ROADMAP: Romidepsin Plus 3BNC117 Phase 2a Study

• Sponsor: Rockefeller University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02850016
• Collaborator: University Hospital of Cologne (Other), Aarhus University Hospital (Other)
• Enrollment: 48
• Locations: 3
• Arms: 2
• Actual Duration (Months): 47.8
• Patients Per Site: 16
• Patients Per Site Per Month: 0.3

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Human Immunodeficiency Virus (HIV)	Drug: 3BNC117; Drug: Romidepsin	Phase 2

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:

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

2. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• 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)
• Actual Study Start Date: Jan 6, 2017
• Actual Primary Completion Date: Dec 31, 2020
• Actual Study Completion Date: Dec 31, 2020

Arms and Interventions

Arm	Intervention/Treatment
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 Names: Monoclonal Antibody ; Drug: Romidepsin; Intravenous Infusion of Romidepsin; Other Names: 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 Names: HDAC inhibitor

Outcome Measures

Primary Outcome Measures

1. Days to Viral Rebound During Analytical Treatment Interruption (ATI) [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

Secondary Outcome Measures

1. Number of of Adverse Events (AE), Serious Adverse Events (SAE), and Serious Unexpected Serious Adverse Reactions (SUSAR). [48 weeks]

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

2. Change in the Size of the Proviral HIV-1 Reservoir [baseline and week 24]

   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).

3. Plasma HIV-1 RNA [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

1. HIV-1 Transcriptional Activity as Determined by Unspliced HIV-1 RNA (CA usHIV-1 RNA) in Circulating Total CD4+ T Cells. [baseline and week 24]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	The Rockefeller University	New York	New York	United States	10065
2	Aarhus University Hospital	Aarhus		Denmark
3	University of Cologne	Cologne		Germany	50937

Sponsors and Collaborators

• Rockefeller University
• University Hospital of Cologne
• Aarhus University Hospital

Investigators

• Principal Investigator: Marina Caskey, MD, Rockefeller University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 10, 2017

More Information

Publications

None provided.

• Responsible Party: Rockefeller University
• ClinicalTrials.gov Identifier: NCT02850016
• Other Study ID Numbers: MCA-0896
• First Posted: Jul 29, 2016
• Last Update Posted: Jul 14, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Rockefeller University: Romidepsin; 3BNC117; Broadly neutralizing antibody
• Additional relevant MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections; Romidepsin; Histone Deacetylase Inhibitors

Study Results

Participant Flow

Recruitment Details	48 participants signed informed consent. 22 met eligibility criteria and were randomized to study groups A or B in a 1:1 ratio. 2 participants withdrew consent prior to receiving the investigational products. 20 were available for analyses.
Pre-assignment Detail	Participants were screened after signing informed consent and underwent a baseline leukapheresis procedure.

Arm/Group Title	Group A	Group B
Arm/Group 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 . 3BNC117: Intravenous Infusion of 3BNC117 Romidepsin: Intravenous Infusion of Romidepsin	Two treatment cycles each consisting of three romidepsin infusions (5mg/m2). Romidepsin will be administered on days 0, 7, 14, 56, 63, and 70 . Romidepsin: Intravenous Infusion of Romidepsin
Period Title: Overall Study
STARTED	11	9
COMPLETED	10	7
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Group A	Group B	Total
Arm/Group 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 . 3BNC117: Intravenous Infusion of 3BNC117 Romidepsin: Intravenous Infusion of Romidepsin	Two treatment cycles each consisting of three romidepsin infusions (5mg/m2). Romidepsin will be administered on days 0, 7, 14, 56, 63, and 70 . Romidepsin: Intravenous Infusion of Romidepsin	Total of all reporting groups
Overall Participants	11	9	20
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	11 100%	9 100%	20 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	40	51	44
Sex: Female, Male (Count of Participants)
Female	2 18.2%	1 11.1%	3 15%
Male	9 81.8%	8 88.9%	17 85%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 9.1%	0 0%	1 5%
Not Hispanic or Latino	10 90.9%	9 100%	19 95%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 18.2%	3 33.3%	5 25%
White	8 72.7%	6 66.7%	14 70%
More than one race	1 9.1%	0 0%	1 5%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	3 27.3%	3 33.3%	6 30%
Denmark	3 27.3%	2 22.2%	5 25%
Germany	5 45.5%	4 44.4%	9 45%

Outcome Measures

1. Primary Outcome

Title	Days to Viral Rebound During Analytical Treatment Interruption (ATI)
Description	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
Time Frame	Week 24 to Week 36

Outcome Measure Data

Analysis Population Description

Of the 11 participants randomized to Group A, 1 chose not to interrupt ART. Of the 9 participants randomized to Group B, 1 stopped ART earlier than planned in the protocol and 1 chose not to interrupt ART.

Arm/Group Title	Group A	Group B
Arm/Group 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 . 3BNC117: Intravenous Infusion of 3BNC117 Romidepsin: Intravenous Infusion of Romidepsin	Two treatment cycles each consisting of three romidepsin infusions (5mg/m2). Romidepsin will be administered on days 0, 7, 14, 56, 63, and 70 . Romidepsin: Intravenous Infusion of Romidepsin
Measure Participants	10	7
Median (Inter-Quartile Range) [days]	18	28

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All participants who received at least a single dose of the investigational products.

