Conditions: Human Immunodeficiency Virus (HIV)
Keywords: Romidepsin 3BNC117 Broadly neutralizing antibody
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 48
Healthy volunteers: no

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.

Arms:
arm 1: 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 . arm 2: Two treatment cycles each consisting of three romidepsin infusions (5mg/m2). Romidepsin will be administered on days 0, 7, 14, 56, 63, and 70 .

Interventions: intervention 1: 3BNC117 intervention 2: Romidepsin
Intervention descriptions: intervention 1: Intravenous Infusion of 3BNC117 intervention 2: Intravenous Infusion of Romidepsin

Protocol document:
Prot_SAP_000.pdf: 
The Rockefeller University
IND: 118225
10 October 2017
PROTOCOL # MCA-896
CONFIDENTIAL
1
A phase 2a, randomized study of romidepsin with or without 3BNC117 to evaluate 
the effects on the HIV-1 reservoir (ROADMAP)
IND Sponsor: 
The Rockefeller University 
IND # 118225
Clinical Director/Principal Investigator:
Marina Caskey, MD
Protocol Chair:
Yehuda Cohen, MD
Draft or Version Number:
Version 1.8
10 October 2017
Confidentiality Statement
This document is confidential and is to be distributed for review only to investigators, 
potential investigators, consultants, study staff, and applicable independent ethics 
committees or institutional review boards. The contents of this document shall not be 
disclosed to others without written authorization from The Rockefeller University, unless 
it is necessary to obtain informed consent from potential study participants.
Statement of Compliance
The clinical trial will be conducted in compliance with the protocol, with the 
International Conference on Harmonization Good Clinical Practice E6 (ICH-GCP), and 
with 45 CFR 46 and 21 CFR 50, 56 and 312. All protocol investigators have completed 
Protection of Human Subjects Training.
Rockefeller University Institutional Review Board
IRB NUMBER: MCA-0896
IRB APPROVAL DATE: 01/27/2018
IRB EXPIRATION DATE: 01/26/2019


The Rockefeller University
IND: 118225
10 October 2017
PROTOCOL # MCA-896
CONFIDENTIAL
2
Signature Page 1
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal and E.U. 
regulations and ICH guidelines.
The Lead Principal Investigator (Protocol Chair) should sign Signature Page 1. A copy of 
this Signature Page 1 should be filed with the holder of the Regulatory documents and a 
copy should be maintained at the site.
Principal Investigator: _______________________________________________
Print/Type
Signed: ______________________________      Date:  ____________________
Name/Title 
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The Rockefeller University
IND: 118225
10 October 2017
PROTOCOL # MCA-896
CONFIDENTIAL
3
Signature Page 2
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal 
regulations and ICH guidelines. 
The Investigator(s) of Record (signature(s) on 1572) from each participating clinical site 
should sign the Signature Page 2 as appropriate. This Signature Page 2 should be 
maintained at each site.
Investigator of Record: _______________________________________________
Print/Type
Signed: _________________________________  Date: ______________________
Name/Title
Investigator of Record: _______________________________________________
Print/Type
Signed: ________________________________   Date: ______________________
Name/Title
Investigator of Record: _______________________________________________
Print/Type
Signed: ________________________________   Date: ______________________
Name/Title
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The Rockefeller University
IND: 118225
10 October 2017
PROTOCOL # MCA-896
CONFIDENTIAL
4
TABLE OF CONTENTS
1
KEY ROLES ......................................................................................................................................12
1.1
INSTITUTIONS ..............................................................................................................................................12
1.2
INDIVIDUALS.................................................................................................................................................14
2
LAY SUMMARY...............................................................................................................................16
3
OBJECTIVES AND RATIONALE ..................................................................................................16
3.1
INTRODUCTION............................................................................................................................................16
3.1.1
Background ...........................................................................................................................................16
3.1.2
3BNC117.................................................................................................................................................19
3.1.3
Romidepsin ............................................................................................................................................22
3.2
HYPOTHESIS.................................................................................................................................................23
3.3
AIMS...............................................................................................................................................................24
3.4
PRIMARY ENDPOINT...................................................................................................................................24
3.5
SECONDARY ENDPOINTS............................................................................................................................24
3.6      EXPLORATORY ENDPOINTS .......................................................................................................................25
4
STUDY DESIGN...............................................................................................................................25
5
STUDY POPULATION ...................................................................................................................26
5.1
INCLUSION CRITERIA..................................................................................................................................26
5.2
EXCLUSION CRITERIA .................................................................................................................................27
6
METHODS AND PROCEDURES ..................................................................................................28
6.1
SCREENING PROCEDURE AND STUDY VISITS..........................................................................................28
6.1.1
Pre-Screening Questionnaire.........................................................................................................28
6.1.2
Screening Visits....................................................................................................................................28
6.1.3
Change in ART regimen....................................................................................................................29
6.1.4
Leukapheresis / Blood Draw visits..............................................................................................29
6.1.5
Treatment Cycles 1 and 2................................................................................................................29
6.1.6
Analytical treatment interruption ..............................................................................................31
6.1.7
ART interruption and re-initiation of combination ART...................................................32
6.1.8
Final Visit/Early Termination Visit ............................................................................................33
6.1.9
Long term safety follow up (Years 2 and 3)............................................................................33
6.1.10
Discontinuation of 3BNC117 infusion and/or volunteer withdrawal from study
33
6.2
STUDY PROCEDURES...................................................................................................................................35
6.2.1
Consent Procedure..............................................................................................................................35
6.2.2
Study Assignment................................................................................................................................36
6.2.3
3BNC117 Administration Procedure..........................................................................................36
6.2.4
Romidepsin Administration Procedure.....................................................................................36
6.2.5
Medical History and Physical Examination.............................................................................37
6.2.6
Blood Collection and Shipment.....................................................................................................38
6.2.7
Monitoring for cytokine release associated adverse events and treatment of 
cytokine release syndrome.............................................................................................................................38
6.2.8
Family Planning Counseling...........................................................................................................38
6.2.9
Compensation.......................................................................................................................................39
6.2.10
Safety Assessments...........................................................................................................................39
6.2.11
Diagnostic work up in the event of graded elevations in total bilirubin .................40
6.2.12
Antiretroviral and Immunogenicity Assessments..............................................................40
6.2.13
Pharmacokinetic evaluations.....................................................................................................42
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IRB NUMBER: MCA-0896
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The Rockefeller University
IND: 118225
10 October 2017
PROTOCOL # MCA-896
CONFIDENTIAL
5
7
INVESTIGATIONAL PRODUCTS ................................................................................................43
7.1
REGIMEN.......................................................................................................................................................43
7.2
STORAGE AND SHIPMENT OF THE INVESTIGATIONAL PRODUCTS......................................................43
7.3
DISPENSING AND HANDLING OF THE INVESTIGATIONAL PRODUCTS ................................................43
7.4
ACCOUNTABILITY AND DISPOSAL OF USED AND UNUSED INVESTIGATIONAL PRODUCT...............44
7.5
CONCOMITANT AND PROHIBITED MEDICATIONS..................................................................................44
8
DATA ANALYSIS ............................................................................................................................44
8.1
ANALYSIS OF ANTIRETROVIRAL EFFECTS, SAFETY AND PHARMACOKINETICS................................44
8.2
SAMPLE SIZE CONSIDERATIONS ...............................................................................................................46
9
DATA AND SAMPLE STORAGE ..................................................................................................46
10
RECRUITMENT PLAN ................................................................................................................47
11
POTENTIAL BENEFITS TO SUBJECTS...................................................................................47
12
POTENTIAL RISKS TO THE SUBJECT....................................................................................48
13
PROCEDURES TO MINIMIZE RISK.........................................................................................50
14
ALTERNATIVE METHODS OR TREATMENTS.....................................................................53
15
DATA AND SAFETY MONITORING PLAN.............................................................................53
15.1
PROTOCOL SAFETY REVIEW TEAM .......................................................................................................53
15.2
SAFETY MONITORING COMMITTEE.......................................................................................................53
15.3
MONITORING.............................................................................................................................................55
15.4
ADVERSE EVENT CLASSIFICATION ........................................................................................................55
15.5
REPORTING ADVERSE EVENTS...............................................................................................................55
Expedited Reporting by Investigator to Celgene..................................................................................55
15.6
REPORTING UNANTICIPATED AES ........................................................................................................56
15.7
CLINICAL LABORATORY IMPROVEMENT AMENDMENT/CLINICAL LABORATORY EVALUATION 
PROGRAM (CLIA/CLEP)......................................................................................................................................56
15.8
STUDY PAUSING RULES ...........................................................................................................................56
15.9
FUTILITY RULE..........................................................................................................................................58
16
CLINICAL TRIAL REGISTRATION...........................................................................................58
BIBLIOGRAPHY.....................................................................................................................................59
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IRB NUMBER: MCA-0896
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The Rockefeller University
IND: 118225
10 October 2017
PROTOCOL # MCA-896
CONFIDENTIAL
6
List of Abbreviations
AU
Aarhus University
AUH
Aarhus University Hospital
3BNC117
Anti-HIV-1 bNAb targeting the CD4 binding site of gp120
Ab
Antibody
AE
Adverse Event/Adverse Experience
ART
Antiretroviral Therapy
ATI
Analytic Treatment Interruption
bNAbs
Broadly Neutralizing Antibodies
CD4
T-cell Surface Glycoprotein CD4
CFR
Code of Federal Regulations
cGMP
Current Good Manufacturing Practices
CONSORT
Consolidated Standards of Reporting Trials
CRF 
Case Report Form
CRSO 
Clinical Research Support Office
CTSA 
Clinical and Translational Science Award
CCTS 
Center for Clinical and Translational Science
CU
Cologne University
CUH
Cologne University Hospital
DC 
Dendritic Cell
DNA
Deoxyribonucleic Acid
DSMB 
Data and Safety Monitoring Board
FDA 
Food and Drug Administration
FWA 
Federal-Wide Assurance
GCP 
Good Clinical Practice
gp120
HIV-1 Envelope Glycoprotein 120
HDAC
Histone deacetylase 
HIPAA 
Health Insurance Portability and Accountability Act
HIV-1 
Human immunodeficiency virus
hu-mice
Humanized Mice
IB
Investigator’s Brochure
ICF 
Informed Consent Form
ICH 
International Conference on Harmonization
I.M. 
Intramuscularly
IND 
Investigational New Drug
IRB 
Institutional Review Board
I.V. 
Intravenously
N 
Number (typically refers to participants)
NIAID 
National Institute of Allergy and Infectious Diseases, NIH
NIH 
National Institutes of Health
OHRP 
Office for Human Research Protections
OHSR 
Office for Human Subjects Research
PBMC
Peripheral Blood Mononuclear Cell
PI 
Principal Investigator
RU 
The Rockefeller University
RUH 
The Rockefeller University Hospital
QA 
Quality Assurance
QC 
Quality Control
RNA
Ribonucleic Acid
SAE 
Serious Adverse Event/Serious Adverse Experience
S.C. 
Subcutaneously
SHIV
Chimeric Simian/Human Immunodeficiency Virus
SOP 
Standard Operating Procedure
T cell
T lymphocyte
V3 loop
Third Variable Loop of the HIV-1 Virion Envelope Glycoprotein 120
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IND: 118225
10 October 2017
PROTOCOL # MCA-896
CONFIDENTIAL
7
Study Schema
Title
A phase 2a, randomized study of romidepsin with or without 3BNC117 to 
evaluate the effects on the HIV-1 reservoir (ROADMAP)
Short Title
Romidepsin plus 3BNC117 phase 2a study
Protocol 
Number
MCA-896
Phase
Phase 2a
IND Sponsor
The Rockefeller University 
Study 
Center(s)
The Rockefeller University (RUH; Coordinating Site), New York, NY, U.S.A.
University Hospital of Cologne, Cologne, Germany
Aarhus University Hospital, Aarhus, Denmark
Principal 
Investigators
Marina Caskey, MD, Ole Sogaard, MD PhD, Gerd Faetkenheuer, MD
Study Design
This is a randomized interventional phase 2a trial of 3BNC117 and romidepsin in 
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 study outline is shown in Figure 1. The targeted 
enrolment 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. 
Rockefeller University Institutional Review Board
IRB NUMBER: MCA-0896
IRB APPROVAL DATE: 01/27/2018
IRB EXPIRATION DATE: 01/26/2019


