A Phase I Study of Intra-anally Administered Lopinavir/Ritonavir in People Living With HIV (PLWH) With High-Grade Anal Intraepithelial Neoplasia (AIN 2/3)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 21
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose (MTD) as determined by the number of participants at each dose level in the escalation cohorts who experienced a dose-limiting toxicity (DLT)
研究概览
简要总结
This study is being done to assess the safety of lopinavir/ritonavir in patients with PLWH with AIN. 30 participants will be recruited and can expect to be on active study for approximately 3 months and long term follow up for 40 weeks.
详细描述
This is a Phase I modified 3 + 3 design, in which the maximum tolerated dose (MTD) will be identified. The 3 + 3 dose escalation will consist of 6 dose levels (18 participants; planned escalation described in arms below) in combination with variation in dosing schedules of the drug lopinavir/ritonavir. This design also allows for some possible intermediate doses to be examined if dose-limiting toxicities (DLTs) occur and de-escalation is needed.
An expansion cohort of 12 participants will occur at the MTD. Once the MTD is determined, then secondary outcomes will be evaluated.
Primary Objective
- To evaluate the safety and tolerability of intra-anal administration of lopinavir/ritonavir, administered via suppository with 3 different schedules, in PLWH with high-grade anal intraepithelial neoplasia (HGAIN) (AIN 2/3).
Secondary Objectives
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •willing to provide informed consent
- •greater than or equal to 18 years of age
- •Diagnosis of biopsy-confirmed HGAIN
- •willing to comply with all study procedures
排除标准
- •Diagnosis of low-grade anal dysplasia (AIN, low-grade squamous intraepithelial lesion (LSIL)) by HRA.
- •CD4 count less than 200 cells/mm^3 at the time of consideration for entry into the study
- •unable to provide informed consent
- •Pregnant or breastfeeding female
- •Currently receiving systemic chemotherapy or radiation therapy for another cancer.
研究组 & 干预措施
Cohort 4: Lopinavir/Ritonavir 600mg/150mg (3 cycles)
Cohort 4 will receive three 5-day cycles of the highest dose of the suppository (Lopinavir/Ritonavir (600mg/150mg)) in Weeks 0, 2, and 4, if the Cohort 3 dose is safe.
干预措施: Lopinavir / Ritonavir (Drug)
Cohort 1: Lopinavir/Ritonavir 200mg/50mg (2 cycles)
Cohort 1 will receive two 5-day cycles of the low dose of the suppository (Lopinavir/Ritonavir (200mg/50mg)) in Weeks 0 and 2
干预措施: Lopinavir / Ritonavir (Drug)
Cohort 2: Lopinavir/Ritonavir 400mg/100mg (2 cycles)
Cohort 2 will receive two 5-day cycles of the higher dose of the suppository (Lopinavir/Ritonavir (400mg/100mg)) in Weeks 0 and 2, if Cohort 1 dose is safe.
干预措施: Lopinavir / Ritonavir (Drug)
Cohort 1b: Lopinavir/Ritonavir 200mg/50mg (3 cycles)
Cohort 1b will receive three 5-day cycles of the low dose of the suppository (Lopinavir/Ritonavir (200mg/50mg)) in Weeks 0, 2, and 4 if Cohort 2 has one dose-limiting toxicity (DLT).
干预措施: Lopinavir / Ritonavir (Drug)
Cohort 2b: Lopinavir/Ritonavir 400mg/100mg (3 cycles)
Cohort 2b will receive three 5-day cycle of the higher dose of the suppository (Lopinavir/Ritonavir (400mg/100mg)) in Weeks 0, 2 and 4 if Cohort 3 has one DLT.
干预措施: Lopinavir / Ritonavir (Drug)
Cohort 3: Lopinavir/Ritonavir 600mg/150mg (2 cycles)
Cohort 3 will receive two 5-day cycles of the highest dose of the suppository (Lopinavir/Ritonavir (600mg/150mg)) in Weeks 0 and 2, if the Cohort 2 dose is safe.
干预措施: Lopinavir / Ritonavir (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD) as determined by the number of participants at each dose level in the escalation cohorts who experienced a dose-limiting toxicity (DLT)
时间窗: up to 5 weeks
The MTD is the highest explored dose of lopinavir/ritonavir is the dose at which less than 33% of patients experienced a DLT. A DLT is defined as any toxicity at least possibly related to ritonavir/lopinavir with a drug-related Grade greater than or equal to 3.
Rate of Grade 3 or above Toxicities in any Organ System in the Escalation Cohorts
时间窗: up to 5 weeks
Grade 3 or above as delineated in Common Terminology Criteria for Adverse Events v 5.0 (CTCAE)
次要结局
- Number of Participants in the Expansion Cohort Who Experience Regression of AIN2/3 Determined by Pathology(week 12, week 40)
- Number of Tissue Samples with evidence of apoptosis measured by presence of Activated Caspase 3(week 12, week 40)
- Number of Tissue Samples with evidence of autophagy measured by presence of LC3β and p62(week 12, week 40)
- Number of Tissue Samples with evidence of HPV positivity measured by presence of p16(week 12, week 40)
- Number of Tissue Samples with p53 expression(week 12, week 40)
- Number of Participants in the Expansion Cohort Determined clear of HPV by PCR test(week 12, week 40)
- Number of Tissue Samples with evidence of cellular proliferation measured by presence of Ki-67(week 12, week 40)