Study to Evaluate Effects of Vorinostat and HXTC on Persistent HIV-1 Infection in HIV-Infected Subjects Started on Antiretroviral Therapy (ART)

NCT03212989 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: 17-04681R01HL132791-01
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase I, single-site, study to evaluate the effects of VOR and HIV-1 Antigen Expanded Specific T Cell Therapy (HXTC) on persistent HIV-1 Infection in HIV-infected individuals suppressed on ART. Twelve participants with durable viral suppression will be enrolled and will complete the study. All participants will receive the same treatment and if eligible, will be dosed with HXTC and VOR. Participants will continue their baseline ART regimen throughout the study.

Conditions

HIV-1 Infection

Keywords

HIV; HXTC; Antiretroviral Therapy; HIV-Infected; Vorinostat; AIDS

Outcome Measures

Primary Outcomes (1)

• Number of Participants w/ at Least One ≥ Grade 3 Adverse Event That is Possibly or Definitely Related to Vorinostat (VOR) or HIV-specific T Cell (HXTC)

  Safety data will include local and systemic signs and symptoms, laboratory measures of safety/toxicity, and all adverse and serious adverse events. Safety data will be routinely collected throughout the duration of the study.

  Up to end of study (weeks 16 through 45)

Secondary Outcomes (1)

• Number of Participants Demonstrating an HIV-specific Immune Response to the Combination of Vorinostat (VOR) and HIV-specific T Cells (HXTC) Therapy as Well as a Change in the Frequency of Latent HIV Infection

  Up to end of study (weeks 16 through 45)

Study Arms (1)

VOR + HXTC arm

EXPERIMENTAL

This is an open label single arm study. All eligible participants receive the following interventions: * Step 2 - Single dose of Vorinostat (VOR) 400 mg PO * Step 4 - Vorinostat (VOR) 400 mg PO every 72 hrs x 10 doses and 2 HXTC infusions * Step 5 - Vorinostat (VOR) 400 mg PO every 72 hrs x 10 doses and 2 HXTC infusions

Drug: Vorinostat; Biological: HXTC

Interventions

Vorinostat DRUG

Participants meeting criteria for Step 1 (exhibit ex-vivo response to VOR) will progress to Step 2 where they will receive a single dose of VOR 400 mg followed by a leukapheresis. If an increase in cell-associated HIV RNA (ca-RNA) is observed in-vivo following the single VOR dose, they will be eligible to donate cells for the manufacture of HXTC (Step 3). Successful manufacturing of the HIV-1 antigen expanded specific T cells will progress participants to combination treatment in Steps 4 and 5. In Steps 4 and Step 5, participants will receive two series of VOR dosing and HXTC infusions, for a total 20 doses of VOR 400 mg and 5 HXTC infusions.

Also known as: ZOLINZA, MK-0683, SAHA

VOR + HXTC arm

HXTC BIOLOGICAL

Participants meeting criteria for Step 1 (exhibit ex-vivo response to VOR) will progress to Step 2 where they will receive a single dose of VOR 400 mg followed by a leukapheresis. If an increase in cell-associated HIV RNA (ca-RNA) is observed in-vivo following the single VOR dose, they will be eligible to donate cells for the manufacture of HXTC (Step 3). Successful manufacturing of the HIV-1 antigen expanded specific T cells will progress participants to combination treatment in Steps 4 and 5. In Steps 4 and Step 5, participants will receive two series of VOR dosing and HXTC infusions, for a total 20 doses of VOR 400 mg and 5 HXTC infusions.

Also known as: HIV-1 antigen expanded specific T-cell

VOR + HXTC arm

Eligibility Criteria

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

You may qualify if:

