IL-12 Gene and in Vivo Electroporation-Mediated Plasmid DNA Vaccine Therapy in Patients With Merkel Cell Cancer

Phase 2

Completed

Conditions: Merkel Cell Carcinoma

Interventions: Biological: Tavokinogene Telseplasmid (tavo)
Device: OncoSec Medical System (OMS)

Registration Number: NCT01440816

Lead Sponsor: OncoSec Medical Incorporated

Brief Summary: This phase II trial studies the effectiveness of ImmunoPulse IL-12® in treating patients with Merkel cell cancer. 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). Placing the gene for interleukin-12 into Merkel cells may help the mount an effective anti-tumor immune response to kill tumor cells.

Detailed Description: PRIMARY OBJECTIVES:

I. To measure the effect of intratumoral injection of tavo followed by in vivo electroporation (EP) (electroporation-mediated plasmid DNA vaccine therapy) on the local expression of interleukin-12 (IL-12) in the tumor microenvironment in patients with Merkel cell carcinoma (MCC).

SECONDARY OBJECTIVES:

I. To assess the safety of tavo-EP in MCC. II. To assess the clinical efficacy of this treatment approach in MCC. III. To assess the immunologic changes resulting from this treatment approach.

OUTLINE:

Patients receive tavo intratumorally (IT) and undergo electrical discharge via OMS around the tumor site for electroporation-mediated plasmid DNA vaccine therapy on days 1, 5, and 8. Patients with unresectable disease may receive a second course of treatment in 12 weeks. Patients with localized disease proceed to definitive treatment as determined by the treating physician starting 2-4 weeks after the first injection.

After completion of study treatment, patients are followed up at weeks 4-8 (for patients who received definitive treatment) or 12 (for patients with unresectable disease) and then annually for up to 5 years.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 15

Inclusion Criteria

Patients must have biopsy-confirmed Merkel cell carcinoma
Patients must have at least one injectable lesion, defined as an easily palpable superficial lesion (cutaneous, subcutaneous or lymph nodal metastasis) that can be accurately localized, stabilized by palpation, and is superficial enough to enable intratumoral injection and electroporation; the injectable lesion must not be in close proximity to another tissue (e.g. nerve, bone) that could put patient safety at risk
Eastern Cooperative Oncology Group (ECOG) performance status score 0 to 2
Life expectancy of greater than three months
Absolute neutrophil count > 1,000/uL
Platelet count > 50,000/uL
Creatinine =< 2.0 x upper limit of normal (ULN)
Bilirubin =< 2.0 x ULN
Prothrombin time (PT) and partial thromboplastin time (PTT) =< 1.5 x ULN
Patients must be willing, at the time of the entry to the study, to undergo the pre-treatment fine needle aspiration (FNA) plus biopsy (if indicated) AND the post-treatment FNA plus biopsy (or surgery) of at least one injected lesion (FNA is essential to determine the primary endpoint of the study); NOTE: The pre-treatment biopsy will be obtained from a superficial not-to-be-injected lesion; the post-treatment biopsy of an injected lesion will be obviated if definitive surgical resection is planned
The effects of this treatment approach on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
Patients must have the ability to understand and the willingness to sign a written informed consent document
Both men and women, and members of all races and ethnic groups are eligible for this trial

Exclusion Criteria

Patients who have had prior chemotherapy, investigational therapy or a major surgical procedure within 4 weeks or radiotherapy within 2 weeks prior to first day of treatment
Patients must not be receiving concurrently any other anti-cancer treatment (including topical agents such as imiquimod) or investigational agents, which could potentially interfere with the study treatment and/or study endpoints
Patients with active untreated brain metastases will be excluded
Pregnant or breast feeding women are excluded because effects of this treatment on the fetus or passage through milk are unknown
Patients with electronic pacemakers or defibrillators or those with a history of life threatening cardiac arrhythmia or uncontrolled seizure disorder are excluded
Use of any immunosuppressive treatments including corticosteroids, cyclosporine, mycophenolate mofetil et cetera, within 4 weeks prior to Day 1 of treatment will not be allowed; NOTE: Patients on topical or physiologic doses (for hormone-replacement therapy) of corticosteroids will be allowed
Patients, who are judged to be immunosuppressed due to uncontrolled human immunodeficiency virus (HIV) infection, severe uncontrolled diabetes, concurrent hematological malignancy, or other comorbidities, will be excluded
Uncontrolled intercurrent illness including, but not limited to, ongoing or active serious infection, symptomatic congestive heart failure, unstable angina pectoris, serious autoimmune conditions or psychiatric illness/social situations that would limit compliance with study requirements
Patients receiving concurrent therapeutic-dose anticoagulation will be excluded

