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

Phase 2CompletedNCT01933594

National Institute of Allergy and Infectious Diseases (NIAID)59 enrolled

Overview

Antiretroviral therapy (ART) can reduce HIV to very low levels in the blood, but it cannot cure HIV infection because a small amount of virus remains in cells as a hidden (latent) form. The purpose of this study was to evaluate the safety and efficacy of single dose and multiple dose administration of romidepsin (RMD) in HIV-infected adults.

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 was to evaluate the safety and efficacy of single dose and multiple dose administration of RMD in HIV-infected adults. Participants were sequentially enrolled into four cohorts and randomly assigned to receive either RMD or placebo. The cohorts differed in the dose of RMD given. Participants in Cohorts 1, 2, and 3 had one intravenous (IV) infusion of RMD or placebo at Day 0. Participants in Cohort 4 had four IV infusions of RMD or placebo at Days 0, 14, 28, and 42. For participants in Cohorts 1, 2, and 3, study duration was 4 weeks. For participants in Cohort 4, study duration was a minimum of 24 weeks and a maximum of 48 weeks. Participants attended several study visits, which could include a physical examination, blood and urine collection, pharmacokinetic (PK) sampling, and an electrocardiogram (ECG).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

HIV Infections

Interventions

RomidepsinDRUG

RMD administered over 4 hours via an intravenous (IV) catheter.

Placebo for RomidepsinDRUG

Placebo for RMD administered over 4 hours via an IV catheter.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (10)

Alabama CRS

Birmingham, Alabama, United States

UCLA CARE Center CRS

Los Angeles, California, United States

University of Colorado Hospital CRS

Aurora, Colorado, United States

Outcomes

Primary Outcomes

Proportion of Participants With Grade 3 or Higher Adverse Events (AEs) in Cohorts 1-3 Romidepsin Arms

Proportion of participants with Grade 3 or higher adverse events (AEs) in Cohorts 1-3 Romidepsin Arms, including signs/symptoms, lab toxicities, and /or clinical events probably, possibly, or definitely related to study treatment (as judged by the core team, blinded to treatment arm). The DAIDS AE Grading Table (Version 1.0) was used.

Time frame: Measured from the time of Romidepsin administration (at entry) until 28 days after the administration

Proportion of Participants With Grade 3 or Higher Adverse Events (AEs) in Cohort 4 Romidepsin Arm

Proportion of participants with Grade 3 or Higher Adverse Events (AEs) in Cohort 4 Romidepsin Arm, including signs/symptoms, lab toxicities, and /or clinical events probably, possibly, or definitely related to study treatment (as judged by the core team, blinded to treatment arm). The DAIDS AE Grading Table (Version 1.0) was used.

Time frame: Measured from the time of the first Romidepsin administration through 28 days after the last administration (at day 42)

Change From Baseline in Plasma HIV-1 RNA Levels as Detected by Single Copy Assay in Cohorts 1-3

Baseline is defined as the average of the pre-entry and entry values. Hour 24/48 is defined as the average of values at 24 and 48 hours after the single administration of Romidepsin or placebo (at study entry). Change was calculated as the value at hour 24/48 minus the value at baseline.

Time frame: Pre-entry, entry, 24 and 48 hours after the single administration of Romidepsin or placebo (at entry)

Change From Baseline in Plasma HIV-1 RNA Levels as Detected by Single Copy Assay in Cohort 4

Baseline is defined as the average of the pre-entry and entry values. Change was calculated as the value at 24 hours after each administration of Romidepsin or placebo (at entry, and days 14, 28 and 42) minus the value at baseline.

Time frame: Pre-entry, entry, 24 hours after each administration of Romidepsin or placebo (at entry, and days 14, 28 and 42)

Data from ClinicalTrials.gov

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Secondary Outcomes

Change From Baseline in Plasma HIV-1 RNA Levels as Detected by Single Copy Assay in Cohorts 1-3

Baseline is defined as the average of the pre-entry and entry values. Change was calculated as the value at 6 hours, 12 hours, 7 days, 14 days and 28 days after administration of Romidepsin or placebo (at entry) minus the value at baseline.

