Romidepsin Plus 3BNC117 Phase 2a Study

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Human Immunodeficiency Virus (HIV)

Intervention / Treatment
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* Drug: 3BNC117
* Drug: Romidepsin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>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<br>* Intravenous Infusion of 3BNC117<br>* Other names: Monoclonal Antibody;Drug: Romidepsin<br>* Intravenous Infusion of Romidepsin<br>* Other names: HDAC inhibitor;|
| Experimental: Group B<br>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<br>* Intravenous Infusion of Romidepsin<br>* Other names: HDAC inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Week 24 to Week 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 48 weeks | 
| 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). | baseline and 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) | 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Romidepsin, 3BNC117, Broadly neutralizing antibody