The Rockefeller University
IND: 118225
10 October 2017
PROTOCOL # MCA-896
CONFIDENTIAL
8
Figure 1. Study Design:
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 
Duration
50 weeks per participant; total planned study duration 24 months
Objectives
Primary Objective:
-
Evaluate the effects of romidepsin plus 3BNC117 or romidepsin alone on 
delaying or preventing viral rebound in HIV-1-infected individuals 
during an analytical interruption of ART.  
Secondary Objectives:
      -     Evaluate the safety of romidepsin plus 3BNC117 or romidepsin alone in 
ART-treated HIV-1 infected individuals;
-
Evaluate the effects of romidepsin plus 3BNC117 or romidepsin alone on 
the size of the replication competent HIV-1 reservoir in ART-treated 
HIV-1-infected individuals;
-
Evaluate the immunomodulatory effects of romidepsin plus 3BNC117 or 
romidepsin alone in ART-treated HIV-1-infected individuals.
Number of 
Subjects
30 (15:15)
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IRB NUMBER: MCA-0896
IRB APPROVAL DATE: 01/27/2018
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The Rockefeller University
IND: 118225
10 October 2017
PROTOCOL # MCA-896
CONFIDENTIAL
9
Study 
Population
HIV-infected males and females, between the ages of 18-65, on ART for at least 
24 months, with HIV-1 RNA plasma level of < 50 copies/ml by standard assays 
for at least 18 months, and with current CD4+ T cell counts > 500 cells/μl.
Inclusion / 
Exclusion 
Criteria
Inclusion Criteria:
1.
Adults age 18-65 years with documented HIV-1 infection
2.
CD4+ T-cell count >500 cells/mm3 at screening
3.
On ART for a minimum of 18 months and HIV-1 RNA plasma level 
of < 50 copies/ml by standard assays for at least 12 months (a single 
viral load measurement > 50 but < 500 copies/ml during this time 
period is allowable). 
4.
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: 
1.
Use of systemic corticosteroids, immunosuppressive anti-cancer, or 
other medications considered significant by the investigators within 
the last 6 months
2.
Pregnancy as determined by a positive urine or serum beta-hCG.
3.
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), non-
estrogen containing formulations of hormonal birth control drugs 
with condom) for the study duration. Romidepsin may interact with 
estrogen-based contraceptives and such agents may be unreliable in 
participants receiving romidepsin. 
4.
Currently breast-feeding. 
5.
History of resistance to 2 or more classes of antiretroviral 
medications
6.
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).
7.
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.
8.
A history of AIDS-defining illness within 3 years prior to 
enrollment.
9.
History of B-cell lymphoma, including CNS lymphoma
10. CD4 nadir < 200 cells/mm3 within the last 5 years.
11. 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.
12. 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
13. Use of QT-prolonging medication, renal or hepatic disease, structural 
heart disease or left ventricular dysfunction
14. Any symptomatic or asymptomatic arrhythmia excluding sinus 
arrhythmia and bradycardia ≥ 50 bps.
15. Use of Coumadin or Coumadin derivatives 
16. Laboratory abnormalities in the parameters listed below: 
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IND: 118225
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PROTOCOL # MCA-896
CONFIDENTIAL
10
a.
Absolute neutrophil count  1,000 cells/μl
b.
Hemoglobin < 11 gm/dL
c.
Platelet count < 125,000 cells/μl
Inclusion / 
Exclusion 
Criteria
d.
ALT  1.25 x ULN
e.
AST  1.25 x ULN
f.
Total bilirubin > 1.0 ULN 
g.
eGFR < 60 mL/min/1.73m2
17. Any vaccination within 14 days prior to 3BNC117 administration
18. Receipt of any therapeutic HIV vaccine in the past
19. Receipt of any anti-HIV monoclonal antibody in the past, or HDAC 
inhibitor of any kind in the past 2 years.
20. Participation in another clinical study of an investigational product 
currently or within past 12 weeks, or expected participation during 
this study.
Study 
Product, 
Dose, Route, 
Regimen
- 3BNC117 (RUhumab-001) is a recombinant, fully human monoclonal antibody 
(mAb) of the IgG1κ isotype that specifically binds to the CD4 binding site 
(CD4bs) within HIV-1 envelope gp-120.
- Romidepsin is an HDAC inhibitor that has emerged as one of the potent inducers 
of HIV-1 transcription. Romidepsin displays isoform specificity towards class I 
HDACis, which are particularly important to maintaining HIV-1 latency. 
Romidepsin will be provided by Celgene for use in this study. 
In Group A, one intravenous infusion of 3BNC117 mAb (30 mg/kg) will be 
administered at week 0 and a second infusion at week 8 via a peripheral vein over 
60 minutes.
In Groups A and B, one intravenous infusion of romidepsin (5 mg/m2) will be 
administered at weeks 0, 1, and 2 (treatment cycle 1), and weeks 8, 9, and 10 
(treatment cycle 2), via a peripheral vein over 120 minutes (Figure 1). In Group 
A, the start of each romidepsin cycle will begin 2 days after the 3BNC117 
infusion.
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IRB NUMBER: MCA-0896
IRB APPROVAL DATE: 01/27/2018
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The Rockefeller University
IND: 118225
10 October 2017
PROTOCOL # MCA-896
CONFIDENTIAL
11
Statistical 
Methodology
The sample size calculation is based on the primary endpoint: time to viral 
rebound during ATI or time to reinitiation of ART in participants who restart ART 
before viral rebound.  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.”  
We will compare days from date of ART interruption until viral rebound or 
restarting of ART in arm A to arm B (1:1 randomization). Given a standard 
deviation (SD) of 10 (days), enrolling 12 patients in each of the two arms, will 
have 80% power to detect ≥ 13 days (approximately 2 weeks) difference in time to 
viral rebound at a 5% significance level (Davey et al., 1999; Hamlyn et al., 2012; 
Hill et al., 2014). To accommodate for dropouts, 30 study subjects may be 
enrolled in the study (15 in each arm).  A dropout rate of 5-15% is anticipated.
The number and percentage of subjects experiencing one or more AEs will be 
summarized by relationship to study drug and severity. AEs will also be 
summarized by severity grade and by relationship to study drug according to the 
CTCAE v4.03 (infusion-related AEs) and DAIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events, Version 2.0 (non-infusion-related AEs) 
grading scales. Changes will be calculated relative to the values collected at 
baseline. 
The Wilcoxon-Mann-Whitney test will be used as primary analysis for the primary 
outcome. The Kaplan-Meier estimator will be used as secondary analysis to assess 
the magnitude of the difference between the survival curves for the two study 
groups. We will use the log-rank test to compare time to viral rebound during ATI 
in the two arms.
Statistical 
Methodology
The Wilcoxon-Mann-Whitney will be used to determine changes from baseline to 
the pre-ATI time-point in reservoir size for each group. Fishers exact or chi-square 
test will be used to compare the proportion of subjects in both groups with 
detectable viremia during each romidepsin treatment. Functional properties of 
cytotoxic T cells and NK cells will be correlated to changes in total HIV-1 DNA 
and IUPM. Flow cytometry data will be evaluated by Boolean partitioning of NK 
and T cell responses into distinct responding populations (Lamoreaux et al., 2006).
Finally, correlation analysis will be performed to identify the markers most likely 
associated with time to viral rebound. As exploratory analysis, a linear regression 
model will be used to determine predictors of log-transformed time to viral 
rebound in both arms. P values <0.05 will be considered statistically significant.
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IRB NUMBER: MCA-0896
IRB APPROVAL DATE: 01/27/2018
IRB EXPIRATION DATE: 01/26/2019


The Rockefeller University
IND: 118225
10 October 2017
PROTOCOL # MCA-896
CONFIDENTIAL
12
1
Key Roles
1.1
Institutions
Study Sites:
The Rockefeller University Hospital, New York NY (Coordinating Site)
1230 York Ave.
New York, NY 10065
Contact Person: Marina Caskey, MD
Phone Number: (212) 327-7396
Fax Number: (212) 327-7234
E-mail: mcaskey@mail.rockefeller.edu
Department of Infectious Diseases
Aarhus University Hospital
Palle Juul-Jensens Boulevard 99
8200 Aarhus, Denmark
Contact Person: Ole Søgaard, MD PhD
Phone Number: + 45 7845 2842
Fax Number: + 45 7845 2840
E-mail: olesoega@rm.dk
Department of Internal Medicine
University Hospital of Cologne
Kerpener Str. 62
50937 Cologne, Germany
Contact Person: Gerd Faetkenheuer, MD
Phone Number: +49 (221) 478-4886
Fax Number: +49 (221) 478-9869
E-mail: gerd.faetkenheuer@uk-koeln.de
Clinical Laboratories:
Memorial Sloan Kettering Cancer Center
1275 York Avenue
NY, NY 10065
New York Presbyterian – Weill Cornell Medical Center
525 East 68th Street
New York, NY 10021
LabCorp
330 W 58th St
New York, NY, 10019
Blood Samples and Biochemistry – Aarhus University Hospital
Palle Juul-Jensens Boulevard 99
8200 Aarhus, Denmark
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IND: 118225
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PROTOCOL # MCA-896
CONFIDENTIAL
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Department of Clinical Immunology – Aarhus University Hospital
Palle Juul-Jensens Boulevard 99
8200 Aarhus, Denmark
Department of Clinical Microbiology – Aarhus University Hospital
Palle Juul-Jensens Boulevard 99
8200 Aarhus, Denmark
Laboratory of Experimental Immunology
Dept. I of Internal Medicine, Center for Molecular Medicine Cologne (CMMC)
University of Cologne                                                                          
Robert-Koch-Str. 21, Building 66
50931 Cologne, Germany
Funders:
American foundation for AIDS research (amfAR)
Data Management
Clinical Trials Centre Cologne
ZKS Köln
Gleueler Strasse 269
50935 Köln
Phone: 0221 478 881 21
Fax: 0221 478 7983
Independent Safety Monitoring: 
International AIDS Vaccine Initiative (IAVI)
125 Broad Street, 9th Floor
New York, NY 10004 
Good Clinical Practice (GCP) unit at Aalborg and Aarhus University Hospitals
Aarhus University
Olof Palmes Allé 15
8200 Aarhus N, Denmark
Acromion GmbH
Europaallee 27-29
50226 Frechen
Phone: +49 (0)2234-20 37 37-20
Fax: +49 (0)2234-20 37 37-9
 
