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

NCT01933594 | Completed Phase 1 Results DMC

• 3 other identifiers: A531511892ACTG 5315
• Study Type: interventional
• Target: 59
• Locations: 1 country
• Sites: 10

Brief Summary

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.

Conditions

HIV Infections

Outcome Measures

Primary Outcomes (6)

• 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.

  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.

  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.

  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.

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

• 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 24 hours after administration of Romidepsin or placebo (at entry) minus the value at baseline.

  Pre-entry and 24 hours after the single administration of Romidepsin or placebo (at entry)

• Change From Baseline in Cell-associated HIV-1 RNA Levels in PBMCs 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.

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

Secondary Outcomes (33)

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

  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

  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

  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

  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

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

Study Arms (8)

Cohort 1-Arm 1A (Romidepsin)

EXPERIMENTAL

Participants in Cohort 1, Arm 1A received Romidepsin intravenously (IV) over 4 hours (beginning at Hour 0) at the Day 0 study visit. Dose of Romidepsin was 0.5 mg/m\^2, with total dose based on the participant's body surface area (determined by participant's height and weight).

Drug: Romidepsin

Cohort 1-Arm 1B (Placebo for Romidepsin)

PLACEBO COMPARATOR

Participants in Cohort 1, Arm 1B received 0.9% sodium chloride for injection IV over 4 hours (beginning at Hour 0) at the Day 0 study visit. Dose of sodium chloride for injection placebo was 0.5 mg/m\^2, with total dose based on the participant's body surface area (determined by participant's height and weight).

Drug: Placebo for Romidepsin

Cohort 2-Arm 2A (Romidepsin)

EXPERIMENTAL

Participants in Cohort 2, Arm 2A received Romidepsin IV over 4 hours (beginning at Hour 0) at the Day 0 study visit. Dose of Romidepsin was 2 mg/m\^2, with total dose based on the participant's body surface area (determined by participant's height and weight).

Drug: Romidepsin

Cohort 2-Arm 2B (Placebo for Romidepsin)

PLACEBO COMPARATOR

Participants in Cohort 2, Arm 2B received 0.9% sodium chloride for injection IV over 4 hours (beginning at Hour 0) at the Day 0 study visit. Dose of sodium chloride for injection placebo was 2 mg/m\^2, with total dose based on the participant's body surface area (determined by participant's height and weight).

Drug: Placebo for Romidepsin

Cohort 3-Arm 3A (Romidepsin)

EXPERIMENTAL

Participants in Cohort 3, Arm 3A received Romidepsin IV over 4 hours (beginning at Hour 0) at the Day 0 study visit. Dose of Romidepsin was 5 mg/m\^2, with total dose based on the participant's body surface area (determined by participant's height and weight).

Drug: Romidepsin

Cohort 3-Arm 3B (Placebo for Romidepsin)

PLACEBO COMPARATOR

Participants in Cohort 3, Arm 3B received 0.9% sodium chloride for injection IV over 4 hours (beginning at Hour 0) at the Day 0 study visit. Dose of sodium chloride for injection placebo was 5 mg/m\^2, with total dose based on the participant's body surface area (determined by participant's height and weight).

Drug: Placebo for Romidepsin

Cohort 4-Arm 4A (Romidepsin)

EXPERIMENTAL

Participants in Cohort 4, Arm 4A received Romidepsin IV over 4 hours (beginning at Hour 0) at the Day 0, 14, 28, and 42 study visits. Dose of Romidepsin was 5 mg/m\^2, with total dose based on the participant's body surface area (determined by participant's height and weight).

Drug: Romidepsin

Cohort 4-Arm 4B (Placebo for Romidepsin)

PLACEBO COMPARATOR

Participants in Cohort 4, Arm 4B received 0.9% sodium chloride for injection IV over 4 hours (beginning at Hour 0) at the Day 0, 14, 28, and 42 study visits. Dose of sodium chloride for injection placebo was 5 mg/m\^2, with total dose based on the participant's body surface area (determined by participant's height and weight).

Drug: Placebo for Romidepsin

Interventions

Romidepsin DRUG

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

Also known as: RMD, Istodax

Cohort 1-Arm 1A (Romidepsin); Cohort 2-Arm 2A (Romidepsin); Cohort 3-Arm 3A (Romidepsin); Cohort 4-Arm 4A (Romidepsin)

Placebo for Romidepsin DRUG

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

Also known as: 0.9% NaCl, 0.9% sodium chloride

Cohort 1-Arm 1B (Placebo for Romidepsin); Cohort 2-Arm 2B (Placebo for Romidepsin); Cohort 3-Arm 3B (Placebo for Romidepsin); Cohort 4-Arm 4B (Placebo for Romidepsin)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (10)

Alabama CRS

Birmingham, Alabama, 35294, United States

Location

UCLA CARE Center CRS

Los Angeles, California, 90035, United States

Location

University of Colorado Hospital CRS

Aurora, Colorado, 80045, United States

Location

Massachusetts General Hospital CRS (MGH CRS)

Boston, Massachusetts, 02114, United States

Location

University of Rochester Adult HIV Therapeutic Strategies Network CRS

Rochester, New York, 14642, United States

Location

Chapel Hill CRS

Chapel Hill, North Carolina, 27599, United States

Location

Ohio State University CRS

Columbus, Ohio, 43210, United States

Location

Penn Therapeutics, CRS

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pittsburgh CRS

Pittsburgh, Pennsylvania, 15213, United States

Location

University of Washington AIDS CRS

Seattle, Washington, 98104-9929, United States

Location

Related Publications (3)

• Ylisastigui L, Archin NM, Lehrman G, Bosch RJ, Margolis DM. Coaxing HIV-1 from resting CD4 T cells: histone deacetylase inhibition allows latent viral expression. AIDS. 2004 May 21;18(8):1101-8. doi: 10.1097/00002030-200405210-00003.

  PMID: 15166525 BACKGROUND

• Klimek VM, Fircanis S, Maslak P, Guernah I, Baum M, Wu N, Panageas K, Wright JJ, Pandolfi PP, Nimer SD. Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes. Clin Cancer Res. 2008 Feb 1;14(3):826-32. doi: 10.1158/1078-0432.CCR-07-0318.

  PMID: 18245545 BACKGROUND

• McMahon DK, Zheng L, Cyktor JC, Aga E, Macatangay BJ, Godfrey C, Para M, Mitsuyasu RT, Hesselgesser J, Dragavon J, Dobrowolski C, Karn J, Acosta EP, Gandhi RT, Mellors JW. A Phase 1/2 Randomized, Placebo-Controlled Trial of Romidespin in Persons With HIV-1 on Suppressive Antiretroviral Therapy. J Infect Dis. 2021 Aug 16;224(4):648-656. doi: 10.1093/infdis/jiaa777.

  PMID: 34398236 DERIVED

Related Links

• DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 2.0, November 2014. Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

MeSH Terms

Conditions

HIV Infections

Interventions

romidepsin; Saline Solution; Sodium Chloride

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social and Scientific Systems, Inc.

ACTGCT.Gov@s-3.com

(301) 628-3313

Study Officials

• John Mellors, MD

  University of Pittsburgh

  STUDY CHAIR

• Deborah McMahon, MD

  University of Pittsburgh

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 28, 2013
• First Posted: September 2, 2013
• Study Start: May 5, 2014
• Primary Completion: April 16, 2018
• Study Completion: April 16, 2018
• Last Updated: November 1, 2021
• Results First Posted: May 23, 2019

Record last verified: 2021-10

Locations

US (10)