Arm/Group Title	Group A	Group B
Arm/Group 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 . 3BNC117: Intravenous Infusion of 3BNC117 Romidepsin: Intravenous Infusion of Romidepsin	Two treatment cycles each consisting of three romidepsin infusions (5mg/m2). Romidepsin will be administered on days 0, 7, 14, 56, 63, and 70 . Romidepsin: Intravenous Infusion of Romidepsin
Measure Participants	11	9
All Adverse events related to Romidepsin	112	66
All Adverse events related to 3BNC117	4	0
Grade 2 or higher Adverse Events Related to Romidepsin	29	5
Grade 2 or higher Adverse Events Related to 3BNC117	1	0

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Participants who completed dosing per protocol and underwent leukapheresis at baseline and following the interventions (week 24).

Arm/Group Title	Group A	Group B
Arm/Group 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 . 3BNC117: Intravenous Infusion of 3BNC117 Romidepsin: Intravenous Infusion of Romidepsin	Two treatment cycles each consisting of three romidepsin infusions (5mg/m2). Romidepsin will be administered on days 0, 7, 14, 56, 63, and 70 . Romidepsin: Intravenous Infusion of Romidepsin
Measure Participants	11	9
Median (Inter-Quartile Range) [HIV-1 DNA per million CD4+ T cells]	58	46

4. Secondary Outcome

Title	Plasma HIV-1 RNA
Description	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)
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

Participants with detectable plasma HIV-1RNA during the treatment cycles measure by commercial assays.

Arm/Group Title	Group A	Group B
Arm/Group 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 . 3BNC117: Intravenous Infusion of 3BNC117 Romidepsin: Intravenous Infusion of Romidepsin	Two treatment cycles each consisting of three romidepsin infusions (5mg/m2). Romidepsin will be administered on days 0, 7, 14, 56, 63, and 70 . Romidepsin: Intravenous Infusion of Romidepsin
Measure Participants	11	9
Count of Participants [Participants]	4 36.4%	4 44.4%

5. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

Participants who completed dosing according to protocol.

Arm/Group Title	Group A	Group B
Arm/Group 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 . 3BNC117: Intravenous Infusion of 3BNC117 Romidepsin: Intravenous Infusion of Romidepsin	Two treatment cycles each consisting of three romidepsin infusions (5mg/m2). Romidepsin will be administered on days 0, 7, 14, 56, 63, and 70 . Romidepsin: Intravenous Infusion of Romidepsin
Measure Participants	11	9
Median (Inter-Quartile Range) [CA-us HIV-1 RNA per million CD4 T cells]	9	11

Adverse Events

Time Frame	48 weeks
Adverse Event Reporting Description	The definition of adverse event and/or serious adverse event DO NOT differ from the clinicaltrials.gov definitions
Arm/Group Title	Group A		Group B
Arm/Group 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 . 3BNC117: Intravenous Infusion of 3BNC117 Romidepsin: Intravenous Infusion of Romidepsin		Two treatment cycles each consisting of three romidepsin infusions (5mg/m2). Romidepsin will be administered on days 0, 7, 14, 56, 63, and 70 . Romidepsin: Intravenous Infusion of Romidepsin
All Cause Mortality
	Group A		Group B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/9 (0%)
Serious Adverse Events
	Group A		Group B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/9 (0%)
Other (Not Including Serious) Adverse Events
	Group A		Group B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/11 (100%)		9/9 (100%)
Blood and lymphatic system disorders
Thrombocytopenia	2/11 (18.2%)	2	2/9 (22.2%)	2
Cardiac disorders
Neutropenia	2/11 (18.2%)	2	0/9 (0%)	0
Prolonged QT interval	1/11 (9.1%)	1	2/9 (22.2%)	2
Eye disorders
Xerostomia	3/11 (27.3%)	3	1/9 (11.1%)	1
Gastrointestinal disorders
Nausea	11/11 (100%)	29	9/9 (100%)	9
Vomiting	4/11 (36.4%)	8	2/9 (22.2%)	2
Constipation	1/11 (9.1%)	3	0/9 (0%)	0
Heartburn	2/11 (18.2%)	2	1/9 (11.1%)	1
Abdominal discomfort	1/11 (9.1%)	1	0/9 (0%)	0
General disorders
Headache	4/11 (36.4%)	13	3/9 (33.3%)	10
Fatigue	5/11 (45.5%)	12	4/9 (44.4%)	4
Chills	3/11 (27.3%)	8	2/9 (22.2%)	2
Malaise	3/11 (27.3%)	5	2/9 (22.2%)	6
Investigations
Decreased phosphorus	1/11 (9.1%)	5	2/9 (22.2%)	5
Musculoskeletal and connective tissue disorders
Arthralgia	3/11 (27.3%)	4	1/9 (11.1%)	1
Myalgia	1/11 (9.1%)	2	1/9 (11.1%)	3
Renal and urinary disorders
Increased creatinine	2/11 (18.2%)	3	0/9 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.