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1.2
Individuals
Rockefeller Site
Aarhus Site
Principal Investigator:
Marina Caskey, MD
Assistant Professor of Clinical Investigation
The Rockefeller University
1230 York Avenue, NY, NY 10065
Phone Number: 212 327-7396
Fax Number: 212 327-7234
E-mail: mcaskey@mail.rockefeller.edu
Principal Investigator
Ole Søgaard, MD PhD
Department of Infectious Diseases
Aarhus University Hospital
Palle Juul-Jensens Boulevard 99
8200 Aarhus, 
Denmark Phone Number: + 45 7845 2842
Fax Number: + 45 7845 2840
E-mail: olesoega@rm.dk
Co-Investigators:
Michel Nussenzweig, MD, PhD
Yehuda Cohen, MD
Allison Butler, FNP-BC
Arlene Hurley, ANP
Irina Shimeliovich, MD, PhD
Katrina Millard, NP
Maggi Pack, PhD
Co-Investigators:
Martin Tolstrup, PhD
Thomas Rasmussen, MD, PhD
Lars Østergaard, MD, PhD
Jesper Damsgaard Gunst, MD
Steffen Leth, MD
Line Vibholm, MD
Yordanas Yehdego, ANP
Cologne Site
Principal Investigator:
Gerd Fäetkenheuer, MD
University Hospital of Cologne
Kerpener Str. 62
50937 Cologne
Phone Number: +49 (221) 478-4886
Fax Number: +49 (221) 478-9869
E-mail:  g.faetkenheuer@uni-koeln.de
Co-Investigators:
Florian Klein, MD
Martin Platten, MD
Henning Grüll, MD
Clara Lehmann, MD
Collaborators:
Michael Seaman, PhD
Beth Israel Deaconess Medical Center
330 Brookline Ave
E/CLS-1001
Boston, MA 02215
Robert Siliciano, MD, PhD
JHU School of Medicine
733 N. Broadway
Rm 879, Edward D. Miller Research Bldg
Baltimore, MD 21205 
Consultants at the Rockefeller Site:
- Paul Cohen, MD, PhD (Cardiologist)
1230 York Ave 
New York, NY 10065
- James Vitarius, MD (Cardiologist)
VA Hudson Valley Health Care System
Castle Point, NY 12511
- Jim Cheung, MD (Cardiologist)
520 East 70th Street, Starr 4 
New York, NY 10021
- Ype de Jong, MD PhD (Hepatologist)
Weill Cornell Medical Center 
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2
Lay Summary
Despite effective combination antiretroviral therapy (ART), HIV-1 persists as latent 
infection. Upon treatment interruption, the virus quickly replicates and viremia rebounds 
to pre-treatment levels. The primary barrier preventing HIV-1 eradication by ART is a 
pool of long-lived latently infected memory CD4+ T-cells. These cells harbor silent 
integrated proviral DNA capable of resuming HIV-1 expression upon activation. In the 
inactive, resting state these cells cannot be recognized or eliminated by the immune 
system or antiretroviral drugs. Importantly, latently HIV-1 infected cells can be induced 
to resume HIV-1 expression by latency reversing agents (LRAs). This in turn could 
expose infected cells to immune-mediated recognition and killing. 3BNC117 is the first 
broadly neutralizing antibody (bNAb) against HIV-1 having demonstrated potent activity 
against HIV-1 in humans. Unlike ART, bNAbs can engage the host immune system by 
virtue of their Fc effector domains and thereby accelerate clearance of cell-free virus, 
induce antibody dependent cytotoxicity to kill infected cells, and produce immune 
complexes that activate dendritic cells to become potent antigen presenting cells.
The aim of this protocol is to evaluate the effect of a combination of a potent LRA (i.e. 
romidepsin) with bNAb-mediated clearance of viral-antigen producing cells as a novel 
approach to reduce the HIV-1 reservoir in chronically infected patients on suppressive 
ART.
3
Objectives and Rationale
3.1
Introduction
3.1.1
Background
Despite the major success of combination antiretroviral therapy (ART) in suppressing 
viral replication and preventing disease progression, HIV-1 infection persists and is not 
eliminated by available antiretroviral drugs. When ART is discontinued, viral rebound 
occurs within 2-3 weeks in most subjects (Davey et al., 1999) (Strategies for 
Management of Antiretroviral Therapy Study et al., 2006). Even in the context of 
suppressive ART, HIV infection is characterized by persistent low level HIV-1 viremia 
and immune activation and cell-associated HIV-1 remain relatively stable (Deeks et al., 
2013). Studies have shown that intensified antiretroviral regimens do not affect low level 
viremia and do not result in lower levels of HIV-1 persistence (Markowitz et al., 2014; 
McMahon et al., 2010).
The primary barrier preventing HIV-1 eradication by ART is a pool of long-lived latently 
infected memory CD4+ T-cells (Chomont et al., 2009; Finzi et al., 1997). These cells 
harbor silent integrated proviral DNA capable of resuming HIV-1 expression upon 
activation (Archin et al., 2009; Bosque and Planelles, 2009; Finzi et al., 1999). In the 
inactive, resting state these cells cannot be recognized or eliminated by the immune 
system or antiretroviral drugs. Importantly, latently HIV-1 infected cells can be induced 
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to resume HIV-1 expression by latency reversing agents (LRAs) (Ylisastigui et al., 2004). 
This in turn could expose infected cells to immune-mediated recognition and killing. 
Recent clinical trials have demonstrated proof-of-concept that the state of HIV-1 latency 
can be disrupted safely in patients on ART by a group of LRAs called histone deacetylase 
inhibitors (HDACi)(Archin et al., 2012; Elliott et al., 2014). However, the outcome of 
these trials plus an accumulating body of ex vivo research also suggest that, in the 
majority of patients, reactivation alone does not reduce the HIV-1 reservoir - possibly 
because of insufficient immune mediated killing of reactivated cells (Ho et al., 2013; 
Shan et al., 2012). This calls for combining LRAs with immune targeted interventions 
such as HIV-1-specific monoclonal antibodies. 
A fraction of HIV-infected individuals (10 – 30%) mount a serologic response that can 
neutralize a broad spectrum of HIV-1 isolates (Simek et al., 2009). Although broadly 
neutralizing antibodies that arise during HIV infection fail to resolve established 
infection, the selection of resistant strains indicates that bNAbs exert selective pressure 
on the virus. Importantly, several different groups of investigators have shown that 
macaque chimeric simian/human immunodeficiency virus (SHIV) infection can be 
prevented by passive transfer of broadly neutralizing anti-HIV-1 monoclonal antibodies, 
(Shingai et al., 2013). Broadly neutralizing antibodies might also play a role in the 
treatment of HIV infection.
Broadly neutralizing antibodies (bNAbs) differ from other therapeutic modalities for HIV 
in several respects. First, they can neutralize the pathogen directly; second, they have the 
potential to clear the virus and infected cells through engagement of innate effector 
responses; and third, immune complexes produced by the passively transferred antibodies 
may enhance the immune response to HIV. In fact, a subset of bNAbs may inhibit cell-to-
cell transmission of HIV at very low concentrations (Malbec et al., 2013). Experiments in 
humanized mice and non-human primates indicate that combinations of bNAbs can lead 
to rapid virologic suppression that is sustained for as long as mAb levels are maintained 
above a certain threshold (Barouch et al., 2013). 
In SHIV-infected nonhuman primates, 3BNC117 induces rapid viral suppression as 
monotherapy (Shingai et al., 2013). Also, 3BNC117 monotherapy is able to prevent 
infection in macaques challenged with SHIVAD8EO or SHIVDH12-V3AD8 more effectively 
than the previously described antibody VRC01(Shingai et al., 2014). While antibody 
monotherapy did not control HIV-1 infection in viremic, untreated hu-mice, a single 
neutralizing antibody, i.e. 3BNC117, was able to sustain undetectable viral loads after 
initial suppression by antiretroviral therapy. Whereas hu-mice that received ART 
normally rebounded immediately after the drugs were terminated, continuing a single 
antibody was sufficient to maintain control after ART interruption in 50-86% of the hu-
mice, for as long as antibody concentrations remained therapeutic (Horwitz et al., 2013a). 
Mice that escaped 3BNC117 carried resistance mutations in the CD4bs at positions 
YU2(279-281) or YU2(458/459). In contrast, viruses that emerged after immunotherapy was 
terminated did not contain antibody resistance mutations and remained sensitive to 
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neutralization by the antibody. Early phase 1 results show that 3BNC117 is active in 
reducing viremia in HIV-1-infected humans (Caskey et al., 2015a).
Passive administration of less potent, first generation anti-HIV-1 bNAbs has been 
evaluated in ART-interruption settings in humans. In these studies, 13-16 antibody 
infusions were administered intravenously at doses ranging from 0.5 to 2 g and were 
generally found to be safe and well tolerated. Furthermore, one of the antibodies (2G12) 
seemed to delay viral rebound in several participants. This effect was rather limited, as 
2G12 did not neutralize the donor’s virus isolates with sufficient potency (Trkola et al., 
2005a) (Mehandru et al., 2007a). 
The SMART randomized trial demonstrated that episodic ART, guided by drop in CD4+ 
count (ART reinitiated if CD4+ T cell count < 250 cells/l), leads to increased risk of 
opportunistic infections or death from any cause, as compared with continuous ART, 
during a median follow-up time of 16 months (Strategies for Management of 
Antiretroviral Therapy Study et al., 2006). While structured treatment interruptions 
(STIs) have traditionally been avoided given safety concerns, it should be noted that, in 
the first 16 weeks following randomization into the SMART study, there were no deaths 
in either treatment group – those that received continuous ART or those that received 
episodic ART guided by CD4 count.  In addition, the differences in risk of opportunistic 
diseases and major cardiovascular, renal, and hepatic diseases between the two groups 
occurred predominantly after 16 weeks, increased over time and were strongly associated 
with low CD4 counts as well as increased viral loads. Recent evidence suggests that short 
analytical treatment interruption, in individuals with preserved CD4 count and virologic 
suppression, is safe and is an accepted tool to evaluate new therapeutic modalities 
(Kutzler and Jacobson, 2008; Rothenberger et al., 2015). Thus, brief ART interruption 
can be used to study the role that recently isolated anti-HIV-1 bNAbs might have in 
controlling or preventing HIV-1 replication.
In support of the idea that bNAbs and inducers can alter the reservoir, combinations of 
these agents were shown to interfere with the establishment of and disrupt the reservoir in 
humanized mice by a mechanism that requires engagement of antibody Fc effector 
functions (Bournazos et al., 2014; Halper-Stromberg et al., 2014). We propose to conduct 
a proof-of-concept study that will combine bNAb-mediated clearance of viral-antigen 
producing cells (i.e. 3BNC117) with a potent LRA (i.e. romidepsin) as a novel approach 
to reduce the HIV-1 reservoir in chronically infected individuals on suppressive ART. 
This study will address several gaps in current knowledge: 1) The effect of combining 
ART+LRA+bNAb vs. ART+LRA alone on the size of the HIV-1 reservoir and time to 
viral rebound following ART interruption; 2) The impact of repeated exposure to a potent 
LRA with an interval of 2 months; 3) Correlates for time to viral rebound in patients 
receiving LRAs and combined LRA+bNAb; 4) The immunomodulatory effects of LRA 
and bNAb treatment by characterizing phenotypic as well as functional changes in 
antigen-presenting (DCs, macrophages/monocytes) and effector cells (NK, NKT, CD8+ 
cells). 
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3.1.2
3BNC117 
3BNC117 is a broadly neutralizing and highly potent anti-HIV-1 antibody. 3BNC117 
was initially cloned from one B cell isolated from a volunteer infected with HIV-1 clade 
B, who controls his HIV-1 infection without antiretroviral therapy. 3BNC117 targets the 
CD4 binding site (CD4bs) within HIV-1 envelope gp-120. It showed an average IC80 on a 
combined group of 95 tier 2 viruses of 1.4 g/ml when evaluated by in vitro 
neutralization assays (Scheid et al., 2011). 3BNC117 also showed in vivo activity in 
experiments in both humanized mice and non-human primates. In chronically infected 
animals, passive administration of 3BNC117 alone or in combination with other potent 
neutralizing antibodies suppressed plasma viremia to levels below detection (Horwitz et 
al., 2013b; Klein et al., 2012; Shingai et al., 2013). Moreover, 3BNC117 administration 
protected both humanized mice (Gruell et al., 2013) and rhesus macaques (Shingai et al., 
2014; Shingai et al., 2013) from challenge with HIV-1 and tier 2 SHIVs, respectively. 
3BNC117 has been manufactured for clinical use under cGMP by Celldex Therapeutics.  
The manufacture of the recombinant human monoclonal 3BNC117 was carried out by in 
vitro serum-free CHO cell culture. 3BNC117 was manufactured as a sterile solution 
intended for parenteral use, in compliance with Good Manufacturing Practices (GMP). 
No animal-derived raw materials were used during the cell culture, purification, and 
formulation of the drug substance. The drug substance was manufactured in a dedicated 
suite utilizing single-use equipment (e.g., WAVE bioreactor) to minimize potential for 
product cross contamination. A low pH step and a nanofiltration step were used for virus 
inactivation and reduction. Viral clearance studies used the model viruses PPV and A-
MuLV. Testing for adventitious agents was performed in accordance to FDA Points to 
Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human 
Use (1997). An ongoing drug product stability testing program monitors the quality of 
3BNC117 over the duration of the clinical dosing period. Stability is evaluated in real 
time at the recommended storage conditions of 5 ± 3°C as well as at accelerated 
temperature conditions of 25 ± 2°C / 60 ± 5% RH. 
3.1.2.1
Clinical Safety of other anti-HIV Monoclonal Antibodies.
Monoclonal antibodies are a growing part of the therapeutic arsenal. While each mAb 
product has unique safety issues related to its mechanism of action, the major safety 
concern related to mAbs in general is infusion/hypersensitivity reactions, which are more 
common for mAbs that contain murine elements. 3BNC117 is a fully human recombinant 
form of a naturally existing human mAb. Passive administration of antibodies is 
successfully used to prevent or treat several viral diseases and several monoclonal 
antibodies are being developed for use in either prevention or treatment of infectious 
diseases.
Passive administration of anti-HIV-1 antibodies has also been evaluated in humans. HIV 
Immune Globulin (HIVIG) was in clinical use in the 1990s before the advent of highly 
effective ART. HIVIG was also evaluated in HIV-infected pregnant females and their 
newborns in a phase III trial to assess whether HIVIG plus single dose nevirapine given 
to mothers and infants would provide additional benefit over single dose nevirapine alone 
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for prevention of peripartum HIV transmission. While there was no demonstrable 
difference in treatment efficacy, the study showed that that there were no significant 
differences in mortality or serious AEs between the two arms of the trial (Onyango-
Makumbi et al., 2011).
Several monoclonal antibodies that target HIV-1 have been evaluated in clinical studies. 
For example, 2F5 and 4E10 are IgG1 (kappa) monoclonal antibodies that target the 
membrane-proximal ectodomain of gp41, while 2G12 binds to a carbohydrate moiety on 
the silent face of gp120. These neutralizing antibodies were evaluated in combination in 
HIV-infected individuals (Armbruster et al., 2004). The antibodies were administered 
intravenously at 0.5 to 1 g doses; 4 to 8 weekly infusions were given. The antibodies 
were safe and well tolerated and no clinical or laboratory abnormalities were observed 
throughout the studies. A low-level antibody response against 2G12 was found in two 
subjects. 
Two other studies included HIV-infected subjects on combination ART and plasma viral 
levels < 50 copies/ml (Trkola et al., 2005a), n = 14; (Mehandru et al., 2007a); n =10. The 
antibodies were administered intravenously at doses ranging from 1 to 2 g for each 
antibody; 13-16 weekly antibody infusions were given. ART was interrupted following 1 
or 4 antibody infusions. Antibody infusions were well tolerated in most subjects; mild 
and transient side effects were reported only occasionally. No serious adverse events 
(SAEs) were recorded. In both studies, the use of mAbs was safe and generally delayed, 
but did not prevent viral rebound. The emergence of resistance to 2G12, however, 
demonstrated that the antibody exerted selective pressure on the circulating viral strains. 
It is important to note that the antibodies used in these studies have far lower potency and 
breadth than the more recently isolated neutralizing antibodies, such as 3BNC117. 
Moreover, in contrast to 3BNC117, these antibodies had very limited effect in the 
treatment of HIV in humanized mice (Poignard et al., 1999).
3.1.2.2
Preclinical Toxicity Studies with 3BNC117 
A tissue cross-reactivity study, performed on a full panel of tissues from humans and rats, 
showed good concordance of binding between the two species. While 3BNC117 showed 
widespread cytoplasmic binding, it is generally understood that cytoplasmic binding is 
considered of little to no toxicologic significance.  Membrane binding of 3BNC117 was 
restricted to two limited/rare cell types in conjunctival recesses and in the urinary bladder 
(neither of which correlated with findings in the repeat dose toxicology study).
The antibody 3BNC117 was evaluated for safety in a multidose study in rats. Despite 
some animals producing anti-drug antibodies, the rats appeared to have maintained 
adequate drug exposure in the study, with twice per week dosing for four weeks. Aside 
from injection site findings, there were no 3BNC117 related effects, in the Main and 
Recovery group animals, on clinical observations, body weight, food consumption, body 
temperature, clinical pathology parameters, organ weights or macroscopic and 
microscopic observations, and the NOEL (no observable effect level) was determined to 
be the high dose of 60 mg/kg twice a week for four weeks. 
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3.1.2.3
Clinical Experience with 3BNC117
3BNC117 is currently being evaluated in a phase 1 study in both HIV-uninfected and 
HIV-infected subjects (protocol MCA-835) and in an exploratory phase 2 study in HIV-
infected subjects (protocol MCA-867). 
In protocol MCA-835, study subjects are administered one or two intravenous infusions 
of 3BNC117 at increasing dose levels (1 mg/kg, 3 mg/kg, 10 mg/kg or 30 mg/kg), and 
are followed for 24 weeks after last infusion. As of 7 November 2015, 55 subjects (22 
HIV-uninfected, 19 viremic HIV-infected and 14 ART-treated HIV-infected individuals) 
have enrolled in the study. Five HIV-uninfected individuals have received two infusions 
of 3BNC117 at 30 mg/kg, 12 weeks apart. Twenty-two subjects (3 HIV-uninfected and 
19 HIV-infected) have been administered one dose of 30 mg/kg.
Overall, 3BNC117 has been generally safe and well-tolerated, mild transient myalgia, 
fatigue and headache have occurred. Some participants reported ophthalmic complaints, 
but a causal relationship with 3BNC117 was not established. No SAEs or grade 3/4 AEs 
deemed related to 3BNC117 have occurred. A safety data summary is included in the 
Investigator’s Brochure (IB).
Preliminary PK data show that 3BNC117’s half-life is 17.6 days in HIV-uninfected and 
9.6 days in viremic HIV-infected individuals. 3BNC117 decay rates following first and 
second 10 mg/kg infusions are similar.  Available PK data in ART-treated HIV-infected 
individuals with HIV-1 viral loads (VL) < 20 copies/ml show that 3BNC117 levels 
decline at slower rate than in viremic individuals.
A transient decline in HIV-1 viremia, of approximately 0.5 log, occurred following the 
administration of 3 mg/kg of 3BNC117 to three HIV-infected subjects with detectable 
viremia. Of the 3 individuals receiving the 10 mg/kg dose of antibody, only 2 responded 
with a decrease in viremia of 0.69 and 1.36 log10. The individual that did not respond was 
infected with 3BNC117-resistant virus (2C4; IC50 > 20µg/ml at baseline). All nine 
viremic individuals that received the 30 mg/kg dose of 3BNC117 showed rapid decreases 
in their viral loads that varied between individuals from 0.8 to 2.5 log10. The median time 
to reach the nadir in viremia was 7 days, and the mean drop in VL was 1.48 log10 at nadir. 
but could be as long as 21 days. Emergence of resistant viral strains was variable, with 
some individuals remaining sensitive to 3BNC117 for a period of 28 days after infusion 
(Caskey et al., 2015b). Virologic data will continue to be analyzed under protocol MCA-
835, as additional HIV-infected subjects are enrolled. 
In protocol MCA-867, HIV-infected individuals on suppressive ART are administered 
two 30 mg/kg intravenous infusions of 3BNC117 at week 0 and week 3. ART is 
discontinued 2 days after the first 3BNC117 infusion. Subjects are followed weekly and 
ART is resumed if viral rebound occurs or CD4+ T cell counts decline to < 350 
cells/mm3. As of 7 November 2015, 8 individuals have been enrolled. 3BNC117 
infusions have been well tolerated, with few mild and moderate AEs reported to date. 
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3.1.3
Romidepsin
Romidepsin is an HDAC Inhibitor that has emerged as one of the potent inducers of HIV-
1 transcription and it is ~1000 fold more potent than SAHA (vorinostat) in inducing 
latent HIV-1 expression (Wei et al., 2014). Romidepsin displays isoform specificity 
towards class I HDACIs, which are particularly important to maintaining HIV-1 latency. 
Romidepsin is FDA-approved for use in the US in patients with cutaneous and peripheral 
T-cell lymphoma, and is used at a dose of 14 mg/m2. In vitro studies have demonstrated 
that Romidpesin is capable of activating HIV RNA expression at doses as low as 15-40 
percent of the clinical dose of 14 mg/m2 (Wei et al., 2014). Additionally, in a proof-of-
concept trial, romidepsin was capable of activating HIV RNA expression at a dose of 
5mg/m2 (Sogaard et al., 2015). Romidepsin will be provided by Celgene for use in this 
study.
3.1.3.1
Preclinical Toxicity Studies with Romidepsin
No specific fertility studies have been conducted with romidepsin in humans. Based on 
non-clinical findings in repeat-dose toxicity studies, romidepsin has the potential to affect 
male and female fertility. In a 26 week study in rats, testicular atrophy or degeneration at 
repeated dosing at ≥ 0.33 mg/kg/week corresponding to 1.98 mg/m2 or a steady state 
mean AUC0-∞ 10.3 ng.hr/mL. In dogs, romidepsin caused hypospermia in the testes at 
doses ≥ 1.0 mg/kg corresponding to 20mg/m2. In rats, at doses ≥0.1 mg/kg/week 
corresponding to 0.6 mg/m2 or a mean steady state AUC0-∞ 4.9 nghr/mL, females 
exhibited atrophy in the ovary, uterus, vagina and mammary glands. Further, maturation 
arrest of ovarian follicles was observed in female rats at ≥ 0.3 mg/kg/week corresponding 
to 1.8 mg/m2. Romidepsin has shown developmental toxicity in non-clinical studies. In 
this study, the use of two contraceptive methods for both female and male study subjects 
is required for the duration of the study; this is specified in the exclusion criteria.
3.1.3.2
Clinical Experience with Romidepsin
In clinical trials, the most common adverse events (AE) associated with romidepsin 
included 
gastrointestinal 
(nausea, 
vomiting, 
diarrhea/constipation), 
hematologic 
(thrombocytopenia, leucopenia (neutro- and lymphopenia) and anemia), asthenic 
(asthenia, fatigue, malaise and lethargy) and electrolyte abnormalities (hypomagnesemia, 
hypokalemia and hypocalcemia), hyperglycaemia and pyrexia. Overall, the most common 
grade 3/4 events reported were anaemia, thrombocytopenia, neutropenia, leukopenia and 
fatigue. These AE should be interpreted in the context of patients with severe 
haematological cancers. The detailed results of the pooled safety analysis are presented in 
the IB.
 
