Conditions: HIV-1 Infection
Keywords: VRC07-523LS Vorinostat HIV-1 Suppressed Latency Reversal Novel Monoclonal Agent Antibody Frequency T Cell Infection ART Resting
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 15
Healthy volunteers: no

Brief summary:
Adult participants (18-64 years old) with HIV-1 Infection on ART with a CD4 T cell count ≥ 350 cells/mm3 and viral suppression for ≥ 24 months will be enrolled on this study. Participants will receive two series of combination therapy consisting of one (1) intravenous (IV) dose of VRC-HIVMAB075-00-AB (VRC07-523LS) followed by 10 oral (PO) doses of Vorinostat (VOR) taken every 72 hours. Each series will last approximately 1 month and the two series will be separated by at least one month. Combination ART is maintained throughout the study. Participants will be on this study for approximately 28 weeks (or about 7 months).

The purpose of this study is to:

* Evaluate the safety of two series of a VRC07-523LS infusion followed by multiple oral doses of VOR
* Determine if combining VRC07-523LS and VOR can have an impact on non-active HIV virus.

Detailed description:
This is a phase I, single-site, open-label study to evaluate the effects of VOR given in combination with VRC07-523LS on persistent HIV-1 Infection in HIV-infected individuals suppressed on ART.

The investigators hypothesize that combination therapy with VRC07-523LS and VOR will be safe and well-tolerated by HIV-1-infected participants suppressed on ART.

In Step 1, all participants will undergo study screening and enrollment. Participants will complete a baseline Leukapheresis (#1). In order to advance to Step 2, participants must be found to have a baseline measurement of the frequency of resting CD4 T cell infection ≥ 0.3 infectious units per million (IUPM) determined by Quantitative Viral Outgrowth Assay (QVOA) (lower limit of detection is 0.03 IUPM), as a further decrease from this low frequency of infection cannot be definitively measured given the QVOA assay threshold.

These criteria assure that eligible enrolled participants will have a measurable endpoint, thus decreasing risk of study participation for participants who would not have a measurable outcome.

Participants progressing to Steps 2 and 3 will receive two series of a single VRC07-523LS infusion followed by multiple doses of VOR.

In the first series (Step 2), participants will receive one VRC07-523LS 40 mg/kg infusion (infusion #1) on Day 0 followed by the 1st dose of VOR 400 mg PO taken at home on Day 2. Participants will take VOR 400 mg PO every 72 hours for a total of 10 doses.

In the second series (Step 3), participants will receive one VRC07-523LS 40 mg/kg infusion (infusion #2) on Day 60 followed by the 1st (of the 2nd series of VOR) dose of VOR 400 mg PO on Day 62. As in the previous Step, participants will take VOR 400 mg PO every 72 hours for a total of 10 doses.

Step 4 consists of 2 visits. The post-study treatment leukapheresis (#2) will be completed 5 - 8 weeks after the 2nd VRC07-523LS infusion. The End of Study Visit (EOS) will be scheduled to 2 - 4 weeks following the final leukapheresis (#2) visit.

Arms:
arm 1: Participants will receive two series of combination therapy consisting of one (1) intravenous (IV) dose of VRC-HIVMAB075-00-AB (VRC07-523LS) followed by 10 oral (PO) doses of Vorinostat (VOR) taken every 72 hours.

Interventions: intervention 1: VRC07-523LS intervention 2: Vorinostat (VOR)
Intervention descriptions: intervention 1: VRC07-523LS 40 mg/kg administered intravenously per series (total of 2 infusions administered) intervention 2: Vorinostat 400 mg administered orally every 72 hours for 10 doses per series (A total of 20 400-mg doses administered)

Protocol document:
Prot_SAP_000.pdf: 
IGHID 11627 - Combination Therapy with the Novel Clearance 
Modality (VRC07-523LS) and the Latency Reversal Agent (Vorinostat) 
to Reduce the Frequency of Latent, Resting CD4+ T Cell Infection (The 
VOR-07 Study) 
 
