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Romidepsin Plus 3BNC117 Phase 2a Study (ROADMAP)

Primary Purpose

Human Immunodeficiency Virus (HIV)

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

3BNC117

Romidepsin

About this trial

This is an interventional treatment trial for Human Immunodeficiency Virus (HIV) focused on measuring Romidepsin, 3BNC117, Broadly neutralizing antibody

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

The Rockefeller University
Aarhus University Hospital
University of Cologne

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Group A

Group B

Arm Description

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 .

Two treatment cycles each consisting of three romidepsin infusions (5mg/m2). Romidepsin will be administered on days 0, 7, 14, 56, 63, and 70 .

Outcomes

Primary Outcome Measures

Days to Viral Rebound During Analytical Treatment Interruption (ATI)

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

Secondary Outcome Measures

Number of of Adverse Events (AE), Serious Adverse Events (SAE), and Serious Unexpected Serious Adverse Reactions (SUSAR).

The occurrence of adverse events was assessed during each follow up visit. Adverse events of grades 1 or higher were reported.

Change in the Size of the Proviral HIV-1 Reservoir

Determined by total HIV-1 DNA and episomal HIV-1 DNA (2-LTR) in circulating total CD4+ T cells at baseline and prior to the ATI period (week 24).

Plasma HIV-1 RNA

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)

Full Information

NCT ID

NCT02850016

First Posted

July 26, 2016

Last Updated

July 12, 2022

Sponsor

Rockefeller University

Collaborators

University Hospital of Cologne, Aarhus University Hospital

1. Study Identification

Unique Protocol Identification Number

NCT02850016

Brief Title

Romidepsin Plus 3BNC117 Phase 2a Study

Acronym

ROADMAP

Official Title

A Phase 2a, Randomized Study of Romidepsin With or Without 3BNC117 to Evaluate the Effects on the HIV-1 Reservoir (ROADMAP)

Study Type

Interventional

2. Study Status

Record Verification Date

July 2022

Overall Recruitment Status

Completed

Study Start Date

January 6, 2017 (Actual)

Primary Completion Date

December 31, 2020 (Actual)

Study Completion Date

December 31, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Rockefeller University

Collaborators

University Hospital of Cologne, Aarhus University Hospital

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Human Immunodeficiency Virus (HIV)

Keywords

Romidepsin, 3BNC117, Broadly neutralizing antibody

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

48 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Group A

Arm Type

Experimental

Arm Description

Arm Title

Group B

Arm Type

Experimental

Arm Description

Two treatment cycles each consisting of three romidepsin infusions (5mg/m2). Romidepsin will be administered on days 0, 7, 14, 56, 63, and 70 .

Intervention Type

Drug

Intervention Name(s)

3BNC117

Other Intervention Name(s)

Monoclonal Antibody

Intervention Description

Intravenous Infusion of 3BNC117

Intervention Type

Drug

Intervention Name(s)

Romidepsin

Other Intervention Name(s)

HDAC inhibitor

Intervention Description

Intravenous Infusion of Romidepsin

Primary Outcome Measure Information:

Title

Days to Viral Rebound During Analytical Treatment Interruption (ATI)

Description

Time Frame

Week 24 to Week 36

Secondary Outcome Measure Information:

Title

Number of of Adverse Events (AE), Serious Adverse Events (SAE), and Serious Unexpected Serious Adverse Reactions (SUSAR).

Description

The occurrence of adverse events was assessed during each follow up visit. Adverse events of grades 1 or higher were reported.

Time Frame

48 weeks

Title

Change in the Size of the Proviral HIV-1 Reservoir

Description

Determined by total HIV-1 DNA and episomal HIV-1 DNA (2-LTR) in circulating total CD4+ T cells at baseline and prior to the ATI period (week 24).

Time Frame

baseline and week 24

Title

Plasma HIV-1 RNA

Description

Time Frame

48 weeks

Other Pre-specified Outcome Measures:

Title

HIV-1 Transcriptional Activity as Determined by Unspliced HIV-1 RNA (CA usHIV-1 RNA) in Circulating Total CD4+ T Cells.

Description

The median fold-change in cell-associated unspliced HIV-1 RNA concentrations after romidepsin administration across all infusions

Time Frame

baseline and week 24

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility 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: Absolute neutrophil count ≤ 1,000 cells/μl Hemoglobin < 11 gm/dL Platelet count < 125,000 cells/μl Alanine Aminotransferase (ALT) ≥ 1.25 x ULN Aspartate Aminotransferase (AST) ≥ 1.25 x ULN Total bilirubin > 1.0 ULN 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Marina Caskey, MD

Organizational Affiliation

Rockefeller University

Official's Role

Principal Investigator

Facility Information:

Facility Name

The Rockefeller University

City

New York

State/Province

New York

ZIP/Postal Code

10065

Country

United States

Facility Name

Aarhus University Hospital

City

Aarhus

Country

Denmark

Facility Name

University of Cologne

City

Cologne

ZIP/Postal Code

50937

Country

Germany

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

35544074

Citation

Gruell H, Gunst JD, Cohen YZ, Pahus MH, Malin JJ, Platten M, Millard KG, Tolstrup M, Jones RB, Conce Alberto WD, Lorenzi JCC, Oliveira TY, Kummerle T, Suarez I, Unson-O'Brien C, Nogueira L, Olesen R, Ostergaard L, Nielsen H, Lehmann C, Nussenzweig MC, Fatkenheuer G, Klein F, Caskey M, Sogaard OS. Effect of 3BNC117 and romidepsin on the HIV-1 reservoir in people taking suppressive antiretroviral therapy (ROADMAP): a randomised, open-label, phase 2A trial. Lancet Microbe. 2022 Mar;3(3):e203-e214. doi: 10.1016/S2666-5247(21)00239-1. Epub 2022 Jan 24.

Results Reference

derived

PubMed Identifier

32838558

Citation

Valente PK, Wu Y, Cohen YZ, Caskey M, Meyers K. Behavioral and social science research to support development of educational materials for clinical trials of broadly neutralizing antibodies for HIV treatment and prevention. Clin Trials. 2021 Feb;18(1):17-27. doi: 10.1177/1740774520948042. Epub 2020 Aug 24.

Results Reference

derived

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Romidepsin Plus 3BNC117 Phase 2a Study

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