A theoretical risk of HDAC inhibitors is that they will induce activation of other 
retroviruses, oncogenes and/or DNA viruses, including CMV, hepatitis B virus and JC 
viruses. A possible association between romidepsin and reactivation of DNA viruses has 
been described in 3 case reports (Ritchie et al., 2009). In this small case series, there was 
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a temporal association with reactivation and administration of the HDACi, but it is 
important to keep in mind that these patients were all patients with advanced cancer and 
immunosuppression. In the CLEAR study, including aviremic adults with HIV-1 
infection, the participants received oral panobinostat (20 mg) three times per week every 
other week for 8 weeks while maintaining ART. Concentrations of cytomegalovirus 
DNA (in urine) and Epstein-Barr virus DNA (in blood) were repeatedly quantified during 
panobinostat treatment, but no evidence of unintended DNA virus reactivation was 
recorded (Rasmussen et al., 2014).
During a pilot study of 6 HIV-1 patients on long-term ART who received 3 infusions of 5 
mg/m2 of romidepsin over the course of 3 weeks, no serious adverse events (SAEs) or 
suspected unexpected serious adverse reactions (SUSAR) were observed (Sogaard et al., 
2015). Forty-one AE were registered during follow-up of which 35 AEs were considered 
related to romidepsin. All drug-related AEs were mild (grade 1, n=35) and resolved 
spontaneously within a few days. The most common romidepsin-related AEs were 
abdominal symptoms (e.g. nausea [n=11], borborygmia [n=4], abdominal pain [n=2]) and 
fatigue (n=5). Modest changes in white blood cell counts (WBC) and T cell counts were 
observed during the study with the lowest levels generally observed after the second 
romidepsin infusion, but no further decline following the third infusion. Reassuringly, 
neutrophil counts below 1,000 cells/mm3, CD4+ cell counts below 350 cells/mm3, or 
platelet counts below 100,000 cells/mm3 were not observed. 
A phase 1b/2a study (REDUC trial) was conducted to evaluate the effects of 
immunizations with a protein vaccine (Vacc-4x/rhuGM-CSF) followed by romidepsin on 
the HIV-1 reservoir of HIV-1-infected individuals on antiretroviral therapy. Study 
participants were administered a series of six intradermal immunizations over 12 weeks. 
The immunization phase was  followed by 5 mg/m2 romidepsin infusions once weekly for 
3 weeks while maintaining ART. Romidepsin was administered intravenously over 4 
hours. 96% the 141 reported adverse events were of grade 1 severity. 57 grade 1  AEs 
were considered related to romidepsin, with fatigue (14 individuals) and nausea (15 
individuals) being the most frequently reported.  The observed adverse events did not  lead 
to dose de-escalation or other modifications of the study regimen. In addition, there were 
no clinically significant adverse effects of the investigational therapies on blood 
biochemistry parameters (Leth et al., in press). 
Romidepsin is also being evaluated in ART-treated HIV-infected individuals in a phase 
1/2 multi-site trial conducted in the US. This study aims to evaluate romidepsin’s safety 
and its ability to induce HIV-1 expression in HIV-infected individuals who are on 
suppressive ART regimens (NCT01933594).
3.2
Hypothesis 
The combined administration of two infusions of 3BNC117 (30 mg/kg) together with six 
infusions of romidepsin (5 mg/m2) will prevent or delay the return of HIV-1 viremia 
during an analytical treatment interruption compared with administration of romidepsin 
alone. 
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3.3
Aims 
Primary Objective:
-
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.  
Secondary Objectives:
-     Evaluate the safety of romidepsin plus 3BNC117 or romidepsin alone in ART-treated 
HIV-1 infected individuals; 
-
Evaluate the effects of romidepsin plus 3BNC117 or romidepsin alone on the size of 
the HIV-1 reservoir in ART-treated HIV-1-infected individuals;
Exploratory Objectives:
-
Evaluate the effects of romidepsin plus 3BNC117 or romidepsin alone on HIV-1 
transcriptional activity and plasma HIV-1 RNA in ART-treated HIV-1-infected 
individuals
-
Evaluate the immunomodulatory effects of romidepsin plus 3BNC117 or romidepsin 
alone in ART-treated HIV-1-infected individuals.
-
Evaluate the pharmacokinetics of romidepsin in HIV-1-infected individuals
3.4
Primary Endpoint
-
Days to viral rebound during ATI or days to reinitiation of ART in participants who 
restart ART before viral rebound.  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.”  
3.5
Secondary Endpoints
-
Safety evaluation, as measured by rate and severity of adverse events (AE), serious 
adverse events (SAE), and serious unexpected serious adverse reactions (SUSAR).
-
Size of the functional, latent HIV-1 reservoir 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. These measurements will be performed in Dr. Siliciano’s 
laboratory.
-
Size of the proviral HIV-1 reservoir as 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, 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).
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3.6      Exploratory Endpoints
-
HIV-1 transcriptional activity as determined by unspliced HIV-1 RNA in circulating 
total CD4+ T cells.
-
Phylogenetically compare viruses grown from PBMCs collected from participants 
while on ART to rebound viruses collected after ART interruption.
-
Plasma cytokine and immune activation biomarker levels.
-
Change from baseline in the capacity of NK and CD8+ T cells to mediate inhibition 
of viral replication ex vivo. 
-
Absolute cell counts and phenotypic characteristics for T and NK cells using standard 
cell marker panels by flow cytometry (e.g. CD3, CD4, CD8, CD45RA, CCR7 for T 
cells and CD16/CD56 for NK cells). 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.
-
Absolute counts, phenotypic characteristics, and functional properties of monocytes 
and dendritic cells using standard cell marker panels by flow cytometry.
-
Romidepsin levels at the end of infusion and at 1 day after each infusion in treatment 
cycle 1. 
4
Study Design
The design is a randomized interventional phase 2a trial of romidepsin with or without 
3BNC117 in 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.  
Enrollment will be competitive; it is anticipated that each site will enroll approximately 
10 participants.
Participants will be randomized 1:1 in a non-blinded fashion to receive one of two 
regimens: 
A) Two treatment cycles each consisting of 3BNC117 infusions (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 closely for viral 
rebound. The study outline is shown in Figure 1. The targeted enrolment is 30 subjects 
(15 per arm).
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Leukapheresis will be performed before and after the two treatment cycles to guarantee 
sufficient material to investigate changes in the reservoir after the interventions. 
Figure 1. Study Design
  
5
Study Population
HIV-infected males and females, between the ages of 18-65, on ART for at least 24 
months, with HIV-1 RNA plasma level of < 50 copies/ml by standard assays for at least 
18 months, and with current CD4+ T cell counts > 500 cells/l. 
5.1
Inclusion Criteria
1. Adults age 18-65 years with documented HIV-1 infection
2. CD4+ T-cell count > 500 cells/mm3 at screening
3. On ART for a minimum of 18 months and HIV-1 RNA plasma level of < 50 
copies/ml by standard assays for at least 12 months (a single viral load 
measurement > 50 but < 500 copies/ml during this 12 month time period is 
allowable). 
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4. Individuals on protease inhibitor, NNRTI-based regimens, or regimens 
containing cobicistat must be willing to switch to an integrase-inhibitor-based 
regimen (raltegravir or dolutegravir) prior to enrollment. 
5.2
Exclusion Criteria
1. Use of systemic corticosteroids, immunosuppressive anti-cancer, or other 
medications considered significant by the investigators within the last 6 months.
2. Pregnancy as determined by a positive urine or serum beta-hCG.
3. 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), non-estrogen containing formulations of 
hormonal birth control drugs with condom) for the study duration. Romidepsin 
may interact with estrogen-based contraceptives and such agents may be 
unreliable in participants receiving romidepsin. 
4. Currently breast-feeding. 
5. History of resistance to 2 or more classes of antiretroviral medication.
6. 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, autoimmune diseases).
7. 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.
8. A history of AIDS-defining illness within 3 years prior to enrollment.
9. History of B-cell lymphoma, including CNS lymphoma
10. CD4 nadir < 200 cells/mm3 within the last 5 years.
11. 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.
12. 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.
13. Use of QT-prolonging medication, renal or hepatic disease, structural heart 
disease or left ventricular dysfunction
14. Any symptomatic or asymptomatic arrhythmia excluding sinus arrhythmia or 
bradycardia ≥ 50 bps.
15. Use of Coumadin or Coumadin derivatives 
16. Laboratory abnormalities in the parameters listed below: 
a.
Absolute neutrophil count  1,000 cells/μl
b. Hemoglobin < 11 gm/dL
c.
Platelet count < 125,000 cells/μl
d. ALT  1.25 x ULN
e.
AST  1.25 x ULN
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f.
Total bilirubin > 1.0 ULN 
g. eGFR < 60 mL/min/1.73m2
17. Any vaccination within 14 days prior to 3BNC117 administration;
18. Receipt of any therapeutic HIV vaccine in the past;
19. Receipt of any anti-HIV monoclonal antibody in the past, or HDAC inhibitor of 
any kind in the past 2 years;
20. Participation in another clinical study of an investigational product currently or 
within past 12 weeks, or expected participation during this study.
6
Methods and Procedures
6.1
Screening Procedure and Study Visits
The Time of Events Schedule summarizes the frequency and timing of various study 
assessments. See Appendix A. Recruitment, screening and all visits during the study 
period are performed either at The Rockefeller University Hospital (RUH) outpatient 
clinic, at the Aarhus University Hospital (AUH) outpatient clinic or at the infectious 
diseases outpatient clinic of the University Hospital of Cologne (UCH).
6.1.1
Pre-Screening Questionnaire
Subjects eligible for enrollment might be recruited at the RUH, AUH or UCH outpatient 
clinics. Potential participants will first undergo pre-screening by telephone to assess 
medical history, preliminary HIV risk assessment, and qualification for the study. 
Potential volunteers will have the opportunity to discuss the study and ask questions of 
the study recruiter at this time. Those who are eligible and interested in participating will 
attend a screening visit at the RUH, the AUH or the UCH Outpatient Clinics.
6.1.2
Screening Visits
Screening Visit (day -56 to 0):
Study personnel will answer any questions about the study. Written informed consent 
will be obtained prior to conducting any study procedures. To ensure informed consent, 
the principal investigator or designee will discuss the following processes individually 
with each volunteer:
1. Pregnancy avoidance counseling. Sexually active males and females, participating 
in sexual activity that could lead to pregnancy, should use two reliable forms of 
contraception for the duration of the trial.
2. Risk reduction counseling. Sexually active males and females will be asked to use 
condoms during the short analytical treatment interruption due to the risk of 
intermittent viremia.
3. One must assume that no improvement in control of HIV infection will occur 
given the exploratory nature of this study.
4. Subjects agree to stopping their antiretroviral medications as planned in the 
protocol and agree to return for scheduled follow up visits for monitoring of 
plasma virus levels.
If the volunteer consents to participate, site personnel will:
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
Obtain a complete medical history (including concomitant medications and 
cardiovascular history);

Assure that all inclusion criteria are met and there are no exclusion criteria;

Review subject’s previous HIV-1 viral load and CD4 measurements (records 
should be available for at least 1.5 years prior to screening);

Perform an ECG;

Perform a general physical examination including height, weight, vital signs 
(pulse, respiratory rate, blood pressure and temperature), examination of skin, 
respiratory, cardiovascular and abdominal systems, and an assessment of cervical 
and axillary lymph nodes;

Collect blood and urine specimens for all tests as indicated in the Time of Events 
Schedule, including plasma HIV-1 RNA levels and CD4 counts;

Perform a pregnancy test for all female volunteers;
6.1.3
Change in ART regimen
Upon meeting eligibility criteria, individuals on protease inhibitor or NNRTI-based 
regimens, or regimens containing cobicistat will be switched to an integrase-inhibitor-
based regimen (raltegravir or dolutegravir) that does not contain cobicistat. The change in 
ART regimen will occur at least 2 weeks prior to baseline leukapheresis (Visit 2, week -
2).
Study investigators will discuss changes in ART regimen with the participant’s primary 
care physician. 
6.1.4
Leukapheresis / Blood Draw visits
Leukapheresis will be performed on day -14 and day 154 (12 weeks after completion of 
treatment cycle 2). 
On leukapheresis visits, site personnel will:

Answer any questions about the study;

Perform leukapheresis;

Obtain changes in concomitant medications;

Assess weight, height and vital signs (pulse, respiratory rate, blood pressure and 
temperature);

Perform a directed physical examination;

Perform a pregnancy test for all female volunteers;

Perform pregnancy avoidance counseling;

Collect blood and urine specimens for all tests as indicated in the Time of Events 
Schedule (Appendix A);

Assess the occurrence of any adverse events;
Leukapheresis samples will be used for viral outgrowth assay and other research assays.
6.1.5
Treatment Cycles 1 and 2
3BNC117 infusion visits (days 0 and 56 for Group A only)
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Prior to drug infusion, site personnel will:

Answer any questions about the study;

Review interim medical history (including concomitant medications);

Review safety laboratory data;

Perform a physical examination including weight, vital signs (pulse, respiratory 
rate, blood pressure and temperature) and any further examination indicated by 
history or observation;

Collect blood and urine specimens for all tests as indicated in the Time of Events 
Schedule (Appendix A);

Perform pregnancy and safe sex counseling;

Perform a pregnancy test for all pre-menopausal female volunteers and obtain 
results prior to drug infusion;

Perform baseline assessment and record any systemic symptoms;

3BNC117 will be prepared for administration according to the Site Pharmacy 
Standard Operating Procedures;

3BNC117 mAb will be administered via a peripheral vein by slow intravenous 
infusion.

The infusion will take approximately 60 minutes. 

Subjects will be observed for adverse reactions at the study site for 1 hour after 
end of infusion. Presence or absence of adverse events will be recorded at 1 hour 
post infusion. 

Vital signs (pulse, respiratory rate, blood pressure and temperature) will be 
monitored at the end of infusion, 30 (+/- 5 min) minutes, and 1 hr (+/- 5 min) post 
infusion. 

If volunteers develop acute infusion reaction during 3BNC117 administration, the 
infusion will be held. Rescue medications, including acetaminophen, 
diphenhydramine and glucocorticoids will be available in the RUH, AUH or UCH 
infusion unit for use if clinically indicated. Infusion may be reinitiated after 
symptoms improve, and the remaining dose will be administered over 3 hours.
Romidepsin infusion visits (days 2, 9, 16, 58, 65, and 72 for Group A; days 0, 7, 14, 56, 
63, and 70 for Group B)
Prior to drug infusion, site personnel will:

Answer any questions about the study;

Review interim medical history (including concomitant medications);

Review safety laboratory data, including electrolytes;

Perform a physical examination including weight, vital signs (pulse, respiratory 
rate, blood pressure and temperature), and any further examination indicated by 
history or observation;

Collect blood and urine specimens for all tests as indicated in the Time of Events 
Schedule (Appendix A);

Perform pregnancy and safe sex counseling;
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
Perform a pregnancy test for all pre-menopausal female volunteers (blood will be 
sent STAT) and obtain results prior to drug infusion;

Perform baseline assessment and record any systemic symptoms;

Participants will be administered prophylactic ondansetron 8 mg, orally (PO), 
approximately 30 minutes prior to starting the infusion.

