Medical Summary
This protocol is an open label non-randomized multicenter phase II study of intratumoral bleomycin electroporation treatment (EPT) in patients with squamous cell carcinoma of the head and neck. Currently, there is no standard palliative care for these patients who fail conventional therapy directed at cure or salvage (i.e., therapy which potentially offers the patient a second chance of being rendered disease free). Refractory and recurrent loco-regional disease remains a major issue in this disease regardless of advances in approaches to curative therapy.
The effectiveness of a pharmaceutical agent is directly related to its ability to reach its site of action. For chemotherapeutic agents, the site of action is commonly intracellular with the primary barrier being the cell membrane. Therefore, the cytotoxic effect of a chemotherapeutic agent is highly dependent upon cell membrane permeability. The delivery of short, intense electrical pulses at an appropriate electrical field strength to living cells results, in vitro and in vivo, in a transient and reversible alteration of the cell membrane allowing for increased entry and cytotoxicity of anti-cancer drugs at lower concentrations than used systemically. The technique of using electrical pulses to increase the permeability of cell membranes is commonly referred to as electroporation. The effectiveness of EPT has been validated in human clinical trials with head and neck cancer patients. Of 40 patients previously treated with bleomycin (10 mg/m2 IV) followed by EPT to the lesion, complete remission was observed in 58% of the treated lesions and partial remission in 15% of lesions. Recently, EPT following intratumor bleomycin injection was investigated in 10 patients with advanced refractory disease. Among 8 patients who received EPT to all of their tumor mass, 5 exhibited a complete response and 3 a partial response. Two patients who received EPT to only part of their tumor mass had a local response but no overall lesion remission. The bleomycin-EPT treatments were well tolerated with no serious adverse events or significant local or systemic side effects related to the EPT. Typical EPT treatment reactions included necrosis, sloughing and induration of the tumor suggestive of tumor response and healing. Transient reactions (erythema, edema and tenderness, mild pain and muscle spasms) within the electroporation treatment field were the common observations following the electroporation procedure.
The proposed protocol will enroll patients with refractory or recurrent disease following standard therapy and who are not suitable to undergo salvage therapy. All patients will receive intratumoral bleomycin and electroporation. Four weeks following treatment patients will be evaluated for response based on bidimensional measurements of tumor size performed weekly over the 12 week response evaluation interval. Responding patients will be monitored every thee months until disease progression. The primary efficacy end point is patient response and secondary end points are duration of response, time to progressive disease and patient survival.

References:

1. Mir LM et. al. Electrochemotherapy potentiation of antitumor effect of bleomycin by local electric pulses. Eur. J. Cancer, 27:68-72, 1991).
2. Belehradek M et. al. Electrochemotherapy, a new antitumor treatment. Cancer, 72:3694-3700, 1993.
3. Orlowski S et. al. Transient electropermeabilization of cells in culture. Increase of the cytotoxicity of anticancer drugs. Biochemical Pharmacology 37:4727-4733, 1988.

Lay Summary
The study is designed to test the effectiveness of a new treatment modality called electroporation, in patients with tumors of the head and neck region that are below a certain size specified by the study. Patients are required to have blood tests and a CT scan prior to being enrolled on the study. This treatment involves first injecting the tumor with a chemotherapeutic drug called Bleomycin, and then electrically stimulating the tumor to increase drug uptake within the individual tumor cells. This treatment is performed in the operating room under general anaesthetic. Depending on the condition of the patient, they are either sent home on the same day or kept in hospital overnight. The patient will be followed in clinic for any side effects and CT scans will be performed to determine whether the tumor demonstrates a response. The procedure can be repeated a second time if necessary.

1. Patients with biopsy confirmed squamous cell carcinoma of the head or neck region that is (1) refractory to the standard therapy or is recurrent following the standard therapy (surgery with radiation therapy and/or chemotherapy or primary radiation with and without chemotherapy when surgery is not indicated) and (2) are not suitable or willing to undergo salvage therapy.
2. Tumors which meet the following study eligible criteria:
   - measurable by objective bidimensional measurement by direct measurement of the tumor or from measurement of CT or MRI scans.
   - accessible for intratumor needle injections of 1% lidocaine hydrochloride / 1:100,000 epinephrine and bleomycin
   - accessible to EPT treatment electrode
   - less than or equal to 80 cm3 in treatable volume.
   
3. Male or female.
4. Age 18 or older.
5. Karnofsky Performance Status >(or =) 60%.
6. Life expectancy greater than 4 months.
7. Signed a written Consent Form prior to receiving any study procedures or treatments.

1. Patients whose study eligible lesion(s) for EPT exceed 80 cm3 in total volume.
2. Patients who have a previous history of hypersensitivity to bleomycin.
3. Patients who have previously received a cumulative lifetime dose of greater than 400 U of bleomycin or will exceed a total lifetime dose of 400 U of bleomycin during treatment under this Protocol.
4. Patients with evidence of severe pulmonary fibrosis or pulmonary function deficit which would preclude the patient from receiving bleomycin.
5. Patients with cardiac pacemakers, implantable defibrillators, or a history of cardiac arrhythmia.
6. Patients who have had a myocardial infarction (MI) within the past 6 months.
7. Patients with clinical or bacteriological evidence of active infection.
8. Patients at risk or unable to receive local epinephrine vasoconstriction with 1% lidocaine hydrochloride / 1:100,000 epinephrine injections to their treatment area.
9. Patients at risk or unable to receive general anaesthesia, if required.
10. Patients who are enrolled in any other investigational study or have received investigational drug or device procedures within 4 weeks prior to study entry.
11. Patients who have received systemic cytotoxic agents within 4 weeks (6 weeks for nitroureas) prior to study entry.
12. Patients who have received local / regional treatment (eg. surgery, radiation therapy, cryotherapy, intralesional chemotherapy) to their study lesions / areas within 4 weeks prior to study.
13. Women who are pregnant or breast-feeding. Females of childbearing potential must have a