Study to Evaluate Effects of Vorinostat and HXTC on Persistent HIV-1 Infection in HIV-Infected Subjects Started on Antiretroviral Therapy (ART)
Condition: HIV-1 Infection
MeSH terms: Infections; Communicable Diseases; HIV Infections
Intervention: Vorinostat; HXTC
Intervention description: 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.; 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.
Intervention MeSH terms: Vorinostat
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 17.0
Sex: All
Minimum age: 18 Years
Maximum age: 64 Years
Healthy volunteers: No
Keywords: HIV; HXTC; Antiretroviral Therapy; HIV-Infected; Vorinostat; AIDS

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. ≥ 18 years and < 65 years of age at screening

          2. 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.

          3. 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.

          4. 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.

          5. Ability and willingness of participant to continue ART throughout the study.

          6. Able and willing to adhere to protocol therapy, schedule, and judged adherent to
             antiretroviral therapy (adherence defined in inclusion criterion 4.)

          7. 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.

          8. Plasma HIV-1 RNA < 50 copies/mL at screening

          9. CD4+ cell count ≥ 350 cells/mm3 at screening

         10. 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.

         11. No active hepatitis B virus (HBV) infection (measureable HBV DNA or HBV surface
             antigen-positive (HBVsAg+)) at or within 90 days of screening

         12. Women with written documentation of any of the following:

               1. prior hysterectomy OR bilateral oophorectomy (removal of both ovaries)

               2. bilateral tubal ligation or non-surgical permanent sterilization

               3. Women with intact uterus and ovaries who have not had a period for ≥ one year AND
                  have a documented follicle stimulating hormone (FSH) level indicating
                  postmenopausal status.

         13. All male study volunteers must agree not to participate in a conception process (e.g.
             active attempt to impregnate, sperm donation, in vitro fertilization) and, if
             participating in sexual activity that could lead to pregnancy, the male study
             volunteer and his female partner must use two reliable methods of contraception
             (condoms, with or without a spermicidal agent; a diaphragm or cervical cap with
             spermicide; an intrauterine device (IUD); or hormonal-based contraception)
             simultaneously while receiving the protocol-specified study products and for 6 weeks
             after stopping the study products. Participants must use a reliable barrier method of
             contraception (condom, cervical cap) along with another form of contraception.

             NOTE: For female partners who are receiving ritonavir, estrogen-based contraceptives
             are not reliable and an alternative method should be suggested.

         14. Ability and willingness to provide adequate locator information.

         15. Ability and willingness to communicate effectively with study personnel

         16. Adequate vascular access for HXTC infusion and leukapheresis.

         17. Able to swallow pills without difficulty.

         18. Potential participant must have adequate organ function as indicated by the following
             laboratory values:

        System Laboratory Value Hematological Absolute neutrophil count (ANC) ≥1,500 /microliter
        (mcL) Platelets ≥125,000 / mcL Hemoglobin ≥ 12 g/dL (male) and ≥ 11.0 g/dL (females) System
        Laboratory Value Coagulation Prothrombin Time (PT) or international normalized ratio (INR)
        ≤1.1x upper limit of normal (ULN) Chemistry K+ levels within normal limits (WNL) Mg++
        levels(footnote 1) WNL Glucose Screening serum glucose ≤ Grade 1 (fasting or non- fasting)
        Albumin ≥ 3.5 g/dL or ≥ lower limit of normal (LLN) Renal Creatinine clearance determined
        by the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equation found at:
        https://www.qxmd.com/calculate/calculator_251/egfr-using-ckd-epi eGFR (epidermal growth
        factor receptor) > 60 mL/min Hepatic Serum total bilirubin Total bilirubin < 1.1 times the
        ULN range. If total bilirubin is elevated, direct bilirubin must be < 2 times the ULN
        range.

        NOTE: If participant is on an atazanavir-containing therapy, then a direct bilirubin should
        be measured instead of the total bilirubin and must be ≤ 1.0 mg/dL.

        Aspartate Aminotransferase (AST) (SGOT) and Alanine Transaminase (ALT) (SGPT) < 1.25 X ULN
        Alkaline Phosphatase < 1.25 X ULN Lipase < 1.1 X ULN

        Footnote 1: LLN for Mg++ per the clinical laboratory's normal range used for this study is
        a grade 1 event per Division of AIDS (DAIDS) Toxicity Table and is allowed for eligibility

        ULN = upper limit of normal LLN = lower limit of normal WNL = within normal limits

        Exclusion Criteria:

          1. Known allergy or sensitivity to components of VOR and its analog or to components in
             the HXTC product.

          2. 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.

          3. 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

          4. All male participants expecting to father children within the projected duration of
             the study.

          5. Receipt of compounds with Histone Deacetylase (HDAC) inhibitor-like activity, such as
             valproic acid within 30 days prior to screening.

          6. Use of any investigational antiretroviral agents within 30 days prior to screening.

          7. 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.

          8. 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.

          9. 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.

         10. Prior use of any HIV immunotherapy or HIV vaccine within 6 months prior to Screening,
             except for prior HXTC infusions.

         11. Received any infusion blood product, immune globulin, or hematopoietic growth factors
             within 90 days prior to study screening.

         12. Pregnancy or breast-feeding.

         13. 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).

         14. Use of topical steroids over a total area exceeding 15 cm-2 within 30 days prior to
             Screening.

         15. Treatment for an active AIDS-defining opportunistic infection within 90 days prior to
             Screening.

         16. Any active malignancy that may require chemotherapy or radiation therapy.

         17. 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.

         18. Known psychiatric or substance abuse disorders that would interfere with participant's
             ability to fully cooperate with the requirements of the trial as assessed by the study
             investigator (or designee).

         19. History or other clinical evidence, as assessed by the study PI (or designee), of
             significant or unstable cardiac disease (e.g., angina, congestive heart failure,
             recent myocardial infarction, significant arrhythmia requiring medical or surgical
             therapy) or clinically significant electrocardiogram (ECG) abnormalities.

         20. Unable to have a person available to drive participant home at infusion visits.

         21. Participation in another investigational clinical research study (with the exception
             of an antiretroviral treatment trial that uses FDA approved antiretroviral agents) or
             use of investigational agents within 30 days prior to screening.

        NOTE: Co-enrollment in observational only studies is permitted.

        NOTE: Co-enrollment in the AIDS Clinical Trials Group (ACTG) 5332 REPRIEVE study
        (NCT023442900) and using FDA approved pitavastatin is permitted provided participant
        enrolled on ACTG 5332 and has taken the study provided medication ≥ 4 months.