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Cohort A: Tavo-EP	OncoSec Medical System (OMS)	Patients in Cohort A received one cycle (3 daily treatments on Days 1, 5, and 8) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, after which they proceeded to definitive treatment (surgery and/or radiation therapy) which started between 2 and 4 weeks after the first injection.
Cohort A: Tavo-EP	Tavokinogene Telseplasmid (tavo)	Patients in Cohort A received one cycle (3 daily treatments on Days 1, 5, and 8) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, after which they proceeded to definitive treatment (surgery and/or radiation therapy) which started between 2 and 4 weeks after the first injection.
Cohort B: Tavo-EP	Tavokinogene Telseplasmid (tavo)	Patients in Cohort B received up to 4 cycles (3 daily treatments on Days 1, 5, and 8, per cycle) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, with 12 planned weeks between each cycle, lasting up to 12 months.
Cohort B: Tavo-EP	OncoSec Medical System (OMS)	Patients in Cohort B received up to 4 cycles (3 daily treatments on Days 1, 5, and 8, per cycle) of intra-tumoral injection(s) of tavo at a fixed dose of 0.5 mg/mL (up to 4 tumor sites) followed immediately by in vivo electroporation, with 12 planned weeks between each cycle, lasting up to 12 months.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Who Experienced At Least 2-Fold Increase in Expression of IL-12 Protein in the Tumor Tissue After Intratumoral (IT) pIL-12 Injections and In Vivo Electroporation	Pre-treatment up to Week 13	The MAGPIX assay was used to assess differential expression of hIL-12 in patient tumor tissue before and after treatment with intratumoral (IT) tavo injections and in vivo electroporation (EP). Expression of hIL-12 was used to identify patients who met the primary endpoint of a 2-fold or higher increase in expression of hIL-12 in tumors after treatment. Fold change was taken as a comparison of hIL-12 expression at Week 3:pre-treatment, Week 6:pre-treatment, Week 8:pre-treatment, or Week 13:pre-treatment over baseline (pre- treatment). The fold change was calculated as log2 (time point/baseline).

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	From signing of informed consent to 8 weeks after the last dose of study treatment (up to 15 months)	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.
Objective Response Rate (ORR) in Injected and Non-injected (Distant) Lesions	3-4 weeks after the first dose in each cycle and then every 3 months until disease progression, death or withdrawal of consent (up to 15 months)	ORR is defined as the percentage of participants with evaluable lesions that achieved a complete response (CR) or partial response (PR) as assessed by the investigator using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions. The same method was used to assess response rate for treated lesions and response rate for non-treated lesions. The best response rate for non-treated lesions was based on the number of patients who had at least one non-treated lesion.
Time to Progression (TTP)	3-4 weeks after the first dose in each cycle and then every 3 months until disease progression, death or withdrawal of consent (up to 15 months)	TTP is defined as the number of days between the treatment initiation date (Study Day 1) and the earliest date of documented disease progression as defined by RECIST 1.1 or death that is not associated with prior disease progression. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Local Regression Rate	3-4 weeks after the first dose in each cycle and then every 3 months until disease progression, death or withdrawal of consent (up to 15 months)	Local regression rate is defined as the percentage of participants with ≥30% regression (decrease in size) of at least one assessed local (injected) lesion.
Overall Survival	From the start of study treatment until death (up to 15 months)	Overall survival is defined as the time in days from the date of first study drug administration to the date of death.
Immunologic Effects of IT pIL-12 Injection and In Vivo EP Measured By: Percentage of Participants With a Positive Fold Change (Log2) in IL-12A Messenger Ribonucleic Acid (mRNA) for Patient Pre- and Post IT pIL 12 EP	Pre-treatment up to Week 13	Nanostring analysis was performed to determine the expression (mRNA) of IL-12. For each study patient, the fold change (log2 transformed) in IL-12A mRNA as measured by Nanostring was determined using the pre-treatment (screening) biopsy as a reference for the post treatment biopsy. A log2 fold change \>=1 is a positive result.
Distant Regression Rate	3-4 weeks after the first dose in each cycle and then every 3 months until disease progression, death or withdrawal of consent (up to 15 months)	Distant regression rate is defined as the percentage of participants with ≥30% regression (decrease in size) of at least one assessed distant (non-injected) lesion.