Evaluating the Safety and Efficacy of Romidepsin in Combination With Antiretroviral Therapy in HIV-Infected Adults With Suppressed Viral Load

A major challenge in eradicating HIV-1 infection is the persistence of virus in long-lived
cells, such as latently infected memory CD4 T cells. One approach for eliminating the HIV-1
reservoir is to activate viral replication in these latently infected CD4 T cells by
targeting cellular mechanisms that repress proviral transcription. Histone deacetylase
inhibitors (HDACis), such as RMD, induce HIV-1 expression by increasing acetylation and
facilitating transcriptional activation of HIV-1. RMD administered in combination with ART
may serve as an important component of a strategy to eradicate the HIV-1 latent reservoir.
The purpose of this study is to evaluate the safety and efficacy of single dose and multiple
dose administration of RMD in HIV-infected adults.

Participants will be sequentially enrolled into four cohorts and randomly assigned to receive
either RMD or placebo. The cohorts will differ in the dose of RMD given. Participants in
Cohorts 1, 2, and 3 will have one intravenous (IV) infusion of RMD or placebo at Day 0.
Participants in Cohort 4 will have four IV infusions of RMD or placebo at Days 0, 14, 28, and
42.

For participants in Cohorts 1, 2, and 3, study duration is 4 weeks. For participants in
Cohort 4, study duration is a minimum of 24 weeks and a maximum of 48 weeks.

Participants will attend several study visits, which may include a physical examination,
blood and urine collection, pharmacokinetic (PK) sampling, and an electrocardiogram (ECG).

Inclusion Criteria: Cohorts 1, 2, & 3

- HIV-1 infection, documented by any licensed rapid HIV test or HIV E/CIA test kit at
any time prior to study entry & confirmed by a licensed Western blot or a 2nd antibody
test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen or
plasma HIV-1 RNA

- Receiving 2 (or more) nucleoside or nucleotide reverse transcriptase inhibitors with
raltegravir, dolutegravir, or efavirenz for at least 90 days prior to study entry with
no intention to change for the duration of the study

- Documentation of at least 2 historical HIV-1 RNA measurements <50 copies/mL while on
ART obtained by standard ultrasensitive assay. Documentation of the 1st measurement
must be from a result obtained between 365-91 days, inclusive, prior to study entry.
Documentation of the 2nd measurement must be from a result obtained between 730-366
days, inclusive, prior to study entry. In addition, there must be no HIV-1 RNA values
≥50 copies/mL for at least 365 days prior to study entry.

- CD4 cell count ≥300 cells/mm^3 obtained within 90-50 days prior to study entry at any
US laboratory that has a CLIA certification or equivalent

- HIV-1 RNA level of <50 copies/mL obtained by standard ultrasensitive assay within
90-50 days prior to study entry

- HIV-1 RNA level of ≥0.4 copies/mL obtained by SCA within 90-50 days prior to study
entry. This result must be available prior to the pre-entry visit

- The following laboratory values obtained within 21-0 days prior to study entry by any
laboratory that has a CLIA certification or equivalent

- ANC ≥1500 cells/mm^3

- Hemoglobin ≥12.0 g/dL for men & >11.0 g/dL for women

- Platelet count ≥120,000/mm^3

- The following laboratory values obtained within 21-7 days prior to study entry by any
laboratory that has a CLIA certification or equivalent

- CrCl ≥60 mL/min

- Potassium & magnesium within normal limits

- AST (SGOT) <2.0 x ULN

- ALT (SGPT) <2.0 x ULN

- Alkaline phosphatase <2.0 x ULN

- Total bilirubin <2.5 x ULN

- HCV antibody negative result within 90-50 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 90-50 days prior to study
entry

- Negative HBsAg result obtained within 90-50 days prior to study entry or a positive
HBsAb result at any time prior to study entry

- For females of reproductive potential, negative serum or urine pregnancy test (latter
with sensitivity of ≤25 mIU/mL) at the screening visit, pre-entry visit within 21-7
days prior to study entry, & at entry prior to romidepsin infusion, by any US
laboratory that has a CLIA certification or equivalent

- Female candidates of reproductive potential must refrain from participating in active
attempts to become pregnant, &, if participating in sexual activity that could lead to
pregnancy, must agree to use at least 2 reliable forms of contraception that are
non-estrogen based. All female participants of reproductive potential must be
instructed to use contraceptives for 6 months/180 days after completing RMD or placebo
infusion

