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

NCT01319383 | Completed Phase 1 Results DMC

• 2 other identifiers: CID 08071U01AI095052-01
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

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

Conditions

HIV-1 Infection

Keywords

HIV-1 Infection; HIV RNA <50 copies/mL; Stable ART; Resting CD4+ T cells; Leukapheresis; Vorinostat; HIV RNA expression; PK visits

Outcome Measures

Primary Outcomes (4)

• 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

  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

  Arm1: Baseline, Visit 5 and Arm 2: Baseline and Visit 3

• 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)

  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.

  Baseline, Visit 18, Visit 29

• Number of Participants With a Significant in Vivo Response in Resting Cell Infection (RCI) and HIV RNA After Paired Doses

  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

  Baseline, Visit 6

• Number of Participants Exhibiting an in Vivo Resting CD4+ T-cell-associated HIV RNA (Rc-RNA) Increase Following Multiple (n = 10) Interval Doses

  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.

  Baseline, Visit 9

Secondary Outcomes (3)

• Number of Participants With Measurable Changes in Plasma HIV-1 RNA

  1 week after last VOR dose

• 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

• 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

Other Outcomes (1)

• Number of Participants Developing Cancer Within 5 Years Following >/= 8 Vorinostat Dose Exposures

  From last dose Vorinostat to 5 years afterwards

Study Arms (1)

Open Label, Translational Research

EXPERIMENTAL

Vorinostat will be administered to all eligible participants in each step of each phase (period) of the study

Drug: Vorinostat

Interventions

Vorinostat DRUG

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

Also known as: Zolinza, SAHA, or MK-0683, VOR

Open Label, Translational Research

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 \>70.
• 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:

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• National Institutes of Health (NIH): collaborator
• Merck Sharp & Dohme LLC: collaborator
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (1)

The University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27514, United States

Location

Related Publications (4)

• Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM, Parker DC, Anderson EM, Kearney MF, Strain MC, Richman DD, Hudgens MG, Bosch RJ, Coffin JM, Eron JJ, Hazuda DJ, Margolis DM. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012 Jul 25;487(7408):482-5. doi: 10.1038/nature11286.

  PMID: 22837004 RESULT

• Archin NM, Bateson R, Tripathy MK, Crooks AM, Yang KH, Dahl NP, Kearney MF, Anderson EM, Coffin JM, Strain MC, Richman DD, Robertson KR, Kashuba AD, Bosch RJ, Hazuda DJ, Kuruc JD, Eron JJ, Margolis DM. HIV-1 expression within resting CD4+ T cells after multiple doses of vorinostat. J Infect Dis. 2014 Sep 1;210(5):728-35. doi: 10.1093/infdis/jiu155. Epub 2014 Mar 11.

  PMID: 24620025 RESULT

• Garrido C, Tolstrup M, Sogaard OS, Rasmussen TA, Allard B, Soriano-Sarabia N, Archin NM, Margolis DM. In-vivo administration of histone deacetylase inhibitors does not impair natural killer cell function in HIV+ individuals. AIDS. 2019 Mar 15;33(4):605-613. doi: 10.1097/QAD.0000000000002112.

  PMID: 30830886 DERIVED

• Archin NM, Kirchherr JL, Sung JA, Clutton G, Sholtis K, Xu Y, Allard B, Stuelke E, Kashuba AD, Kuruc JD, Eron J, Gay CL, Goonetilleke N, Margolis DM. Interval dosing with the HDAC inhibitor vorinostat effectively reverses HIV latency. J Clin Invest. 2017 Aug 1;127(8):3126-3135. doi: 10.1172/JCI92684. Epub 2017 Jul 17.

  PMID: 28714868 DERIVED

MeSH Terms

Interventions

Vorinostat

Intervention Hierarchy (Ancestors)

Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids

Results Point of Contact

• Title: Dr. David Margolis
• Organization: UNC Chapel Hill School of Medicine

dmargo@med.unc.edu

919-966-6388

Study Officials

• David Margolis, MD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Masking Details: Open label
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: All participants eligible for study received the same open label drug

Study Record Dates

• First Submitted: March 17, 2011
• First Posted: March 21, 2011
• Study Start: February 1, 2011
• Primary Completion: March 31, 2016
• Study Completion: March 31, 2016
• Last Updated: June 29, 2017
• Results First Posted: June 29, 2017

Record last verified: 2017-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)