The Effect of Vorinostat on HIV RNA Expression in the Resting CD4+ T Cells of HIV+ Pts on Stable ART
Condition: HIV-1 Infection
MeSH terms: Infections
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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:

        1. 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

        2. That repeated exposure to VOR will reduce the frequency of HIV infection within resting
           CD4+ T cells (RCI)
    

Detailed description: 
      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)

      Step 1: Enrollment into this study period was similar to the procedures in Period 1.
      Participants were consented to protocol v6.0, completed screening and after meeting
      eligibility, enrolled on the study at Visit 2. The leukapheresis, scheduled for Visit 2, was
      optional based on prior ascertainment of baseline parameters. Omission of this leukapheresis
      was determined by study PI, after analysis of lab data from previous leukapheresis
      procedures. Regardless of the completion of the leukapheresis procedure at Visit 2, study
      enrollment and collection of required research assays was completed at Visit 2. Participant
      were screened and enrolled into Step 1 until 12 evaluable participants successfully completed
      the multiple doses of VOR (Step 4), or until the study-stopping rules are met. It is
      estimated that up to 30 eligible participants may be screened and enrolled to provide a total
      of 12 evaluable participants who complete Step 3.

      Step 2 included several visits: administration of VOR (visit 3), modified/abbreviated 8 hour
      PK analysis, leukapheresis procedure and safety follow up (Visit 4). After assessment and
      ascertainment of safe to proceed clinical status, each participant receive a single dose of
      VOR 400 mg. Participant remained in the clinic for observation and the collection of samples
      for the abbreviated PK. Four hours after the dose, the leukapheresis procedure was initiated.
      It was anticipated that the completion of Step 1 and 2 would occur over a minimum of 8 weeks.
      All participants must complete Step 2 prior to moving to Step 3. All participants are
      assessed after the Visit 3 leukapheresis for an in vivo response to the 400 mg of VOR.

      Progression from Step 2 (single dose) to Step 3 (paired doses) was based on each
      participant's increase in RCVL following their first dose of 400 mg VOR (Visit 3), compared
      to that measured at baseline (Visit 2). Progression from Step 3 (paired doses) to Step 4
      (multiple doses) will be based on each participant's increase in RCVL following the 2nd in a
      paired dose VOR 400 mg (total doses = 3, Visit 6), compared to that measured at baseline
      (Visit 2).

      The goal of protocol v6.0 is to determine the optimal interval between two doses of VOR (Step
      2), and the response of RCI (and secondarily RCLV) to repeated doses at this interval (Step
      3).

      Step 3 will be initiated at least 4 weeks after the completion of the Step 2 safety follow up
      visit (Visit 4). If greater than 60 days elapse between Visit 4 and Visit 5, participants
      will repeat screening Visit labs to qualify for continued study participation. In Step 3, two
      paired doses of VOR 400 mg will be administered. The interval between the 2 paired doses can
      be as short as 48 hours (2 days), and as much as 96 hours (4 days) apart from each other.
      Participants were assessed for in vivo response via a 3rd leukapheresis after the second of
      the paired doses of 400 mg VOR. The first three (3) participants will first be assessed for
      an in-vivo response after the 2nd dose of the paired doses given 48 hours (2 days) apart.
      Subsequent participants will be assessed for responses to paired doses separated by 48 hours,
      or the interval may be lengthened to as much 96 hours (4 days), as dictated by the
      accumulated responses observed in subsequent participants.

      If at least 2 of the 3 participants with 48-hour intervals respond (defined as a significant
      within-subject increase in cell-associated HIV RNA), then 3 subsequent participants will
      receive 48-hour intervals. If 2 of these 3 respond (4 of 6 total), then 3 additional
      participants will receive 48-hour intervals. If among the first 6 evaluable participants
      receiving 48-hour intervals there are 3 non-responders, then subsequent participants will
      receive 72-hour intervals. Participants receiving 72-hour intervals will then be assessed in
      the same way as those receiving 48-hour intervals, to either continue additional participants
      at 72-hour intervals or to increase to 96-hour intervals. Step 3 will enroll until a total of
      12 evaluable subjects with a measureable increase in cell-associated HIV RNA are obtained,
      and these participants have advanced to Step 4.

