Selective Estrogen Receptor Modulators to Enhance the Efficacy of Viral Reactivation With Histone Deacetylase Inhibitors

The selective estrogen receptor modulator (SERM) tamoxifen may enhance the ability of the
histone deacetylase inhibitor (HDACi) vorinostat to reverse HIV-1 latency. This study will
evaluate the safety of tamoxifen therapy combined with vorinostat and the effectiveness of
this combination on latent virus reactivation in HIV-1 infected post-menopausal women with
virologic suppression on antiretroviral therapy (ART), when compared to vorinostat alone.

The study will be conducted in two steps. During Step 1, the study will enroll women with HIV
into two groups. Arm A will receive tamoxifen daily for 38 days, plus a single dose of
vorinostat on Days 35 and 38. Arm B will have a 38-day observation period with no tamoxifen,
plus a single dose of vorinostat on Days 35 and 38. All participants will continue to take
the antiretroviral (ARV) drugs prescribed by their doctors. ARV drugs will not be provided by
the study.

Study visits during Step 1 will occur at Days 0, 28, 35, 38, 45, and 65. Study visits may
include physical examinations, blood collection, electrocardiograms, and adherence
assessments.

During Step 2, all participants will be followed for 240 additional weeks for annual
long-term safety follow-up. These visits will be conducted by phone and will collect
information from participants on vital status and any new cancer diagnoses.

Step 1 Inclusion Criteria:

- HIV-1 infection, documented 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 Food and Drug Administration (FDA)-approved
kit. World Health Organization (WHO) and Centers for Disease Control and Prevention
(CDC) 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.

- Women between 18 and 65 years of age up until the 66th birthday at the time of study
entry.

- Women who are postmenopausal at the time of study entry and have agreed not to
participate in assisted reproductive technology in the future. Menopausal status will
be verified by any one of the following:

- Age greater than or equal to 40 years, amenorrhea greater than or equal to 12
months, and FSH greater than 40 mIU/mL with a negative serum or urine beta-HCG
(urine test must have a sensitivity of less than or equal to 25 mIU/mL) and no
oral or injectable exogenous hormone use within 12 months prior to study entry.

- Any woman greater than or equal to 18 years of age is eligible for consideration
if there is a documented history of surgical removal of both of the ovaries
greater than 6 months prior to study entry and no injectable or oral exogenous
hormone therapy for a period of greater than or equal to 12 months prior to study
entry.

- CD4+ cell count greater than 300 cells/uL obtained within 90 days prior to study entry
at any US laboratory that has Clinical Laboratory Improvement Amendments (CLIA)
certification or its equivalent.

- Continuous antiretroviral therapy (ART) containing nucleoside or nucleotide reverse
transcriptase inhibitors with a non-nucleoside reverse transcriptase inhibitor, a
pharmacologically-boosted protease inhibitor, or an integrase inhibitor for at least 2
years prior to enrollment with no known interruption in therapy for greater than 7
days within 90 days prior to study entry.

- NOTE: Other ART regimens may be acceptable. Sites must consult the core protocol
team for a case-by-case basis review of ART regimens not specified above.

- NOTE: Regimens composed of three nucleoside reverse transcriptase inhibitors are
not acceptable.

- NOTE: Regimen changes within the 2-year period are acceptable, but candidates
must have been on a stable regimen for at least 30 days prior to study entry.

- Site investigator anticipates that a fully active alternative ART regimen could be
constructed in the event of virologic failure on the current ART regimen.

- At least one documented plasma HIV-1 RNA that is below the limit of detection of the
FDA-approved assays (limit of detection: 75, 50, 40, or 20 copies/mL) between 13 and
24 months prior to the screening HIV-1 RNA in the protocol.

- Plasma HIV-1 RNA level of less than 20 copies/mL obtained by Roche HIV-1 viral load
assay or less than 40 copies/mL obtained by the Abbott assay, within 90 days prior to
study entry by any US laboratory that has CLIA certification or its equivalent.

- The following laboratory values obtained within 21 days prior to study entry by any US
laboratory that has CLIA certification or its equivalent.

- Absolute neutrophil count (ANC) greater than or equal to 1500 neutrophils/mm^3

- Hemoglobin greater than or equal to 11.0 g/dL

- Platelet count greater than or equal to 125,000 platelets/uL

- Creatinine less than or equal to 1.3 x upper limit of normal (ULN) OR, if serum
creatinine levels greater than 1.3 x ULN, calculated creatinine clearance (as
estimated by the Cockcroft-Gault equation) greater than or equal to 50mL/min.
NOTE: A calculator for the Cockcroft-Gault equation is available on the Data
Management Center (DMC) website at www.fstrf.org.