- Karnofsky performance score ≥80 within 21-7 days prior to study entry

- Men and women age ≥ 18 years

- Ability & willingness to provide written informed consent

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

Exclusion Criteria: Cohorts 1, 2, & 3

- History of or current malignancy requiring cytotoxic therapy

- Bacterial, fungal, or viral infection (other than HIV) requiring systemic therapy
within 30 days prior to entry

- History of or current CMV end organ disease (eg, retinitis)

- History of or current AIDS-related syndromes or symptoms that pose a perceived
excessive risk for study drug-related morbidity, as determined by the investigator

- Chronic, acute, or recurrent infections that are current & serious in the opinion of
the investigator & for which the participant has not completed at least 14 consecutive
days of therapy within 30 days prior to study entry and/or is not clinically stable

- Active autoimmune disorders including but not limited to: inflammatory bowel diseases,
scleroderma, severe psoriasis as determined by the investigator, systemic lupus
erythematosus, rheumatoid arthritis & optic neuritis

- History of seizure disorders

- History of anticonvulsant use within 60 days prior to study entry

- History of MI within 6 months prior to study entry, history of QTc prolongation
(defined as ECG with QTc intervals >450 ms) at any time prior to study entry, NYHA
class III or IV heart failure at any time prior to study entry, or family history of
prolonged QTc syndrome

- Breastfeeding

- Use of immunomodulators (eg, interleukins, interferons, cyclosporine), HIV vaccine,
systemic cytotoxic chemotherapy, or investigational therapy within 60 days prior to
study entry

- Any vaccination within 30 days prior to entry or intent to receive an elective
vaccination (eg, flu shot, hepatitis A or B vaccine) during the course of the study

- Intent to use cytokines (e.g., IL-2 or IL-12) during the course of the study. Prior
administration of cytokines is not an exclusion criterion; however, at least 60 days
between the most recent cycle of any cytokine and study entry is required

- Within 60 days prior to study entry, use of systemic azole antifungals (voriconazole,
itraconazole, ketoconazole); dexamethasone; macrolide antibiotics (azithromycin,
clarithromycin, erythromycin); ARVs that are inhibitors of, or are metabolized by,
CYP3A4 (atazanavir, ritonavir, nelfinavir, indinavir, saquinavir, darunavir,
lopinavir, rilpivirine, maraviroc); cobicistat; warfarin; nefazodone; rifamycins
(rifabutin, rifampin, rifapentine); St. John's Wort; carbamazepine; phenytoin;
phenobarbital; amiodarone; dofetilide; pimozide; procainamide; quinidine; sotalol; &
birth control products containing estrogen; drugs that are p-glycoprotein inhibitors;
& drugs that prolong the QTc interval with a risk of Torsades de Pointes

- Known allergy, sensitivity, or any hypersensitivity to components of RMD or its
formulation

- Use of histone deacetylase inhibitors (eg, vorinostat, valproic acid) at any time
prior to study entry

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

- Acute or serious illness requiring systemic treatment and/or hospitalization that is
not resolved within 30 days prior to entry

- Psychosocial conditions that would prevent study compliance and follow-up, as
determined by the investigator

- Documented opportunistic infections within 60 days prior to entry

Inclusion Criteria: Cohort 4, Step 1

- HIV-1 infection, documented by any licensed rapid HIV test or HIV E/CIA test kit at
any time prior to study entry & confirmed by a licensed Western blot or a 2nd antibody
test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen or
plasma HIV-1 RNA

- Receiving 2 or more nucleoside or nucleotide reverse transcriptase inhibitors with
raltegravir or dolutegravir for at least 90 days prior to study entry with no
intention to change for the duration of the study

- Documentation of at least 2 historical HIV-1 RNA measurements <50 copies/mL while on
ART obtained by standard ultrasensitive assay. Documentation of the first measurement
must be from a result obtained between 365-61 days, inclusive, prior to study entry.
Documentation of the second measurement must be from a result obtained between 730-366
days, inclusive, prior to study entry. In addition, there must be no HIV-1 RNA values
≥50 copies/mL for at least 365 days prior to study entry

- CD4 cell count ≥300 cells/mm^3 obtained between 36-60 days prior to study entry
(screening visit) at any US laboratory that has a CLIA certification or equivalent

- HIV-1 RNA level of <50 copies/mL obtained by standard ultrasensitive assay at
screening (between 36-60 days prior to study entry)

- The following laboratory values obtained at pre-entry (between 3-14 days prior to
study entry) by any laboratory that has a CLIA certification or equivalent