Additional details regarding romidepsin administration are described below in 
Section 6.2.4

If volunteers develop acute infusion reaction during romidepsin administration, 
the infusion will be held. Rescue medications, including acetaminophen, 
diphenhydramine and glucocorticoids will be available at the site infusion unit for 
use if clinically indicated. Infusion may be reinitiated after symptoms improve as 
per Appendix D.
Post-infusion follow up visits (days 3, 10, 12, 17, 23, 30, 59, 66, 68, 73, 75, 82 for Group 
A; days 1, 8, 10, 15, 21, 28, 57, 64, 66, 71, 73, 80 for Group B).
After romidepsin infusions, follow up visits will be performed two to three times a week 
(see the Time of Events Schedule, Appendix A).
On these visits, site personnel will:

Answer any questions about the study;

Review interim medical history (including concomitant medications);

Review safety laboratory data;

Perform a directed physical examination including vital signs (pulse, respiratory 
rate, blood pressure and temperature), and any further examination indicated by 
history or observation;

On the visits that occur the day following romidepsin infusion, an ECG will be 
performed;

Collect blood and urine specimens for all tests as indicated in the Time of Events 
Schedule (Appendix A);

Assess the occurrence of any adverse events;
Specific procedures to be performed at each clinic visit are illustrated in the Time of 
Events Schedule (Appendix A).  
Contact only visit (day 119 for Group A, day 119 for Group B)
Six weeks after the conclusion of the second treatment cycle, participants will be 
contacted by phone or email to assess for any changes to their medication or adverse 
events.
6.1.6
Analytical treatment interruption
During ART interruption follow up visits will be performed on a weekly basis (Appendix 
A, Time of Events Schedule).

Answer any questions about the study;
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
Review of interim medical history and use of concomitant medications;

Assessment of adverse events;

Pregnancy counseling (monthly) and pregnancy testing (every 2 weeks);

Review of safety laboratory data (monthly);

Directed physical examination including weight, vital signs (pulse, respiratory 
rate, blood pressure and temperature), and any further examination indicated 
by history or observation;

Collection of blood and urine specimens for all tests as indicated in the Time 
of Events Schedule (Appendix A);

In case of adverse event(s), the volunteer will be assessed and followed up by 
the clinical team. Supplemental visit(s) for further investigation can be 
planned at the discretion of the principal investigator or designee. 
Supplemental visit(s) may be recommended if clinically indicated or to clarify 
observations. Any abnormalities (adverse events) attributed to study drug, 
including laboratory abnormalities, should be subsequently followed until the 
event or its sequelae resolve or stabilize. 
6.1.7
ART interruption and re-initiation of combination ART
ART regimen will be discontinued at week 24, 16 weeks after the second 3BNC117 
infusion. ART will be discontinued for 12 weeks and if viral rebound does not occur, 
subjects can remain off ART with continued follow up. 
At week 36, if a subject’s HIV-1 VL remains undetectable, the subject will have the 
option to restart ART at that time or to continue weekly follow up through the end of the 
study (week 48). During the ATI, ART will be resumed if plasma HIV-1 RNA level ≥ 
200 copies/ml in 2 consecutive measurements or if CD4+ count drops < 350 cells/l and 
the result is confirmed upon repeat measurement.  In this case repeat measurements are 
performed at the next scheduled visit. If the HIV-1 RNA level is found to be ≥ 1000 
copies/ml the subject will be contacted to return to clinic as soon as the result becomes 
available. Upon viral rebound, viral genotyping will be performed to determine if any 
resistance mutations are present.  ART will also be reinitiated if the participant becomes 
pregnant, or if otherwise clinically indicated. 
Subjects who experience viral rebound during the ATI will be followed on a modified 
schedule (Appendix B).  These subjects will have study visits every 2 weeks until their 
HIV-1 VL is undetectable on 2 consecutive measurements.  At that point, they will be 
followed every 8 weeks until the final visit at week 48.  
Subjects’ primary care physicians will be contacted when virologic rebound occurs and 
periodically throughout the study. 
During ATI phase of the study subjects may be at increased risk of transmitting HIV to 
their partners and of HIV-1 superinfection from an HIV-infected partner. Therefore, 
subjects will be asked to use male or female condoms for the duration of ART 
interruption. In the event of a high-risk exposure to an HIV-infected partner, a subject 
may re-initiate ART as clinically indicated by his/her HIV primary care physician.
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6.1.8
Final Visit/Early Termination Visit
Assessments will be undertaken according to the Time of Events Schedule (Appendix A).
6.1.9
Long term safety follow up (Years 2 and 3)
Volunteers will be contacted by telephone or email 2 and 3 years after last romidepsin 
infusion 
to 
collect 
information 
regarding 
new 
health 
concerns, 
diagnoses, 
hospitalizations, or congenital abnormalities.
6.1.10 Discontinuation of 3BNC117 infusion and/or volunteer withdrawal from 
study
6.1.10.1 Discontinuation of 3BNC117 infusion
The 3BNC117 infusion will be discontinued for any of the following reasons:
1. Any immediate hypersensitivity reaction (such as urticarial rash; bronchospasm; 
laryngeal edema; anaphylaxis; syncope).
2. Life threatening medical event during 3BNC117 infusion.
6.1.10.2 Discontinuation from subsequent 3BNC117 infusion
Volunteers will be discontinued from second 3BNC117 infusion for any of the 
following reasons:
1. A disease or condition or an adverse event that may develop, regardless of 
relationship to 3BNC117, if the principal investigator or designee is of the 
opinion that another 3BNC117 infusion will jeopardize the safety of the 
volunteer.
2. Any immediate hypersensitivity reaction (such as urticarial rash; bronchospasm; 
laryngeal edema; anaphylaxis; syncope).
3. Life threatening medical event following 3BNC117 unless not related to the 
investigational product.
4. Intercurrent use of immunosuppressive medication considered significant by the 
trial physician (e.g., systemic corticosteroids).
5. Pregnancy.
6. Subject’s request to discontinue further 3BNC117 infusions.
7. ALT or AST increases of or exceeding 3 x the upper limit of normal with 
concurrent increase in total bilirubin of or exceeding 2 x the upper limit of 
normal.
6.1.10.3 Discontinuation of Romidepsin infusion
The romidepsin infusion will be discontinued for any of the following reasons:
1. Any immediate hypersensitivity reaction (such as urticarial rash; bronchospasm; 
laryngeal edema; anaphylaxis; syncope).
2. Life threatening medical event during romidepsin infusion.
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6.1.10.4 Discontinuation from subsequent Romidepsin infusions and Romidepsin 
dosing modification
Participants should continue to receive therapy until they complete the planned infusions 
or study treatment is not tolerated. If study drug-related toxicities are observed, treatment 
can be resumed only if these toxicities have returned to baseline level or their severity 
decreased to ≤ grade 1 according to the Common Terminology Criteria for Adverse 
Events v.4.03 (CTCAE) for infusion-related toxicity and the DAIDS Table for Grading 
the Severity of Adult and Pediatric Adverse Events, Version 2.0 for non-infusion-related 
toxicity. Discontinuation from subsequent romidepsin infusions will occur for the 
following reasons:
1. Grade 3 or 4 adverse events deemed related to romidepsin.  Review by the 
protocol safety review team (PSRT) and the safety monitoring committee (SMC) 
will occur to determine if romidepsin may be restarted at a reduced dose.  
Guidelines for romidepsin dose reduction are provided in Appendix D. 
2. A second occurrence of a grade 3 abnormality of ALT, AST, total bilirubin, ANC, 
platelet count, or hemoglobin.
3. Grade 4 abnormalities of ANC, platelet count, or hemoglobin. A review by the 
PSRT and SMC will occur to determine if a study pause is required.
4. ALT or AST increases of or exceeding 3 x the upper limit of normal with 
concurrent increase in total bilirubin of or exceeding 2 x the upper limit of 
normal. In this instance, discontinuation of 3BNC117 will occur as well. A review 
by the PSRT and SMC will occur to determine if a study pause is required.
The dose of romidepsin may be modified for a participant (Appendix D). 3BNC117 dose 
modification is not allowed.
6.1.10.5 Withdrawal from the study (Early Termination)
     Volunteers may be withdrawn from the study permanently for the following reasons:
1. Volunteers may withdraw from the study at any time if they wish to do so, for any 
reason.
2. Following an adverse event at the discretion of the investigator (or designee).
3. Request of the primary care provider if s/he thinks the study is no longer in the 
best interest of the subject.
4. Subject judged by the investigator to be at significant risk of failing to comply 
with the protocol in a manner that might lead to harm to self or seriously interfere 
with the validity of the study results.
5. At the discretion of the FDA, Danish Health Authority, the PEI, the BfArm or 
investigator.
6.1.10.6 Follow up after withdrawal from the study (Early Termination)
Any adverse event resulting in withdrawal of a volunteer will be followed up until 
resolution or until the adverse event is judged by the principal investigator or designee to 
have stabilized where possible.
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At the time of withdrawal, provided the volunteer is willing, all visit procedures from the 
final study visit will be performed as per the Time of Events Schedule (Appendix A).
The date and reason for withdrawal from the study (early termination) should be 
collected and reported to the Sponsor at the RU, the SMC and the local IRBs. Volunteers 
who are withdrawn from the study (early termination) after receiving at least one dose of 
3BNC117 or romidepsin will not be replaced, but, wherever possible, will be followed 
until the time of their final planned visit.
A pregnant volunteer will not receive a 3BNC117 and/or romidepsin infusion. If 
pregnancy occurs after any 3BNC117 and/or romidepsin infusion, the participant will be 
asked to return for follow up every 4-6 weeks until delivery. Approximately 2-4 weeks 
after delivery, the baby will be examined by a pediatrician of the participant’s choosing 
to assess the health status of the baby. Financial assistance will be provided to pay for the 
visit if necessary. The health status of the baby will be reported to the Sponsor at the RU, 
the SMC and the local IRBs.
6.2
Study Procedures
6.2.1
Consent Procedure
Prior to the initiation of any study related procedures, the potential subjects will be given 
a copy of the most recent IRB approved informed consent to read. Additionally, the PI or 
study staff member who has been designated to consent will discuss the specifics of the 
study including but not limited to the purpose of the research, procedures, time 
commitment, required tasks, test article or device, alternative treatments, benefits, risks, 
confidentiality etc. in a comprehensible (non-scientific) manner, using language readily 
understandable by the subject. Subjects will be told that participation is voluntary and 
that, if they do not consent, they will not be penalized. The person consenting will assure 
the voluntariness of the subject.
A private, confidential setting will be provided for the potential subject to read and 
discuss the informed consent free from coercion, undue influence or constraints of time. 
All subjects will be given a chance to ask questions and express concerns. They will be 
given the option to take the consent home and discuss it with family, friends, and /or 
health care providers. After a subject and the person conducting the consenting signs and 
dates the consent, the subject will be given a copy of the signed informed consent form. 
An enrollment note will be written in the source document as to who obtained consent, 
how, when were questions asked and answered, and that a copy of the informed consent 
was given to the subject.
 
The "Teach Back" method will be used in the clinical research setting to ask research 
participants to repeat or “teach back” the information, concepts and directions that the 
staff member has attempted to convey to the subject. This method is used to assess 
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comprehension and retention of protocol requirements, adverse event information, risks 
and benefits, and the subject's rights described in the Informed Consent process.
 
Subjects for whom English, German or Danish is not a primary language will not be 
included in this study. 
6.2.2
Study Assignment
This is a randomized, open-label study. The study drugs are dispensed as specified by the 
randomization scheme generated by the Institute of Medical Statistics, Informatics and 
Epidemiology (IMSIE), University of Cologne. Participants are centrally assigned to a 
single treatment according to randomly permuted blocks of varying length. 
Randomization is stratified by study site and implemented as a 24-7 Internet service. 
6.2.3
3BNC117 Administration Procedure
3BNC117 will be provided in single-use vials containing 5 ml of the product at a 
concentration of 20 mg/ml. The site research pharmacist will calculate the volume of 
3BNC117 to be administered. 3BNC117 will be administered as a slow intravenous 
infusion over 60 minutes in the site infusion unit. The calculated dose of 3BNC117 will 
be diluted in 0.9% Sodium Chloride, USP to a volume of 250 ml. 3BNC117 should be 
administered within 3 hours of preparation.
3BNC117 will be administered intravenously, via a peripheral vein in one of the upper 
extremities. The administration site should be free of potentially complicating 
dermatologic conditions. At the end of infusion, the IV line will be flushed with 20 ml of 
Normal Saline to ensure all the medication has been delivered.
Volunteers will remain in the infusion unit for 1 hour after drug infusion.  If volunteers 
develop acute infusion reaction during 3BNC117 administration, the infusion will be 
held. 
Rescue 
medications, 
including 
acetaminophen, 
diphenhydramine 
and 
glucocorticoids will be available for use if clinically indicated. Infusion may be 
reinitiated after symptoms improve, and the remaining dose will be administered over 3 
hours.
6.2.4
Romidepsin Administration Procedure
Romidepsin is supplied as a kit containing 1 vial of romidepsin, 10 mg, and 1 vial of 
diluent for romidepsin, 2 mL, per carton. The volume of romidepsin to be administered 
will be calculated by the site research pharmacist, and diluted in 500 mL 0.9% Sodium 
Chloride, USP. Romidepsin is chemically stable for up to 8 hours at room temperature, 
upon reconstitution. When diluted in 500 mL 0.9% Sodium Chloride, USP, solution is 
stable for 24 hours. Romidepsin infusions will be administered over 120 minutes. Only 
staff trained to administer chemotherapeutic agents will administer romidepsin.  
Romidepsin infusions will be administered by a trained research nurse with extensive 
experience with IV medication and the treatment of acute infusion-related reactions. 
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
Check electrolytes prior to infusion. Infusion will be administered if potassium, 
magnesium and calcium levels are within normal range. If potassium, magnesium 
and/or calcium level(s) are outside of the normal range, a repeat measurement will 
be obtained. If the electrolyte abnormality is confirmed, the infusion will be 
postponed. The participant will be supplemented as medically indicated and 
retested prior to infusion.

Premedicate with ondansetron 8mg orally at least 30 min prior to infusion, to 
prevent nausea or vomiting

Perform ECG 30 min after ondansetron, before infusion starts. The pre-infusion 
ECG will be read by a cardiologist. Infusion will be administered if QTc < 450 
msec. (QTc measured from lead V3 or V4, using the Fridericia formula).

Participants will be kept on continuous cardiac monitoring during infusion and a 
repeat ECG will be performed at 1 hour, during the infusion. If at 1 hour of 
infusion the QTc is > 450 msec or if it increases > 10 msec, hold infusion and 
consult with a cardiologist to determine appropriate monitoring and/or 
management, as clinically indicated;

ECG will be repeated at the end of the infusion. If the QTc is > 450 msec or if it 
increases > 10 msec from the post-antiemetic ECG, repeat ECGs will be 
performed and vital signs measured at 2 and 4 hours post infusion and a 
cardiologist will be consulted to determine appropriate monitoring and/or 
management, as clinically indicated. 

Allergic reactions to romidepsin are uncommon but during the first 10 minutes of 
infusion all subjects will be under direct observation for acute allergic reactions.

Vital signs (pulse, respiratory rate, blood pressure and temperature) will be 
monitored at the end of infusion, 30 (+/- 5) minutes, and 1 hour (+/- 5 min) post 
infusion. 

Subjects will be observed for adverse reactions at the study site for 1 hour after 
end of infusion. 

The study sites will have full and immediate access to handle and treat all acute 
medical emergencies including severe drug reactions. 

A medical doctor dedicated to the study will be present at all times at the study 
site during the infusions. 

