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Clinical Trials

MainTitle

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

This study is currently recruiting participants. (see Contacts and Locations)

Verified July 2017 by Julia Sung, MD

Sponsor
Julia Sung, MD

Collaborator
National Heart, Lung, and Blood Institute (NHLBI)

Information provided by (Responsible Party)
Julia Sung, MD, University of North Carolina, Chapel Hill

ClinicalTrials.gov Identifier
NCT03212989

First received: June 29, 2017
Last updated: July 6, 2017
Last Verified: July 2017
History of Changes
Purpose

Purpose

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 cART. 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 cART regimen throughout the study.

Condition Intervention Phase
HIV-1 Infection

Drug : Vorinostat
Biological : HXTC
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: IGHID 11627 - A Phase I Study to Evaluate the Effects of Vorinostat and HIV-1 Antigen Expanded Specific T Cell Therapy (HXTC) on Persistent HIV-1 Infection in HIV-Infected Individuals Started on Antiretroviral Therapy (The XTRA Study)

Further study details as provided by Julia Sung, MD, University of North Carolina, Chapel Hill:

Primary Outcome Measures

  • Number of participants w/ at least one ≥ Grade 3 adverse event including signs/symptoms, lab toxicities, and/or clinical events that is possibly or definitely related to VOR or HXTC any time from the first day of study treatment through the end of study [ Time Frame: Up to end of study, approximately 96 weeks ]
    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.
Secondary Outcome Measures:
  • Number of participants demonstrating an HIV-specific immune response to the combination of VOR and HXTC therapy as well as a change in the frequency of latent HIV infection [ Time Frame: Through End of study, approximately 96 weeks ]

Estimated Enrollment: 12
Study Start Date: June 27, 2017
Estimated Study Completion Date: June 2021
Estimated Primary Completion Date: June 2020 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
Experimental: VOR + HXTC arm
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

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.

Other Name:
  • ZOLINZA
  • MK-0683
  • SAHA

Biological: HXTC

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.

Other Name: HIV-1 antigen expanded specific T-cell

Detailed Description:

Purpose: This study will test the use of special immune system cells called expanded HIV-specific T Cell (HXTC) Therapy to stimulate the immune system to respond better to HIV. HXTC Therapy will be given in combination with the drug Vorinostat (VOR) which has been shown to stimulate some cells infected with HIV to become active and start making HIV virus. The purpose of this study is to:

  1. Evaluate the safety of a series of HXTC infusions in combination with serial doses of VOR and
  2. Help scientists evaluate ways of re-activating latent (non-active) HIV virus and
determine if the immune system can be made stronger to eliminate the activated HIV virus.
Participants: HIV-infected men and women, ≥ 18 and < 65 years of age, with durable viral suppression for ≥ 24 months as measured on standard HIV RNA assays. Eligible participants must be on stable cART and have a CD4 count ≥ 350 cells/mm3. We plan to enroll up to 12 participants at UNC who complete all 6 Steps of this study.
Procedures (methods):
In Step 1 and prior to initiating the two series of VOR and HXTC combined therapies, all participants will undergo study screening where they will be required to: 1. Demonstrate a baseline measurement of the frequency of resting CD4 T cell infection ≥ 0.3 infected cells per million as determined by QVOA, as a further decrease from this low frequency of infection cannot be definitively measured given the QVOA assay threshold, and 2. Exhibit ex-vivo (Step 1) response to VOR
Participants progressing to Step 2 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.
In the first series (Step 4), participants will receive VOR 400 mg PO every 72 hours for 10 doses and 2 infusions of HXTC. The first HXTC infusion will be administered six hours after the first dose of VOR (HXTC #1) and the 2nd HXTC infusion (HXTC #2) will occur 6 hours after the 6th dose of VOR.
In the second series in Step 5, participants will receive an additional 10 doses of VOR 400 mg PO every 72 hours and 3 HXTC infusions. The first HXTC infusion in Step 5 (HXTC #3) will occur 6 hours after the 11th dose of VOR (1st dose in Step 5), the 2nd HXTC infusion (HXTC #4) will occur 6 hours after the 16th dose of VOR, and the 3rd HXTC infusion (HXTC #5) will occur 1 - 3 days after the 20th dose of VOR. If there are insufficient cells manufactured to allow 5 infusions, the first infusion in Step 5 (HXTC #3) will be omitted.
Following the final HXTC infusion in Step 5, participants will move into Step 6 for a minimum of 6 additional visits at weeks 13, 17, 21, 33, 45, and 57 after the 1st HXTC infusion. The 3rd and final leukapheresis will occur at Week 21 (Step 6, Visit 22), approximately 9 weeks after the last HXTC infusion to evaluate the effect of study treatment on IUPM by QVOA.
All participants who receive greater than 8 doses of VOR in the study will be required to enter a study cancer registry where they will be contacted once a year for 5 years after completion of their study participation. The registry is created because of genotoxic findings that were associated with the use of VOR. All participants will be monitored for development of future malignancies.

