Safety and Anti-HIV Activity of Autologous CD4+ and CD8+ T Cells Transduced With a Lentiviral Vector Encoding Bi-specific Anti-gp120 CAR Molecules (LVgp120duoCAR-T) in Anti-retroviral Drug-treated HIV-1 Infection
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 18
- 试验地点
- 4
- 主要终点
- Number of participants reporting a new Grade 3 or greater adverse event that is definitely, probably, or possibly related to study treatment within 1 year of product administration.
研究概览
简要总结
This is a limited-center, open-label dose escalating phase I/IIa study of autologous T cells expressing LVgp120duoCAR molecules in people with HIV infection. It will follow a 3+3 design. Dose escalation decisions will be made when a minimum of three participants have completed the safety-evaluation period (45 days) at a given dose level. Cohort 1 will undergo infusion of a single low-dose regimen of LVgp120duoCAR-T cells. Cohort 2 will undergo non-ablative conditioning with cyclophosphamide, followed by infusion of a single low-dose regimen of LVgp120duoCAR-T cells. Cohort 3 will undergo non-ablative conditioning with cyclophosphamide, followed infusion of a single high-dose regimen of LVgp120duoCAR-T cells. Following administration of the experimental therapy, HIV medications will be paused for participants in each group during an analytic treatment interruption.
详细描述
A limited-center, open-label dose escalating phase I/IIa study of autologous T cells expressing LVgp120duoCAR molecules will be performed. Participants will be enrolled sequentially in up to three cohorts following a 3+3 design. Dose escalation decisions will be made when a minimum of three participants have completed the safety-evaluation period (45 days) at a given dose level. No dose escalation will be allowed in an individual participant, and participants who have dose limiting adverse events will reinstate ART therapy at first available opportunity.
Following a 3+3 design, each cohort will enroll at least 3 participants. If there are no safety issues with dosing in a cohort, the investigators will proceed to the following cohort. If one participant in a cohort experiences a safety issue, an additional 3 individuals will be enrolled in that cohort to assess safety prior to proceeding to the next cohort. See below for Dose Escalation Procedures.
The first 3 participants start at Cohort 1. Data from Cohort 1 will be submitted for FDA review prior to dosing Cohorts 2 and 3 to determine if cyclophosphamide conditioning is needed.
Cohort 1: Participants will NOT undergo non-ablative conditioning with cyclophosphamide. A single dose of 3 x 105 cells/kg LVgp120duoCAR-T cells will be infused. ART will be interrupted immediately after infusion.
Cohort 2: Participants will undergo non-ablative conditioning with cyclophosphamide. A single dose of 3 x 105 cells/kg LVgp120duoCAR-T cells will be infused. ART will be interrupted immediately after infusion.
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 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female, age ≥ 18 and ≤ 65 years
- •HIV-1 infection
- •On continuous antiretroviral therapy for at least 12 months without any interruptions of greater than 14 consecutive days, and on a stable regimen that does not include a non-nucleoside reverse transcriptase inhibitor (NNRTI) for at least 4 weeks or any long-acting ART drug that may be active in the participant after ART interruption for up to one year, without plans to modify ART during the study period
- •Screening plasma HIV RNA levels below the limit of quantification on all available determinations in past 12 months (isolated single values ≥ 40 but < 200 copies/mL will be allowed if they were preceded and followed by undetectable viral load determinations)
- •CD4+ T cell count nadir > 300 cells/mm3
- •Screening CD4+ T-cell count ≥ 500 cells/mm3
- •Available ART treatment history and the capacity to construct an effective antiretroviral treatment regimen
- •Willing to pause ART as part of the study
排除标准
- •Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study
- •ART regimen that includes a long-acting anti-HIV drug and/or NNRTI that may be active in the participant for up to one year after ART interruption
- •ART regimen that includes protease inhibitor(s) and/or AZT. These drugs may increase the toxicity of cyclophosphamide.
- •Any history of an HIV-associated malignancy, including Kaposi's sarcoma and any type of lymphoma, or virus-associated cancers
- •History of or current active hepatitis B (HBV) infection defined as positive HBV surface antigen test. A positive anti-HBc regardless of HBsAg status.
