Phase 1 Dose-escalation Study of FluBHPVE6E7 in HPV16-infected Women

Study Overview
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Brief Summary
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BS-02 is a randomised, double-blind, placebo-controlled, phase 1 dose escalation study to assess the safety, tolerability and immunogenicity of FluBHPVE6E7, in women infected with HPV-16. with cervical cytological evaluation negative for intraepithelial lesion or malignancy (NILM), atypical squamous cells of undetermined significance (ASC-US), low grade squamous intraepithelial lesion (LSIL), or low-grade cervical intraepithelial neoplasia (CIN1).

Detailed Description
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FluBHPVE6E7 is an influenza virus vector that was modified on several levels to be used as an immunotherapeutic agent against human papillomavirus (HPV) infections, and precancers and cancers induced by HPV. Study BS-02 investigates the safety, tolerability and immunogenicity of FluBHPVE6E7 in HPV-16 infected women. FluBHPVE6E7 is administered three times at two dose levels. The first dose is administered into the cervix, subsequent doses are administered intramuscularly.

Official Title
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Randomised, Double-blind, Placebo-controlled Phase 1 Dose-escalation Study of FluBHPVE6E7 in HPV16-infected Women With NILM, ASC-US, LSIL or Low-grade CIN

Conditions
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HPV Infection, HPV-Related Cervical Carcinoma

Intervention / Treatment
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* Biological: FluBHPVE6E7
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females, 18-49 years of age with HPV16 infection and cervical cytological evaluation negative for intraepithelial lesion or malignancy (NILM), atypical squamous cells of undetermined significance (ASC-US), low grade squamous intraepithelial lesion (LSIL), or low-grade cervical intraepithelial neoplasia (CIN1) HPV16 infection has been confirmed at least twice by a validated HPV test separated by at least 3 months Satisfactory colposcopy 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. Provides written informed consent Exclusion Criteria: Any vaccination within 6 weeks of day 0 Active significant viral infections including influenza, CMV, and EBV within 30 days of receiving study treatment Co-infection with hepatitis B, hepatitis C, or HIV or having other immune deficient states Current Bacterial Vaginosis (BV) infection Current high-grade cervical intraepithelial neoplasia (CIN2/3) Prior history of or current malignancy, 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) within 3 months of day 0 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 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, and biologic disease modifying drugs. Any immunosuppressive agents containing corticosteroids or monoclonal antibodies specific for the treatment of obstructive airway, ear or vestibular diseases 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 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

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>intracervical and intramuscular 0.5 ml per dose 3 doses (12 weeks) | Biological: FluBHPVE6E7<br>* Intracervical administration for first dose followed by intramuscular administration for subsequent doses at recommended dose level and determined schedule<br>|
| Placebo Comparator: Placebo<br>intracervical and intramuscular 0.5 ml per dose 3 doses (12 weeks) | Drug: Placebo<br>* Intracervical administration for first dose followed by intramuscular administration for subsequent doses at determined schedule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and severity of adverse events (AEs) | The severity of the adverse event is assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0. | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Hemagglutination Inhibition (HAI) Geometric Mean Titers (GMTs) following FluBHPVE6E7 administration | To evaluate the induction of systemic vector-specific antibodies by HAI assay. | 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 saliva | To evaluate the presence of FluBHPVE6E7 by qualitative real-time PCR assay specific for influenza B virus (positive or negative). | 16 weeks | 
| Viral shedding: Detection of FluBHPVE6E7 in vaginal secretion samples | To evaluate the presence of FluBHPVE6E7 by quantification of FluBHPVE6E7 genome copies in vaginal secretion samples by RT-qPCR (copies per sample). | 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 |