High-grade Squamous Intraepithelial Lesions (HSIL)
Conditions
Keywords
High-grade squamous intraepithelial lesions, HPV-16 infection, Gene Editing Therapy
Brief summary
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 6 patients with HPV-16 Related HSIL of the Cervix will be enrolled and divided into two arms. Participant in Arm 1(n=1) receive topically low-dose of BD114 with intraepithelial injection of lesions, and participants in Arm 2 (n=5) receive high-dose of BD114 with intraepithelial injection of lesions. The total follow-up 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 or clearness and virologically HPV-16 clearness for efficacy evaluation are conducted and explored during follow-up visits.
Interventions
GENETICBD114VLP, 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.
Sponsors
Shanghai BDgene Co., Ltd.
Obstetrics & Gynecology Hospital of Fudan University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
1. Female, aged 18 to 50 years, without childbearing demand; 2. Confirmed histopathological evidence of cervical HSIL (CIN3) at the screening period or within 1 month prior to screening; 3. 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; 4. 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; 5. No evidence of precancerous lesions or malignancy by endocervical curettage (ECC) ; 6. The biopsy sampling of cervical lesions are performed; 7. Visible residual cervical lesions after screening biopsy; 8. 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); 9. Good compliance to protocol-specified procedure in study duration assessed by investigator; 10. Voluntarily participating in the study and willing to provided signed informed consent.
Exclusion criteria
1. 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; 2. Confirmed histopathologically epithelial carcinoma, glandular carcinoma or precancerous lesions in the endometrium at screening; 3. Confirmed histopathologically or macroscopically high-grade intraepithelial neoplasia or invasive carcinoma in the vulva, vagina or anus at screening; 4. HSIL with partial location in cervical canal and incomplete colposcopic visualization ; 5. Undergone the treatment for cervical HSIL within 4 weeks prior to screening; 6. Vaccination history of any therapeutic HPV vaccine; 7. Family history of malignancy, or a history/current presence of any malignant tumor; 8. 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; 9. Pregnant (a positive urine or serum pregnancy test) or lactating women; 10. Participating in another drug or device clinical trial at screening, or participated in one within 3 months prior to screening; 11. The history of any form of gene and/or cell therapy; 12. Drug abuse or alcohol addiction no compliance to protocol-specific procedure; 13. Any other condition unsuitable for participating this study judged by the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse events (AEs) and serious adverse events (SAEs) | ~36 weeks | All AEs and SAEs occurring during the study period (from informed consent signing to Week 36 post-BD114 intervention) were recorded and assessed according to the NCI-CTCAE v5.0 grading system, including their classification by System Organ Class (SOC), severity grade, number of affected Participants, and incidence rates. Gynecological AEs (beyond NCI-CTCAE v5.0 specifications) shall be evaluated by investigators for classification and severity grading according to current clinical guidelines/expert consensus. |
| Percentage of Participants with No Histologic Evidence of HSIL | Week 24, Week 36 | Cervical tissue biopsies obtained at Week 24 and Week 36 undergo histopathological evaluation, and judge the HSIL Clearance by complete regression or disappear of the original lesions, with clearance rates calculated per the following formula: Percentage of Participants with No Histologic Evidence of HSIL (%) = Number of Participants Achieving HSIL Clearance / Total number of Participants treated with BD114 ×100% |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants with No Histologic Evidence of HSIL and No Evidence of HPV-16 | Week 24, Week 36 | Virological HPV-16 assessment was performed using clinically validated type-specific HPV testing kits, meanwhile colposcopy-guided cervical tissue biopsies are histopathologically evaluated. The calculating formula as follow: Percentage of Participants with No Histologic Evidence of HSIL and No Evidence of HPV-16 = Number of Participants with No Histologic Evidence of HSIL and No Evidence of HPV-16 / Total number of Participants treated with BD114 ×100% |
| Percentage of Participants with No Evidence of HPV-16 | Week 24, Week 36 | Histological samples (cervical exfoliated cells) is detected for HPV-16 by real-time fluorescent quantifying PCR technology. The calculating formula as follow: Percentage of Participants with No Evidence of HPV-16 = Number of Participants with No Evidence of HPV-16 / Total number of Participants treated with BD114 ×100% |
| Percentage of Participants with No Evidence of HSIL or LSIL | Week 36 | Cervical biopsies at Week 36 are performed for histopathological evaluation, no histologically evidence of HSIL or LSIL of histological samples are judged as no histology findings of HSIL or LSIL. The calculating formula as follow: Percentage of Participants with No Evidence of HSIL or LSIL = Number of Participants with No Evidence of HSIL or LSIL / Total number of Participants treated with BD114 ×100% |
| Percentage of Participants with No Evidence of HSIL or LSIL and No Evidence of HPV-16 | Week 36 | Cervical biopsies at Week 36 are performed for histopathological evaluation, no histologically evidence of HSIL or LSIL of histological samples are judged as no histology findings of HSIL or LSIL. Histological samples (cervical exfoliated cells) is detected HPV-16 by real-time fluorescent quantifying PCR technology. Calculation Formula: Percentage of Participants with No Evidence of HSIL or LSIL and No Evidence of HPV-16 = Number of Participants A with No Evidence of HSIL or LSIL and No Evidence of HPV-16 / Total number of Participants treated with BD114 ×100% |
| Changes in Serum Inflammatory Cytokine (IL-1/IL-6/TNF-α/IFN-γ) Levels Relative to Baseline | Day0, Day 2, Week 1, Week 2, Week 4, Week 12, Week 24, and Week 36. | Blood samples were collected and analyzed using clinically validated ELISA kits to quantify serum levels of four inflammatory cytokines (IL-1, IL-6, TNF-α, and IFN-γ). |
| Concentrations of Cas9 Protein and gRNA in Peripheral Blood | At Day0, Day 2, Week 1, Week 4, Week 12. | The concentration of Cas9 protein are tested by ELISA and gRNA are detected by qPCR in blood. |
| Detection of Anti-p24/Cas9 Protein Antibodies in Peripheral Blood | At Day0, Week 2, Week 4, Week 36 | The detection of anti-p24/Cas9 protein antibodies in blood are performed at scheduled study visits. |
| Off-Target Analysis | D0, Week 1 | Off-Target analysis of cervical biopsy samples is conducted by applying DNA deep sequencing or whole genome sequencing (WGS) to assess BD114-related off-target effects based on the sequencing results. |
Countries
China
Outcome results
None listed