- •Active hepatitis C (HCV) infection
- •Active or latent tuberculosis infection
- •Chronic liver disease
- •Active and poorly controlled atherosclerotic cardiovascular disease
- •Unwillingness to abstain from sex or use barrier protection for any sexual activity during the treatment interruption.
研究组 & 干预措施
Low Dose CAR-T Cells Only
Participants will NOT undergo non-ablative conditioning with cyclophosphamide. A single dose of 3 x 10^5 cells/kg LVgp120duoCAR-T cells will be infused. ART will be interrupted immediately after infusion.
干预措施: LVgp120duoCAR-T cells, low dose (Biological)
Low Dose CAR-T Cells Only
Participants will NOT undergo non-ablative conditioning with cyclophosphamide. A single dose of 3 x 10^5 cells/kg LVgp120duoCAR-T cells will be infused. ART will be interrupted immediately after infusion.
干预措施: Analytic Treatment Interruption (Other)
Conditioning + Low Dose CAR-T Cells
Participants will undergo non-ablative conditioning with cyclophosphamide. A single dose of 3 x 10^5 cells/kg LVgp120duoCAR-T cells will be infused. ART will be interrupted immediately after infusion.
干预措施: Analytic Treatment Interruption (Other)
Conditioning + High Dose CAR-T Cells
Participants will undergo non-ablative conditioning with cyclophosphamide. A single dose of 1 x 10^6 cells/kg LVgp120duoCAR-T cells will be infused into the participant. ART will be interrupted immediately after infusion.
干预措施: Analytic Treatment Interruption (Other)
Conditioning + Low Dose CAR-T Cells
Participants will undergo non-ablative conditioning with cyclophosphamide. A single dose of 3 x 10^5 cells/kg LVgp120duoCAR-T cells will be infused. ART will be interrupted immediately after infusion.
干预措施: LVgp120duoCAR-T cells, low dose (Biological)
Conditioning + High Dose CAR-T Cells
Participants will undergo non-ablative conditioning with cyclophosphamide. A single dose of 1 x 10^6 cells/kg LVgp120duoCAR-T cells will be infused into the participant. ART will be interrupted immediately after infusion.
干预措施: LVgp120duoCAR-T cells, high dose (Biological)
Conditioning + Low Dose CAR-T Cells
Participants will undergo non-ablative conditioning with cyclophosphamide. A single dose of 3 x 10^5 cells/kg LVgp120duoCAR-T cells will be infused. ART will be interrupted immediately after infusion.
干预措施: Cyclophosphamide (Drug)
Conditioning + High Dose CAR-T Cells
Participants will undergo non-ablative conditioning with cyclophosphamide. A single dose of 1 x 10^6 cells/kg LVgp120duoCAR-T cells will be infused into the participant. ART will be interrupted immediately after infusion.
干预措施: Cyclophosphamide (Drug)
结局指标
主要结局
Number of participants reporting a new Grade 3 or greater adverse event that is definitely, probably, or possibly related to study treatment within 1 year of product administration.
时间窗: Within 1 year of product administration
The primary safety outcome will be the number of participants reporting a new Grade 3 or greater adverse events assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, including signs/symptoms, lab toxicity or clinical event, that is definitely, probably, or possibly related to study treatment within 1 year of product administration.
Number of participants achieving post-treatment control within 36 weeks of product administration.
时间窗: Week 36
The primary efficacy outcome will be the proportion of individuals who achieve study-defined post-treatment control. The investigators will define post-treatment control in two ways. First, participants who fail to show any consistent rebound above 400 copies RNA/mL between Weeks 12 and Week 36 will be considered as having achieved post-treatment control. Second, participants who exhibit a rebound and eventually achieve 24 weeks of virus control will be considered as having achieved post-treatment control.
次要结局
- Persistence of LVgp120duoCAR-T cells in tissues during therapy(Week 12 through Week 36)
- Change in quantitative virologic measures of the HIV reservoir pre- and post-therapy(Baseline and 36 weeks)
- Persistence of LVgp120duoCAR-T cells in blood during therapy(Week 12 through Week 36)
研究者
Steven Deeks
Professor
University of California, San Francisco