Phase II Intratumoral IL12 Plasmid Electroporation in Cutaneous Lymphoma

Study Overview
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Brief Summary
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A single arm, open label, multi-center, phase 2 study to assess the safety and anti-tumor activity of ImmunoPulse IL-12® in participants with stage IB to IIIB mycosis fungoides. ImmunPulseIL12® is the combination of intrtumoral 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). All participants may receive up to four cycles of treatment consisting of three treatment days, Days 1, 5 and 8, in a 12-week cycle as per Protocol version 6 (see Limitations and Caveats section of this record for protocol version information). Patients will receive intra-tumoral injection of tavo at a concentration of 1.0 mg/mL (maximum volume of 1 mL/day distributed over 2-4 lesions), followed immediately by electrical discharge around the tumor site resulting in electroporation of plasmid deoxyribonucleic acid (DNA) into tumor cells.

Detailed Description
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This is a single arm, open label, multi-center phase 2 study to assess the safety and anti-tumor activity of intratumoral tavo electroporation in participants with stage IB to IIIB mycosis fungoides. All participants received up to four cycles of treatment consisting of three treatment days, Days 1, 5 and 8, in a 12-week cycle. Patients will receive intra-tumoral injection of tavo at a concentration of 1.0 mg/mL (maximum volume of 1 mL/day distributed over 2-4 lesions), followed immediately by electrical discharge around the tumor site resulting in electroporation of plasmid deoxyribonucleic acid (DNA) into tumor cells. Prior to the first cycle of treatment, the investigator will select at least one lesion, or affected area in erythrodermic patients, to be left untreated for the duration of the study to allow for clinical observation of an untreated site. Participants will be followed for safety and clinical evaluation every 4 weeks. Quality of Life will be assessed using the Skindex29, Functional Assessment of Cancer Therapy - General (FACT-G) and Visual Analog Scale for Pruritus (VAS-P) instruments. Survival follow up will occur at 3-month intervals over 2 years following end of study.

Official Title
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A Multicenter Phase II Trial of Intratumoral IL12 Plasmid Electroporation in Cutaneous Lymphoma

Conditions
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Cutaneous T Cell Lymphomas (CTCL), Mycosis Fungoides (MF)