 
 
 
NCT number NCT03803605 
     Document Date 03/18/2020 
as per Clarification Memo #2 


IGHID 11802                 Protocol Version 4.0 Clarification Memo #2 – March 18, 2020 
Page 1 of 2 
Clarification Memo # 2 
 
IGHID 11802 - Combination Therapy with the Novel Clearance Modality (VRC07‐523LS) and 
the Latency Reversal Agent (Vorinostat) to Reduce the Frequency of Latent, Resting CD4+ T 
Cell Infection (The VOR-07 Study) 
 
Protocol Version 4.0, May 9, 2019 
IND Number: 138852 
DAIDS‐ES ID 38536 
 
Date of Clarification Memo: March 18, 2020 
 
Summary of Revisions and Rationale 
1. Clarification added to section 8.1 to permit study team to conduct some site visits remotely 
under certain conditions.  
2. COVID-19-related modification  
 
Implementation 
 
This Clarification Memo does not change the informed consent form.  
 
The plan is to incorporate the modifications included in this Clarification Memo into the next full 
protocol amendment. Text noted below with a strikethrough will represent deletion; text appearing 
below in bold will represent an addition.  
 
1. In Section 8.1, Efficacy Assessments (on page 57 before the Research Laboratory Assays sub-
section), the paragraph below is being added. 
 
Remote Data Collection 
Study visits may be conducted remotely (e.g., telephone, facetime) in the following 
situations:  
• 
a participant is unable to attend a visit because of a debilitating illness; the site 
must inform the protocol team in advance  
• 
the site is temporarily unable to conduct non-essential visits in the clinic per 
University policies at the time of the visit; the site must inform the protocol team 
in advance  
• 
at the discretion of the protocol team if the risk of an on-site visit is felt to pose 
more risk than potential benefit to the participant; a message from the team will 
be sent to the study team 
Regardless of the situation, the study team should designate which visits were conducted 
remotely and attempt to obtain as much of the visit-specific required information, based 
on the Schedule of Events, and record it on the relevant study specific checklist. The 
reason for conducting the visit remotely must also be recorded and documented in the 
participant’s study file.   
 
2. In section 7.2, PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY, 
in the Early Study Discontinuation sub-section (page 51), 1st bullet is being revised as shown 


IGHID 11802                 Protocol Version 4.0 Clarification Memo #2 – March 18, 2020 
Page 2 of 2 
below:  
 
• 
Failure by the participant to attend multiple clinic visits.  
NOTE: This criterion is not applicable when study visits are being conducted 
remotely, as described in section 8.1. 


IGHID 11802 – VOR-07 
Protocol v4.0 LOA #2 – January 30, 2020 – DAIDS-ES-ID 38536 
Page 1 of 5 
 
Letter of Amendment #2 
IGHID 11802 - Combination Therapy with the Novel Clearance Modality (VRC07-523LS) 
and the Latency Reversal Agent (Vorinostat) to Reduce the Frequency of Latent, Resting 
CD4+ T Cell Infection (The VOR-07 Study), A Phase 1 Study 
Protocol Version 4.0, dated 09 May 2019  
Letter of Amendment (LoA) #1 Date: August 12, 
2019 
Clarification Memo #1 Date: September 17, 2019 
DAIDS-ES Document Number:  DAIDS-ES ID 38536 
IND Number: IND 138852 
Letter of Amendment (LoA) #2 Date: January 30, 2020 
 
 
This Letter of Amendment affects the IGHID 11802 study, including the study main informed 
consent form. Submission to the UNC Institutional Review Board (IRB) overseeing this research 
will occur as soon as possible after DAIDS review and approval. The UNC IRB must approve this 
Letter of Amendment before implementation. 
Upon receiving final IRB and any other applicable Regulatory Entity (RE) approval(s) for this 
LoA, UNC will implement per unit SOP. UNC’s Regulatory Department retains a copy of this LoA 
and any associated DAIDS and IRB correspondence in the study’s regulatory file. Any future full 
amendment of the IGHID 11802 protocol will incorporate this Letter of Amendment. 
 