Time frame: Pre-entry, entry, 6 hours, 12 hours, 7 days, 14 days and 28 days after the single administration of Romidepsin or placebo (at entry)

Change From Baseline in Plasma HIV-1 RNA Levels as Detected by Single Copy Assay in Cohort 4

Baseline is defined as the average of the pre-entry and entry values. Change was calculated as the value at 72 hours after the second administration of Romidepsin or placebo (at day 14) minus the value at baseline.

Time frame: Pre-entry, entry and 72 hours after the second administration of Romidepsin or placebo (at day 14)

Change From Baseline in Cell-associated HIV-1 RNA Levels in Resting CD4 T Cells in Cohorts 1-3

Baseline is defined as the pre-entry value. Change was calculated as the value at 14 days after administration of Romidepsin or placebo (at entry) minus the value at baseline.

Time frame: Pre-entry and 14 days after the administration of RMD or placebo (at entry)

Change From Baseline in Cell-associated HIV-1 RNA Levels in PBMCs in Cohort 4

Baseline is defined as the pre-entry value. Change was calculated as the value at 72 hours after the second administration of Romidepsin or placebo (at day 14) minus the value at baseline.

Time frame: Pre-entry and 72 hours after the second administration of Romidepsin or placebo (at day 14)

Change From Baseline in Histone Acetylation (Median FITC Ac-Histone) in CD3+ Cells in Cohorts 1-3

Baseline is defined as the value at Hour 0, right before the single administration of Romidepsin or placebo. Change was calculated as the value at 24 hours after administration of Romidepsin or placebo (at entry) minus the value at baseline. Median Fluorescent Intensity (MFI) data describes a shift in the expression of a fluorescently labeled marker on a population of cells. The reported MFI is an arbitrary value dependent on the voltage applied to the corresponding flow cytometer detector.

Time frame: Hour 0 and 24 hours after the single administration of RMD or placebo (at entry)

Change From Baseline in Histone Acetylation in (Median FITC Ac-histone) in CD3+ Cells in Cohort 4

Baseline is defined as the value right before the first administration of Romidepsin or placebo (at entry). Change was calculated as the value at 24 hours after each administration of Romidepsin or placebo (at entry, and days 14, 28 and 42) and 72 hours after the second administration minus the value at baseline. Median Fluorescent Intensity (MFI) data describes a shift in the expression of a fluorescently labeled marker on a population of cells. The reported MFI is an arbitrary value dependent on the voltage applied to the corresponding flow cytometer detector.

Time frame: Entry, 24 hours after each administration of Romidepsin or placebo (at entry, and days 14, 28 and 42), and 72 hours after the second administration (at day 14)

Change From Baseline in Total HIV-1 DNA in Resting or Total CD4 T Cells in Cohorts 1-3

Baseline is defined as the pre-entry value. Change was calculated as the value at 24 hours and 14 days after administration of Romidepsin or placebo (at entry) minus the value at baseline.

Time frame: Pre-entry, 24 hours and 14 days after the single administration of Romidepsin or placebo (at entry)

Change From Baseline in Total HIV-1 DNA in PBMCs in Cohort 4

Time frame: Pre-entry, 24 hours after each administration of Romidepsin or placebo (at entry, and days 14, 28 and 42) and 72 hours after the second administration (at day 14)

PK Parameters for Romidepsin and Co-administered Antiretroviral Drugs (Efavirenz, Dolutegravir, or Raltegravir) in Cohorts 1-3

Hour 0 is right before the single administration of Romidepsin or placebo (at entry). Hour 4 is at the completion of Romidepsin or placebo administration. Hours 6, 12 and 24 are 2, 8 and 20 hours after the completion of Romidepsin or placebo administration. PK concentration (ng/mL) for Romidepsin at hours 0, 4, 6, 12 and 24. PK concentration (ng/mL) for co-administered antiretroviral drugs (Efavirenz \[EFV\], Dolutegravir \[DTG\], or Raltegravir \[RAL\]) at hours 0 and 24.

