their general condition. During the first operation, right portal vein will be ligated and metastases on the left side will be excised or ablated with radiofrequency ablation. At the same time, up to three metastases on the right side were treated with electrochemotherapy. During the second operation, both treated and non-treated metastases on the right side will be removed with right hemihepatectomy.

Electrochemotherapy will be offered to the patients also when they refuse standard treatment.

Depending on the position of metastases, appropriate electrodes will be selected; hexagonal needle electrodes with fixed geometry for metastases not larger than 3 cm in diameter, where their lower edge is located up to 3 cm below the liver capsule. ECT will be performed based on standard operating procedures for treatment of cutaneous and subcutaneous tumors / metastases with ECT.

Individual electrodes, positioned according to the prepared treatment plan will be used for metastases up to 5 cm in diameter, or located near vena cava or large hepatic or portal veins.

Electrochemotherapy will be performed within 8-28 min after intravenous in bolus administration of bleomycin (15 mg/m2).

Triggering of electric pulses will be synchronized with ECG signals, through the ECG triggering device AccuSync to avoid delivery of pulses in vulnerable period of the heart.

All patients will be treated after the procedure has been thoroughly described to them, and have signed informed consent.

Treatment of Liver Metastases With Electrochemotherapy (ECTJ) Phase II

Recording of adverse events according to CTCAE criteria

Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI/CT:

Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

University Medical Centre Ljubljana

University Medical Centre Maribor

University of Ljubljana

Institute of Oncology Ljubljana

adverse events observed in 3 out of 23 patients, no serious adverse events

All patients were administered with intravenous bolus of bleomycin (15,000 IU/m2, Bleomycin medac, Medac, Hamburg, Germany), after intraoperative ultrasound confirmed the correct electrode placement. Eight minutes after bleomycin injection, electric pulses were delivered by Cliniporator®VITAE (IGEA SpA, Carpi, Italy).

Age, Categorical

Sex: Female, Male

Race (NIH/OMB)

Slovenia

Region of Enrollment

Patients presented with CRC liver metastases

CRC liver metastases

Dr Gregor Serša

Evaluation of Safety Related to Electrochemotherapy

Response to Treatment (Determined by Modified RECIST Criteria).

Overall Study

Exploration, anesthesia, adhesiolysis, mobilization of liver, intra-operative US or CT, bleomycin administration, electroporation

Positioning of electrodes, 8-28 min after administration of bleomycin application of electric pulses (8 pulses, duration 100 microseconds, frequency 8 Hz with amplitude adequate to cover the whole treated lesion with electric field necessary for reversible plasma membrane permeabilization), removal of electrodes.

The maximum duration of procedure is 90 minutes, after liver mobilization.

Intravenous in bolus administration of bleomycin (15 mg/m2)

Mihajlo Djokic, MD

Blaz Trotovsek, MD, PhD

Borut Stabuc, MD, PhD

Dragoje Stanisavljevic, MD

Valentin Sojar, MD, PhD

The aim of the study is to evaluate toxicity and effectiveness of electrochemotherapy with bleomycin in treatment of primary liver tumors in clinical study phase I and II.

The study will include 10 patients in phase I clinical study and additional 15 patients in phase II clinical study (or in the extension of the clinical study), which will fulfill inclusion criteria.

Treatment effectiveness will be evaluated by DCE-US or CT perfusion, to detect early events in tumor perfusion after ECT compared to tumor perfusion before ECT. Long term effectiveness of the treatment will be evaluated by modified RECIST criteria, which will take into account difference in size and density, determined from images obtained by CT perfusion of the treated tumor nodules before and after ECT. Tumor volume will be calculated by following formula , where a will be shorter and b longer tumor diameter.

The secondary objectives of the trial are to quantify the impact of the treatment on the patient's quality of life, tolerance to the therapy and suitability for larger study to be conducted.

The study will be conducted on patients with primary liver tumors. 10 patients will be included in phase I clinical study and additional 15 patients in phase II clinical study (or in the extension of the clinical study).

Depending on the position of tumors, appropriate electrodes will be selected; hexagonal needle electrodes with fixed geometry for tumors not larger than 3 cm in diameter, where lower edge of the tumor is located up to 3 cm below the liver capsule or longer single needle electrodes. Individual electrodes, positioned according to the prepared treatment plan will be used for tumors up to 7 cm in diameter, or located near vena cava or large hepatic or portal veins.

Electrochemotherapy will be performed within 8-28 min after intravenous in bolus administration of bleomycin (15 mg/m2).

Triggering of electric pulses will be synchronized with ECG signals, through the ECG triggering device AccuSync to avoid delivery of pulses in vulnerable period of the heart.

All patients will be treated after the procedure has been thoroughly described to them, and have signed informed consent.

Treatment of Primary Liver Tumors With Electrochemotherapy (ECT)

Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI/CT:

Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

Masa Bosnjak

PhD, MPharm

Electrochemotherapy: Exploration, anesthesia, adhesiolysis, mobilization of liver, intra-operative US or CT, bleomycin administration, electroporation

Cliniporator Vitae®: Positioning of electrodes, 8-28 min after administration of bleomycin application of electric pulses (8 pulses, duration 100 microseconds, frequency 8 Hz with amplitude adequate to cover the whole treated lesion with electric field necessary for reversible plasma membrane permeabilization), removal of electrodes.

The maximum duration of procedure is 90 minutes, after liver mobilization.

Bleomycin PHC 15 e. (United States Pharmacopeia - USP): Intravenous in bolus administration of bleomycin (15 mg/m2)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Treatment of Liver Metastases With Electrochemotherapy (ECTJ) Phase II	NCT02352259	Liver Metastase...	Electrochemothe... Cliniporator Vi... Bleomycin PHC 1...	18 Years -	Institute of Oncology Ljubljana
Treatment of Liver Metastases With Electrochemotherapy (ECTJ) Phase II	NCT02352259	Liver Metastase...	Electrochemothe... Cliniporator Vi... Bleomycin PHC 1...	18 Years -	Institute of Oncology Ljubljana
Treatment of Primary Liver Tumors With Electrochemotherapy (ECT)	NCT02291133	Liver Cancer	Electrochemothe... Cliniporator Vi... Bleomycin PHC 1...	18 Years -	University Medical Centre Ljubljana
Treatment of Primary Liver Tumors With Electrochemotherapy (ECT)	NCT02291133	Liver Cancer	Electrochemothe... Cliniporator Vi... Bleomycin PHC 1...	18 Years -	University Medical Centre Ljubljana

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