CLINIPORATOR LEADING CLINICAL ELECTROPORATION. A simple solution for challenging situations

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1 CLINIPORATOR LEADING CLINICAL ELECTROPORATION A simple solution for challenging situations

PHYSICS AND CHEMISTRY TOGETHER IN THE FIGHT AGAINST TUMOURS PHYSICS The application of electric pulses to the tumour tissue induces the formation of pores across the plasma membrane: electroporation.

Cell membrane Electroporated cell membrane 2 % nodules objective response 31% Bleomycin 78% Bleomycin+Electroporation IN CLINICAL PRACTICE The combination of physics and chemistry is the foundation

2 PHYSICS AND CHEMISTRY TOGETHER IN THE FIGHT AGAINST TUMOURS PHYSICS The application of electric pulses to the tumour tissue induces the formation of pores across the plasma membrane: electroporation. CHEMISTRY The pores allow the diffusion into the cell of poorly permeant drugs, significantly increasing the drug intracellular concentration and thus its cytotoxicity. Cell membrane Electroporated cell membrane 2 % nodules objective response 31% Bleomycin 78% Bleomycin+Electroporation IN CLINICAL PRACTICE The combination of physics and chemistry is the foundation for electrochemotherapy and its efficacy, which is independent of the tumour histology. The efficacy of bleomycin in the treatment of melanoma is increased by over 100% when associated with electroporation. Bleomycin i.t. vs Bleomycin i.t. + Electroporation in metastatic melanoma [Byrne CM, 2005].

3 THE COMBINATION OF HIGH POWER ELECTRONICS AND MICROELECTRONICS The easy to use CLINIPORATOR system completes electroporation of tumour cells in just a few minutes, minimising operating room usage. The short treatment time allows multiple lesions to be treated in a single session. The TOUCH SCREEN facilitates the CLINIPORATOR use through a simple and clear graphic interface. TECHNOLOGY : FAST AND EFFECTIVE The REALTIME MEASUREMENT of the electric current passing through the tumour tissue provides an indication of effective electroporation. Electroporation is obtained using DEDICATED ELECTRODES designed for cutaneous lesions, mucosa and subcutaneous tumour tissue up to a depth of 3 cm. Large tumour nodules can be treated with repeated applications of electric pulses.. 3 Adjustable Electrodes (Hexagonal) Adjustable Electrodes (Linear) Finger electrodes for the treatment of nodules in body cavities Needle electrodes CLINIPORATOR complies with the requirements of the Medical Device Directive and it is marked under the control of The Notified Body IMQ.

PROTOCOL STANDARD OPERATING PROCEDURES 0 30 Minutes PHASE 1 Injection of the

PHASE 3 Pores resealing and entrapment of the chemotherapetic drug, cytotoxic activity.

Standard Operating Procedures for Electrochemotherapy), describe precisely the drug dosing,

positive results on all tumour types [Mir LM, 2006].

and subcutaneous metastatic lesions regardless of tumour histology and ongoing or previous

Demonstrated effectiveness, complete response and long term tumour control, justify its use

4 PROTOCOL STANDARD OPERATING PROCEDURES 0 30 Minutes PHASE 1 Injection of the chemotherapetic drug. PHASE 2 Electtroporation and diffusion of the chemotherapetic drug. PHASE 3 Pores resealing and entrapment of the chemotherapetic drug, cytotoxic activity. The STANDARD OPERATING PROCEDURES, prepared and validated in the ESOPE study (European Standard Operating Procedures for Electrochemotherapy), describe precisely the drug dosing, the electric field amplitude applied and the treatment schedule to obtain reproducible positive results on all tumour types [Mir LM, 2006]. INDICATIONS FOR USE 4 Electrochemotherapy is indicated in the local treatment of cutaneous and subcutaneous metastatic lesions regardless of tumour histology and ongoing or previous treatments. Demonstrated effectiveness, complete response and long term tumour control, justify its use in the early treatment of cutaneous metastases. Squamous Cell Carcinoma Breast Cancer ADVANTAGES Thirty minutes treatment time Outpatient procedure Repeatability Does not preclude other treatments Minimal side effects Merkel cell carcinoma

IS INDICATED IN PATIENTS WITH STAGE III B/C AND IV M1 MELANOMA AND CAN BE CONSIDERED AN ELECTIVE TREATMENT FOR METASTASES LOCATED ON THE TRUNK.

system. The palliation of bleeding and painful lesions occurs within a few days of the therapy. Treatment response can be assessed by two weeks post procedure.

