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

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.

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, polyribonucleoside, or diticarb 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, diopyramide, dofetilide, domperidone, droperidol, erythromycin,
halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone,
pentamidine, pimozidine, probucol, procanimide, quinidine, sotalol, sparfloxacxin,
terfenadine, thioridizine.

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).