Time frame: At hours 0, 4, 6, 12 and 24

PK Parameters for Romidepsin and Co-administered Antiretroviral Drugs (Dolutegravir or Raltegravi) in Cohort 4

PK concentration (ng/mL) for Romidepsin pre and post the third and fourth administrations of Romidepsin or placebo. PK concentration (ng/mL) for co-administered antiretroviral drugs (Dolutegravir \[DTG\], or Raltegravir \[RAL\]) 24 hours after the third and fourth administrations of Romidepsin or placebo.

Time frame: Pre, post and 24 hours after the third and fourth administrations of Romidepsin or placebo (at days 28 and 42)

HIV-1 RNA Levels in Cohorts 1-3

HIV-1 RNA levels at 7 days after the single administration of Romidepsin or placebo (at entry)

Time frame: 7 days after the administration of Romidepsin or placebo (at entry)

HIV-1 RNA Levels in Cohort 4

HIV-1 RNA levels at 7 days after each administration of Romidepsin or placebo (at entry, and days 14, 28 and 42)

Time frame: 7 days after each administration of Romidepsin or placebo (at entry, and days 14, 28 and 42)

Number of Participants With Reported Grade 2-4 AEs in Cohorts 1-3

Number of participants with reported grade 2-4 adverse events including signs/symptoms, lab toxicities, and clinical events that are at least possibly related to study treatment. The DAIDS AE Grading Table (Version 1.0) was used.

Time frame: Measured from study entry to off study

Number of Participants With Reported Grade 2-4 AEs in Cohort 4

Time frame: Measured from study entry to off study

Change From Baseline in CD4+ and CD8+ T Cell Percent in Cohorts 1-3

Change in CD4+ and CD8+T cell percent from baseline to after the single administration of Romidepsin or placebo

Time frame: Measured through participant's last study visit

Change From Baseline in CD4+ T Cell Percent in Cohort 4

Baseline is defined as the average of the pre-entry and entry values. Change was calculated as the value at 24 hours post each administration of Romidepsin or placebo (at entry, and days 14, 28 and 42) and 2, 5, 10 and 18 weeks post the fourth administration minus the value at baseline

Time frame: Pre-entry, entry, 24 hours after each administration of Romidepsin or placebo (at entry, and days 14, 28 and 42), and 2, 5, 10 and 18 weeks after the fourth administration (at day 42)

Change From Baseline in CD8+ T Cell Percent in Cohort 4

Change in CD8+ T cell percent from baseline to after each administration of Romidepsin or placebo (at entry, and days 14, 28 and 42)

Time frame: Measured through 28 days after the single administration of RMD or placebo (at entry, and days 14, 28 and 42)

Change From Baseline in Cellular Markers of Immune Activation (CD38/HLA-DR Expression on CD4+ T-cells) in Cohorts 1-3

Baseline is defined as the value at hour 0, where hour 0 is right before the single administration of Romidepsin or placebo (at entry). Change was calculated as the value at 48 hours, 7 days and 28 days after the single administration of Romidepsin or placebo minus the value at baseline.

Time frame: Hour 0 and 48 hours, 7 days and 28 days after the single administration of Romidepsin or placebo (at entry)

Change From Baseline in Cellular Markers of Immune Activation (CD38/HLA-DR Expression on CD8+ T-cells) in Cohorts 1-3

Time frame: Hour 0 and 48 hours, 7 days and 28 days after the single administration of Romidepsin or placebo (at entry)

Change From Baseline in Cellular Markers of Immune Activation (CD69/CD25 Expression on CD4+ T-cells) in Cohorts 1-3

Time frame: Hour 0 and 48 hours, 7 days and 28 days after the single administration of Romidepsin or placebo (at entry)

Change From Baseline in Cellular Markers of Immune Activation (CD69/CD25 Expression on CD8+ T-cells) in Cohorts 1-3

Time frame: Hour 0 and 48 hours, 7 days and 28 days after the single administration of Romidepsin or placebo (at entry)

Change From Baseline in Cellular Markers of Immune Activation (CD38/HLA-DR Expression on CD4+ T-cells) in Cohort 4

Baseline is defined as the average of the two pre-entry values. Change was calculated as the value at 24 hours post first and fourth administration of Romidepsin or placebo (at entry and day 42) and 10 weeks post the fourth administration (at day 42) minus the value at baseline.

