Study of Treatment for HPV16+ ASC-US or LSIL

Study Overview
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Brief Summary
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Phase I clinical trial to assess safety of pNGVL4aCRTE6E7L2 DNA and TA-CIN protein vaccinations, and to seek the appropriate dose of the pNGVL4aCRTE6E7L2 DNA vaccine

Detailed Description
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Primary Objectives To determine the safety and feasibility of intra-muscular administration of pNGVL4aCRTE6E7L2 DNA vaccine in patients with persistent HPV16+ ASC-US/LSIL. To determine the appropriate intra-muscular injection dose of pNGVL4aCRTE6E7L2 DNA vaccine as determined by toxicity and immunogenicity for a subsequent phase II clinical trial. To determine the safety and feasibility of intra-muscular administration of pNGVL4aCRTE6E7L2 DNA vaccine prime, TA-CIN protein vaccine boost in patients with persistent HPV16+ ASC-US/LSIL.

Official Title
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Phase I Clinical Trial Assessing the Safety and Feasibility of Intramuscular pNGVL4aCRTE6E7L2 and TA-CIN Administration for the Treatment of Patients With Persistent HPV16+ ASC-US or LSIL

Conditions
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ASC-US, LSIL

Intervention / Treatment
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* Biological: pNGVL4aCRTE6E7L2
* Biological: TA-CIN


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with persistent (>6 month period) ASC-US/LSIL determined by cervical cytology at study entry (ThinPrep with imaging) Patients whose cytologic samples are persistent (>6 month period) HPV16+ by Roche Cobas 4800, Roche Linear Array HPV Genotyping test or other FDA-approved HPV genotyping test at study entry. Co-infections with HPV types other than HPV16 are permissible for study entry. Age ≥ 19 years Baseline Eastern Cooperative Oncology Group Patients must have adequate organ function at the time of enrollment as defined by the following parameters: White blood cell count > 3,000 Absolute lymphocyte number > 500 Absolute neutrophil count > 1,000 Platelets > 90,000 Hemoglobulin > 9 Total bilirubin <3 X the institutional limit of normal AST(SGOT)/ALT(SGPT) <3 X the institutional limit of normal Creatinine < 2.5X the institutional limit of normal Women of child-bearing potential must agree to use two forms of contraception (hormonal and barrier) prior to study entry and for 3 months after study completion. Ability to understand and the willingness to sign a written informed consent document. Subject is able to adhere to the study visit schedule and other protocol requirements. Exclusion Criteria: Patients with ASC-US/LSIL determined by cervical cytology at study entry that are HPV16 negative. Histologic evidence of CIN2+ Patients with a diagnosis of immunosuppression or prolonged, active use of immunosuppressive medications such as steroids. Prior vaccination with any HPV antigen (prophylactic or therapeutic). Patients who are receiving any other investigational agents within 28 days prior to the first dose. 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 with a history of autoimmune disease such as multiple sclerosis, exclusive of a history of thyroiditis, psoriasis, Sjrogen's, or inflammatory bowel disease. Patients with a history of allergic reactions attributed to compounds used in agent preparation. Patients who are pregnant or breast feeding. Patient with active or chronic infection of HIV, HCV, or HBV. Patients who have had a prior LEEP or cervical conization procedure. History of prior malignancy permitted if patient has been disease free for ≥ 5 years; however individuals with completely resected basal cell or squamous cell carcinoma of the skin within this interval may be enrolled. Inability to understand or unwillingness to sign an informed consent document.

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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Female

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose escalation study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: pNGVL4aCRTE6E7L2 0.3mg dose<br>Low dose of pNGVL4aCRTE6E7L2 plasmid DNA is administered by intramuscular injection at weeks 0, 4 and 8. | Biological: pNGVL4aCRTE6E7L2<br>* Naked pNGVL4aCRTE6E7L2 DNA plasmid<br>|
| Experimental: pNGVL4aCRTE6E7L2 1 mg dose<br>Intermediate dose of pNGVL4aCRTE6E7L2 plasmid DNA is administered by intramuscular injection at weeks 0, 4 and 8. | Biological: pNGVL4aCRTE6E7L2<br>* Naked pNGVL4aCRTE6E7L2 DNA plasmid<br>|
| Experimental: pNGVL4aCRTE6E7L2 3 mg dose<br>High dose of pNGVL4aCRTE6E7L2 plasmid DNA is administered by intramuscular injection at weeks 0, 4 and 8. | Biological: pNGVL4aCRTE6E7L2<br>* Naked pNGVL4aCRTE6E7L2 DNA plasmid<br>|
| Experimental: PVX-6<br>Selected dose of pNGVL4aCRTE6E7L2 plasmid DNA is administered by intramuscular injection at weeks 0 and 4, and the TA-CIN protein is administered by intramuscular injection at week 8. | Biological: pNGVL4aCRTE6E7L2<br>* Naked pNGVL4aCRTE6E7L2 DNA plasmid<br>Biological: TA-CIN<br>* TA-CIN is a single fusion protein comprised of HPV16 L2, E7 and E6 proteins linked in tandem.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and feasibility of pNGVL4aCRTE6E7L2 DNA vaccination | To determine the safety and feasibility of intra-muscular administration of pNGVL4aCRTE6E7L2 DNA vaccine in patients with persistent HPV16+ ASC-US/LSIL | 12 months | 
| Dose finding | To determine the appropriate intra-muscular injection dose of pNGVL4aCRTE6E7L2 DNA vaccine as determined by toxicity and immunogenicity for a subsequent phase II clinical trial | 12 months | 
| Safety and feasibility of PVX-6 vaccination | To determine the safety and feasibility of intra-muscular administration of pNGVL4aCRTE6E7L2 DNA vaccine prime, TA-CIN protein vaccine boost in patients with persistent HPV16+ ASC-US/LSIL | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HPV16 antibody response | To evaluate the levels of circulating antibody specific for HPV-16 in the peripheral blood pre- and post-vaccination | 12 months | 
| HPV16 CD8 T cell response | To evaluate the levels of circulating HPV-16 E6- and E7-specific CD8+ T cells and T regulatory cells in the peripheral blood pre- and post-vaccination | 12 months | 
| HPV16 L2E7E6 T cell proliferative response | To evaluate the proliferative responses of peripheral blood mononucleocytes pre- and post-vaccination in response to stimulation by HPV16 E6, E7 and L2 | 12 months | 
| Clearance of HPV16 | To evaluate the presence of high risk HPV, and specifically HPV16 in cytologic specimens pre- and post-vaccination | 12 months | 
| Cytologic clearance | To evaluate changes in the cytopathology of ectocervical and endocervical specimens taken pre- and post-vaccination | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HPV16