Reducing the Residual Reservoir of HIV-1 Infected Cells in Patients Receiving Antiretroviral Therapy - Full Text View

Purpose

This study is a prospective, open-label, randomized, two-arm, dose-escalation exploratory pilot clinical trial involving HIV-1 infected participants treated with suppressive combination antiretroviral combination therapy (cART). The study will test whether combined treatment with the histone deacetylase inhibitor panobinostat and the immunomodulatory cytokine Interferon-alpha2a can reduce the residual reservoir of HIV-1 infected cells that persist during treatment with currently available antiretroviral drugs.

Condition	Intervention	Phase
HIV Infection	Drug: Panobinostat Drug: Pegylated Interferon-alpha2a	Phase 1 Phase 2


Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Parallel Assignment Masking: No masking Primary Purpose: Treatment
Official Title:	A Phase I-II Pilot Study to Assess the Safety and Efficacy of Combined Administration With Pegylated Interferon-alpha2a and the Histone Deacetylase Inhibitor (HDACi) Panobinostat for Reducing the Residual Reservoir of HIV-1 Infected Cells in cART-Treated HIV-1 Positive Individuals

Resource links provided by NLM:

MedlinePlus related topics: HIV/AIDS

Drug Information available for: Interferon Interferon Alfa-2a Interferon Alfa-2b Peginterferon Alfa-2a Panobinostat

U.S. FDA Resources

Further study details as provided by Mathias Lichterfeld, Massachusetts General Hospital:

Primary Outcome Measures:

Occurrence of Grade ≥ 1 Adverse Events (AEs) [ Time Frame: Measured through 1 month after administration of panobinostat and/or interferon-alpha2a ]
Cumulative frequency and severity of Grade ≥ 1 adverse events, Grade ≥ 1 lab abnormalities or serious adverse events
Change in CD4 T Cell-Associated Proviral HIV-1 DNA from Baseline [ Time Frame: Measured through 1 week after administration of panobinostat and/or interferon-alpha2a ]
Operational measurement of HIV-1 reservoir

Secondary Outcome Measures:

Change from baseline in levels of infectious viral units per million CD4 T cells [ Time Frame: Measured through 1 week after study drug administration ]
Change from baseline in histone H3 acetylation in CD4 T cells [ Time Frame: Measured through 1 week after study drug administration ]
Change from baseline in levels of CD4 T cell-associated HIV-1 RNA [ Time Frame: Measured through 1 week after study drug administration ]
Change from baseline in levels of plasma HIV-1 RNA [ Time Frame: Measured through 1 week after study drug administration ]
Change from baseline in levels of CD4 T cell-associated HIV-1 2-LTR circles and chromosomally integrated proviral HIV-1 DNA [ Time Frame: Measured through 1 week after study drug administration ]
Change from baseline in levels of HIV-1 DNA in different CD4 T cell subsets (naïve, T memory stem cells, central-memory, effector-memory, terminally-differentiated) [ Time Frame: Measured through 1 week after study drug administration ]
Change from baseline in frequency and function of innate and adaptive immune effector cell responses [ Time Frame: Measured through 1 week after study drug administration ]
Change from baseline in levels of cellular and soluble immune activation markers [ Time Frame: Measured through 1 week after study drug administration ]
Change from baseline in expression patterns of interferon-stimulated genes (ISG) [ Time Frame: Measured through 1 week after study drug administration ]
Comparison of all immunologically and virological parameters in study participants treated with pegylated Interferon-alpha2a and panobinostat according to HLA class I and IL-28b genotypes [ Time Frame: Measured through 1 week after study drug administration ]


Estimated Enrollment:	8
Study Start Date:	May 2016
Estimated Study Completion Date:	February 2020
Estimated Primary Completion Date:	September 2018 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Arm A Participants in Arm A will receive panobinostat as an oral tablet on days 0, 2, and 4 of the treatment week. The dose of panobinostat will be a 10 mg tablet.	Drug: Panobinostat Panobinostat will be administered orally. Other Names: Farydak LBH589
Experimental: Arm B Participants in Arm B will receive one subcutaneous injection of pegylated Interferon-alpha2a on day 0. The dose of pegylated IFN-alpha2a will be 180 mcg. Simultaneously with interferon-alpha2a, a 10 mg tablet of panobinostat will be administered on day 0. Participants will also receive panobinostat as an oral tablet on days 2 and 4 of the treatment week.	Drug: Panobinostat Panobinostat will be administered orally. Other Names: Farydak LBH589 Drug: Pegylated Interferon-alpha2a Pegylated Interferon-alpha2a will be administered subcutaneously in one shot. Other Name: Pegasys

Detailed Description:

This study is a prospective, double-arm, randomized, open-label, dose-escalation exploratory clinical trial involving HIV-1 infected participants treated with suppressive combination antiretroviral combination therapy (cART). The primary objective of this study is to evaluate a new strategy for reducing the residual reservoir of HIV-1 infected cells that persists despite treatment with current HIV drugs. The clinical trial is conducted in the Infectious Diseases Clinical Trials Unit (CTU) at the Massachusetts General Hospital.

The study medication includes two agents: Panobinostat is an oral tablet that can reverse HIV-1 latency and awaken HIV from a "sleeping" condition during which it is protected from the human immune system. The second drug is interferon-alpha2a, an injectable cytokine that activates the immune system. The combined use of both agents may lead to immune-mediated elimination of HIV-1 infected cells in which viral latency has been reversed by panobinostat.

