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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, University of North Carolina, Chapel Hill
Sponsor:
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
  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: No masking
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)

Resource links provided by NLM:


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
Actual 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 Names:
  • 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

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 64 Years   (Adult)
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.

  5. 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.

  6. Stable cART regimen for ≥ 6 months prior to Screening (Visit 1). NOTE: The cART regimen is defined by current treatment guidelines.
  7. Ability and willingness of participant to continue cART throughout the study.
  8. Able and willing to adhere to protocol therapy, schedule, and is judged adherent to antiretroviral therapy (adherence defined in inclusion criterion 5.)
  9. 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.

  10. Plasma HIV-1 RNA < 50 copies/mL at screening.
  11. CD4+ cell count ≥ 350 cells/mm3 at screening.
  12. 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.
  13. No active HBV infection (measureable HBV DNA or HBVsAg+) at or within 90 days of screening (Visit 1).
  14. 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.
  15. 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.

  16. Ability and willingness to provide adequate locator information.
  17. Ability and willingness to communicate effectively with study personnel; considered reliable, willing, and cooperative in terms of compliance with the protocol requirements.
  18. Adequate vascular access for HXTC infusion and leukapheresis.
  19. Able to swallow pills without difficulty.
  20. 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
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

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 ( U.S. NIH Grant/Contract )
Study First Received: June 29, 2017
Last Updated: July 6, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Vorinostat
Antineoplastic Agents
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 26, 2017