Eligibility

Eligibility

Ages Eligible for Study: 18 Years to 64 Years  
Sexes Eligible for Study: All  
Accepts Healthy Volunteers: No  

Criteria

Inclusion Criteria:

    1. ≥ 18 years and < 65 years of age
    2. Ability and willingness of participant to give written informed consent. Note: Due to the lack of foreseeable benefit to study volunteers, illiterate or mentally incompetent volunteers will not be enrolled.
    3. Karnofsky performance status > 70.
    4. 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 potent antiretroviral therapy 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 (2) consecutive days or more than four (4) cumulative days) in the 24 weeks prior to Screening (Visit 1).

  • 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.
  • Stable cART regimen for ≥ 6 months prior to Screening (Visit 1). NOTE: The cART regimen is defined by current treatment guidelines.
  • Ability and willingness of participant to continue cART throughout the study.
  • Able and willing to adhere to protocol therapy, schedule, and is judged adherent to antiretroviral therapy (adherence defined in inclusion criterion 5.)
  • Plasma HIV-1 RNA < 50 copies/mL at two time points in the previous 6 months prior to study entry and never > 50 copies/mL on two consecutive time points in the last 24 months.

  • NOTE: A single unconfirmed plasma HIV RNA > limit of detection but < 1000 c/mL is allowed if a subsequent assay was below the limit of detection; 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 (Visit 1). Note: No active HCV defined as negative HCVAb or if HCVAb is positive, reflex HCV RNA is negative.
  • No active HBV infection (measureable HBV DNA or HBVsAg+) at or within 90 days of screening (Visit 1).
  • Women with written documentation of any of the following:
      1. prior hysterectomy OR bilateral oophorectomy (removal of both ovaries)
      2. bilateral tubal ligation
      3. Women with intact uterus and ovaries who have not had a period for ≥ one year AND have a documented FSH level indicating postmenopausal status.
    1. 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 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.
  • Ability and willingness to provide adequate locator information.
  • Ability and willingness to communicate effectively with study personnel; considered reliable, willing, and cooperative in terms of compliance with the protocol requirements.
  • Adequate vascular access for HXTC infusion and leukapheresis.
  • Able to swallow pills without difficulty.
  • Potential participant must have adequate organ function as indicated by the following laboratory values:

  • System Laboratory Value Hematological Absolute neutrophil count (ANC) ≥1,500 /mcL Platelets ≥125,000 / mcL Hemoglobin ≥ 12 g/dL (male) and ≥ 11.5 g/dL (females) System Laboratory Value Coagulation Prothrombin Time or INR ≤1.5x upper limit of normal (ULN) Chemistry K+ levels Within normal limits Mg++ levels ≥ 1.2 mEq/L but <1.5 x ULN Glucose Screening serum glucose ≤ Grade 1 (fasting or non- fasting) Albumin ≥ 3.3 g/cL Renal Creatinine clearance determined by the CKD-Epi equation found at: https://www.qxmd.com/calculate/calculator_251/egfr-using-ckd-epi eGFR > 60mL/min Hepatic Serum total bilirubin Total bilirubin < 1.5 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.
    AST (SGOT) and ALT (SGPT) ≤ 2.0 X ULN Alkaline Phosphatase ≤ 2.5 X ULN Lipase < 1.6 X ULN ULN = upper limit of normal