Intervention / Treatment
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* Biological: Tavokinogene Telseplasmid (tavo)
* Device: OncoSec Medical System (OMS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Biopsy confirmed mycosis fungoides of stage IB - IIIB; Participants must have failed or have been intolerant to at least one standard of care therapy; Participants must have a minimum of one lesion, or affected area in erythrodermic patients (T4/stage III), that meets all following criteria: Accessible for pIL-12 electroporation; Adequate size such that 6-mm biopsy can be collected prior to treatment; Participants must have one additional lesion, or affected area in erythrodermic patients, that remains untreated for the duration of the study; Age ≥ 18 years old; Participants must have Eastern Cooperative Oncology Group (ECOG) performance status 0-2; Required wash out period of 4 weeks from last dose for the following prior therapies: Topical therapy; Radiotherapy (including photo therapy); Multi-agent chemotherapy; Systemic biological therapy; Histone deacetylase inhibitors (HDAC) inhibitors; Interferon alpha and other investigational therapies; For women of childbearing potential, negative pregnancy serum test within 14 days to the first study drug administration, and use of birth control from 30 days prior to the first day study drug administration and 30 days following last day study drug administration; Male participants must be surgically sterile, or must agree to use contraception during the study and at least 30 days following the last day of study drug administration. Life expectancy of at least 6 months; The patient must have adequate renal and hepatic function as assessed by standard laboratory criteria within 4 weeks prior to enrollment: Creatinine < 2 x upper limit of normal (ULN); Serum bilirubin within institutional normal limits; Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 1.5 x ULN; Absolute neutrophil count (ANC) > 1000/mm; Platelet count > 100,000 /mm; Able to give informed consent and able to follow guidelines given in the study. Exclusion Criteria Prior therapy with IL-12 or prior gene therapy; Prior treatment with Campath (alemtuzumab) within 1 year of enrollment; Concurrent immunotherapy, chemotherapy, or radiation therapy for duration of patient participation on study; Concurrent steroid therapy; Concurrent anticoagulant therapy (acetylsalicylic acid [ASA]≤ 325mg/day allowed); Evidence of significant active infection (e.g., pneumonia, cellulitis, wound abscess, etc.) at time of study enrollment; Patients with current evidence of large cell transformation (LCT) with aggressive disease at study entry (patients with a history of LCT are eligible if pathologic evidence at study entry indicates there is no presence of LCT); Known history of human immunodeficiency virus (HIV), Human T-cell leukemia virus (HTLV) -1/2 infection, hepatitis B or hepatitis C (active, prior treatment, or both); No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 2 years; Significant cardiovascular disease (i.e. New York Heart Association [NYHA] class 3 congestive heart failure; myocardial infarction within the past 6 months; unstable angina; coronary angioplasty with the past 6 months; uncontrolled atrial or ventricular cardiac arrhythmias); Any other medical history, including laboratory results, deemed by the investigator to be likely to interfere with patient's participation in the study, or to interfere with the interpretation of the results; Participants 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 as effects on the fetus are unknown and there may be a risk of increased fetal wastage.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Participants received up to 4 cycles of treatment (3 daily treatments on Days 1, 5 and 8, in a 12-week cycle) of intratumoral injection(s) of tavo at a concentration of 1.0 mg/mL (maximum volume of 1 mL/day distributed over 2-4 lesions), followed immediately by electrical discharge around the tumor site resulting in electroporation of plasmid deoxyribonucleic acid (DNA) into tumor cells. | Biological: Tavokinogene Telseplasmid (tavo)<br>* Patients received intratumoral injection(s) of tavo.<br>* Other names: plasmid IL-12;Device: OncoSec Medical System (OMS)<br>* Electroporation via OMS was performed immediately following intratumoral injection of tavo. A sterile applicator containing 6 stainless steel electrodes arranged in a circle were placed around the tumor. The applicator was connected to the OMS power supply and six pulseswere administered to each tumor lesion at the approximate point of tavo injection.<br>* Other names: MedPulser;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate Assessed by Modified Severity Weighted Assessment Tool (mSWAT) Score in the Skin | ORR is defined as the percentage of participants that achieved a complete response (CR) or partial response (PR) as assessed by mSWAT score. The mSWAT defines 3 lesion types and assigns each a weighing factor: patch (no induration or significant elevation)=1; plaque (induration, crusting, ulceration or poikiloderma)=2; tumor (solid or nodular ≥ 1 cm in diameter with evidence of deep infiltration and/or vertical growth)=4. Lesions are assessed by body surface area (BSA) where palm + fingers = approximately 1% BSA in each of 12 areas (head, neck, anterior trunk, arms, forearms, hands, posterior trunk, buttocks, thighs, legs, feet, groin), and the sum of each area of BSA is multiplied by its weighing factor. An overall sum of each subtotal represents the mSWAT score (0=no lesions; 400=lesions covering all areas). CR=100% clearance of skin lesions; PR= 50%-99% clearance of skin disease from baseline without new tumors ( ≥1.0 cm in diameter) in patients with T1, T2 or T4 only skin disease. | Every 28 days for the first 24-weeks of treatment | 
| Objective Response Rate Assessed by Modified Severity Weighted Assessment Tool (mSWAT) Composite Global Score | ORR is defined as the percentage of participants that achieved a complete response (CR) or partial response (PR) as assessed by mSWAT Composite Global Score. This assessment evaluated skin, lymph node, blood and visceral involvement. The response generated in each category was used to determine the Global ORR: CR=complete disappearance of all clinical evidence of disease or, no involvement of disease at baseline through time of response evaluation (NI); PR=regression of measurable disease as follows: 100% clearance of skin lesions, all other categories do not have CR/NI and no category has progressive disease (PD) -OR- 50%-99% clearance of skin disease from baseline without new tumors ( ≥1.0 cm in diameter) in patients with T1, T2 or T4 only skin disease, and if any other category was involved at baseline, at least one has CR/PR and no category has PD. | Every 28 days for the first 24-weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product, medical treatment or procedure and which did not necessarily have to have had a causal relationship with this treatment. An adverse event could have, therefore, been any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, medical treatment or procedure whether or not considered related to the medicinal product. An SAE was defined an any untoward medical occurrence that at any dosage resulted in one or more of the following: death, A life-threatening adverse event (real risk of dying), inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly, required intervention to prevent permanent impairment of damage. | From the start of study treatment up to 340 days | 
| Duration of Overall Objective Response Assessed by mSWAT Skin Score | Duration of overall objective response (CR or PR) is defined as the number of days from the initial documentation of an objective response to the most current evaluation of that response or to documentation of progression assessed by mSWAT Skin Score: CR=100% clearance of skin lesions; PR= 50%-99% clearance of skin disease from baseline without new tumors ( ≥1.0 cm in diameter) in patients with T1, T2 or T4 only skin disease. | From first documented response until disease progression (Up to 340 days) | 
| Time to Overall Objective Response Assessed by mSWAT Skin Score | Time to overall objective response (CR or PR) is the number of days from the start of therapy to the first documentation of objective response assessed by mSWAT Skin Score: CR=100% clearance of skin lesions; PR= 50%-99% clearance of skin disease from baseline without new tumors ( ≥1.0 cm in diameter) in patients with T1, T2 or T4 only skin disease. | From start of study treatment until overall objective response (Up to 340 days) | 
| Quality of Life (QoL) | Participants were to complete the following QoL assessments prior to clinical evaluations every 4 weeks: Skindex29, FACT-G (Functional Assessment of Cancer Therapy -General) and VAS-P (Visual Analog for Pruritus) questionnaires. | Every 28 days for up to 340 days |