A Phase I/II Investigation of the Effect of Vorinostat (VOR) on HIV RNA Expression in the Resting CD4+ T Cells of HIV-Infected Patients Receiving Stable Antiretroviral Therapy
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 25
- 试验地点
- 1
- 主要终点
- Number of Participants Exhibiting an in Vivo Resting CD4+ T-cell-associated HIV RNA (Rc-RNA) Increase Following Each of Two Multiple Dose Cycles (11 Doses/Cycle)
研究概览
简要总结
The purpose of this study is to compare HIV RNA expression and infection within resting (CD4)+ cells in HIV-infected patients on stable ART before and after a single exposure to Vorinostat (VOR), after exposure to short intervals of VOR, and after repeated short interval exposure to VOR dosed over several weeks.
Hypotheses:
- The frequency of resting CD4+ T cell- associated HIV RNA (RCVL) will be increased following single and repeated exposure to VOR when given at appropriate intervals, and
- That repeated exposure to VOR will reduce the frequency of HIV infection within resting CD4+ T cells (RCI)
详细描述
This is a Phase I-II single-center study in participants (ppts) with HIV-1 infection receiving stable ART, with plasma HIV RNA < 50 copies/mL. Baseline ART will be maintained throughout the study. Participants will be screened for study entry, and then undergo an initial leukapheresis evaluation at study entry to obtain resting CD4+ T cells for quantitation of resting CD4+ T cell infection (RCI) and resting CD4+ T cell- associated HIV RNA (RCVL) at a baseline evaluation. All 1st time leukapheresis participants, and others as requested based on prior latent pool determinations, will have HIV-1 DNA PCR done. All participants who enter the study will receive VOR at assigned study visits, and undergo repeat leukapheresis to measure the effects of VOR exposure.
Period One - Single and Multiple Dose Vorinostat (protocol versions (v) 3.0 and 5.0)
After signing the informed consent, completing screening and meeting all eligibility requirements, participants are enrolled and undergo a baseline leukapheresis (Visit 2). Participants exhibiting or not exhibiting a response [quantitation of resting CD4+ T cell infection (RCI) and resting CD4+ T cell- associated HIV RNA (RCVL)] to an ex vivo exposure to VOR will be evaluated for an in vivo response to a single dose of VOR 400 mg. Additionally participants complete a modified 24 hour pharmacokinetics (PK) analysis. All are monitored for adverse events (AEs) especially those that are dose-limiting. Safety monitoring included clinical labs, physical exams and assessment of medications and the onset of new signs and symptoms at all study visits.
Participants demonstrating in vivo a significant increase in the resting CD4+ T cell- associated HIV RNA (RCVL) after the single dose of VOR (protocol v3.0 and v5.0) are eligible to advance into Step 2. In Step 2 (protocol v5.0), participants are administered multiple doses of VOR. Each participant receives 22 total doses of VOR via 2 cycles of 11 doses each. Each cycle is 4 weeks in length. VOR 400 mg is administered on Monday, Tuesday and Wednesday followed by 4 days of no drug during the 1st 3 weeks. The 4th week of the cycle will have VOR administered on Monday and Tuesday, followed by a leukapheresis approximately 4 hours after the 11th dose (estimated peak drug level). Participants will be monitored throughout the 4 weeks for safety which includes the documentation of AEs, especially dose-limiting AEs, and other AEs associated with study procedures and events. After a rest period (approximately 5 - 8 weeks), participants repeat the 4 week cycle. Each cycle is analyzed for significant increase in resting CD4+ T cell- associated HIV RNA (RCVL) as compared to baseline (ex-vivo) and step 1 (single dose in-vivo) responses.
Period Two - Single, Paired Interval and Multiple Interval Doses of VOR (protocol v6.0)
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Open label
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
- •HIV-1 infection
- •Men, women age ≥18 years.
- •Ability, willingness to give written informed consent.
- •Able, willing to provide adequate locator information.
- •Karnofsky performance status >
- •Able, willing to adhere to therapy and adherent to ART.
- •Able,willing to comply with time requirements for study visits and evaluations.
- •On potent ART, defined as at least 2 nucleoside/nucleotide reverse transcriptase inhibitors plus a non-nucleoside reverse transcriptase inhibitor, integrase inhibitor, or a protease inhibitor without interruption (defined as missing doses for more than two consecutive days or more than four cumulative days) in the 24 weeks immediately prior to entry. Other potent fully suppressive antiretroviral combinations will be considered on a case-by-case basis. Prior changes in or elimination of medications for easier dosing schedule, intolerance, or other reasons are permitted if an alternative suppression regimen was maintained.
- •Adequate vascular access for leukapheresis.
- •Able to swallow pills without difficulty.
- •On combination ART for ≥ 18 months prior to study entry, no consecutive HIV-1 RNA values >50 copies/mL in that time period
- •CD4 cell count ≥ 300 cells/µl at screening.
- •All male study volunteers must agree not to participate in a conception process.
- •Must be seronegative for Hep C RNA, Hep B sAg within 90 days of entry
- •Must have adequate organ function as indicated by the following lab values:
- •Hematological: Absolute Neutrophil Count (ANC) ≥ 1,500/mcL Platelets ≥ 125,000/mcL Hgb ≥ 12 g/dL
- •Coagulation: Prothrombin Time or International Normalized Ratio (INR) ≤ 1.5x upper limit of normal (ULN)
- •Chemistry: K+ levels Within normal limits Mg++ levels > Lower limits of normal (LLN) but <1.5 x ULN Glucose Screening serum glucose(fasting/non-fasting) below 120 mg/dl.