    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, or bilateral tubal ligation.
      3. All male participants expecting to father children within the projected duration of the study.
      4. Receipt of compounds with HDAC inhibitor-like activity, such as valproic acid within 30 days prior to screening. Potential participants may enroll after a 30-day washout period.
      5. Use of any investigational antiretroviral agents within 30 days prior to screening (Visit 1).
      6. If the study PI or protocol team is unable to construct a fully active alternative cART regimen based on previous resistance testing and/or treatment history.
      7. Use of the following medications that carry risk of torsade des pointes: amiodarone, arsenic trioxide, astemizole, bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, diopyramide, dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozidine, probucol, procanimide, quinidine, sotalol, sparfloxacxin, terfenadine, thioridizine.
      8. Use of any of the following within 90 days prior to entry: immunomodulatory, cytokine, or growth stimulating factors such as systemic corticosteroids, cyclosporine, methotrexate, azathioprine, anti-CD25 antibody, IFN, interleukin-2 (IL-2), coumadin, warfarin, or other Coumadin derivative anticoagulants.
      9. Prior use of any HIV immunotherapy or HIV vaccine within 12 months prior to Screening, except for prior HXTC infusions.
      10. Received any infusion blood product, immune globulin, or hematopoietic growth factors within 90 days prior to study entry.
      11. Pregnancy or breast-feeding.
      12. History or other 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, for at least 90 days prior to screening.
      13. Use of topical steroids over a total area exceeding 0.5mg/kg/day within 30 days prior to Screening.
      14. Treatment for an active AIDS-defining opportunistic infection within 90 days prior to Screening.
      15. Any active malignancy that may require chemotherapy or radiation therapy.
      16. 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.
      17. 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.
      18. History or other clinical evidence of significant or unstable cardiac disease (e.g., angina, congestive heart failure, recent myocardial infarction, significant arrhythmia) or clinically significant electrocardiogram (ECG) abnormalities. Any history of cardiac rhythm disturbance requiring medical or surgical therapy.
      19. Unable to have a person available to drive participant home at infusion visits.
      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.

    contacts and locations

    Contacts and Locations

    Choosing to participate in a study is an important personal decision.Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.For general information, see Learn About Clinical Studies.

    Please refer to this study by its ClinicalTrials.gov identifier: NCT03212989

    Contacts

    Contact:   JoAnn Kuruc, MSN, RN 919-966-8533 joann_kuruc@med.unc.edu
    Contact:   Julia Sung, MD 919-843-1550 julia_sung@med.unc.edu

    Locations

    United States, North Carolina
    University of North Carolina Health Care Recruiting
    Chapel Hill, North Carolina, United States, 27514
    Contact: JoAnn Kuruc, MSN, RN    919-966-8533    joann_kuruc@med.unc.edu
    Contact: Julia Sung, MD    919-843-1550    julia_sung@med.unc.edu
    Principal Investigator: Julia Sung, MD
    Sub-Investigator: David Margolis, MD
    Sub-Investigator: Cynthia Gay, MD, MPH
    Sub-Investigator: Joseph Eron, Jr., MD

    Sponsors and Collaborators

    Julia Sung, MD
    National Heart, Lung, and Blood Institute (NHLBI)

    Investigators

    Principal Investigator: Julia Sung, MD University of North Carolina, Chapel Hill
    Principal Investigator: David Margolis, MD University of North Carolina, Chapel Hill
    Principal Investigator: Cynthia Gay, MD, MPH University of North Carolina, Chapel Hill
    More Information

    More Information


    Responsible Party: Julia Sung, MD, Clinical Assistant Professor, University of North Carolina, Chapel Hill  
    ClinicalTrials.gov Identifier: NCT03212989   History of Changes  
    Other Study ID Numbers: 17-0468  
      1R01HL132791-01  
    Study First Received: June 29, 2017  
    Last Updated: July 6, 2017  

    Studies a U.S. FDA-regulated Drug Product: Yes  
    Studies a U.S. FDA-regulated Device Product: No  

    Keywords provided by Julia Sung, MD, University of North Carolina, Chapel Hill:

    HIV
    HXTC
    Antiretroviral Therapy
    HIV-Infected
    Vorinostat
    AIDS

    Additional relevant MeSH terms:
    Infection
    Communicable Diseases
    HIV Infections
    Vorinostat

    ClinicalTrials.gov processed this data on October 17, 2017
    This information is provided by ClinicalTrials.gov.