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Romidepsin Plus 3BNC117 Phase 2a Study (ROADMAP)

This study is currently recruiting participants.
Verified December 2016 by Rockefeller University
Sponsor:
ClinicalTrials.gov Identifier:
NCT02850016
First Posted: July 29, 2016
Last Update Posted: December 26, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
University Hospital of Cologne
Aarhus University Hospital
Information provided by (Responsible Party):
Rockefeller University
  Purpose
The aim of this protocol is to evaluate the effects of romidepsin plus 3BNC117 or romidepsin alone on delaying or preventing viral rebound in ART-treated HIV-1-infected individuals during an analytical interruption of ART.

Condition Intervention Phase
Human Immunodeficiency Virus (HIV) Drug: 3BNC117 Drug: Romidepsin Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2a, Randomized Study of Romidepsin With or Without 3BNC117 to Evaluate the Effects on the HIV-1 Reservoir (ROADMAP)

Resource links provided by NLM:


Further study details as provided by Rockefeller University:

Primary Outcome Measures:
  • Days to viral rebound during analytical treatment interruption (ATI) [ Time Frame: Week 24 to Week 36 ]
    Viral rebound is defined as HIV-1 RNA ≥ 200 copies/mL on 2 consecutive measurements during ATI. If viral rebound occurs, the date of the first measurement of HIV-1 RNA ≥ 200 copies/mL will be defined as "date of viral rebound

  • Days to reinitiation of ART in participants who restart ART before viral rebound. [ Time Frame: Week 24 to Week 36 ]

Secondary Outcome Measures:
  • Number of of adverse events (AE), serious adverse events (SAE), and serious unexpected serious adverse reactions (SUSAR). [ Time Frame: 48 weeks ]
  • Size of the functional, latent HIV-1 reservoir [ Time Frame: Day -14 and Day 154 ]
    As determined by the number of infectious units per 106 resting memory CD4+ T cells (IUPM) using a viral outgrowth assay before and after therapy. Post therapy measurements will occur after the second cycle, just before ATI.

  • Size of the proviral HIV-1 reservoir [ Time Frame: 48 weeks ]
    Determined by total HIV-1 DNA and episomal HIV-1 DNA (2-LTR) in circulating total CD4+ T cells at baseline, after each romidepsin cycle, prior to the ATI period (week 24), and at the end of the study (week 48).

  • Plasma HIV-1 RNA [ Time Frame: 48 weeks ]
    As measured by a routine clinical assay (Cobas Taqman; detection limit 20 copies/mL), a transcription mediated amplification (TMA)-based assay (detection limit 12 copies/ml) and/or a single copy assay (detection limit 1-2 copies/mL)


Other Outcome Measures:
  • HIV-1 transcriptional activity as determined by unspliced HIV-1 RNA in circulating total CD4+ T cells. [ Time Frame: 48 weeks ]
  • Phylogenetically compare viruses grown from PBMCs collected from participants while on ART to rebound viruses collected after ART interruption. [ Time Frame: 48 weeks ]
  • Plasma cytokine and immune activation biomarker levels. [ Time Frame: 48 weeks ]
  • Change from baseline in the capacity of NK and CD8+ T cells to mediate inhibition of viral replication ex vivo. [ Time Frame: 48 weeks ]
  • Absolute cell counts T and NK cells [ Time Frame: 48 weeks ]
    using standard cell marker panels by flow cytometry (e.g. CD3, CD4, CD8, CD45RA, CCR7 for T cells and CD16/CD56 for NK cells).

  • Phenotypic characteristics for T and NK cells [ Time Frame: 48 weeks ]
    Functional properties of cytotoxic T cells and NK cells will be investigated by analyzing cytokine secretion properties (e.g. IL-2, IFN-γ, TNF-α) and surface expression of CD107a/b as a surrogate marker of cytotoxic activities. CD69, CD161, NKp46, NKG2, and CD85J expression will be analysed on NK cells.


Estimated Enrollment: 30
Study Start Date: December 2016
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: August 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group A
Two treatment cycles each consisting of 3BNC117 infusions (30mg/kg) + three romidepsin infusions (5mg/m2). 3BNC117 will be administered on Days 0 and 56. Romidepsin will be administered on days 2, 9, 16, 58, 65, and 72 .
Drug: 3BNC117
Intravenous Infusion of 3BNC117
Other Name: Monoclonal Antibody
Drug: Romidepsin
Intravenous Infusion of Romidepsin
Other Name: HDAC inhibitor
Experimental: Group B
Two treatment cycles each consisting of three romidepsin infusions (5mg/m2). Romidepsin will be administered on days 0, 7, 14, 56, 63, and 70 .
Drug: Romidepsin
Intravenous Infusion of Romidepsin
Other Name: HDAC inhibitor

Detailed Description:

This is a randomized interventional phase 2a trial of 3BNC117 and romidepsin in human immunodeficiency (HIV-1) infected patients on ART, conducted as a multi-center study at the Department of Infectious Diseases, Aarhus University Hospital, Denmark, the Rockefeller University Hospital, USA, and the University Hospital of Cologne, Germany.

Participants will be randomized 1:1 in a non-blinded fashion to receive one of two regimens:

A) Two treatment cycles each consisting of one 3BNC117 infusion (30mg/kg) + three romidepsin infusions (5mg/m2); or

B) Two treatment cycles each consisting of three romidepsin infusions (5mg/m2).

ART will be discontinued 16 weeks after the start of the second treatment cycle (analytical treatment interruption, ATI) and subjects will be monitored weekly for safety and viral rebound. The targeted enrollment is 30 subjects (15 per arm).

Leukapheresis will be performed before and after the two treatment cycles to guarantee sufficient material to investigate changes in the reservoir after the interventions.