- Aspartate aminotransferase (AST) (SGOT) less than or equal to 1.5 x ULN

- Alanine aminotransferase (ALT) (SGPT) less than or equal to 1.5 x ULN

- Alkaline phosphatase less than or equal to 2.5 x ULN

- Total bilirubin less than 1.5 x ULN, OR if the total bilirubin is elevated,
direct bilirubin will be measured and the potential participant is eligible if
the direct bilirubin is less than 2 x ULN. NOTE: For participants on
atazanavir-based ART, if total bilirubin is greater than 1.5 x ULN and there is
no transaminase elevation, enrollment is acceptable if the indirect bilirubin
(calculated value of total bilirubin minus direct bilirubin) is less than 3 x
ULN.

- No history of opportunistic infections within 90 days prior to study entry.

- Karnofsky performance score greater than or equal to 70 within 90 days prior to study
entry.

- Weight greater than or equal to 52.2 kg at time of screening. (This stipulation is
because of the blood draw volumes involved with this trial.)

- Body Mass Index (BMI) less than or equal to 40 kg/m^2 at time of screening. NOTE: A
program for calculating BMI is available on the DMC website at www.fstrf.org.

- HCV antibody negative result within 90 days prior to study entry or, for study
candidates who are HCV antibody positive (based on testing performed at any time prior
to study entry), a negative HCV RNA result obtained within 90 days prior to study
entry.

- Negative HBsAg result obtained within 90 days prior to study entry or a positive HBsAb
result at any time prior to study entry.

- QTc interval less than or equal to 450 milliseconds within 90 days prior to study
entry. NOTE: A program for calculating QTc by Fridericia's correction is available on
the DMC website at www.fstrf.org.

- Ability and willingness of potential participant to provide written informed consent.

Step 1 Exclusion Criteria:

- History of venous thromboembolism.

- History of stroke.

- Known history of hypercoagulable state including Factor V Leiden mutation, Protein C
and S deficiency, or decompensated cirrhosis.

- Tobacco smoking or e-cigarette use within 90 days prior to study entry. NOTE: If
recent cessation of smoking, must have been without cigarettes and e-cigarettes for
greater than or equal to 90 days prior to study entry.

- History of any malignancy requiring systemic chemotherapy or systemic immunotherapy.

- History of endometrial or breast cancer or known genetic testing with BRCA positive
results indicating an increased risk for breast and ovarian cancer. NOTE: If
additional genetic testing for breast or ovarian cancer exists, study sites should
contact the core protocol team for review.

- History of cardiac arrhythmia requiring surgical or ablative therapy.

- History of myocardial infarction (MI) within 6 months prior to study entry, New York
Heart Association (NYHA) class III or IV heart failure at any time prior to study
entry, or personal or family history of prolonged QTc syndrome.

- Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV vaccine,
or investigational therapy within 60 days prior to study entry. NOTE: Study candidates
receiving stable physiologic glucocorticoid doses, defined as the equivalent of
prednisone 10 mg/day or less, will not be excluded. Study candidates receiving inhaled
or topical corticosteroids will not be excluded.

- Any systemic hormonal therapy defined as oral or injectable contraceptives, estrogen
and combined estrogen-progesterone replacement therapy in the prior 12 months, or a
hormone containing intrauterine device (IUD) within 6 months prior to study entry.
NOTE: Hormonal therapy also includes aromatase inhibitors and suppressors of ovarian
function including gonadotropin releasing hormone (GnRH) agonists and
luteinizing-hormone releasing hormone (LH-RH) agonists. Topical estrogen cream use in
the prior 12 months is acceptable, but should not be used during the study period.

- Use of any study-prohibited medications that carry the risk of torsades de pointes
within 60 days prior to study entry. NOTE: A list of prohibited medications is
available on the protocol-specific web page (PSWP).

- Use of any study-prohibited medication in the HDACi class or use of any
study-prohibited medication with HDACi-like activity within 60 days prior to study
entry. NOTE: A list of prohibited medications is available on the PSWP.

- Known allergy/sensitivity or any hypersensitivity to components of study drugs or
their formulations.

- Active drug or alcohol use or dependence or psychiatric illness that, in the opinion
of the site investigator, would interfere with adherence to study requirements.

- Acute or serious illness requiring systemic treatment, antibiotics, and/or
hospitalization within 90 days prior to study entry.

Step 2 Inclusion Criteria:

- Received at least one dose of tamoxifen or at least one dose of vorinostat.

Step 2 Exclusion Criteria:

- There are no exclusion criteria for Step 2.