Phase II Intratumoral pIL-12 Electroporation in Cutaneous Lymphoma

• Patient safety when treated with this procedure [ Time Frame: 56 days from day 1 of treatment ] [ Designated as safety issue: Yes ]
  Safety observations and measurements including drug exposure, adverse events, laboratory tests, vital signs, and physical examinations will be documented and reported. Adverse Events will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
• Progression free survival of patients treated with this procedure [ Time Frame: From Day 1 of treatment to disease progression (estimated up to 6 months) ] [ Designated as safety issue: No ]
  PFS is measured from the date of first treatment to the date of disease progression. It will be calculated using the Kaplan-Meier procedure.
• Exploratory objective: immune responses in patients treated with pIL-12 [ Time Frame: 28 days from day 1 of treatment ] [ Designated as safety issue: Yes ]

  Examine changes of tumor-infiltrating cells in treated and regressing MF lesions versus stable lesions by immunochemistry staining, as well as anti-tumor elements.

  In addition, also examine peripheral blood to determine the cytokine profile of T cells, as well as NK/T-cell activity pre- and post- treatment with pIL-12 electroporation.

This is a multi-institution Phase II trial of intra-tumoral electroporation of IL-12 plasmid (pIL12) in patients with mycosis fungoides/Sezary syndrome. All patients will receive at least one cycle of treatment consisting of 3 treatments on days 1, 5 and 8 (±1 day). Patients will receive intra-tumoral injection of pIL-12 at a concentration of 1mg/ml followed immediately by electrical discharge around the tumor site resulting in electroporation of plasmid DNA into tumor cells.

Patients will receive intra-tumoral injection of pIL-12 at a concentration of 1mg/ml followed immediately by electrical discharge around the tumor site resulting in electroporation of plasmid DNA into tumor cells. The volume of pIL12 used per treatment is in proportion of the total volume of the skin lesions treated, which is calculated as described in Section 6.2. The maximum volume of each treatment (including up to 4 electroporated lesions) per patient is 1 ml and the total volume of pIL12 to be injected is not to exceed 3 ml per cycle. Patients, who do not have progressive disease at non-electroporated sites as judged by modified SWAT or intolerability of the treatment, can receive additional treatment every 3 months for a total of 4 cycles (12 months).

One cycle of treatment consists of three electroporations applied per lesion, to at least two and a maximum of four lesions each day on days 1, 5 and 8 (±1 day). Prior to plasmid injection, using sterile precautions, 1% lidocaine may be injected around the lesion to obtain local anesthesia (prior history of lidocaine hypersensitivity will be assessed prior to administration of local lidocaine injections).

For each cycle, previous untreated sites or previously treated sites that have evidence of persistent disease will be selected as the new electroporation sites.

All grade 3 and 4 toxicities from previous treatments must resolve completely before initiating a new cycle of treatment. Treatment response at untreated sites will be evaluated according to the standard modified SWAT. Response at the electroporated sites will be recoded separately.

Three skin biopsies will be performed during a course of 1 year of treatment. Additional biopsies may be obtained if judged necessary by the treating physician and consented to by the patient.

After the completion of the treatment period of the trial, subjects will be followed for survival at a 6-month interval for a period of 5 years. This follow up period starts after the last scheduled assessment in the treatment period of the study.

• Cutaneous T Cell Lymphomas (CTCL)
• Mycosis Fungoides (MF)

• Drug: IL-12 plasmid
  All patients will receive at least one cycle of treatment consisting of 3 treatments on days 1, 5 and 8 (±1 day). Patients will receive intra-tumoral injection of IL-12 plasmid (pIL12) at a concentration of 1mg/ml (pIL12)
  Other Name: Interleukin-12
• Device: Electroporation
  One cycle of treatment consists of three electroporations applied per lesion, to at least two and a maximum of four lesions each day on days 1, 5 and 8 (±1 day).
  Other Name: Electropermeabilization

Inclusion Criteria:

• Biopsy confirmed mycosis fungoides of stage IB-IVA.
• Patients must have failed or have been intolerant of at least 2 topical or one systemic treatment.
• Patients must have a minimum of 4 lesions, 2 for electroporation, and 2 for evaluation of response.
• Age > 18 years old
• Patients must have ECOG performance status 0-2
• Patients must have creatinine < 2 x upper limit of normal, and serum bilirubin within institutional normal limits obtained within 4 weeks prior to first dosing.
• Patients must have absolute neutrophil count (ANC) > 1000/mm and platelet count > 75,000 /mm within 4 weeks prior to first dosing.
• Required wash out periods for prior therapy:
• Topical therapy: 2 weeks from first dosing
• Chemotherapy: 4 weeks from first dosing
• Radiotherapy (including photo therapy): 4 weeks from first dosing
• Systemic biological therapy for mycosis fungoides: 4 weeks from first dosing
• Other investigational therapy: 4 weeks from first dosing
• Patients of reproductive potential and their partners must agree to use an effective (>90% reliability) form of contraception during the study and for 4 weeks following the last study drug administration.
• Women of reproductive potential must have negative urine pregnancy test.
• Life expectancy greater than 4 months from first dosing.
• Patients must be able to give informed consent and able to follow guidelines given in the study

Exclusion Criteria:

• Patients with active infection or with a fever >38.50 C within three days prior to the first scheduled treatment
• CNS metastases
• Known history of human immunodeficiency virus (HIV), hepatitis B or hepatitis C (active, prior treatment, or both).
• Prior malignancy (active within 5 years of screening) except basal cell or completely excised non-invasive squamous cell carcinoma of the skin, or in situ squamous cell carcinoma of the cervix
• Current anticoagulant therapy (ASA<= 325mg/day allowed).
• Significant cardiovascular disease (i.e. NYHA class 3 congestive heart failure; myocardial infarction with the past 6 months; unstable angina; coronary angioplasty with the past 6 months; uncontrolled atrial or ventricular cardiac arrhythmias).
• Pregnant or lactating.
• Any other medical history, including laboratory results, deemed by the investigator to be likely to interfere with their participation in the study, or to interfere with the interpretation of the results.
• Patients with electronic pacemakers or defibrillators are excluded from this study as the effect of electroporation on these devices is unknown.
• Pregnant and breast feeding women are excluded from the study because effects on the fetus are unknown and there may be a risk of increased fetal wastage.