• ≥ 18 years and \< 65 years of age at screening
• Ability and willingness of participant to give written informed consent. NOTE: Due to the lack of foreseeable benefit to study volunteers, the study will not enroll illiterate or mentally incompetent volunteers.
• Confirmation of HIV-1 infection HIV infection is defined as documentation by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load.
• NOTE: The term "licensed" refers to a US FDA-approved kit.
• WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load.
• On antiretroviral therapy for at least 24 months and on potent antiretroviral therapy for greater than or equal to 6 months prior to Screening (Visit 1).
• Potent ART is defined by current treatment guidelines and consists of 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 more than 9 total days in the 12 weeks prior to Screening.
• 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, toxicity, or other reasons are permitted if an alternative suppressive regimen was maintained.
• Ability and willingness of participant to continue ART throughout the study.
• Plasma HIV-1 RNA \< 50 copies/mL at two time points in the previous 12 months prior to study screening (one time point can be at screening) and never \> or equal to 50 copies/mL on two consecutive time points in the last 24 months.
• NOTE: A single unconfirmed plasma HIV RNA \> or equal to 50 copies/mL but \< 1000 c/mL is allowed if a subsequent assay was \< 50 copies/mL; but none in the 6 months preceding the study screening visit.
• Plasma HIV-1 RNA \< 50 copies/mL at screening
• CD4+ cell count ≥ 350 cells/mm3 at screening
• No active HCV infection at or within 90 days of screening.
• Note: No active hepatitis C virus (HCV) defined as negative HCV antibody (HCVAb) or if HCVAb is positive, reflex HCV RNA is negative.

You may not qualify if:

• Known allergy or sensitivity to components of VOR and its analog or to components in the HXTC product.
• Women without written documentation of menopause (absence of a period for ≥ one year and FSH level indicating menopause), hysterectomy or bilateral oophorectomy, non-surgical permanent sterilization, or bilateral tubal ligation.
• Untreated syphilis infection (defined as a positive rapid plasma reagin (RPR) without clear documentation of treatment).
• Note: In cases of untreated syphilis, participant may re-screen following documentation of adequate treatment of syphilis
• All male participants expecting to father children within the projected duration of the study.
• Receipt of compounds with Histone Deacetylase (HDAC) inhibitor-like activity, such as valproic acid within 30 days prior to screening.
• Use of any investigational antiretroviral agents within 30 days prior to screening.
• If the study PI (or designee) is unable to construct a fully active alternative cART regimen based on previous resistance testing and/or treatment history.
• Use of the following medications that carry risk of torsade des 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.
• Use of any of the following within 90 days prior to screening: immunomodulatory, cytokine, or growth stimulating factors such as systemic corticosteroids, cyclosporine, methotrexate, azathioprine, anti-CD25 antibody, interferon (IFN), interleukin-2 (IL-2), coumadin, warfarin, or other Coumadin derivative anticoagulants.
• Prior use of any HIV immunotherapy or HIV vaccine within 6 months prior to Screening, except for prior HXTC infusions.
• Received any infusion blood product, immune globulin, or hematopoietic growth factors within 90 days prior to study screening.
• Pregnancy or breast-feeding.
• History or other clinical evidence of severe illness, malignancy, immunodeficiency other than HIV, or any other condition that would make the participant unsuitable for the study in the opinion of the investigator (or designee).
• Use of topical steroids over a total area exceeding 15 cm-2 within 30 days prior to Screening.

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27514, United States

Location

Related Publications (1)

• Gay CL, Hanley PJ, Falcinelli SD, Kuruc JD, Pedersen SM, Kirchherr J, Raines SLM, Motta CM, Lazarski C, Chansky P, Tanna J, Shibli A, Datar A, McCann CD, Sili U, Ke R, Eron JJ, Archin N, Goonetilleke N, Bollard CM, Margolis DM. The Effects of Human Immunodeficiency Virus Type 1 (HIV-1) Antigen-Expanded Specific T-Cell Therapy and Vorinostat on Persistent HIV-1 Infection in People With HIV on Antiretroviral Therapy. J Infect Dis. 2024 Mar 14;229(3):743-752. doi: 10.1093/infdis/jiad423.

  PMID: 38349333 DERIVED

MeSH Terms

Conditions

Acquired Immunodeficiency Syndrome

Interventions

Vorinostat

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Cynthia Gay, MD, MPH
• Organization: University of North Carolina at Chapel Hill

cynthia_gay@med.unc.edu

919-966-6712

Study Officials

• David Margolis, MD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

• Cynthia Gay, MD, MPH

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

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

Study Record Dates

• First Submitted: June 29, 2017
• First Posted: July 11, 2017
• Study Start: June 27, 2017
• Primary Completion: June 7, 2022
• Study Completion: July 5, 2022
• Last Updated: May 12, 2023
• Results First Posted: May 12, 2023

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)