Study of FluBHPVE6E7 in HPV-16 Infected Women

Study Overview
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Brief Summary
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BS-01 is a randomised, double-blind, placebo-controlled, phase 1 dose escalation study assessing safety, tolerability and immunogenicity of FluBHPVE6E7, changes in the HPV infection status and cervical cytology, and biodistribution in HPV-16 infected women with normal cytology, CIN1 or CIN2. The safety and immunogenicity of two dose levels, 7.5 log10 and 9.0 log10 fTCID50/dose of FluBHPVE6E7 are assessed after three subcutaneous administrations. In addition the safety of 9.0 log10 fTCID50/dose of FluBHPVE6E7 is assessed after three intradermal or intramuscular administrations.

Detailed Description
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BS-01 is a randomised, placebo-controlled, double- blind phase 1 dose-escalation study in women with normal cytology, CIN1 or CIN2. The primary objective is to assess the safety and tolerability of FluBHPVE6E7. Secondary objectives are the assessment of the systemic immune responses to immunisations with FluBHPVE6E7, changes in HPV infection status and cervical cytology, and biodistribution. Study medication is administered three times (Day 0, Week 4, Week 12). Study participants are randomised at a ratio of 3:1 for FluBHPVE6E7 or placebo. The first cohort is treated subcutaneously at dose level 7.5 log10 fTCID50/dose. The second cohort is treated subcutaneously at 9.0 log10 fTCID50/dose. Interim safety reviews are performed by a Data Monitoring Committee. After completion of the dose-escalation and in order to collect additional safety data on the highest safe and tolerated dose level, additional study participants are enrolled into expansion cohorts treated three times subcutaneously, intradermally or intramuscularly at 9.0 log10 fTCID50/dose.

Official Title
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Randomised, Double-blind, Placebo-controlled Phase 1 Dose-escalation Study of FluBHPVE6E7 in HPV-16 Infected Women With Normal Cytology, CIN1 or CIN2

Conditions
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HPV Infection

Intervention / Treatment
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* Biological: FluBHPVE6E7


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Females in general good health, EITHER 18-49 years of age with HPV-16 infection and cervical cytological evaluation with a normal result, OR 25-49 years of age, with HPV-16 infection, and histologically confirmed cervical intraepithelial neoplasia 1 (CIN1) or 2 (CIN2) for whom a wait-and-see approach for the study period is indicated HPV-16 infection has been confirmed at least twice by a validated HPV test separated by at least 3 months Satisfactory colposcopy (i.e. the entire cervix as well as the entire squamocolumnar junction can be visualized by colposcopy and there is no evidence of invasive cancer) No clinically significant out of range haematological, renal or hepatic laboratory tests Normal screening ECG or screening ECG with no clinically significant findings, as judged by the investigator Negative serum pregnancy test at screening Agree to use a reliable form of contraception during the whole study period. Reliable forms of contraception are hysterectomy or bilateral tubal ligation, hormonal methods (oral, injected, implanted or transdermal), intrauterine device, barrier method plus spermicide, history of a single male partner with vasectomy, or a history of abstinence deemed credible by the investigator. Furthermore, male partners should use condoms during the whole study period. Provides written informed consent Exclusion criteria: Seropositivity (i.e. HAI titres >1:20) to the vector-derived wild type virus Any vaccination within 6 weeks of receiving study treatment Active significant viral infections including influenza, CMV, and EBV within 30 days of receiving study treatment Current cervical intraepithelial neoplasia 3 (CIN3) Co-infection with hepatitis B, hepatitis C, or HIV or having other immune deficient states Prior history of or current malignancy, high-grade cervical intraepithelial neoplasia (CIN2/3), vulvar intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VAIN), atypical glandular cells (AGC), adenocarcinoma in situ (AIS) or any suspicion of either micro-invasive or invasive disease Pregnancy, breastfeeding Influenza-like illness (ILI) during the preceding 3 months Known hypersensitivity to oseltamivir or any of its components Any anatomical condition of the cervix, including that resulting from previous cervical surgery, congenital malformation or other condition, that would interfere with a complete evaluation of the cervix Current pelvic inflammatory disease, cervicitis, or other gynaecological infection as per colposcopy and clinical examination Serious, concomitant disorder, including active systemic infection requiring treatment Presence of acute or chronic bleeding or clotting disorder, or use of blood thinners (e.g. anticoagulants or antiplatelet drugs) within 2 weeks of day 0 A proven or suspected autoimmune disease Immunosuppression including any concurrent condition requiring the continued use of systemic or topical steroids, or the use of immunosuppressive agents, disease modifying doses of anti-rheumatic drugs (e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate), and biologic disease modifying drugs such as TNF-α inhibitors (e.g. infliximab, adalimumab or etanercept). Corticosteroids must be discontinued > 4 weeks prior to day 0 of study medication administration. Eye drops or ear drops containing corticosteroids are permissible. Acute or history of Herpes genitalis Prior major surgery within 4 weeks of day 0 Administration of any blood product within 3 months of enrolment Any current significant cardiac, hepatic or renal disease or history of clinically significant, medically unstable disease (e.g. chronic renal failure; angina, myocardial ischemia or infarction, congestive heart failure, cardiomyopathy, or clinically significant arrhythmias) Any current or history of neurological disease including history of seizures Participation in another experimental protocol/use of investigational drug during the prior two months Any condition that, in the judgment of the investigator, might prevent safe participation in the study or interfere with study objectives Unability to comply with the protocol requirements

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 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: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FluBHPVE6E7<br>Multiple administration of FluBHPVE6E7 | Biological: FluBHPVE6E7<br>* Multiple subcutaneous, intradermal or intramuscular administrations<br>* Other names: Placebo;|
| Placebo Comparator: Placebo<br>Multiple administration of buffer solution | Biological: FluBHPVE6E7<br>* Multiple subcutaneous, intradermal or intramuscular administrations<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (type, frequency, severity). | To assess the safety and tolerability of FluBHPVE6E7 by monitoring the type, frequency, and severity of AEs | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemagglutination Inhibition (HAI) Geometric Mean Titers (GMTs) following FluBHPVE6E7 administration | To evaluate of the induction of systemic vector-specific antibodies by HAI assay | 16 weeks | 
| Induction of HPV-specific T-cell response following FluBHPVE6E7 administration | To evaluate the induction of HPV16 E6- and E7-specific T-cells (%) by IFN-gamma ELISPOT analysis | 16 weeks | 
| Induction of HPV-specific CD4+ and CD8+ T-cells following FluBHPVE6E7 administration | To evaluate the induction of HPV16 E6- and E7 specific T-cells (%) by ICS and FACS analysis | 16 weeks | 
| Local HPV clearance | To evaluate the status of HPV-16 infection by HPV test (yes or no) | 16 weeks | 
| Cervical cytology | To evaluate changes in cervical cytology by Pap smear. Results are reported as Pap results according to the Bethesda System | 16 weeks | 
| Biodistribution: Detection of FluBHPVE6E7 in blood samples | To evaluate the presence of FluBHPVE6E7 by quantification of FluBHPVE6E7 genome copies in blood samples by RT-qPCR (copies per ml blood) | 16 weeks | 
| Biodistribution: Detection of FluBHPVE6E7 in nasal secretions | To evaluate the presence of FluBHPVE6E7 by qualitative real-time PCR assay specific for influenza B virus (positive or negative) | 16 weeks | 
| Number of participants with adverse events (type, frequency, severity). | To assess the safety and tolerability of FluBHPVE6E7 by monitoring the type, frequency, and severity of AEs | 16 weeks |