      Our preliminary results from protocol version 5.0 (period 1) are consistent with the
      hypothesis that the complex cellular effects of HDAC inhibitor exposure require more than 24
      hours to resolve. We observed what appears to be an antagonistic effect where a VOR dose
      blunts the effect of the next dose when two doses are given within 24 hours of each other.
      The purpose of Step 3 is to establish the optimal dosing interval in which a response to
      Vorinostat is sustained. Step 3 will study dosing intervals; starting with a 48-hour interval
      and moving to longer intervals between doses depending on the effect observed with the
      ultimate goal to determine the shortest interval that yields an optimal effect of VOR.

      If a participant fails to respond in their initial Step 3 dosing interval, they can be
      eligible to repeat Step 3. They can re-enter or repeat Step 3 one time only. They will only
      re-enter Step 3 to test a longer dosing interval. Again, if > 60 days elapses between the
      final safety visit of step 3 (Visit 7) and their re-entry to Step 3, they will re-screen
      (visit 1 only) to qualify to continue in the study.

      Step 4: After a period of at least 6 weeks, to allow data analysis, participants who
      demonstrate an in vivo response to the 2nd of the paired dose of VOR will proceed to Step 4
      and receive 10 doses of VOR 400 mg administered at the same interval at which cell-associated
      HIV-RNA induction was observed in Step 3. If greater than 60 days elapse between Visit 7 and
      Visit 8, participants will repeat the screening visit labs to qualify for continued
      participation in the study. At the completion of 10 doses, participants will then be assessed
      via a 4th and final leukapheresis for in vivo response to the serial dosing of VOR.

      It is anticipated that Step 4 will occur over a minimum of 4 weeks; however this may vary
      among participants based on their Step 3 dosing interval stage. Accumulated blood volumes and
      the timing between leukapheresis procedures will determine the length of time between each
      step. Participants completing this protocol (version 6.0), who respond initially in Step 3
      will receive a total of 5200 mg of Vorinostat. Participant completing the study, who repeat
      Step 3, will receive a total of 6000 mg of Vorinostat. For reference, participants who
      completed the previous version (5.0) received a total of 10,000 mg of Vorinostat without
      clear evidence of any durable drug-associated toxicity thus far.

      The change in the frequency of HIV-1 infection per million resting CD4 + cells will be
      measured after repeated short interval dosing with VOR in Step 4. The 4th leukapheresis
      (Visit 12) will be compared to the baseline leukapheresis done at Visit 2. If the VOR 400 mg
      dosing in Step 4 is interrupted due to toxicity or intolerance, then the leukapheresis will
      be performed as soon as possible after the VOR interruption. This is justified as if a
      depletion of resting cell infection can occur; new resting cell infection is unlikely to
      occur in the presence of ART. Test dosing in this Step will continue until the study's
      stopping (lack of response in five) or toxicity rules are met.
    

Intervention name(s): Vorinostat
Intervention type(s): Drug
Intervention description(s): Vorinostat (VOR) 400mg will be given as single doses by mouth. Participants eligible to advance in study will have opportunity to receive more than one dose of VOR. Each participant will only take one dose of VOR in a 24 hour period. Repeat doses will be administered at least 24 hours apart, with option for dosing at intervals up to 96 hour
Other intervention name(s): Zolinza; SAHA, or MK-0683; VOR
Intervention MeSH terms: Vorinostat
Intervention model: Single Group Assignment
Intervention model description: All participants eligible for study received the same open label drug
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: HIV-1 Infection; HIV RNA <50 copies/mL; Stable ART; Resting CD4+ T cells; Leukapheresis; Vorinostat; HIV RNA expression; PK visits