- •Renal: Serum creatinine/calculated creatinine clearance* ≤ 1.3 X ULN OR ≥ 60 mL/min for participants with creatinine levels > 1.3 X ULN
- •Hepatic: Serum total bilirubin Total bilirubin < 1.5 times ULN. If total bilirubin is elevated, direct bilirubin will be measured and the participant will be eligible if the direct bilirubin is < 2 X ULN.
- •Aspartate amino transferase (AST) (SGOT) and Alanine amino transferase (ALT) (SGPT)≤ 2.0 X ULN Lipase <1.6 X ULN Alkaline Phosphatase ≤ 2.5 X ULN
- •*Creatinine clearance should be calculated per institutional standard.
排除标准
- •Received blood transfusions or hematopoetic growth factors within 90 days.
- •All women unless there is written documentation of menopause (absence of a period for ≥ one year), hysterectomy, oophorectomy, or tubal ligation.
- •The study PI is unable to construct a fully active alternative regimen based on previous resistance testing and/or treatment history
- •Use of atazanavir and raltegravir in background antiretroviral regimens.
- •Any antiretroviral medications that cannot be co-administered with Vorinostat within the 4 weeks of the first Vorinostat dose and anytime thereafter while on study.
- •Use of any of the following within 90 days prior to entry: systemic cytotoxic chemotherapy; investigational agents; immunomodulators (colony-stimulating factors, growth factors, systemic corticosteroids, HIV vaccines, immune globulin, interleukins, interferons); coumadin, warfarin, or other Coumadin derivative anticoagulants.
- •Any serious illness requiring systemic treatment or hospitalization, the subject must either complete therapy or be clinically stable on therapy, in the opinion of the site investigator, for at least 90 days prior to entry.
- •Compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric illness or a physical illness, e.g., infectious disease. Prisoner recruitment and participation is not permitted.
- •Treatment for an active AIDS-defining opportunistic infection within 90 days prior to screening.
- •Any history of cardiac rhythm disturbance requiring medical or surgical therapy.
- •Any history of acute or chronic pancreatitis.
- •Use of the following medications that carry risk of torsades de pointes: amiodarone, arsenic trioxide, astemizole, bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide, dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, probucol, procainamide, quinidine, sotalol, sparfloxacin, terfenadine, thioridazine.
- •Receipt of compounds with HDAC inhibitor-like activity, such as valproic acid within the last 30 days. Potential participants may enroll after a 30-day washout period.
- •Known hypersensitivity to the components of VOR or its analogs.
- •Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- •Pregnancy or breast feeding, or expecting to father children within the projected duration of the study.
- •Inability to communicate effectively with study personnel.
研究组 & 干预措施
Open Label, Translational Research
Vorinostat will be administered to all eligible participants in each step of each phase (period) of the study
干预措施: Vorinostat (Drug)
结局指标
主要结局
Number of Participants Exhibiting an in Vivo Resting CD4+ T-cell-associated HIV RNA (Rc-RNA) Increase Following Each of Two Multiple Dose Cycles (11 Doses/Cycle)
时间窗: Baseline, Visit 18, Visit 29
Participants in Arm 1, Step 3 were analyzed for an in vivo increase in the resting CD4+ T cell- associated HIV RNA (RCVL) after 11 doses of VOR 400 mg PO. This cycle was repeated after a 5 - 8 week rest period for a 2nd series and measurement.
Number of Participants Exhibiting an in Vivo Resting CD4+ T-cell-associated HIV RNA (Rc-RNA) Increase Following Multiple (n = 10) Interval Doses
时间窗: Baseline, Visit 9
Participants in Arm 2, Step 4 were analyzed for an in vivo increase in the resting CD4+ T cell- associated HIV RNA (RCVL) after administration of 10 doses of VOR 400 mg PO, given 72 hours apart.
Number of Participants Exhibiting an in Vivo Resting CD4+ T Cell- Associated HIV RNA (RCVL) Increase After Receiving a Single Dose of VOR 400 mg PO
时间窗: Arm1: Baseline, Visit 5 and Arm 2: Baseline and Visit 3
Participants in Arm 1 and 2 were analyzed in Step 2 for an in vivo increase in resting CD4+ T cell- associated HIV RNA (RCVL) after administration of a single dose of VOR 400 mg PO
Number of Participants With a Significant in Vivo Response in Resting Cell Infection (RCI) and HIV RNA After Paired Doses
时间窗: Baseline, Visit 6
Induction of significant in vivo RCI and RCLV response after 2 doses of VOR 400 mg PO administered 48 hours apart or 72 hours apart
次要结局
- Number of Participants With Measurable Changes in Plasma HIV-1 RNA(1 week after last VOR dose)
- Number of Participants With Confirmed Hematologic Toxicity >/= Grade 2 and Related to VOR Per Division of AIDS (DAIDS) Grading Table(24 hrs following single dose and 1 week after last of multiple dose sequence)
- Number of Participants With Confirmed Non-hematologic Toxicity >/= Grade 3 and Related to VOR Per Division of AIDS (DAIDS) Grading Table(24 hrs following single dose and 1 week after last of multiple dose sequence)