A Clinical Study on the Evaluation of BD114 for the Treatment HPV-16-Related Cervical HSIL

Official title

An Open-Label, Two-Arm, Non-Randomized Clinical Study On The Safety And Efficacy Of Instantaneous CRISPR/Cas9 Gene Editing Therapy For Treating Chinese Patients With HPV-16-Related High-Grade Squamous Intraepithelial Lesions (HSIL)

Overview

This study is intented to evaluate the safety, and tolerability and preliminary efficacy of Instantaneous CRISPR/Cas9 Gene Editing Therapy (BD114 virus-like particle, also BD114) for the treatment of high-grade squamous intraepithelial lesions (HSIL) associated with HPV-16 infection.

Detailed description

This study is an open-label, two-arm, balanced-group, single-dose, non-randomized exploration clinical study. A total of 12 patients with HPV-16 Related HSIL of the Cervix will be enrolled and divided into two arms. Participants in Arm 1 receive topically BD114 intraepithelial injection of lesions, and Participants in Arm 2 receive BD114 gel topical application of lesions, with 6 Participants allocated in each arm. Each study arm is further divided into the low-dose subgroup assigned 1 Participant and the high-dose subgroup assigned 5 Participants. The total study duration for each Participant is 40 weeks (including screening stage). The treatment-emergent adverse events (TEAEs) for safe evaluation, components detection of the BD114 for pharmacokinetics (PK) assessment, histologically lesion regression and virologically HPV-16 clearness for efficacy evaluation are observed and explored during follow-up visits.

Interventions

• Genetic BD114VLP, or BD114
  CRISPR/Cas9 instantaneous gene editing therapy, called BD114VLP (also BD114) which is a developing product of gene therapy from modified third-generation integrated defective lentivirus, can deliver gRNA/Cas9 ribonucleoprotein complex (RNP). It works to knock out or knock down HPV-16 E6/E7 genes integrated in HSIL cell genome resulting to lesion clearness or regression. A single dosing BD114 injection by topical intraepithelial injection of HSIL lesion.
• Genetic BD114VLP or BD114 plus Gel
  Genetic: BD114VLP or BD114 plus Gel CRISPR/Cas9 instantaneous gene editing therapy, called BD114VLP (also BD114) which is a developing product of gene therapy from modified third-generation integrated defective lentivirus, can deliver gRNA/Cas9 ribonucleoprotein complex (RNP). It works to knock out or knock down HPV-16 E6/E7 genes integrated in HSIL cell genome resulting to lesion clearness or regression. Multiple dosing BD114 gel (BD114 injection :Gel, 1:1) topical application on HSIL, one tim

Primary outcome measures

• Adverse events (AEs) and serious adverse events (SAEs) [Time frame: ~36 weeks]
• Percentage of Participants with No Histologic Evidence of HSIL [Time frame: Week 24, Week 36]

Secondary outcome measures (8)

• Percentage of Participants with No Histologic Evidence of HSIL and No Evidence of HPV-16 [Time frame: Week 24, Week 36]
• Percentage of Participants with No Evidence of HPV-16 [Time frame: Week 24, Week 36]
• Percentage of Participants with No Evidence of HSIL or LSIL [Time frame: Week 36]
• Percentage of Participants with No Evidence of HSIL or LSIL and No Evidence of HPV-16 [Time frame: Week 36]
• Changes in Serum Inflammatory Cytokine (IL-1/IL-6/TNF-α/IFN-γ) Levels Relative to Baseline [Time frame: Arm 1: at Day 2, Week 1, Week 2, Week 4, Week 12, Week 24, and Week 36. Arm 2: at Day 10, Day 15, Day 22, Day 36, Week 12, Week 24, and Week 36]
• Concentrations of Cas9 Protein and gRNA in Peripheral Blood [Time frame: Arm 1: at Day 2, Week 1, Week 4, Week 12. Arm 2: at Day 10, Day 15, Day 36, Week 12]
• Detection of Anti-p24/Cas9 Protein Antibodies in Peripheral Blood [Time frame: Arm 1: Week 2, Week 4, Week 36. Arm 2: Day 22, Day 36, Week 36]
• Off-Target Analysis [Time frame: Arm 1: Week 1. Arm 2: Day 15]

Eligibility criteria

Inclusion criteria

• Female, aged 25 to 50 years, without childbearing demand;
• Confirmed histopathological evidence of cervical HSIL (CIN3) at the screening period or within 1 month prior to screening;
• Confirmed cervical HPV-16 positive by HPV test during the screening period or within 1 month prior to screening, without other high-risk HPV types detected;
• Complete visibility of both the squamocolumnar junction (SCJ Types 1/2) and the upper margin of acetate-white epithelium or suspected HSIL lesions under colposcopy examine during the screening period or within 1 month prior to screening;
• No evidence of precancerous lesions or malignancy by endocervical curettage (ECC) ;
• The biopsy sampling of cervical lesions are performed;
• Visible residual cervical lesions after screening biopsy;
• Willing to maintain abstinence or use a highly effective contraceptive method (oral contraceptives, injections, implants, or barrier methods) for women of childbearing potential (WOCBP) from enrollment until Week 36, or her partner undergone surgical sterilization (e.g., vasectomy);
• Good compliance to protocol-specified procedure in study duration assessed by investigator;
• Voluntarily participating in the study and willing to provided signed informed consent.

Exclusion criteria

• Positive detection of antibodies or viral test of human immunodeficiency virus (HIV), or hepatitis B virus (HBV), or hepatitis C virus (HCV), or Treponema pallidum (TP) at screening;
• Confirmed histopathologically epithelial carcinoma, glandular carcinoma or precancerous lesions in the endometrium at screening;
• Confirmed histopathologically or macroscopically high-grade intraepithelial neoplasia or invasive carcinoma in the vulva, vagina or anus at screening;
• HSIL with partial location in cervical canal and incomplete colposcopic visualization ;
• Undergone the treatment for cervical HSIL within 4 weeks prior to screening;
• Vaccination history of any therapeutic HPV vaccine;
• Family history of malignancy, or a history/current presence of any malignant tumor;
• Severe uncontrolled diseases of major organs, including but not limited to: acute myocardial infarction, stroke, liver cirrhosis, severe kidney disease, diabetes mellitus, chronic obstructive pulmonary disease (COPD), hematologic disorders, psychiatric disorders, etc;
• Pregnant (a positive urine or serum pregnancy test) or lactating women;
• Participating in another drug or device clinical trial at screening, or participated in one within 3 months prior to screening;
• The history of any form of gene and/or cell therapy;
• Drug abuse or alcohol addiction no compliance to protocol-specific procedure;
• Any other condition unsuitable for participating this study judged by the investigator.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Obstetrics & Gynecology Hospital of Fudan University — Shanghai

Identifiers

NCT: NCT07170254 · BD-HSIL-114001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