Pilot Trial of the Effect of Vorinostat and AGS-004 on Persistent HIV-1 Infection (VORVAX)

IGHID 11424 - A Pilot Trial of the Effect of Vorinostat and AGS-004 on Persistent HIV-1 Infection (The VOR VAX Study)

The purpose of this research study is to 1) evaluate the safety of a series of injections with the AGS-004 product in combination with a series of Vorinostat doses and 2) to help scientists evaluate ways of reactivating latent (non-acting) HIV virus and determine if the immune system can be made stronger to eliminate the activated HIV virus.

Study Overview

• Status: Terminated
• Conditions: HIV-1 Infection
• Intervention / Treatment: Drug: Vorinostat; Biological: AGS-004

Detailed Description

Purpose: Phase I study to measure the potential of AGS-004 combined with Vorinostat to: 1) stimulate expression of persistent proviral HIV from resting CD4+ cells, 2) generate an HIV-specific immune response, and 3) when combined, clear persistent infection in HIV-infected participants in whom viral replication and spread is inhibited by uninterrupted antiretroviral therapy (ART).

This is a phase I, single-site, pilot study intended to evaluate the association of serial AGS-004 vaccinations in combination with serial VOR doses on the expression of persistent proviral HIV, HIV-specific immune responses, and the frequency of resting CD4+T cell infection. Twelve participants with durable viral suppression will be enrolled. All participants will receive the same treatment and doses of AGS-004 and VOR and continue their baseline ART regimen throughout the study.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7030
      • University of North Carolina Hospitals

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 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 (eg, indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load.

2. Ages ≥ 18 to < 65 years old.
3. Karnofsky performance status >70.
4. 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.
5. Able and willing to provide adequate locator information.

6. On antiretroviral therapy (ART) for at least 24 months and on potent ART for > or equal to 6 months prior to Screening (Visit 1).

   Note: 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 doses for more than two (2) consecutive days or more than four (4) cumulative days) in the 24 weeks immediately 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.

7. All participants must continue cART throughout the study.
8. Able and willing to adhere to protocol therapy and judged adherent to antiretroviral therapy.
9. Plasma HIV-1 RNA < 50 copies/mL at screening (Visit 1).

10. Plasma HIV-1 RNA< 50 copies/mL at two time points in the previous 12 months prior to study screening and never > or equal to 50 copies/mL on two consecutive time points in the last 24 months prior to screening.

    Note: A single unconfirmed plasma HIV RNA > or equal to 50 copies (c)/mL but < 1000 c/mL is allowed if a subsequent assay was < 50 c/mL but not in the 6 months preceding the study screening visit (Visit 1).

11. CD4+ cell count ≥ 300 cells/mm3 at screening (Visit 1).
12. No history of auto-immune disease or auto-immune manifestations.
13. No active HCV infection (HCV antibody negative or no measureable HCV RNA) at or within 90 days of screening (Visit 1).
14. No active HBV infection (measureable HBV DNA or HBVsAg+) at or within 90 days of screening (Visit 1).
15. Ability and willingness to communicate effectively with study personnel; considered reliable, willing, and cooperative in terms of compliance with the protocol requirements.
16. Adequate vascular access for leukapheresis.
17. Able to swallow pills without difficulty.
18. Able and willing to receive Intradermal (ID) injections without difficulty.

19. 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 FSH level indicating postmenopausal status.

20. 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.

    For the female partners of male study volunteers who are receiving ritonavir, estrogen-based contraceptives are not reliable and an alternative method should be suggested.

21. 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 (males) and ≥ 11.5 g/dL (females) Coagulation Prothrombin Time or INR ≤1.1 x upper limit of normal (ULN) Chemistry K+ levels Within normal limits Mg++ levels ≥ 1.4 mEq/L Glucose Screening serum glucose ≤ Grade 1 (fasting or non-fasting) Albumin ≥ 3.5 g/dL Renal Creatinine clearance determined eGFR > 60mL/min by the CKD-Epi equation found at: https://www.qxmd.com/calculate/calculator_ 251/egfr-using-ckd-epi Hepatic Serum total bilirubin Total bilirubin <1.1 X ULN range, unless history of Gilbert's disease or deemed related to treatment with atazanavir. If total bilirubin is elevated, direct bilirubin must be <2 X ULN range.

