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

• Status: Completed
• Trial end date: 2016-03-31
• Target enrollment: 0
• Participant gender: All

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)

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of North Carolina, Chapel Hill
• Collaborators: Merck Sharp & Dohme Corp.; National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH)
• Treatments: Vorinostat

Criteria

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.