The following criteria will require resumption of ART:

  • CD4+ T cell-count <350 cells/mm³ (confirmed by repeat measurement)
  • 2 consecutive plasma HIV-1 RNA measurements ≥ 200 copies/mL or above their setpoint viremia (if documented)
  • Subject request
  • Continued ART interruption will, in the opinion of the investigator or study advisers, pose an unacceptable risk to the subject.

If HIV-1 RNA remains undetectable at week 36, subjects will be offered to continue off ART with close monitoring, in conjunction with the subject's primary medical provider, as long as HIV-1 viral rebound does not occur. ART resumption will follow same criteria as detailed above. All subjects will be followed for a total of 48 weeks from enrollment.

  Eligibility

Information from the National Library of Medicine

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, Learn About Clinical Studies.


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

Inclusion Criteria:

  • Adults age 18-65 years with documented HIV-1 infection
  • CD4+ T-cell count >500 cells/mm3 at screening
  • On ART for a minimum of 24 months and HIV-1 RNA plasma level of < 50 copies/ml by standard assays for at least 18 months (a single viral load measurement > 50 but < 500 copies/ml during this time period is allowable).
  • Individuals on protease inhibitor or NNRTI-based regimens, or regimens containing cobicistat must be willing to switch to an integrase-inhibitor-based regimen (raltegravir or dolutegravir) prior to enrollment.

Exclusion Criteria:

  • Use of systemic corticosteroids, immunosuppressive anti-cancer, or other medications considered significant by the investigators within the last 6 months
  • Pregnancy as determined by a positive urine or serum beta-hCG.
  • Participant unwilling to use two reliable contraception methods (i.e. condom with spermicide, diaphragm with spermicide, progestin-only containing intrauterine device (IUD) (eg, Mirena, Implanon, Nuva Ring), non-estrogen containing formulations of hormonal birth control drugs with condom) for the study duration.
  • Currently breast-feeding.
  • History of resistance to 2 or more classes of antiretroviral medications
  • Any medical, psychiatric, social, or occupational condition that, as judged by the investigators, would interfere with the evaluation of study objectives (such as severe alcohol or drug abuse, dementia).
  • Acute or chronic hepatitis B or C infection as indicated by the presence of Hepatitis B surface antigen (HBsAg) or hepatitis C virus RNA (HCV-RNA) in blood.
  • A history of AIDS-defining illness within 3 years prior to enrollment.
  • History of B-cell lymphoma, including CNS lymphoma
  • CD4 nadir < 200 cells/mm3
  • History of significant coronary artery disease, myocardial infarction, percutaneous coronary intervention with placement of cardiac stents, or family history of sudden death at age < 50 years.
  • ECG at screening that shows QTc >450 msec when calculated using the Fridericia formula from either lead V3 or V4, pathological Q-waves (Q-wave > 40 msec or depth > 0.4-0.5 mV), evidence of a ventricular pre-excitation syndromes, complete or incomplete LBBB or RBBB, second or third degree heart block, QRS duration > 120 msec, or bradycardia defined by sinus rate < 50 bps
  • Use of QT-prolonging medication, renal or hepatic disease, structural heart disease or left ventricular dysfunction
  • Any symptomatic or asymptomatic arrhythmia excluding sinus arrhythmia and bradycardia ≥ 50 bps.
  • Laboratory abnormalities in the parameters listed below:

    1. Absolute neutrophil count ≤ 1,000 cells/μl
    2. Hemoglobin < 11 gm/dL
    3. Platelet count < 125,000 cells/μl
    4. Alanine Aminotransferase (ALT) ≥ 1.25 x ULN
    5. Aspartate Aminotransferase (AST) ≥ 1.25 x ULN
    6. Total bilirubin > 1.0 ULN
    7. Creatinine > 1.0 ULN
  • Any vaccination within 14 days prior to 3BNC117 administration
  • Receipt of any therapeutic HIV vaccine in the past
  • Receipt of any monoclonal antibody or HDAC inhibitor of any kind in the past.
  • Participation in another clinical study of an investigational product currently or within past 12 weeks, or expected participation during this study.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02850016


Contacts
Contact: Katelyn Bastert 800-782-2737 rucares@rockefeller.edu

Locations
United States, New York
The Rockefeller University Recruiting
New York, New York, United States, 10065
Contact: Katelyn Bastert    800-782-2737    rucares@rockefeller.edu   
Principal Investigator: Marina Caskey, MD         
Denmark
Aarhus University Hospital Not yet recruiting
Aarhus, Denmark
Contact: Ole Sogaard, MD, PhD    +45 7845 2842    olesoega@rm.dk   
Principal Investigator: Ole Sogaard, MD, PhD         
Germany
University of Cologne Not yet recruiting
Cologne, Germany, 50937
Contact: Gisela Kremer, RN    +41-221-478-3324    gisela.kremer@uk-koeln.de   
Principal Investigator: Gerd Kaetkenheuer, MD         
Sponsors and Collaborators
Rockefeller University
University Hospital of Cologne
Aarhus University Hospital
Investigators
Principal Investigator: Marina Caskey, MD Rockefeller University
  More Information

Responsible Party: Rockefeller University
ClinicalTrials.gov Identifier: NCT02850016     History of Changes
Other Study ID Numbers: MCA-0896
First Submitted: July 26, 2016
First Posted: July 29, 2016
Last Update Posted: December 26, 2016
Last Verified: December 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Rockefeller University:
Romidepsin
3BNC117
Broadly neutralizing antibody

Additional relevant MeSH terms:
Immunologic Deficiency Syndromes
Acquired Immunodeficiency Syndrome
HIV Infections
Immune System Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Antibodies
Romidepsin
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Antineoplastic Agents


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