AST (SGOT) and ALT (SGPT) <1.25 X ULN Lipase <1.1 X ULN Alkaline Phosphatase <1.25 X ULN

Exclusion Criteria:

1. Known allergy or sensitivity to the components of the investigational immunotherapy or the components of VOR or its analogs or DMSO.
2. HIV-2 antibody positive in the absence of a positive HIV-1 Western Blot as measured at the Screening Visit (Visit 1).

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. Received any infusion blood product, immune globulin, or hematopoetic growth factors within 90 days prior to study entry.
5. All women unless there is written documentation of menopause (absence of a period for ≥ one year and FSH level indicating menopause), hysterectomy, oophorectomy, or tubal ligation.
6. All male participants expecting to father children within the projected duration of the study.
7. Use of any of the following within 90 days prior to screening: immunomodulatory, cytokine, or growth stimulating factors such as systemic cytotoxic chemotherapy, systemic corticosteroids, immune globulin, interferon, cyclosporine, methotrexate, azathioprine, anti-CD25 antibody, IFN, interleukins, interleukin-2 (IL-2), hydroxyurea, thalidomide, sargramostim (granulocyte macrophage-colony stimulating factor [GM-CSF]), growth factors, dinitrochlorobenzene (DNCB), thymosin alpha, thymopentin, inosiplex, polyribonucleotide, or ditiocarb sodium, coumadin, warfarin, or other Coumadin derivative anticoagulants.
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, procainimide, quinidine, sotalol, sparfloxacin, terfenadine, thioridazine.
9. 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.
10. Use of any investigational antiretroviral agents within 30 days prior to Screening (Visit 1).
11. Use of antiretroviral medications that cannot be co-administered with Vorinostat within the 4 weeks of the first dose and anytime thereafter while on the study.
12. If the HIV care provider or study investigator is unable, as assessed by the study PI or protocol team, to construct a fully active alternative ART regimen based on previous resistance testing and/or treatment history.

13. Use of systemic corticosteroids or use of topical steroids over a total area exceeding 15 cm2 within 30 days prior to Screening, or anticipated need for periodic use of corticosteroids during the study.

    NOTE: For participants receiving ritonavir (as a booster or protease inhibitor (PI) as part of their ART regimen, the concomitant use of oral/systemic/topical/inhaled/intranasal corticosteroids is prohibited.

14. Any serious illness requiring systemic treatment or hospitalization, the participant 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.
15. Known history of a bone marrow disorder
16. Treatment for an active AIDS-defining opportunistic infection within 90 days prior to Screening.
17. Any active malignancy that may require chemotherapy or radiation therapy.
18. History of lymph node irradiation or dissection.
19. Evidence of hepatic decompensation in cirrhotic participants: history of ascites, hepatic encephalopathy, or bleeding esophageal varices.
20. 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.
21. Any history of acute or chronic pancreatitis.
22. Any renal disorder deemed clinically significant by the investigator.

23. Active autoimmune disease or condition including, but not limited to:

    Rheumatoid arthritis (RF positive arthritis with current or recent flare); Inflammatory bowel disease/ulcerative colitis/Crohn's Disease; Systemic lupus erythematosis (clinical evidence confirmed with ANA >1:80); Ankylosing spondylitis; Hashimoto's disease; Scleroderma; Multiple sclerosis; Autoimmune hemolytic anemia (AHA); Thyroiditis Immune thrombocytopenic purpura; and, Type I diabetes mellitus (insulin therapy for Type II diabetes is permitted).

