Trial of pIL-12 Electroporation Malignant Melanoma

A Multicenter Phase II Trial of Intratumoral pIL-12 Electroporation in Advanced Stage Cutaneous and in Transit Malignant Melanoma

This study will assess the safety and effectiveness of different dosing regimens of ImmunoPulse IL-12® in malignant melanoma. ImmunoPulse IL-12® is the combination of intratumoral interleukin-12 gene (also known as tavokinogene telseplasmid [tavo]) and in vivo electroporation-mediated plasmid deoxyribonucleic acid [DNA] vaccine therapy (tavo-EP) administered using the OncoSec Medical System (OMS). ImmunoPulse IL-12® is a gene therapy approach to directly induce a pro-inflammatory response within a tumor to initiate and/or enhance anti-tumor immunity.

Plasmid IL-12 (pIL-12) at a concentration of 0.5 mg/mL will be injected intratumorally at a dose volume of ¼ of the calculated lesion volume and a dose volume per lesion of 0.1 mL for lesions of volume < 0.4 cm3. Six pulses at field strengths of (E+) of 1500 V/cm and pulse width of 100 μs at 1-second intervals will be administered using the OncoSec Medical System (OMS) to each previously injected tumor.

Three treatment regimens will be explored:

Main Study: Treatment on Days 1, 5 and 8 for 1 cycle. Additional cycles may be repeated every 3 months at the Investigator's discretion.

Addendum Regimen A: Treatment on Days 1, 8 and 15 every 6 weeks. Subsequent cycles may be given at 6-week intervals, for up to 9 treatment cycles in total.

Addendum Regimen B: Treatment on Days 1, 5 and 8 every 6 weeks. Subsequent cycles may be given at 6-week intervals, for up to 9 treatment cycles in total.

NOTE: An Addendum was added to the Main Protocol with the purpose of exploring the safety and efficacy of an increased treatment frequency schedule.

Inclusion Criteria:

• Patients with advanced cutaneous or subcutaneous in-transit or metastatic melanoma (main and addendum)
• Age ≥ 18 years of age (main and addendum).
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (main and addendum).
• Patients may have had prior chemotherapy or immunotherapy (vaccines, interferon, ipilimumab, or IL-2) with progression or persistent disease. All chemotherapy or immunotherapy (prior therapies for cancer per the addendum) must have been stopped 4 weeks prior to electroporation (main part) or prior to enrollment (addendum), unless the sponsor medical monitor approval was obtained.
• Patients may have had radiation therapy, but must have progressive disease after radiation therapy if the lesions to be treated are within the radiation field. Per the main study Protocol Amendment 10 (Version 11.0), dated 27 April 2016, all prior treatment toxicities had to be resolved to Grade 1. Per the study Addendum Amendment 5, dated 27 April 2016, all prior chemotherapy or immunotherapy treatment-related adverse events (AEs) must have been resolved to baseline or Grade 1 at the time of study enrollment; and all prior radiation treatment AEs must have been resolved to baseline at the time of study enrollment.
• Had a minimum of 2 eligible tumors and could have had up to 4 eligible tumors treated with electroporation (main part).
• Must have had a lesion at baseline eligible for treatment, meeting all of the following criteria: at least 0.3 cm x 0.3 cm in longest perpendicular diameters; and accessible for electroporation (addendum).
• Must have had at least 1 additional lesion that could have been followed for distant regression and that met all of the following criteria: must have remained untreated for duration of the study; and had longest perpendicular diameters at least 0.3 cm x 0.3 cm by clinical measurement; or at least 1.0 cm x 1.0 cm by computed tomography (CT) for non-nodal lesions; or at least 1.5 cm x 1.5 cm by CT for malignant lymph nodes (addendum).
• For women of childbearing potential, a negative serum or urine pregnancy test within 14 days to the first study drug administration, and use of birth control from 30 days prior to the first day of study drug administration and 30 days following last day study drug administration was required. Male patients must have been surgically sterile, or must have agreed to use contraception during the study and at least 30 days following the last day of study drug administration (addendum).
• Had a creatinine level < 2 x upper limit of normal (ULN), and serum bilirubin within institutional normal limits obtained within 4 weeks prior to enrollment (main part and addendum).
• Had aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 1.5 x ULN within 4 weeks prior to enrollment (addendum).
• Had an absolute neutrophil count (ANC) > 1000/mm and platelet count > 100,000 /mm within 4 weeks prior to registration (main part) or enrollment (addendum).
• Were able to give informed consent and to follow guidelines given in the study (main part and addendum).

Exclusion Criteria:

• Prior therapy with IL-12 or prior gene therapy (main and addendum).
• Had an ECOG performance score of 3 or 4 (main part).
• Concurrent immunotherapy, chemotherapy, or radiation therapy for duration of patient participation on study (main part and addendum). For the study addendum, approved anti PD1 agents could have been permitted at the investigator's discretion and in consultation with the sponsor's medical monitor.
• Evidence of significant active infection (e.g., pneumonia, cellulitis, wound abscess, etc.) at time of study entry (main part) or enrollment (study addendum).
• Pregnant or breast-feeding women (main part and addendum).
• Women of childbearing age must have had a negative pregnancy test and had to be willing to use a highly effective method of contraception. Men who were sexually active must also have been willing to use an accepted and effective method of contraception (main part).
• Patients with electronic pacemakers or defibrillators are excluded from this study (main part and addendum).
• The patient is known to be positive for Human Immunodeficiency Virus (HIV) or has another confirmed or suspected immunosuppressive or immunodeficient condition (patients with thyroiditis are eligible) (addendum).
• Life expectancy of less than 6 months (main part and addendum).
• Had significant disease or uncontrolled disease, ie, cardiovascular renal, hepatic, endocrine, metabolic, neurologic, or other significant disease that could have limited the patient's ability to participate in the study as determined by the investigator or medical monitor (main part).
• History of significant cardiovascular disease (i.e. New York Heart Association (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) (study addendum).
• Other clinically significant co-morbidities such as uncontrolled pulmonary disease, uncontrolled diabetes, active central nervous system (CNS) disease, active infection or any other condition that could compromise the patients participation in the study according to the investigator (study addendum).