 
Summary of the Revisions and Rationale 
The protocol team is implementing this amendment for the following reasons: 
1. To clarify that the acetylation assay and VOR PK samples at the Day 29 and Day 89 visits 
are collected after taking the 10th Vorinostat dose.  
 
2. To clarify that a POCT urine test is done on Day 0 and Day 60. Serum pregnancy test will 
only be done at screening.   
 
3. To clarify that the Product Lot # will not be on the IP label due to limited space. The lot 
number is written on the VRC07 523-LS chain of custody form and in the IDS pharmacy 
logs. 
 
4. To clarify the dispensing of Vorinostat to participants, providing increased reinforcement 
of dosing regimen of every 3rd day. 
 
 
Implementation 


IGHID 11802 – VOR-07 
Protocol v4.0 LOA #2 – January 30, 2020 – DAIDS-ES-ID 38536 
Page 2 of 5 
 
In changes listed below, additions to current protocol will appear as bolded text while 
deletions to current protocols will appear as crossed out text. 
 
 
Protocol Changes 
1. Clarification to the collection of research labs after 10th dose of Vorinostat in each series.  
a) Section 1.3, Schedule of Events, page 12 
 
Please note that the grey cells in the isolated segment of the Schedule of Events table below 
indicate no change. Deleted text appears as crossed out text and any added text appears as bolded 
text within the table.  
 
 
 
 
 
 
 
 
 
 
       
 
 4 Draw samples approximately 4 hours post dose (+/- 1 hour)  
 
b) Research Laboratory Assays, page 58 
This modification is added to correct a typographical error. There are only 2 VOR PK 
samples collected on the study, but erroneously listed as 3 in this text.  
 
Vorinostat PK samples  
Pharmacokinetic samples will be collected at 2 3 time points in the study per SOE. 
These will be processed and stored for testing as required. 
 
c) Research Laboratory Assays, page 58  
Acetylation, Virology and Viral Sequence Analysis  
Samples will be collected per the SOE. Samples will be processed, stored, and analyzed 
as required. 
 
2. Clarification of Pregnancy Testing  
a) Section 1.3, Schedule of Events, page 11. 
 
Please note that the grey cells in the isolated segment of the Schedule of Events table below 
indicate no change. Deleted text appears as crossed out text and any added text appears as bolded 
text within the table.  
 
 
Step 1 
Step 2 
Step 3 
Step 4 
 
All 
Visit 
All 
Visits 
Day 
29 
All 
visits 
Day 
89 
All 
visits 
Research Lab Procedures 
 
 
 
 
 
 
All other samples  
 
 
 
 
 
 
Single PK sample (VOR)4 
 
 
X 
 
X 
 
Acetylation, Virology and 
Viral Sequence Analysis 
 
 
X4 
 
X4 
 


IGHID 11802 – VOR-07 
Protocol v4.0 LOA #2 – January 30, 2020 – DAIDS-ES-ID 38536 
Page 3 of 5 
 
 
 
 
 
 
 
 
 
 
 
 
3 Serum pregnancy test will be performed at any time during the study, if pregnancy 
suspected. serum pregnancy test must be completed on day of intervention to confirm 
pregnancy status 
 
b) Section 8.2 Safety and other Assessments 
 
Clinical Laboratory Testing for Safety, page 61  
 
Serum and Urine Pregnancy Test, 2nd paragraph 
A negative serum urine pregnancy test (POCT) is required at each visit prior to each 
VRC07-523LS infusion, and within 72 hours of the first VOR dose in Step 2 and Step 3 
regardless of documented procedures that prohibit pregnancy.   
  
