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

HIV-1 Infection Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01319383
• Other study ID #: CID 0807
• Secondary ID: 1U01AI095052-01
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: March 17, 2011
• Last updated: June 3, 2016
• Start date: March 2011
• Est. completion date: April 2016

Study information

• Verified date: June 2016
• Source: University of North Carolina, Chapel Hill
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review BoardUnited States: Federal Government
• Study type: Interventional

Clinical Trial 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)

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 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 37
• Est. completion date: April 2016
• Est. primary completion date: April 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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.

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• HIV-1 Infection

Intervention

Drug:
• Vorinostat
Drug administration - Step 1 - 400mg Vorinostat will be given as single doses by mouth at visits 2 and 5. Step II - 400 mg VOR for 3 consecutive days a week (for a maximum of 8 weeks).

Locations

Country	Name	City	State
United States	The University of North Carolina at Chapel Hill	Chapel Hill	North Carolina

Sponsors (4)

Lead Sponsor	Collaborator
University of North Carolina, Chapel Hill	Merck Sharp & Dohme Corp., National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To compare RCVL in HIV-infected patients on stable ART, before and after a single exposure to VOR, after a pair of exposures to VOR, and after multiple exposures to VOR.	HIV RNA expression per 1 million resting CD4+ cells (RCVL) after the second of a pair of VOR doses, in participants who exhibited an increase in HIV RNA expression per 1 million resting CD4+ cells after a single 400 mg dose of VOR (HIV RNA per million resting CD4+ T cells). We will compare the HIV RNA expression per 1 million resting CD4+ cells obtained at the leukapheresis after paired VOR doses to the level obtained at baseline leukapheresis on stable ART.	3 years	Yes
Secondary	To compare the change in HIV RNA expression per million resting CD4 + cells after multiple (10) VOR doses.	HIV RNA per million resting CD4+ T cells at leukapheresis after ten 400 mg VOR doses vs. level at baseline leukapheresis on stable ART.	3 years	Yes
Secondary	Changes on plasma HIV-1 RNA	By standard assay and single copy assay.	3 years	Yes
Secondary	To assess safety, tolerability, and PK profile of VOR		3 years	Yes
Secondary	To assess the alterations in global histone acetylation within resting lymphocytes		3 years	No
Secondary	To compare the frequency of resting CD4+ T cell infection (RCI) after multiple (10) repeated short interval dosing with VOR	Leukapheresis on ART and VOR vs. leukapheresis on baseline ART	3 years	Yes