Non Melanoma 82% Skarlatos I, 2011 85 30 89 17 268 654 100% Curatolo P, 2011 23 532 100% Di Monta G, 2014 19 At 2 years, the local tumor control rate was 74,5% [Quaglino P, 2008].

5 IS INDICATED IN PATIENTS WITH STAGE III B/C AND IV M1 MELANOMA AND CAN BE CONSIDERED AN ELECTIVE TREATMENT FOR METASTASES LOCATED ON THE TRUNK. Several independent clinical studies (validated by a systematic review and meta analysis have demonstrated that more than 80% of metastases from melanoma respond to treatment using the CLINIPORATOR system. The palliation of bleeding and painful lesions occurs within a few days of the therapy. Treatment response can be assessed by two weeks post procedure. MELANOMA AND OTHER SKIN TUMOURS % patient objective response Patient Nodules 93% Quaglino P, % Testori A, % Campana LG, % Ricotti F, % Caracò C, 2015 Melanoma Non Melanoma 82% Skarlatos I, % Curatolo P, % Di Monta G, At 2 years, the local tumor control rate was 74,5% [Quaglino P, 2008]. INDICATIONS LOCAL RECURRENCES FOLLOWING ARE RARE Complete response is confirmed by the absence of tumour cells, as shown by histological analysis [Quaglino P, 2008]. Before Therapy After 6 months 5 Melanoma ADVANTAGES Objective response rate > 80% Repeatability Tissue sparing and preservation of organ function Long term local control OTHER SKIN TUMOURS Electrochemotherapy is successfully used for the treatment of: Basal cell carcinoma Squamous cell carcinoma Kaposi s Sarcoma GorlinGoltz syndrome Merkel cell carcinoma

INDICATIONS LOCAL RECURRENCES AND CUTANEOUS METASTASES FROM BREAST CANCER THE IMPORTANCE OF LOCAL TUMOUR CONTROL A metaanalysis conducted by Clarke M [Lancet, 2005] demonstrates that the association

Clinical evidence from multiple independent reports demonstrates that electrochemotherapy is an effective treatment for local recurrences and skin metastases from breast cancer, with an objective

Local Systemic PRIMARY BREAST CANCER CHEMOTHERAPY BIOLOGICAL THERAPIES HORMONE THERAPY SURGERY: quadrantectomy mastectomy RADIOTHERAPY DISEASE RELAPSE recurrence or skin metastases CHEMOTHERAPY

6 INDICATIONS LOCAL RECURRENCES AND CUTANEOUS METASTASES FROM BREAST CANCER THE IMPORTANCE OF LOCAL TUMOUR CONTROL A metaanalysis conducted by Clarke M [Lancet, 2005] demonstrates that the association of systemic and local control in breast cancer treatment improves by 4.9% the overall survival at 15 years. Clinical evidence from multiple independent reports demonstrates that electrochemotherapy is an effective treatment for local recurrences and skin metastases from breast cancer, with an objective response rate of 70%. Local Systemic PRIMARY BREAST CANCER CHEMOTHERAPY BIOLOGICAL THERAPIES HORMONE THERAPY SURGERY: quadrantectomy mastectomy RADIOTHERAPY DISEASE RELAPSE recurrence or skin metastases CHEMOTHERAPY BIOLOGICAL THERAPIES HORMONE THERAPY SURGERY (if feasible) RADIOTHERAPY (if feasible) BRACHYTHERAPY % patient objective response Patient Nodules 73% Larkin JO, % Campana LG, % Benevento R, % Campana LG, % Cabula C, Local tumour control in 35 BC patients treated with ECT for refractory chest wall recurrence. (a) Local progressionfree survival (LPFS) on the electroporated metastases. (b) New lesionfree survival (NLFS) (e.g., free from new skin lesions on the chest wall in nonelectroporated areas) [Campana LG, 2012]. ADVANTAGES Breast Cancer Objective response rate > 70% Efficacy in areas previously treated with radiation therapy Palliation of painful, ulcerated or bleending lesions Improved quality of life and cosmetic results Concomitant use with other therapies Before therapy Afther 2 months

93% 100% 80% HEAD AND NECK CANCERS 91% Head and Neck cancers are most often associated with squamous cell carcinoma and are characterised by locally aggressive lesions and high risk of relapse.