Time frame: Pre-entry, 24 hours after the first and fourth administration of Romidepsin or placebo (at entry and day 42), and 10 weeks after the fourth administration (at day 42)

Change From Baseline in Cellular Markers of Immune Activation (CD38/HLA-DR Expression on CD8+ T-cells) in Cohort 4

Time frame: Pre-entry, 24 hours after the first and fourth administration of Romidepsin or placebo (at entry and day 42), and 10 weeks after the fourth administration (at day 42)

Change From Baseline in Cellular Markers of Immune Activation (CD69/CD25 Expression on CD4+ T-cells) in Cohort 4

Baseline is defined as the average of the two pre-entry values. Change was calculated as the value at 24 hours post first and fourth administration of Romidepsin or placebo (at etnry and day 42) and 10 weeks post the fourth administration (at day 42) minus the value at baseline.

Time frame: Pre-entry, 24 hours after the first and fourth administration of Romidepsin or placebo (at etnry and day 42), and 10 weeks after the fourth administration (at day 42)

Change From Baseline in Cellular Markers of Immune Activation (CD69/CD25 Expression on CD8+ T-cells) in Cohort 4

Time frame: Pre-entry, 24 hours after the first and fourth administration of Romidepsin or placebo (at etnry and day 42), and 10 weeks after the fourth administration (at day 42

Change From Baseline in Percentage of CD4+ T-cells Expressing Annexin V and/or 7 Amino-actinomycin D (7-AAD) in Cohorts 1-3

Time frame: Hour 0 and 48 hours, 7 days and 28 days after the single administration of Romidepsin or placebo (at entry)

Change From Baseline in Percentage of CD8+ T-cells Expressing Annexin V and/or 7 Amino-actinomycin D (7-AAD) in Cohorts 1-3

Time frame: Hour 0 and 48 hours, 7 days and 28 days after the single administration of Romidepsin or placebo (at entry)

Change From Baseline in Percentage of CD4+ T-cells Expressing Annexin V and/or 7 Amino-actinomycin D (7-AAD) in Cohort 4

Time frame: Pre-entry, 24 hours after the first and fourth administration of Romidepsin or placebo (at entry and day 42), and 10 weeks after the fourth administration (at day 42)

Change From Baseline in Percentage of CD8+ T-cells Expressing Annexin V and/or 7 Amino-actinomycin D (7-AAD) in Cohort 4

Time frame: Pre-entry, 24 hours after the first and fourth administration of Romidepsin or placebo (at entry and day 42), and 10 weeks after the fourth administration (at day 42)

Change From Baseline in PTEF-b Phosphorylation (pNFKB+% and pS175%) in CD4+ T-cells in Cohorts 1-3

Baseline is defined as the value at hour 0, where hour 0 is right before the single administration of Romidepsin or placebo (at entry). Change was calculated as the value at 24 hours after the single administration of Romidepsin or placebo (at entry) minus the value at baseline.

Time frame: Hour 0 and 24 hours after the single administration of Romidepsin or placebo (at entry)

Change From Baseline in PTEF-b Phosphorylation (pNFKB+% and pS175%) in CD8+ T-cells in Cohorts 1-3

Time frame: Hour 0 and 24 hours after the single administration of Romidepsin or placebo (at entry)

Change From Baseline in PTEF-b Phosphorylation (pNFKB+%) in CD4+ T-cells in Cohort 4

Time frame: Pre-entry, entry, 24 hours after each administration of Romidepsin or placebo (at entry, and days 14, 28 and 42) and 72 hours after the second administration (at day 14)

Change From Baseline in PTEF-b Phosphorylation (pS175+%) in CD4+ T-cells in Cohort 4

Time frame: Pre-entry, entry, 24 hours after each administration of Romidepsin or placebo (at entry, and days 14, 28 and 42) and 72 hours after the second administration (at day 14)