24. 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 (or designee) Note: A history of non-melanoma skin cancer (e.g., basal cell carcinoma or squamous cell skin cancer) is not exclusionary with documentation of complete resection.
25. History of neoplastic disease with extensive involvement of the bone marrow or lymphatic system or participants severely compromised hematopoietic function.
26. Inability to communicate with study personnel.
27. Compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric illness or a physical illness, e.g., infectious disease.
28. Prisoner recruitment and participation is not permitted.
29. 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).
30. 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 (Visit 1).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Vorinostat + AGS-004; Vorinostat (VOR) 400 mg PO - two paired doses at Step 2 (Enrollment) - Only participants demonstrating an in vivo response to the 2nd of the paired VOR doses will proceed to the AGS-004 manufacturing and treatment in Steps 3 through 7. Step 4 - AGS-004 vaccination. AGS-004 product will be delivered in three intradermal (ID) injections of 0.2 mL (0.6 mL total volume) for a total of 1.2 x 10-7 viable cells. AGS-004 will be administered every 3 weeks for 4 doses.

Drug: Vorinostat; At Step 2 (Enrollment) - subjects receive two paired oral doses of Vorinostat (VOR) 400 mg. Step 5 - Approximately 7- 10 days after the 4th dose of AGS-004 in Step 4 (Visit 11), ten (10) doses of VOR 400 mg will be administered at 72 hour intervals. Steps 6 - 7 & EOS visit - Repeat cycles of AGS-004 and VOR. Participants will undergo a second series of 4 AGS-004 vaccinations (Step 6) followed by 10 doses of VOR 400 mg PO (Step 7).; Other Names: Zolinza; Biological: AGS-004; Step 4 - AGS-004 vaccination. AGS-004 product will be delivered in three intradermal injections of 0.2 mL (0.6 mL total volume) for a total of 1.2 x 10-7 viable cells. AGS-004 will be administered every 3 weeks for 4 doses. Steps 6 - 7 & EOS visit - Repeat cycles of AGS-004 and VOR. Participants will undergo a second series of 4 AGS-004 vaccinations (Step 6) followed by 10 doses of VOR 400 mg PO (Step 7).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the frequency of HIV infection per million resting CD4+T cells (RCI) from baseline to post-VOR/AGS.	Change in the frequency of HIV infection per million resting CD4+T cells (RCI) from baseline to post-VOR/AGS.	First day of study treatment to between approximately week 43 and week 72 on study
Occurrence of 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 AGS-004 any time from the first day of study treatment through the end of study.	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.	First day of study treatment to between approximately week 73 and week 96 on study

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: David M Margolis, MD, FACP, University of North Carolina, Chapel Hill; Principal Investigator: Cynthia L Gay, MD, MPH, University of North Carolina, Chapel Hill

Publications and helpful links

General Publications

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• Coull JJ, Romerio F, Sun JM, Volker JL, Galvin KM, Davie JR, Shi Y, Hansen U, Margolis DM. The human factors YY1 and LSF repress the human immunodeficiency virus type 1 long terminal repeat via recruitment of histone deacetylase 1. J Virol. 2000 Aug;74(15):6790-9. doi: 10.1128/jvi.74.15.6790-6799.2000.
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Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2016
• Primary Completion (Actual): July 11, 2018
• Study Completion (Actual): July 11, 2018

Study Registration Dates

• First Submitted: March 3, 2016
• First Submitted That Met QC Criteria: March 8, 2016
• First Posted (Estimate): March 14, 2016

Study Record Updates

• Last Update Posted (Actual): October 7, 2019
• Last Update Submitted That Met QC Criteria: October 2, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Vorinostat; AIDS; AGS-004; HIV virus
• Additional Relevant MeSH Terms: Pathologic Processes; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Disease Attributes; HIV Infections; Infections; Communicable Diseases; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Histone Deacetylase Inhibitors; Vorinostat
• Other Study ID Numbers: 15-1626; U01AI117844-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No