3. Clarification of Investigational Product Lot # on IV bag 
a) Section 6.2.4 Preparation, page 48  
 
VRC07-523LS, Section 3, Intravenous Infusion Preparation Instructions 
g) Label the IV bag with:  
  (last bullet) 
• lot number 
 
4. Clarification of Vorinostat Dispensing  
a) Section 6.1.2 Dosing and Administration   
 
Vorinostat, page 43 
 
The study provides the Vorinostat 400 mg to the participants. In Step 2 and Step 3, 
participants will take their first dose of VOR 400 mg PO at home two (2) days after the 
VRC07-523LS infusion. All participants will be dispensed 5 doses of VOR 400 mg at the 
infusion visits on Day 0 and Day 60. All participants will be provided with instructions for 
the safe administration of VOR at home. VOR will be dispensed at the following study 
visits:  
Day 0 – 2 doses  
Day 7 – 3 doses  
 
Step 1 
Step 2 
Step 3 
Step 4 
 
Screen  Day 0  
All 
other 
visits 
Day 60 
All 
other 
visits 
All 
visits 
Clinical Lab Procedures 
 
 
 
 
 
 
All other samples  
 
 
 
 
 
 
Serum Pregnancy Test  
X 
X 
X3 
X 
X3 
X3 
Urine Pregnancy Test (POCT)  
 
X 
 
X 
 
 


IGHID 11802 – VOR-07 
Protocol v4.0 LOA #2 – January 30, 2020 – DAIDS-ES-ID 38536 
Page 4 of 5 
 
Day 14 – 5 doses 
Day 60 – 5 doses 
Day 74 – 5 doses  
Participants will return to the CTRC on the day of their 5th dose (Day 14 and Day 74) for 
safety labs and evaluations. and to receive their last 5 doses of VOR 400 mg.   
 
 
 
Informed Consent Changes 
 
1. Page 6 - Day 0, Visit 3 
2nd bullet point - If female, we will do a pregnancy urine blood test.  
8th bullet point - Give you 5 2 doses of VOR 400 mg to take home with you.  
 
2. Page 6 – Day 7, Visit 4 
1st bullet point – Come to clinic. Bring your empty medication bottle, Post-infusion and 
VOR Dosing Logs.  
6th bullet - Review and discuss your VOR dosing log.  
Add 7th bullet – Give you the next 3 doses of VOR and a new VOR dosing log.  
Add 8th bullet – Review the VOR dosing schedule with you and provide you with a dosing 
log that will list the days you need to take your doses.   
 
3. Page 7, Day 29, Visit 6  
1st bullet – Come to clinic approximately 4 hours after taking you 10th (last) dose of VOR. 
Discuss with your study coordinator, the time you will take your last dose of VOR and 
the time you should be at your clinic visit.  
 
4. Page 7, Day 60, Visit 8     
2nd bullet point - If female, we will do a pregnancy urine blood test. 
 
5. Page 8, Day 89, Visit 11 
1st bullet – Come to clinic approximately 4 hours after taking you 10th (last) dose of VOR. 
Discuss with your study coordinator, the time you will take your last dose of VOR and 
the time you should be at your clinic visit.  
 


IGHID 11802 – VOR-07 
Protocol v4.0 LOA #2 – January 30, 2020 – DAIDS-ES-ID 38536 
Page 5 of 5 
 
Letter of Amendment #2 
IGHID 11802 - Combination Therapy with the Novel Clearance Modality (VRC07-523LS) and 
the Latency Reversal Agent (Vorinostat) to Reduce the Frequency of Latent, Resting CD4+ T 
Cell Infection (The VOR-07 Study), A Phase 1 Study 
Protocol Version 4.0, dated 09 May 2019  
Letter of Amendment (LoA) #1 Date: August 12, 2019 
Clarification Memo #1 Date: September 17, 2019 
 
DAIDS-ES Document Number:  DAIDS-ES ID 38536 
IND Number: IND 138852 
 
Letter of Amendment (LoA) #2 Date: January 30, 2020 
 
 
 
SIGNATURE PAGE 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable U.S. Food and Drug Administration 
regulations; standards of the International Conference on Harmonization Guideline for Good 
Clinical Practice (E6); Institutional Review Board/Ethics Committee determinations; all applicable in- 
country, state, and local laws and regulations; and other applicable requirements (e.g., US National 
Institutes of Health, Division of AIDS) and institutional policies. 
 
