The Effect of Vorinostat on HIV RNA Expression in the Resting CD4+ T Cells of HIV+ Pts on Stable ART

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 pools 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.

Participants with and without an ex vivo response to VOR (baseline leukapheresis [Visit
2.0]) will be evaluated for an in vivo response to the single dose of VOR 400 mg.
Participants who completed Step 1 in protocol v3.0 and v5.0 are eligible to enroll directly
into Step 2 after being consented to Version 6.0 and completing Step 1, Visits 1 and 2 of
this protocol. The leukapheresis at Visit 2 will be optional based on prior ascertainment of
baseline parameters. Omission of the leukapheresis at visit 2 will be determined by study
PI. Enrollment and completion of required research assays will be completed at this study
visit. Enrollment into Step 1 will continue until 12 evaluable participants have
successfully completed multiple doses of VOR (Step 3), or until the study-stopping rules are
met.

Step 1 includes four visits: screening (visit 1), enrollment and baseline Leukapheresis
(Visit 2), single dose administration of VOR (visit 3) and safety follow up (Visit 4). 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. VOR 400 mg will be administered as a
single dose at study Visit 3. Each participant will only receive 400 mg VOR at this one time
point. An abbreviated pharmacokinetics (PK) as well as a leukapheresis procedure will be
part of Visit 3. It is anticipated that Step 1 will occur over a minimum of 8 weeks. All
participants must complete Step 1 prior to moving to Step 2. All participants will be
assessed after the Visit 3 leukapheresis for an in vivo response to the 400 mg of VOR.

Progression from Step 1 (single dose) to Step 2 (paired doses) will be 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 2 (paired doses) to Step 3
(multiple doses) will be based on each participant's increase in RCVL following the 3rd dose
of 400 mg VOR (Visit 6), compared to that measured at baseline (Visit 2).

The goal of this study 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 2 will be initiated at least 4 weeks after the completion of the Step 1 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 2,
two paired doses of VOR 400 mg will be administered. The interval between the 2 paired doses
can be as short as 48 hours, and as much as 4 days apart from each other, and participants
will be assessed via a 3rd leukapheresis for in vivo response to 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, see Fig 3), 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 2
will enroll until a total of 12 evaluable subjects with a measureable increase in
cell-associated HIV RNA are obtained, and these volunteers have advanced to Step 3.

Our preliminary results from version 5.0 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 2 is
to establish the optimal dosing interval in which a response to Vorinostat is sustained.
Step 2 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 2 dosing interval, they can be
eligible to repeat Step 2. They can re-enter or repeat Step 2 one time only. They will only
re-enter Step 2 to test a longer dosing interval. Again, if > 60 days elapses between the
final safety visit of step 2 (Visit 7) and their re-entry to Step 2, they will re-screen
(visit 1 only) to qualify to continue in the study.

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 3 and receive 10
doses of VOR 400 mg administered at the same interval at which cell-associated HIV-RNA
induction was observed in Step 2. 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 3 will occur over a minimum of 4 weeks; however this may vary
among participants based on their Step 2 dosing interval stage. Accumulated blood volumes
and the timing between leukapheresis procedures will determine the length of time between
each stepsParticipants completing this protocol (version 6.0), who respond initially in Step
2 will receive a total of 5200 mg of Vorinostat. Participant completing the study, who
repeat Step 2, 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 3. This 4th leukapheresis
(Visit 12) will be compared to the baseline leukapheresis done at Visit 2. If the VOR 400 mg
dosing in Step 3 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.

Inclusion Criteria:

1. HIV-1 infection

2. Men, women age ≥18 years.

3. Ability, willingness to give written informed consent.

4. Able, willing to provide adequate locator information.

5. Karnofsky performance status >70.

6. Able, willing to adhere to therapy and adherent to ART.

7. Able,willing to comply with time requirements for study visits and evaluations.

8. 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.

9. Adequate vascular access for leukapheresis.

10. Able to swallow pills without difficulty.

11. On combination ART for ≥ 18 months prior to study entry, no consecutive HIV-1 RNA
values >50 copies/mL in that time period

12. CD4 cell count ≥ 300 cells/µl at screening.

13. All male study volunteers must agree not to participate in a conception process.

14. Must be seronegative for Hep C RNA, Hep B sAg within 90 days of entry

15. 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.

Exclusion Criteria:

1. Received blood transfusions or hematopoetic growth factors within 90 days.

2. All women unless there is written documentation of menopause (absence of a period for
≥ one year), hysterectomy, oophorectomy, or tubal ligation.

3. The study PI is unable to construct a fully active alternative regimen based on
previous resistance testing and/or treatment history

4. Use of atazanavir and raltegravir in background antiretroviral regimens.

5. 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.

6. 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.

7. 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.

8. 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.

9. Treatment for an active AIDS-defining opportunistic infection within 90 days prior to
screening.

10. Any history of cardiac rhythm disturbance requiring medical or surgical therapy.

11. Any history of acute or chronic pancreatitis.

12. 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.

13. 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.

14. Known hypersensitivity to the components of VOR or its analogs.

15. Known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the trial.

16. Pregnancy or breast feeding, or expecting to father children within the projected
duration of the study.

17. Inability to communicate effectively with study personnel.