All participants will receive one week of treatment with panobinostat (10mg, dosed every second day on Monday, Wednesday, Friday), followed by three weeks off-treatment. Participants will be randomized to receive this treatment course with panobinostat alone (Arm A, 2 participants total), or in combination with pegylated IFN-alpha2a (Arm B, 6 participants total). Subcutaneous injections with pegylated Interferon-alpha2a will be administered at the start of the week-long treatment course, simultaneously with the first dose of panobinostat. ART will be continued during the entire treatment duration in all study participants.

Participants will undergo close monitoring for side effects during the entire time of study participation. The total study duration will be 2 months.

Eligibility


Ages Eligible for Study:	18 Years to 65 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Ability and willingness to provide informed consent
HIV-1 infection prior to entry
Receiving suppressive ART therapy for a minimum of 24 consecutive months prior to screening with no interruption of therapy (same ART regimen for at least 12 weeks prior to screening)
Documented suppressed HIV-1 RNA (plasma HIV-1 RNA values <50 copies/ml)
CD4 T cell count ≥ 400 cells/mm3
Negative Hepatitis B surface antigen (HBsAg) or Negative HBV DNA PCR
Negative anti-Hepatitis C virus antibodies (anti-HCV) or negative HCV PCR if anti-HCV antibodies are positive
Negative TB Test (if positive, completed a recommended treatment course for latent TB)
Vaccinated for pneumococcal disease within last 5 years
No clinically significant eye disease
No evidence of clinical coronary heart disease
Not pregnant, planning to become pregnant, or breastfeeding
Willingness to continue to use contraceptives for 90 days after completing treatment
If male, willingness to use a condom during intercourse while taking panobinostat and total of 80 hours after stopping treatment
Not pregnant, planning to become pregnant, or breastfeeding
No evidence of coronary heart disease

Exclusion Criteria:

HIV-1 RNA > 50 copies/mL within 24 months of screening
Severe psychiatric disease, chronic liver disease, past or current evidence of immunologically mediated disease
Severe retinopathy due to diabetes, hypertension, cytomegalovirus or macular degeneration
Evidence of coronary heart disease
History of active thyroid disease requiring medication
Breastfeeding
Presence of a bacterial, fungal, viral or protozoal infection requiring systemic anti-infective therapy
Uncontrolled seizure disorders
History or other evidence of severe illness or other conditions
History of malignancy of any organ system within the past 5 years
Female participants who are pregnant or nursing
History of solid organ transplantation with an existing functional graft
Use of any immunomodulatory agents within 30 days prior to study enrollment or planned use during the trial
Active drug or alcohol use or dependence
Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the participant in case of participation in the study
Use of HIV protease inhibitor or other strong or moderately strong CYP3A4 inhibitors
History of anaphylaxis, allergy or serious adverse reactions to Interferon-alpha2a/Interferon-alpha2b or panobinostat
Has taken: interleukins, systemic interferons or systemic chemotherapy

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02471430

Contacts


Contact: Theresa Flynn, MSN, ANP	617-724-0072	tflynn@partners.org

Locations


United States, Massachusetts
Massachusetts General Hospital CRS (MGH CRS)	Recruiting
Boston, Massachusetts, United States, 02114
Contact: Theresa Flynn, R.N., M.S.N., A.N.P, B.S.N. (617) 724-0072 tflynn@partners.org

Sponsors and Collaborators

Massachusetts General Hospital

Novartis

Genentech, Inc.

Investigators


Principal Investigator:	Mathias Lichterfeld, MD, PhD	Massachusetts General Hospital
Principal Investigator:	Daniel R Kuritzkes, MD	Massachusetts General Hospital
Principal Investigator:	Rajesh T Gandhi, MD	Massachusetts General Hospital

More Information

Publications:

Rasmussen TA, Tolstrup M, Brinkmann CR, Olesen R, Erikstrup C, Solomon A, Winckelmann A, Palmer S, Dinarello C, Buzon M, Lichterfeld M, Lewin SR, Østergaard L, Søgaard OS. Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial. Lancet HIV. 2014 Oct;1(1):e13-21. doi: 10.1016/S2352-3018(14)70014-1. Epub 2014 Sep 15.


Responsible Party:	Mathias Lichterfeld, Assistant Professor of Medicine, Massachusetts General Hospital
ClinicalTrials.gov Identifier:	NCT02471430 History of Changes
Other Study ID Numbers:	U01AI117841 ( U.S. NIH Grant/Contract ) 12049 ( Other Identifier: Division of AIDS (DAIDS-ES) )
Study First Received:	June 11, 2015
Last Updated:	June 20, 2017

Additional relevant MeSH terms:


HIV Infections Lentivirus Infections Retroviridae Infections RNA Virus Infections Virus Diseases Sexually Transmitted Diseases, Viral Sexually Transmitted Diseases Immunologic Deficiency Syndromes Immune System Diseases Panobinostat Interferons	Interferon-alpha Peginterferon alfa-2a Histone Deacetylase Inhibitors Antineoplastic Agents Antiviral Agents Anti-Infective Agents Immunologic Factors Physiological Effects of Drugs Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 17, 2017

Reducing the Residual Reservoir of HIV-1 Infected Cells in Patients Receiving Antiretroviral Therapy (ACTIVATE)