A prescription for ondansetron will be given to participants to ameliorate any 
symptoms that may develop in the 48 hours following romidepsin infusion.
6.2.5
Medical History and Physical Examination
At the time of screening, a past medical history will be collected that will include details 
of any previous reaction to vaccination, and contraceptive practices. Interim medical 
histories will be collected at time-points according to the Time of Events Schedule 
(Appendix A). 
A general physical examination will be conducted including weight, height, vital signs, 
and examination of skin, respiratory, cardiovascular, central nervous and abdominal 
systems. At the time of 3BNC117 and romidepsin infusions and at selected time-points 
thereafter, general and/or directed physical examinations will be performed according to 
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the Time of Events Schedule (Appendix A). A directed physical examination will include 
vital signs and any further examination indicated by history or observation.
6.2.6
Blood Collection and Shipment
Venous blood will be collected at every study visit, usually from the antecubital fossa, 
according to the Time of Events Schedule (Appendix A). Total volume collected during 
the study will not exceed 550 ml in any 8-week period.
All specimens will be handled according to Processing Laboratory SOPs. Frozen 
PBMCs, plasma and serum will be processed and stored at the study sites.
6.2.7
Monitoring for cytokine release associated adverse events and treatment of 
cytokine release syndrome
Based on previous clinical experience with similar monoclonal antibodies and with 
3BNC117 (protocols MCA-835, MCA-866 and MCA-867), it is unlikely that 
administration of 3BNC117 will lead to cytokine release syndrome. However, a potential 
side effect of a monoclonal antibody can be the stimulation of a massive release of 
cellular cytokines, which can have profound effects on blood pressure, vascular integrity, 
and myocardial, lung, liver, and kidney functions. If cytokine release syndrome occurs, 
the volunteer may need to be treated with intravenous fluids, vasopressors, and high-dose 
corticosteroids and may require ventilatory support. 
Study participants will be monitored for 1 hour post infusion in the site infusion unit. 
Access to a twenty-four hour on-call physician is available at all sites. The study sites are 
equipped with crash carts for immediate medical care. Supportive medications, including 
acetaminophen, diphenhydramine and glucocorticoids, will be available at both clinical 
sites for use if clinically indicated. In case of an emergency, after stabilization of the 
volunteer, he/she will be transferred to a tertiary care center for specialized medical care. 
6.2.8
Family Planning Counseling
During screening and subsequent study visits, study personnel will counsel volunteers 
about the importance of prevention of pregnancies and the use of condoms, as well as 
other effective family planning methods. Condoms will be provided.
Participants will be required to use 2 effective forms of contraception (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.
Pregnancy tests will be conducted at each clinic visit as outlined in the Time of Events 
Schedule (Appendix A). Should pregnancy be detected before administration of 
3BNC117 or romidepsin, the volunteer will not receive the infusion. Should pregnancy 
be detected after any 3BNC117 or romidepsin infusion, a pregnant volunteer will be 
asked to return for follow up every 4-6 weeks until delivery. Should pregnancy occur, 
ART will not be discontinued or will be resumed as soon as the study investigators 
become aware of the pregnancy. Approximately 2-4 weeks after delivery, the baby will 
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be examined by a pediatrician of the participant’s choosing to assess the health status of 
the baby. Financial assistance will be provided to pay for the visit if necessary. The 
outcome of the pregnancy and the health status of the baby will be reported to the 
Sponsor at the RU, the local IRBs, and the SMC.
6.2.9
Compensation
Study volunteers will be compensated according to local standards. 
6.2.10 Safety Assessments
6.2.10.1 Solicited Adverse Events
Solicited adverse events in this study include presence of feverishness, chills, headache, 
nausea, vomiting, diarrhea, malaise, myalgia and arthralgia, as well as ocular complaints 
such as conjunctival erythema, excessive tearing or burning within 2 weeks of 3BNC117 
and/or romidepsin administration, and will be collected prospectively by structured 
interviews on the 3BNC117 and romidepsin infusion and post-infusion follow up visits; 
recorded and graded according to pre-established criteria (see C). The CTCAE v4.03 
grading scale will be used to grade infusion-related adverse events. The DAIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0 will be used to 
grade all non-infusion-related adverse events. 
Vital signs (pulse, respiratory rate, blood pressure and temperature) will be measured 
prior to 3BNC117 or romidepsin administration, at the end of infusion, at 30 minutes, and 
1 hour after the infusion is completed, graded according to Appendix C and recorded. 
Similarly, the occurrence of adverse events will be assessed and graded. All medications 
required for treatment of adverse events will be recorded.
6.2.10.2 Other Adverse Events
Other adverse events will be recorded following an open question to volunteers, with the 
dates of commencement and resolution and any medication required. All adverse events 
will be followed to resolution. Serious adverse events will be collected during the entire 
study period. They will be graded as indicated in Appendix C. 
Safety monitoring at each clinical site will be conducted by an external monitor and by an 
external Study Monitoring Committee (SMC). The RUH, AUH and UCH IRBs will 
conduct the initial review of the proposed study and will follow progress through annual 
reports and by immediate notification of serious and unanticipated adverse events. Any 
serious adverse events will be reviewed by the study investigators immediately. Site 
investigators will notify the local IRB and the sponsor at the Rockefeller University 
within 2 working days from the investigators being made aware of the event. The RU 
sponsor will notify the FDA, Danish Health Authority, PEI, and BfArm per 21 CFR 312 
(Appendix G). The SMC will be available to the investigators for consultation and review 
of severe adverse events if needed.
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6.2.10.3 Routine Laboratory Parameters
As outlined in the Time of Events Schedule, laboratory parameters will include CD4+ T 
cell counts and HIV-1 VLs, hematology, clinical chemistry, and urinalysis. ANA will be 
performed at screening. 
Prior to each 3BNC117 or romidepsin infusion, pre-menopausal female volunteers will 
have serum beta-HCG assessed and at follow up visits they will have urine beta-HCG 
checked. The laboratory samples for these tests will be collected at the time points 
indicated in the Time of Events Schedule (Appendix A). In the event of an abnormal 
laboratory value, volunteers may be asked to have an additional sample collected at the 
discretion of the principal investigator or designee. 
Volunteers will be screened for syphilis and viral hepatitis (HBsAg and HCV-RNA) at 
the Screening Visit. 
6.2.11 Diagnostic work up in the event of graded elevations in total bilirubin 
Any participant with a graded elevation in total bilirubin will undergo a diagnostic work 
up that includes right upper quadrant ultrasound, testing for gamma glutamyl transferase 
(GGT) HAV (IgM and IgG), HBV (hepatitis B surface antigen and IgM anti-hepatitis B 
core antigen), HCV (anti-hepatitis C antibody and HCV PCR), EBV (IgM and IgG VCA 
and EBNA antibodies), CMV (IgM and IgG), VZV (IgM and IgG) and HSV (IgM and 
IgG), and any other relevant laboratory tests as determined by the investigators.  
Participants will be referred for evaluation by a hepatologist in the event of ALT or AST 
increase equal to or greater than 3x the upper limit of normal with concurrent increase in 
total bilirubin equal to or greater than 2x the upper limit of normal, and if otherwise 
clinically indicated.
These evaluations will be of no cost to the participant.
6.2.12 Antiretroviral and Immunogenicity Assessments
HIV-1 levels will be assessed by (Appendix A):
1. Standard HIV-1 viral load assay (Cobas Taqman) (CLEP-certified) will be 
performed at a contracted laboratory, LabCorp (RUH site) and at the AUH and 
CUH clinical virology labs. The detection range of the assay is 20-10x106 
copies/ml. HIV-1 viral load will be determined at multiple time points before and 
after 3BNC117 administration.
2.
Transcription mediated amplification is a qualitative method to detect plasma 
HIV-1 RNA (Procleix Ultrio Plus, Genprobe). It has 50% sensitivity at 3.8 
copies/mL and 95% sensitivity at 12 copies/mL. TMA results are considered 
binary and defined as positive or negative according to assay outcomes.
3. Single copy assay has a detection limit of 1-2 copies HIV-1 RNA/mL of plasma. 
This assay will be performed in the Laboratory of Molecular Immunology. This 
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assay will be performed on samples collected at baseline (week -2 and day 0), and 
1 day after the second romidepsin infusion in each treatment cycle.
4. HIV-1 cell-associated unspliced HIV-1 RNA dd PCR assay. This assay provides 
an accurate quantification of HIV-1 transcriptional activity and will be performed 
at the AUH site. This assay has a limit of detection of 1 HIV-RNA copy per 1 
million CD4+ T cells.
5. HIV-1 cell associated DNA levels in CD4+ T cells will be measured at the AUH 
site, before and after administration of 3BNC117. This assay has a limit of 
detection of 10 DNA copies per 106 CD4+ T cells. This assay will be performed at 
the AUH site.
6. The size of the functional HIV-1 reservoir will be determined by the number of 
infectious unit per 106 resting memory CD4+ T cells (IUPM) using a viral 
outgrowth assay before (week -2) and after therapy, just before ATI (week 22). 
Given the large number of cells required for this assay, viral outgrowth assays will not be 
performed at a later time point. The size of the reservoir in participants who remain 
virologically suppressed during ATI or are re-suppressed following ART resumption will 
be evaluated by levels of cell-associated HIV-1 DNA, performed at week 48.
In addition, the effects of 3BNC117 on host immune responses and on circulating HIV-1 
strains will be evaluated by the following assays (Appendix A):
7. TZM-bl neutralization assay will performed in the laboratory of Dr. Michael 
Seaman of the Beth Israel Deaconess Hospital in Boston (a Core Laboratory 
sponsored by the Collaboration for AIDS Vaccine Discovery, CAVD). In vitro 
neutralization assays will be performed with serum from study subjects before 
and after administration of 3BNC117. 
8. Phenotypic characteristics for T and NK cells using standard cell marker panels 
by flow cytometry (e.g. CD3, CD4, CD8, CD45RA, CCR7 for T cells and 
CD16/CD56 for NK cells) will be determined before and after each treatment 
cycle. These assays will be performed at the RUH and/or AUH sites.
9. Functional properties of cytotoxic T cells and NK cells before and after each 
treatment cycle 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. In addition, change from baseline in the 
capacity of NK and CD8+ T cells to mediate inhibition of viral replication ex vivo 
will be analyzed. These assays will be performed at the RUH site and the 
laboratory of Dr. Richard Koup at the Vaccine Research Center (VRC) at NIH, a 
core lab of the Collaboration for AIDS Vaccine Development (CAVD).
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10. Levels of inflammation markers, such as C-reactive protein, D-dimers, IL-6, and 
soluble CD14 will be performed in plasma or serum samples, prior to and after 
3BNC117 infusions. These will be performed at the Laboratory of Molecular 
Immunology, or by clinical assays at LabCorp.
11. Sequencing – If latently infected virus can be isolated/cultured ex-vivo, 
sequencing and phylogenetic analysis of HIV-1 env will be performed in samples 
collected before and after the first and second treatment cycles and at the time of 
virologic rebound. These analyses will use similar approach to the reported in 
Caskey et al (2015) and Schoofs et al (2016). This will allow us to compare 
viruses grown from PBMCs collected from subjects while on ART to rebound 
viruses collected after treatment interruption and analyze the induction of escape 
mutations.  This will be performed at the RUH and/or the UCH site.
12. Genotypic analysis of antiretroviral resistance in rebounding viral strains (with 
HIV-1 RNA levels > 400 copies/ml) will be performed by clinical assays at all 
sites.
13. Evaluation of HIV-1 integration sites by deep sequencing will be performed at the 
RUH site, before and after the first and second treatment cycles.
Pharmacokinetics and immunogenicity assays (Appendix A):
14. Measurement of 3BNC117 levels by validated sandwich ELISA using a murine 
anti-idiotype antibody to 3BNC117 and will be performed at Celldex 
Therapeutics. 3BNC117 levels will be measured in serum or plasma.
15. Anti-drug (3BNC117) antibody responses in serum or plasma. Validated Assays 
will be performed at Celldex Therapeutics Inc.
16. Measurement of romidepsin levels by validated sandwich ELISA will be 
performed on samples collected before, at the end of the infusion, and 1 day after 
each romidepsin infusion during treatment cycle 1. 
Research samples collected at all clinical sites will be processed and stored locally, until 
samples are transferred to a pre-determined site for specific assays, as outlined above. 
Optimal sample collection, processing, cryopreservation, archiving and storage will be 
maintained. Additional studies will be performed as warranted at the discretion of the 
investigators.
6.2.13 Pharmacokinetic evaluations
Pharmacokinetic parameters will be calculated using standard non-compartmental 
analysis methods. Descriptive results will be presented for the pharmacokinetic 
parameters. 
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3BNC117 PK assessments will be performed on plasma or serum samples in Group A 
before the first 3BNC117 and at multiple time points as outlined in the Time of Events 
Schedule (Appendix A).  Romidepsin PK assessments will be performed on plasma or 
serum samples. These measurements will be performed during the first treatment cycle at 
baseline, end of infusion, and 1 day after each romidepsin infusion.
7
Investigational Products 
- 3BNC117 is manufactured by Celldex Therapeutics, Inc. 3BNC117 is a recombinant, 
fully human monoclonal antibody (mAb) of the IgG1κ isotype that specifically binds 
HIV envgp120. 3BNC117 is being investigated under USFDA IND 118,225. 
- Romidepsin (Istodax®) is manufactured by Celgene Corporation. This histone 
deacetylase (HDAC) inhibitor is a bicyclic depsipeptide. 
7.1
Regimen
- 3BNC117 will be administered intravenously at 30 mg/kg dose level on day 0 and day 
56 (Group A only).
 