Electrochemotherapy is indicated for Head and Neck cancers due to the treatment efficacy and the MINIMAL EFFECT ON NORMAL TISSUE AND ON ORGAN FUNCTION.

7 93% 100% 80% HEAD AND NECK CANCERS 91% Head and Neck cancers are most often associated with squamous cell carcinoma and are characterised by locally aggressive lesions and high risk of relapse. This disease is usually controlled with LOCAL TREATMENTS INDICATIONS % patient objective response Mevio N, 2012 Gargiulo M, 2012 Benevento R, % Campana LG, 2014 Rotunno R, 2015 Electrochemotherapy is indicated for Head and Neck cancers due to the treatment efficacy and the MINIMAL EFFECT ON NORMAL TISSUE AND ON ORGAN FUNCTION. Patient Nodules Electrochemotherapy in Head and Neck cancers is an effective tool for radical local disease control and as a neoadjuvant treatment. For locally advanced challenging Head and Neck cancers it can be a first line treatment [Gargiulo M, 2010]. 7 Squamous Cell Carcinoma ADVANTAGES Before therapy Effective treatment for local recurrence and skin metastases Cytoreduction as adjuvant to surgery Preservation of normal tissue and organ function Palliation of painful, ulcerated or bleending lesions Efficacy in previously irradiated areas Repeatability After 2 months Courtesy of Fondazione IRCCS Policlinico San Matteo University Pavia.

PRODUCT CODE DESCRIPTION CLINIPORATOR ECT IG0020B Electroporator for electrochemotherapy (EPS02 B) CLINIPORATOR ECT + EGT IG0020F Electroporator for electrochemotherapy and gene transfer (EPS02 F)

