Phase II Study of Treatment for HPV16+ ASC-US, ASC-H and LSIL

Study Overview
=================
Brief Summary
-----------------
To evaluate the safety and tolerability of the dual IM pNGVL4a Sig/E7(detox)/HSP70 DNA and single IM TA-CIN immunization regimen To evaluate the efficacy of dual IM pNGVL4a-Sig/E7(detox)/HSP70 DNA and single IM TA-CIN immunization regimen on Human Papillomavirus (HPV) 16 clearance by Month 6

Official Title
-----------------
A Randomized Double-Blind, Placebo-controlled Phase II Trial With Safety Run-In of Intramuscular pNGVL4a-Sig/E7(Detox)/HSP70 and TA-CIN for the Treatment of Patients With HPV16+ Atypical Squamous Cells of Undetermined Significance (ASC-US) or Cannot Exclude High Grade SIL (ASC-H) Cytology or Low-grade Squamous Intraepithelial Lesion (LSIL)

Conditions
-----------------
ASC-US, ASC-H Atypical Squamous Cells, Cannot Rule Out High-Grade Squamous Intra-Epithelial Lesion, LSIL

Intervention / Treatment
-----------------
* Biological: PVX-2
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Female subjects age 25-70 years with confirmation of ASC-US, ASC-H, or LSIL by liquid-based cytology HIV uninfected Patients whose cytologic specimen is HPV16+ by Aptima HPV 16 18/45 Genotype Assay Body Mass Index ≤ 32 kg/m2 Hepatitis B surface antigen negative Anti-hepatitis C virus antibody (anti-HCV) negative or negative HCV PCR if anti-HCV positive Patients who are able and willing to comply with all study procedures and voluntarily sign an informed consent form, and with anticipated availability for the planned follow-up period of one year Patients who are of childbearing potential agree to remain sexually abstinent, use methods of contraception (e.g. oral contraception, barrier methods, spermicide, intrauterine device (IUD)), or have a partner who is sterile (i.e., vasectomy) through 6 months. Patients must have adequate organ function at the time of enrollment as defined by the following parameters: white blood cell count >3,000/mcL; lymphocyte number >500/mcL; absolute neutrophil count >1,000/mcL; platelets >90,000/mcL; hemoglobin >9 g/dL; total bilirubin <3 X the institutional limit of normal; aspartate aminotransferase (AST [SGOT]) / alanine aminotransferase (ALT [SGPT]) <3 X the institutional limit of normal; creatinine <2.5X the institutional limit of normal. Histologic diagnosis of <CIN2 upon screening colposcopic examination with mandatory ECC, and cervical biopsy(ies) as clinically indicated. Exclusion Criteria: Patients who are attempting pregnancy within 6 months, pregnant, or breastfeeding. Patients with immunodeficiency, or treatment with immunosuppressive medications Administration of any blood product within 3 months of enrollment. Administration of any licensed vaccine within 2 weeks of enrollment (4weeks for measles vaccine) Participation in a study with an investigational compound or device within 30 days of signing informed consent. History of seizures (unless seizure free for 5 years) Patients with positive serological test for human immunodeficiency virus (HIV). Previous cancer history within the past 5 years. Patients who have had chemotherapy, radiation, biological cancer therapy, or other investigational agents within 28 days prior to the first dose of study drug. Patients who have had surgery within 28 days, excluding minor procedures (dental work, skin biopsy, etc). Patients with an uncontrolled intercurrent illness including, but not limited to, ongoing, or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Patients who have an active autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's Disease, multiple sclerosis (MS), ankylosing spondylitis). Patients with a recognized immunodeficiency disease including cellular immunodeficiencies, hypogammaglobulinemia, or dysgammaglobulinemia; patients who have acquired, hereditary, or congenital immunodeficiencies; patients being chronically treated with immunosuppressive drugs such as cyclosporin, adrenocorticotropic hormone (ACTH), or systemic corticosteroids Previous cervical conization or LEEP procedure or previous total hysterectomy due to cervical lesions at enrollment.

Ages Eligible for Study
-----------------
Minimum Age: 25 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Safety run-in followed by randomized double-blind, placebo-controlled study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PVX-2<br>Prime: 3 mg pNGVL4a-Sig/E7(detox)/HSP70 DNA Boost: 0.1 mg TA-CIN protein | Biological: PVX-2<br>* pNGVL4a-Sig/E7(detox)/HSP70 (naked DNA plasmid priming vaccine) TA-CIN (HPV16 L2E7E6 fusion protein booster vaccine)<br>|
| Placebo Comparator: Placebo<br>Prime: PBS (Phosphate Buffered Saline) Boost: PGC (Phosphate Glycine Cysteine Buffer) | Other: Placebo<br>* PBS and PGC<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v5.0 | To evaluate the safety and tolerability of the dual IM pNGVL4a Sig/E7(detox)/HSP70 DNA and single IM TA-CIN immunization regimen | 12 months | 
| Percent of patients that have cleared HPV16 at Month 6 | To evaluate the efficacy of dual IM pNGVL4a-Sig/E7(detox)/HSP70 DNA and single IM TA-CIN immunization regimen on Human Papillomavirus (HPV) 16 clearance by Month 6 | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of patients that have cleared HPV16 at Month 12 | To evaluate the efficacy of dual IM pNGVL4a-Sig/E7(detox)/HSP70 DNA and single IM TA-CIN immunization regimen on maintenance of Human Papillomavirus (HPV) 16 clearance by Month 12 | 12 months | 
| Percent of patients that have normal cytology at Month 6 | To evaluate the efficacy of dual IM pNGVL4a-Sig/E7(detox)/HSP70 DNA and single IM TA-CIN immunization regimen on regression to cytology with no evidence of intraepithelial lesion or malignancy (NILM) at Month 6 | 6 months |