- Romidepsin will be administered intravenously at 5 mg/m2 dose level on days 2, 9, 16, 
58, 65, and 72 for Group A and days 0, 7, 14, 56, 63, and 70 for Group B. 
7.2
Storage and Shipment of the Investigational Products
- 3BNC117 will be shipped from Celldex Therapeutics and will be stored in the site 
research pharmacy at 2- 8C. 3BNC117 is a clear liquid, provided in single-use vials 
containing 5 ml of product at 20 mg/ml concentration. For further information refer to the 
3BNC117 IB.
- Romidepsin will be provided by Celgene Corporation and will be stored in the site 
research pharmacy. At room temperature, romidepsin is a white powder. For further 
information refer to the romidepsin IB.
7.3
Dispensing and Handling of the Investigational Products
- 3BNC117 will be dispensed by the site research pharmacy. Trial personnel will ensure 
that the study ID number on the piggy-back matches the study ID assigned to the 
volunteer prior to administration. 
3BNC117 will be provided in single-use vials containing 5 ml of 3BNC117 at a 20 
mg/ml concentration. The appropriate dose will be calculated by the site research 
pharmacist according to subject’s weight. 3BNC117 will be dispensed in a piggy-back, 
and diluted in normal saline (NaCl 0.9%), to a volume of 250 ml. It will be dispensed 
ready for administration by the study investigators and be good for infusion for 3 hours.
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- Romidepsin will be dispensed by the site research pharmacy. Trial personnel will ensure 
that the study ID number on the piggy-back matches the study ID assigned to the 
volunteer prior to administration. 
7.4
Accountability and Disposal of Used and Unused Investigational Product
The date, allocation number and location of storage of the vials will be recorded in a log 
at each study site.  During the trial, the product accountability form, and the dispensing 
log will be monitored. At the end of the trial, unused 3BNC117 vials will be returned to 
Celldex Therapeutics or destroyed; unused romidepsin vials will be returned to Celgene 
Corporation or destroyed. 
7.5
Concomitant and Prohibited Medications
- As per the manufacturer of romidepsin, the prophylactic use of antiemetics such as 
ondansetron is strongly encouraged.
- Any medications listed in Appendix E, which may cause QTc prolongation or induce 
torsades de pointes should not be used. 
- Concomitant use of CYP3A4 or Pgp inhibitors with romidepsin should be avoided 
(excluding granisetron and ondansetron) to prevent potential increase in romidepsin 
exposure during concomitant treatment with these drugs.  Should a patient already 
enrolled on this study require treatment with these drugs (as listed in Appendix F) 
romidepsin must be interrupted prior to starting these drugs and should not resume until a 
washout period of at least 5 half-lives has elapsed. All participants taking protease 
inhibitors, which are strong inhibitors of P450 3A4, will be switched to an integrase 
inhibitor prior to enrollment. In addition, participants on regimens that contain cobicistat 
(a CYP3A4 and Pgp inhibitor) will be switched to an integrase inhibitor-based regimen 
that does not include cobisistat.
- Any medications that have the potential to alter serum electrolytes (e.g., diuretics) 
should be monitored very closely for electrolyte abnormalities as these can contribute to 
the risk of QT prolongation and ventricular arrhythmias. 
- Romidepsin can prolong PT and elevate INR in patients receiving warfarin.  Patients on 
warfarin will be excluded from the study. 
8
Data Analysis
8.1
Analysis of Antiretroviral effects, Safety and Pharmacokinetics
Primary Endpoint:
1.
Days to viral rebound during ATI or days to reinitiation of ART in participants who 
restart ART before viral rebound.  Viral rebound is defined as HIV-1 RNA ≥ 200 
copies/ml on 2 consecutive measurements during ATI. If viral rebound occurs, the 
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date of the first measurement of HIV-1 RNA ≥ 200 copies/mL will be defined as 
“date of viral rebound.”  As primary analysis, we will use the Wilcoxon-Mann-
Whitney test to compare the median time to viral rebound between the two study 
groups. As secondary analysis, we will use the Kaplan-Meier estimator and log-rank 
test to assess the significance of the difference between the survival curves in the two 
study arms. 
Secondary and Exploratory Endpoints:
1. Safety evaluation:
The number and percentage of subjects experiencing one or more AEs will be 
summarized by relationship to study drug, and severity. AEs will also be summarized by 
severity grade and by relationship to study drug according to the CTCAE v4.03 and 
DAIDS v2.0 grading scale. Changes will be calculated relative to the values collected at 
baseline. 
2. Size of the functional HIV-1 reservoir:
The size of the functional HIV-1 reservoir will be determined by the number of infectious 
unit per 106 resting memory CD4+ T cells (IUPM) using a viral outgrowth assay before 
(week -2) and after therapy, just before ATI (week 22). Paired student t-test or paired 
Wilcoxon test will be used to determine changes in reservoir size from baseline to the 
pre-ATI time-point for each group. 
Total HIV-1 DNA, episomal HIV-1 DNA (2-LTR), and unspliced HIV-1 RNA in 
circulating total CD4+ T cells will also be determined at baseline (week -2, week 0), 
before and after each treatment cycle, at the pre-ATI time point (week 24), and at and the 
end of the study (week 48). A 95% repeated measures ANOVA F-test will be used to 
compare changes in these variables during the study. 
3. Plasma HIV-1 RNA:
Plasma HIV-1 RNA levels will be 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). 
Fishers exact or chi-square test will be used to compare the proportion of subjects in both 
groups with detectable viremia during each romidepsin treatment. 
4. Host immune responses: 
Functional properties of cytotoxic T cells and NK cells will be correlated to changes in 
total HIV-1 DNA and IUPM. Flow cytometry data will be evaluated by Boolean 
partitioning of NK and T cell responses into distinct responding populations (Lamoreaux 
et al., 2006). 
Finally, linear regression will be used to identify predictors of log-transformed time to 
viral rebound in both arms. P values <0.05 will be considered statistically significant.
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5. Other measurements:
The frequency and levels of anti-3BNC117 antibodies, after each 3BNC117 infusion, will 
be calculated and displayed in tables. Levels of romidepsin will similarly be calculated 
and displayed in tables. Pharmacokinetic parameters will be calculated using standard 
non-compartmental analysis methods, using WinNolin software, version 6.4. 
Pharmacokinetic parameters, including AUC, Cmax, T½, Tmax and others will be 
summarized.
Genotyping of HIV-1 isolates will be performed by reverse transcription followed by 
PCR amplification and sequencing of HIV-1 envelope genes. Sequence analysis to 
identify potential 3BNC117-induced escape mutations will be descriptive. 
Continuous data will be summarized by descriptive statistics, including the sample size, 
mean, standard deviation, median and range. Categorical data will be summarized by the 
number and percentage of participants. If necessary Log2 of variables will be used.
8.2
Sample Size Considerations
The sample size calculation is based on the primary analysis for the primary endpoint. 
We will compare days from day of ART interruption until day of viral rebound or day of 
reinitiation of ART without viral rebound in arm A to arm B (1:1 randomization) with the 
Wilcoxon-Mann-Whitney test. Given a standard deviation (SD) of 10 (days), enrolling 12 
patients in each of the two arms, will have 80% power to detect ≥ 13 days difference in 
time to viral rebound at a 5% significance level (Davey et al., 1999; Hamlyn et al., 2012; 
Hill et al., 2014). The power calculation for this primary analysis
 was performed in 
G*power using the minimum Asymptotic Relative Efficiency method. 
To accommodate for dropouts, we aim to enroll 30 study subjects in the study (15 in each 
arm). A dropout rate of ~20% is anticipated.
9
Data and Sample Storage
The Principal Investigator(s) will oversee how the data are collected, entered, and 
protected. All study data will be collected by the clinical study staff using designated 
source documents and entered onto the appropriate electronic case report forms (eCRFs). 
Clinical Trials Centre Cologne will provide a secure web-based database that will be used 
for data management. Data collection forms (DCFs) will be provided for use as source 
documents as appropriate. All study data must be verifiable to the source documentation. 
All source documents will be kept in a locked facility at the clinical sites and remain 
separate from volunteer identification information (name, address, etc.) to ensure 
confidentiality.  All data with volunteer identifiers will be kept in a locked facility and/or 
encrypted files.  Source documentation will be available for review to ensure that the 
collected data are consistent with the eCRFs. 
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All eCRFs and laboratory reports will be reviewed by the site’s clinical team, who will 
ensure that they are accurate and complete.
All research samples will have a unique identifier.  The site PI will be responsible for 
ensuring project compliance, data analysis and entry, regulatory monitoring, and 
coordination of the activities of the entire study team.  Standard GCP practices will be 
followed to ensure accurate, reliable and consistent data collection.
Source documents include, but are not limited to:
-
Signed Informed Consent Documents
-
Dates of visits including date of 3BNC117 and romidepsin infusions
-
Documentation of any existing conditions or past conditions relevant to eligibility 
-
Reported laboratory results
-
All adverse events 
-
Concomitant medications 
10
Recruitment Plan
Both men and women ages 18 through 65 will be recruited for the study from the 
community at large and will be referred by physicians in the community. We will make 
every effort to recruit minorities and women. We project screening 60 subjects in order to 
achieve at least 30 evaluable subjects. Enrollment will be competitive across the three 
trial sites. In case of drop-outs an over-enrollment of 10% will be allowed.
-
At RUH, the Clinical Research Support Office at the Rockefeller University Hospital 
(CRSO) will utilize the Volunteer Repository. Advertisements will also be placed: 
online (e.g. Craiglist, CenterWatch, etc.), in newspapers (Metro, AMNY) and on 
campus. In addition, participants will be recruited at Montefiore Medical Center. 
Recruitment fliers will be placed in the clinic, and interested participants will contact 
study recruiters at Montefiore. The pre-screening procedure will take place over the 
phone or in person at Montefiore clinic. Recruiters will collect participant’s medical 
history and other relevant information and will provide the participant a brief 
description of the study. Potential participants will also have an opportunity to ask 
questions about the study. If participants show interest and agree to be contacted, 
their contact information will be shared with Rockefeller site investigators (via secure 
email) for scheduling of screening visit. Informed consent and all other study-related 
procedures will occur at the Rockefeller site.
-
At AUH, written invitations to participate in the study will be sent to eligible HIV 
patients.
 
-
At UCH, eligible HIV infected individuals will be invited by phone to participate in 
the study.
11
Potential Benefits to Subjects
It is unlikely that study subjects will benefit from participating in this study.
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12
Potential risks to the subject 

This study entails moderate risk to subjects since 3BNC117 is an investigational new 
drug with limited human safety data and romidepsin has potential side effects. The 
study also includes a period of ART interruption. It has been shown that episodic 
ART guided by CD4+ count decline leads to increased risk of opportunistic infections 
as compared with continuous ART (Strategies for Management of Antiretroviral 
Therapy Study et al., 2006). However, different groups have now shown that short 
analytical treatment interruption is safe (Routy et al., 2012). ART will be resumed if 
plasma HIV-1 RNA levels increase to ≥ 200 copies/ml and are confirmed upon 
repeated measurement.

If the HIV-1 viremia rebounds after ART is discontinued, absolute CD4+ counts 
might drop. However subjects will be followed very closely and ART will be 
resumed if the CD4+ cell count drops < 350 cells/l and this is confirmed upon repeat 
measurement. 

During ART interruption, subjects might experience symptoms of acute retroviral 
syndrome, such as fever, rash, lymphadenopathy, headache, sore throat, nausea, 
vomiting. ART will be resumed if acute retroviral syndrome is suspected by study 
investigators.

Resistant viral strains to previous ART medications might arise during the analytical 
treatment interruption. 

 During the ART-interruption phase of the study subjects may be at increased risk of 
transmitting HIV to their partners, if they become viremic, and of HIV-1 
superinfection from an HIV-infected partner. Therefore, subjects will be asked to use 
male or female condoms for the duration of ART interruption. In the event of a high-
risk exposure to an HIV-infected partner, a subject may re-initiate ART as clinically 
indicated by his/her primary care physician.

3BNC117 has now been administrated to 63 volunteers and was generally safe and 
well tolerated in all doses tested. To date, 8 ART-treated HIV-infected individuals 
have received two 3BNC117 infusions, administered 3 weeks apart. This is the first 
time 3BNC117 will be administered in combination with romidepsin.

While each mAb product has unique safety issues related to its mechanism of action, 
the major safety concern related to mAbs in general is an infusion/hypersensitivity 
reaction. These types of reactions are more common for mAbs that contain murine 
elements compared to human mAbs, such as 3BNC117. Passive administration of 
anti-HIV-1 antibodies has been evaluated in humans in the past. As observed with 
other monoclonal antibodies, anti-HIV-1 antibodies were generally safe and well 
tolerated and most adverse events observed were infusion-related events. (Mehandru 
et al., 2007b; Trkola et al., 2005b). 
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
Immunologic symptoms such as listed below are possible with administration of a 
monoclonal antibody and will be considered adverse events of interest.  Potential 
allergic-type reactions during and immediately following the administration of 
3BNC117 will be carefully monitored.  
o
Constitutional symptoms, such as fever, rigors/chills;
o
Injection site reaction/extravasation changes, pruritus, urticaria;
o
Serum sickness like syndromes as evidenced by fever, rash, arthralgia, 
arthritis, nephritis;
o
Deposition of immune complexes in the kidneys leading to renal 
insufficiency; 
o
Adult Respiratory Distress Syndrome, bronchospasm/wheezing, anaphylaxis;
o
Cytokine release syndrome/ acute infusion reaction. 

3BNC117-resistant viral strains might arise following administration of 3BNC117. 
Development of 3BNC117 resistance might limit the future use of 3BNC117 by the 
study subject, if this monoclonal antibody is licensed for clinical use by the FDA. 

In the cross-reactivity study in human tissues, 3BNC117 was found to bind to cells in 
the conjunctival recesses. It is possible that this binding could lead to conjunctival 
toxicity. However, when rats and non-human primates were administered 3BNC117, 
conjunctival toxicity was not observed. Sixty-three participants have received 
3BNC117 to date, and 12 participants reported mild ophthalmic complaints (such as 
pruritus, conjunctival erythema, increased lacrimation) during study follow up. In all 
instances symptoms resolved without specific treatment and ophthalmologic 
evaluations 5 months after 3BNC117 administration did not show changes from 
baseline. 

The adverse effects 3BNC117 administration would have in a fetus or unborn child 
are unknown. 

Most studies with romidepsin were performed in patients with severe haematological 
malignancies and used doses up to 15 mg/m2. The most common adverse events 
associated 
with 
romidepsin 
involve 
the 
GI 
system 
(nausea, 
vomiting, 
diarrhea/constipation), hematologic condition (thrombocytopenia, leucopenia (neutro- 
and lymphopenia) and anemia), asthenic conditions (asthenia, fatigue, malaise and 
lethargy) and finally electrolyte abnormalities (hypomagnesiamia, hypokalemia and 
hypocalcemia), hyperglycaemia and pyrexia. Overall, the most common grade 3/4 
events reported were anaemia, thrombocytopenia, neutropenia, leukopenia and 
fatigue.  

QT prolongation as well as several morphological changes in ECGs (including T-
wave and ST segment changes) has been reported in clinical studies of romidepsin. 
Many of the ECG morphologic abnormalities were also observed at baseline. These 
ECG changes were transient and were not associated with functional cardiovascular 
changes or with symptoms. The clinical significance of these changes is unknown.
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
In a pilot study in 6 HIV-1-infected participants on long-term ART, who received 3 
infusions of 5 mg/m2 of romidepsin over the course of 3 weeks, no serious adverse 
events (SAEs) or suspected unexpected serious adverse reactions (SUSAR) was 
observed. Thirty-five AEs were considered related to romidepsin. All drug-related 
AEs were mild (grade 1, n=35) and resolved spontaneously within a few days. The 
most common romidepsin-related AEs were abdominal symptoms (e.g. nausea 
[n=11], borborygmia [n=4], abdominal pain [n=2]) and fatigue (n=5). Modest 
changes in white blood cell counts (WBC) and T cell counts were observed during the 
study. Neutrophil counts below 1000 cells/mm3, CD4+ cell counts below 350 
cells/mm3, or platelet counts below 100,000 cells/mm3 were not observed. 

A theoretical risk of HDAC inhibitors is that they will induce activation of other 
retroviruses, oncogenes and/or DNA viruses, including CMV, hepatitis B virus and 
JC viruses. However in a study in HIV-infected participants who received 
panobinostat over a course of 8 weeks (another HDAC inhibitor), CMV DNA (in 
urine) and EBV DNA (in blood) were monitored and there was no evidence of 
unintended virus reactivation.

Clinical data is not available with romidepsin during pregnancy. In this study, use of 
two contraceptive methods for both female and male study subjects is required for the 
duration of the study.

Based on non-clinical findings in repeat-dose toxicity studies, romidepsin has the 
potential to affect male and female fertility. Testicular atrophy or degeneration 
occurred in rats at doses corresponding to 1.98 mg/m2. In dogs, romidepsin caused 
hypospermia at doses corresponding to ≥ 20mg/m2. In rats, at doses ≥ 0.1 
mg/kg/week corresponding to 0.6 mg/m2 or a mean steady state AUC0-∞ 4.9 
nghr/mL, females exhibited atrophy in the ovary, uterus, vagina and mammary 
glands. Further, maturation arrest of ovarian follicles was observed in female rats at ≥ 
0.3 mg/kg/week corresponding to 1.8 mg/m2.  It is not known if romidepsin can 
impair fertility in humans, although since the FDA approval of romidepsin in 2009, 
no cases of fertility-related adverse effects have been reported. If romidepsin does 
result in ovarian or testicular atrophy, symptoms related to decreased sex hormone 
production could also occur, such as early menopause, decreases in bone density or 
libido, and alterations in mood or body habitus. Until now, however, such symptoms 
have not been observed among HIV patients (n=23) receiving romidepsin at a dosing 
of 5 mg/m2 in other experimental trials (Søgaard et al. 2015, Leth et al. 2016).

