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)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 2
- 试验地点
- 3
- 主要终点
- Adverse events (AEs) and serious adverse events (SAEs)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Female, aged 18 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.
排除标准
- •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.
研究组 & 干预措施
BD114 Low-dose group
BD114 Low-dose group: Low-dose (n=1)
- Small lesions (≤5 mm^2): BD114 injection, 0.2 mL
- Large lesions (>5 mm^2): BD114 injection 0.4 mL
干预措施: BD114VLP, or BD114 (Genetic)
BD114 High-dose group
BD114 High-dose group: High-dose (n=5)
- Small lesions (≤5 mm^2): BD114 injection, 0.3 mL
- Large lesions (>5 mm^2): BD114 injection 0.6 mL
干预措施: BD114VLP, or BD114 (Genetic)
结局指标
主要结局
Adverse events (AEs) and serious adverse events (SAEs)
时间窗: ~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
时间窗: 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%
次要结局
- 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.)
- Concentrations of Cas9 Protein and gRNA in Peripheral Blood(At Day0, Day 2, Week 1, Week 4, Week 12.)
- Detection of Anti-p24/Cas9 Protein Antibodies in Peripheral Blood(At Day0, Week 2, Week 4, Week 36)
- Off-Target Analysis(D0, Week 1)
- Percentage of Participants with No Histologic Evidence of HSIL and No Evidence of HPV-16(Week 24, Week 36)
- Percentage of Participants with No Evidence of HPV-16(Week 24, Week 36)
- Percentage of Participants with No Evidence of HSIL or LSIL(Week 36)
- Percentage of Participants with No Evidence of HSIL or LSIL and No Evidence of HPV-16(Week 36)
- Changes in Serum Inflammatory Cytokine (IL-1/IL-6/TNF-α/IFN-γ) Levels Relative to Baseline(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(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(Arm 1: Week 2, Week 4, Week 36. Arm 2: Day 22, Day 36, Week 36)
- Off-Target Analysis(Arm 1: Week 1. Arm 2: Day 15)