8 PRODUCT CODE DESCRIPTION CLINIPORATOR ECT IG0020B Electroporator for electrochemotherapy (EPS02 B) CLINIPORATOR ECT + EGT IG0020F Electroporator for electrochemotherapy and gene transfer (EPS02 F) GREEN HANDLE IG0M915 Handle for hexagonal electrodes ELECTRODES IG0E100 Box of 5 electrodes N10HG Hexagonal 10mm IG0E102 Box of 5 electrodes N20HG Hexagonal 20mm IG0E104 Box of 5 electrodes N30HG Hexagonal 30mm BLUE HANDLE IG0M910 Handle for linear electrodes ELECTRODES IG0E150 Box of 5 electrodes N104B Linear 10mm IG0E152 Box of 5 electrodes N204B Linear 20mm IG0E154 Box of 5 electrodes N304B Linear 30mm IG0E251 Box of 5 electrodes P308B Plate 30mm FINGER ELECTRODES IG0E350 Finger Electrode F05LG 5mm/longitudinal IG0E351 Finger Electrode F05OR 5mm/orthogonal IG0E360 Finger Electrode F10LG 10mm/longitudinal IG0E361 Finger Electrode F10OR 10mm/orthogonal ADJUSTABLE ELECTRODES IG0E070 Adjustable electrode, linear configuration 30 mm (30), Standard IG0E050 Adjustable electrode, hexagonal configuration 30 mm (30), Standard IGEA/E002/04/16 BIBLIOGRAPHY Pellegrino A, et al. Outcomes of Bleomycinbased electrochemotherapy in patients with repeated locoregional recurrences of vulvar cancer. Acta Oncol Feb 17:16. [Epub ahead of print]. Cabula C, et al. Electrochemotherapy in the Treatment of Cutaneous Metastases from Breast Cancer: A Multicenter Cohort Analysis. Ann Surg Oncol Dec;22 Suppl 3: Perrone AM, et al. Palliative ElectroChemotherapy in Elderly Patients With Vulvar Cancer: A Phase II Trial. J Surg Oncol Oct;112(5): Ruggeri R, et al. Electrochemotherapy: a good idea in recurrent basal cell carcinoma treatment. Melanoma Manag. (2015) 2(1), Mozzillo N, et al. Assessing a novel immunooncologybased combination therapy: Ipilimumab plus electrochemotherapy. OncoImmunology 4:6, e ; June Brizio M, et al. Complete regression of melanoma skin metastases after electrochemotherapy plus ipilimumab treatment: an unusual clinical presentation. Eur J Dermatol MayJun;25(3):2712. Mercantini P, et al. Electrochemotherapy Treatment of Cutaneous Metastases from Breast Cancer. Am Surg May;81(5):E2225. Valpione S, et al. Consolidation electrochemotherapy with bleomycin in metastatic melanoma during treatment with dabrafenib. Radiol Oncol 2015; 49(1): Quaglino P, et al. Predicting patients at risk for pain associated with electrochemotherapy. Acta Oncol Mar;54(3): Campana LG, et al. Electrochemotherapy in nonmelanoma head and neck cancers: a retrospective analysis of the treated cases. Br J Oral Maxillofac Surg Dec;52(10): Spratt DE, et al. Efficacy of SkinDirected Therapy for Cutaneous Metastases From Advanced Cancer: A MetaAnalysis. J Clin Oncol Oct 1;32(28): Cadossi R, et al. Locally enhanced chemotherapy by electroporation: clinical experiences and perspective of use of Electrochemotherapy. Future Oncol. (2014) 10(5), Campana LG, et al. Bleomycin electrochemotherapy in elderly metastatic breast cancer patients: clinical outcome and management considerations. J Cancer Res Clin Oncol Sep;140(9): Queirolo P, et al. Electrochemotherapy for the management of melanoma skin metastasis: a review of the literature and possible combinations with immunotherapy. Arch Dermatol Res Aug;306(6):5216. Caracò C, et al. Longlasting response to electrochemotherapy in melanoma patients with cutaneous metastasis. BMC Cancer Dec 1;13(1):564. Gerlini G, et al. Dendritic cells recruitment in melanoma metastasis treated by electrochemotherapy. Clin Exp Metastasis Jan;30(1):3745. Mali B, et al. Antitumor effectiveness of electrochemotherapy: A systematic review and metaanalysis. EJSO 39 (2013) 416. Curatolo P, et al. Electrochemotherapy in the Treatment of Kaposi Sarcoma Cutaneous Lesions: A TwoCenter Prospective Phase II Trial. Ann Surg Oncol. (1):1928, Campana LG, et al. Electrochemotherapy for disseminated superficial metastases from malignant melanoma. Br J Surg. 99(6):82130, Campana LG, et al. The activity and safety of electrochemotherapy in persistent chest wall recurrence from breast cancer after mastectomy: a phaseii study. Breast Cancer Res Treat. 134(3):116978, Gargiulo M, et al. Electrochemotherapy for nonmelanoma head and neck cancers: clinical outcomes in 25 patients. Annals of Surgery. 255(6):115864, Mevio N, et al. Electrochemotherapy for the treatment of recurrent head and neck cancers: preliminary results. Tumori. 98(3):30813, Gerlini G, et al. Enhancing antimelanoma immunity by electrochemotherapy and in vivo dendriticcell activation. Oncoimmunology. 1(9): , Jarm T, et al. Antivascular effects of electrochemotherapy: implications in treatment of bleeding metastases. Expert Rev. Anticancer Ther. 10(5), , Mir LM, et al. Standard operating procedures of the electrochemotherapy: Instructions for the use of bleomycin or cisplatin administered either systemically or locally and electric pulses delivered by the CliniporatorTM by means of invasive or noninvasive electrodes. Eur J Cancer, S4:1425, Marty M, et al. Electrochemotherapy an easy, highly effective and safe treatment of cutaneous and subcutaneous metastases. Results of ESOPE (European Standard Operating Procedures of Electrochemotherapy) study. Eur J Cancer, S4:313, IGEA S.p.A. Headquarters Via Parmenide 10/A, Carpi (MO), Italy Phone oncologia@igeamedical.com IGEA DE Sonnenstrasse 23/D, München Germany Phone +49 (0) info.de@igeamedical.com IGEA UK Thremhall Park, Start Hill, Bishop s Stortford, Herts, CM22 7WE, Great Britain Phone +44 (0) info.uk@igeamedical.com

NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE

NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE INTERVENTIONAL PROCEDURES PROGRAMME Interventional procedure overview of electrochemotherapy for melanoma metastases in the skin Treating melanoma