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

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).

Eligibility Criteria:
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.