Blood drawing and phlebotomy can be associated with pain, bruising, anemia or 
infection at the site of venipuncture. Rarely, fainting may follow phlebotomy.
13
Procedures to minimize risk

As outlined above, this study will be an exploratory phase 2 trial of a combination of 
romidepsin and 3BNC117 in humans. Potential trial volunteers will be informed 
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about the possible risks of the monoclonal antibody administration and that there may 
be unknown risks. 

In the US, medical records and routine laboratory data will be handled with HIPAA 
compliance. Medical records will be protected by the rules and regulations of RUH, 
AUH and UCH.  

With any new medicine or monoclonal antibody, there is a possibility of totally 
unexpected side effects. Subjects will be monitored for 1 hour post 3BNC117 or 
romidepsin infusions in the site infusion unit. The study site infusion units are 
equipped for providing emergency medical interventions in the unlikely event of 
acute allergic or other reactions. In case of an emergency, after stabilization of the 
subject, he/she will be transferred to a tertiary care center, for specialized medical 
care.

Subjects will be closely monitored for the development of symptoms of ocular 
disease (such as blurry vision, increased lacrimation, redness, dryness, pain). If 
subjects develop symptoms or signs of ocular disease, they will be referred to an 
ophthalmologist for diagnosis and management. These evaluations will be performed 
at no cost to the subject.

During the treatment interruption phase of the study, plasma HIV-1 RNA levels will 
be monitored weekly and CD4+ T cell counts will be monitored every 2 weeks. ART 
regimen will be resumed if plasma HIV-1 RNA level is ≥ 200 copies/ml in 2 
consecutive measurements or if CD4+ is found to be < 350 cells/μl on two 
consecutive measurements, the participant becomes pregnant, or if otherwise 
clinically indicated.

In order to minimize the risk of transmitting HIV to their partners if subjects become 
viremic, and of HIV-1 superinfection from an HIV-infected partner, subjects will be 
asked to use male or female condoms for the duration of ART interruption. In the 
event of a high-risk exposure to an HIV-infected partner, a subject may re-initiate 
ART as clinically indicated by his/her primary care physician.

To minimize risks associated with phlebotomy, blood drawing will be performed by 
experienced phlebotomists. Should discomfort occur, they will provide appropriate 
treatment.

To minimize risks associated with blood drawing, volunteers will be closely 
monitored for signs and symptoms of anemia.

Females of childbearing potential and who participate in sexual activity that might 
lead to pregnancy will be advised to use two reliable forms of contraception (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 
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duration. Romidepsin may interact with estrogen-based contraceptives and such 
agents may be unreliable in participants receiving romidepsin. 

In addition, a pregnancy test will be performed at screening, on the days of drug 
infusion, and throughout the course of the study.  Males who are not anatomically 
sterile and who participate in sexual activity that might lead to pregnancy will be 
advised to use two reliable forms of contraception during the study to avoid 
pregnancy in a spouse or partner. 

Subjects will have regularly scheduled visits to the outpatient clinic and routine safety 
laboratories will be checked according to the Time of Events Schedule (Appendix A). 
HIV-infected individuals will have close monitoring of HIV-1 viral load and CD4 
counts according to the Time of Events Schedule (Appendix A). 

In view of potential ECG changes associated with romidepsin, ECGs will be 
performed as described above (section 6.2.4). Serum potassium, magnesium and 
calcium will also be checked before each infusion.  Any emergent ECG findings, 
including asymptomatic findings, will be assessed by a cardiologist and appropriate 
monitoring and/or management will be instituted as clinically indicated.

Participants will be counseled during the informed consent process regarding the 
possible effects on fertility that may occur as a result of romidepsin.  If requested, 
participants will be given information on centers where sperm or egg banking could 
be performed.

Infusion-related adverse events including cytokine release syndromes will be 
monitored and graded using the CTCAE v4.03 grading scale ; all non-infusion-related 
adverse events will be graded using the DAIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events, Version 2.0 (Appendix C).

Adverse events will be managed by the study site investigators who will assess and 
treat the event as appropriate, including referral to an independent physician and/or 
department. Participants who develop graded elevations in total bilirubin will undergo 
a diagnostic workup at no cost to the participant that includes right upper quadrant 
ultrasound, testing for gamma glutamyl transferase (GGT), HAV, HBV, HCV, EBV, 
CMV, VZV and HSV serologies, and any other relevant laboratory tests as 
determined by the investigators.  

Safety monitoring at each clinical site will be conducted by an external monitor and 
by an external Study Monitoring Committee (SMC). The RUH, AUH and UCH IRBs 
will conduct the initial review of the proposed study and will follow progress through 
annual reports and by immediate notification of serious and unanticipated adverse 
events. Any serious adverse events will be reviewed by the study investigators 
immediately. Site investigators will notify the local IRB and the sponsor at the 
Rockefeller University within 2 working days from the investigators being made 
aware of the event. The RU sponsor will notify the FDA, Danish Health Authority, 
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PEI, and BfArm per 21 CFR 312. The SMC will be available to the investigators for 
consultation and review of severe adverse events if needed. 
14
Alternative methods or treatments
This does not apply to this study.
15
Data and Safety Monitoring Plan
This is an exploratory Phase II study, which exposes the subjects to “moderate risk.”
15.1
Protocol Safety Review Team
The Protocol Safety Review Team (PSRT) will include the available site PIs and co-
investigators. Additional members could include senior clinical research nursing staff and 
site staff.  The PSRT will meet on a weekly basis to review any adverse events; minutes 
will be recorded.  For any AE Grade 3 or above deemed possibly, probably or definitely 
related to 3BNC117 and/or romidepsin, the site PI will notify the PSRT within 24 hours 
and the PSRT will convene within 1 business day to review these AEs.  The PSRT will 
decide by consensus whether AEs should also be reviewed by the SMC.
15.2
Safety Monitoring Committee
A Study Monitoring Committee (SMC) will be established to monitor the study. The 
charter of the SMC is to provide an ongoing assessment of volunteer safety during the 
conduct of the study.  The SMC will consist of three independent individuals who have 
no relationship to the Principal Investigators and Co-Investigators involved in the trial. 
No member of the SMC will have any direct responsibility for the clinical care of trial 
volunteers.  No representative of Celldex Therapeutics, Celgene Corporation or the 
Rockefeller University, or their designees may be a member of the SMC. However, the 
SMC may invite the principal investigators (PI) or designee and a Celldex Therapeutics, 
Celgene Corporation and/or Rockefeller University representative to an open session of a 
SMC meeting to provide information on study conduct, present data, or to respond to the 
members’ questions. 
The names, university affiliation and title, area of expertise, and contact information of 
each of the SMC members are provided below: 
Rajesh T. Gandhi, MD
Associate Professor of Medicine
Massachusetts General Hospital
55 Fruit Street
Boston MA, 02114-2696
Email: RGANDHI@mgh.harvard.edu 
Phone: 617-726-8403 
Expertise: treatment of HIV-1 infection, HIV eradication clinical trials
Steven M. Horwitz, MD
Assistant Attending 
Memorial Sloan Kettering Cancer Center
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1275 York Avenue
New York, NY 10065
Email: horwitzs@mskcc.orgPhone: (212) 639-3045
Expertise: treatment of T-cell lymphoma, romidepsin clinical trials, clinical experience 
with romidepsin.
Jean-Pierre Routy, MD
Professor of Medicine 
McGill University Health Centre: Glen site
Research Institute, Block E
Suite EM 3-3232, Mezzanine 3M
1001 Boulevard Décarie
Montréal, Qc H4A 3J1
Phone: (514) 843-1558 
Email: jean-pierre.routy@mcgill.ca
Expertise: treatment of HIV infection, therapeutic HIV vaccines.
At least two members of the SMC must be in attendance (phone, video, or in-person 
meetings) to constitute a quorum for an SMC meeting. SMC members may also review 
and comment by email, if scheduling cannot be worked out in a timely manner.  One 
member of the SMC will be appointed as chair of the committee.  The SMC chair (or 
his/her alternate) will be responsible for summarizing and communicating in writing 
SMC acknowledgments and recommendations to the PI within 5 business days following 
each SMC meeting and/or review.  
All available safety data will be reviewed by the SMC three weeks after the first five 
participants receive the second 3BNC117 infusion, and every 6 months thereafter. The 
study will not pause, but following the review, SMC member(s) will make a 
recommendation to the principal investigator(s) regarding the continuation of the trial.
SAEs and unanticipated adverse events will be reported to the SMC within 2 working 
days of the site becoming aware of the event. If there is one grade 4 SAE judged as 
possibly, probably or definitely related to the administration of 3BNC117 or romidepsin 
by the principal investigator or designee, no additional enrollment will take place pending 
a review by at least two members of the SMC. Following this review, 
the SMC member(s) will make a recommendation to the principal investigator regarding 
the continuation of the trial.
All updated versions of the protocol will be provided to the SMC members. The review 
of trial data by the SMC will take place at least every 6 months. For these reviews, the 
study team will provide the SMC with updated records of all adverse events (AEs) of a 
grade 2 or greater toxicity.
   
The SMC will provide a written report to the sponsor at the RU and the site PIs after each 
evaluation. The PIs will, in turn, distribute these reports to the study team, the local IRBs 
and the FDA.
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15.3
Monitoring
Safety monitoring at both sites will be conducted by the study investigators and by an 
external monitor. External monitoring reports will be reviewed and approved by the 
Sponsor. An external SMC will review SAE’s and Unanticipated AEs and will be 
available to the study investigators for consultation. The RU, AU and UC IRBs will 
conduct the initial review of the proposed study and will follow progress through annual 
reports and by immediate notification of SAEs and UAEs.  External monitoring will 
occur at least quarterly at all clinical sites. 
15.4
Adverse Event Classification
The CTCAE v4.03 grading scale and DAIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events, Version 2.0 will be used for all occurring adverse events 
(Appendix C). Serious adverse events are defined as those that result in death, are life 
threatening, require inpatient hospitalization, result in significant disability or incapacity, 
is a congenital anomaly or birth defect, or is judged by the investigators to be a 
significant medical event.
 
15.5
Reporting Adverse Events
All adverse events will be reported to the local IRBs at least annually.  Serious Adverse 
Events, (SAEs) will be reported to the local IRBs and to the sponsor at the Rockefeller 
University according to policy, within two working days of identification of the SAE.  
The RU sponsor will report SAEs directly to the FDA, Danish Health Authority, PEI, and 
BfArm per 21 CFR 312 (Appendix G).
Expedited Reporting by Investigator to Celgene
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene 
in writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 
24 hours of being aware of the event.  The written report must be completed and supplied 
to Celgene by facsimile within 24 hours/1 business day.  The initial report must be as 
complete as possible, including an assessment of the causal relationship between the 
event and the investigational product(s), if available.  Information not available at the 
time of the initial report (e.g., an end date for the adverse event or laboratory values 
received after the report) must be documented on a follow-up report.  A final report to 
document resolution of the SAE is required.  The Celgene tracking number (RV-XX-PI-
###) and the institutional protocol number should be included on SAE reports (or on the 
fax cover letter) sent to Celgene.  A copy of the fax transmission confirmation of the SAE 
report to Celgene should be attached to the SAE and retained with the patient records.
Celgene Drug Safety Contact Information:
Celgene Corporation     
Global Drug Safety and Risk Management   
Connell Corporate Park     
300 Connell Dr.  Suite 6000    
Berkeley Heights, NJ  07922       
Fax: 
(908) 673-9115
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E-mail:
drugsafety@celgene.com
15.6
Reporting Unanticipated AEs
Unanticipated Adverse Events (UAEs) will be reported to the local IRBs.  UAEs that are 
related and greater than moderate severity must be reported to the local IRBs and to the 
sponsor at the Rockefeller University according to policy, within two working days of 
identification of the UAE. The RU sponsor will report UAEs to the FDA, Danish Health 
Authority, PEI, and BfArm per 21 CRF 312. 
15.7
Clinical 
Laboratory 
Improvement 
Amendment/Clinical 
Laboratory 
Evaluation Program (CLIA/CLEP)
This study includes tests that are not CLIA/CLEP certified. The results of such tests will 
not be used in clinical decision-making or shared with subjects or their health care 
providers.
15.8
Study Pausing Rules
If the trial is placed on safety pause, all enrollment and infusions will be suspended 
pending review. The AEs that may lead to a safety pause or prompt PSRT AE review are 
summarized in Table 1.
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Table 1 Adverse events that may lead to a safety pause
Event and 
relationship to 
study product
Severity
Occurrence
Action
SAE, related
Grade 3 or 4
First
Immediate pause until 
PSRT 
and 
SMC 
determination 
to 
resume enrollment
AE1, related
Grade 3 or 42 
Second3
Immediate pause until 
PSRT 
and 
SMC 
determination 
to 
resume enrollment
ALT or AST 
increase > 3 x 
ULN with 
concurrent 
increase in total 
bilirubin > 2 x 
ULN, any 
relatedness
N/A
First
PSRT and SMC review 
to consider pause
Abnormality of 
ANC, platelet 
count, or 
hemoglobin, any 
relatedness
Grade 4
First
PSRT and SMC review 
to consider pause
AE1, related
Grade 3 or 42
First
PSRT review within 1 
business 
day 
to 
consider pause
1 Does not include subjective solicited symptoms (fatigue/malaise, myalgia, arthralgia, chills, headache, 
nausea). 
2 If no evidence of disease is present other than an abnormal laboratory value, the test must be repeated at 
least one time. 
3 PSRT and SMC will determine whether the reported related AE (Grade 3 or 4) is a second occurrence of a 
previously reported AE (Grade 3 or 4). 
If a study pause is triggered, all enrollment and infusions will be held until review by the 
PSRT or SMC. Resumption of enrollment and study treatment may be determined by the 
PSRT or SMC (in consultation with the FDA, if required) following a cumulative review 
of the available safety data as outlined in the charter. If a decision to resume study 
enrollment and study treatment administration is made, the PSRT and/or SMC will record 
its judgment.  As needed, the appropriate regulatory authorities will be informed in 
writing of the decision by the PSRT and/or SMC to resume or discontinue study 
activities. Sites are responsible for notifying their IRBs according to local standards and 
regulations. 
Volunteers will be withdrawn from the study if: a) the study team feels that continued 
participation in the study would be harmful to the health of a subject; b) if the study 
volunteer fails to comply with the study procedures and/or fails to keep study visit 
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IRB EXPIRATION DATE: 01/26/2019


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appointments; c) The RU, AU or UC IRBs decided to stop or cancel the study for any 
reason.
15.9
Futility Rule
If 10 participants in a single group rebound before week 26 (2 weeks following ATI), 
additional participants from that group will not undergo ATI.  In the case in which the 
futility rule is applied to both arms and only 10 participants undergo ATI in each arm, 
there will be 80% power to detect ≥ 14 days difference in time to viral rebound at 5% 
significance.
16
Clinical Trial Registration
The proposed study involves testing of FDA regulated drugs or biologics and will be 
registered at www.ClinicalTrials.gov.
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IRB EXPIRATION DATE: 01/26/2019


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