- ANC ≥1500 cells/mm^3

- Hemoglobin ≥12.0 g/dL for men & >11.0 g/dL for women

- Platelet count ≥120,000/mm^3

- CrCl ≥60 mL/min

- Potassium & magnesium within normal limits

- AST (SGOT) <2.0 x ULN

- ALT (SGPT) <2.0 x ULN

- Alkaline phosphatase <2.0 x ULN

- Total bilirubin <2.5 x ULN

- HCV antibody negative result at screening (between 36-60 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 at screening

- Negative HBsAg result obtained at screening (between 36-60 days prior to study entry)
or a positive HBsAb result at any time prior to study entry

- For females of reproductive potential, negative urine pregnancy test (with a
sensitivity of ≤25 mIU/mL) at screening (between 36-60 days prior to study entry), at
pre-entry (between 3-14 days prior to study entry), & at entry prior to infusion, by
any US laboratory that has a CLIA certification or equivalent

- Female candidates of reproductive potential must refrain from participating in active
attempts to become pregnant, &, if participating in sexual activity that could lead to
pregnancy, must agree to use at least 2 reliable forms of contraception that are
non-estrogen based. All participants of reproductive potential will be instructed to
use contraceptives for 6 months or 180 days after completing RMD/placebo infusion

- Karnofsky performance score ≥80 at pre-entry (between 3-14 days prior to study entry)

- Men and women age ≥ 18 years

- Ability & willingness to provide written informed consent

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

Exclusion Criteria: Cohort 4, Step 1

- History of or current malignancy requiring cytotoxic therapy

- Bacterial, fungal or viral infection (other than HIV) requiring systemic therapy
within 30 days prior to entry

- History of or current CMV end organ disease (eg, retinitis)

- History of or current AIDS-related syndromes or symptoms that pose a perceived
excessive risk for study drug-related morbidity, as determined by the investigator

- Chronic, acute, or recurrent infections that are current & serious, in the opinion of
the investigator, for which the participant has not completed at least 14 consecutive
days of therapy within 30 days prior to study entry and/or is not clinically stable

- Active autoimmune disorders including but not limited to inflammatory bowel diseases,
scleroderma, severe psoriasis as determined by the investigator, systemic lupus
erythematosus, rheumatoid arthritis, & optic neuritis

- History of seizure disorders

- History of anticonvulsant use within 60 days prior to study entry

- History of MI within 6 months prior to study entry, history of QTc prolongation
(defined as ECG with QTc intervals >450 ms) at any time prior to study entry, NYHA
class III or IV heart failure at any time prior to study entry, or family history of
prolonged QTc syndrome

- Breastfeeding

- Use of immunomodulators (eg, interleukins, interferons, cyclosporine), HIV vaccine,
systemic cytotoxic chemotherapy, or investigational therapy within 60 days prior to
study entry

- Any vaccination within 30 days prior to entry or intent to receive an elective
vaccination (eg, flu shot, hepatitis A or B vaccine) during the course of the study

- Intent to use cytokines (eg, IL-2 or IL-12) during the course of the study

- Within 60 days prior to study entry, use of systemic azole antifungals (voriconazole,
itraconazole, ketoconazole), dexamethasone, macrolide antibiotics (azithromycin,
clarithromycin, erythromycin), antiretrovirals that are inhibitors of, or are
metabolized by CYP3A4 (atazanavir, ritonavir, nelfinavir, indinavir, saquinavir,
darunavir, lopinavir, rilpivirine, maraviroc), cobicistat, warfarin, nefazodone,
rifamycins (rifabutin, rifampin, rifapentine), St. John's Wort, carbamazepine,
phenytoin, phenobarbital, amiodarone, dofetilide, pimozide, procainamide, quinidine,
sotalol, & birth control products containing estrogen, drugs that are p-glycoprotein
inhibitors, & drugs that prolong the QTc interval with a risk of Torsades de Pointes

- Known allergy/sensitivity or any hypersensitivity to components of RMD or its
formulation

- Use of histone deacetylase inhibitors (eg, vorinostat, valproic acid) at any time
prior to study entry

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

- Acute or serious illness requiring systemic treatment and/or hospitalization that is
not resolved within 30 days prior to entry

- Psychosocial conditions that would prevent study compliance & follow-up as determined
by the investigator

- Documented opportunistic infections within 60 days prior to entry

- Use of any of the medications listed in the Prohibited Medications table in the
protocol

See the protocol for Inclusion and Exclusion Criteria for Cohort 4, Steps 2, 3, and 4.