 
 
 
Protocol Principal Investigator:   
 
Print/Type 
 
 
Signed: 
Date:   
 
 
 
Title:   
 


IGHID 11802                 Protocol Version 4.0 Clarification Memo #1 – September 17, 2019 
Page 1 of 1 
Clarification Memo # 1 
 
IGHID 11802 - Combination Therapy with the Novel Clearance Modality (VRC07‐ 523LS) and 
the Latency Reversal Agent (Vorinostat) to Reduce the Frequency of Latent, Resting CD4+ T 
Cell Infection (The VOR-07 Study) 
 
Protocol Version 4.0, May 9, 2019 
 
IND Number: 138852 
 
DAIDS‐ ES ID 38536 
 
Date of Clarification Memo: September 17, 2019 
 
Summary of Revisions and Rationale 
 
The protocol team would like to clarify the Prohibited Medications found in section 6.4 of the 
protocol, removing a few medications no longer regarded as prohibited. 
 
 
Implementation 
 
This Clarification Memo does not change the informed consent form.  
 
The plan is to incorporate the modifications included in this Clarification Memo into the next full 
protocol amendment. Text noted below with a strikethrough will represent deletion; text appearing 
below in bold will represent an addition.  
 
Prohibited Medications (section 6.4 Concomitant Medications, page 49)  
 
1. Prohibited HIV ART: Ongoing use of investigational ART. Prior use of investigational ART is 
permitted, provided it has been replaced with another class of ART and last dose was taken >90 
days prior to study screening visit;  
2. Concomitant use with oral or parenteral corticosteroids, immunosuppressive agents (including 
but not limited to azathioprine, and cyclosporine) or any immunotherapy or immunomodulatory 
agents;  
Note: On-study use of short course steroids for treatment of acute conditions may be 
approved on a case-by-case basis by the PI. The PI may adjust additional doses of study 
product and its timing based on their determination of safety and end-points. 
3. Use of any agent that suppresses lymphocytes or monocyte function;  
4. Use of chemotherapeutic agents, growth factors, cytokines, or chemokines, white lineage 
colony stimulating factors (e.g., granulocyte-colony stimulating factor [G-CSF] and GM-CSF);  
5. Chronic use of topical corticosteroids that are applied to large areas of the skin (exceeding the 
cumulative area of the palm of the participant’s hand) or any corticosteroids or antihistamines 
used on or near the infusion site.  
6. Standard and live vaccinations (e.g., varicella, measles, mumps, rubella, MMR; yellow fever, 
oral polio) are permitted but timing of vaccine must be discussed and approved by the study PI 
or designee.  
7. Antihistamine can be administered only if needed to treat an anaphylactic reaction. 


IGHID 11802 – VOR-07      Protocol v4.0 LoA #1 – August 12, 2019 – DAIDS-ES-ID 38536  
Page 1 of 4 
 
Letter of Amendment #1  
IGHID 11802 - Combination Therapy with the Novel Clearance Modality (VRC07-523LS) and 
the Latency Reversal Agent (Vorinostat) to Reduce the Frequency of Latent, Resting CD4+ T 
Cell Infection (The VOR-07 Study), A Phase 1 Study 
Protocol Version 4.0, dated 09 May 2019  
DAIDS-ES Document Number:  DAIDS-ES ID 38536 
IND Number: IND 138852 
Letter of Amendment (LoA) #1 Date: August 12, 2019 
 
This Letter of Amendment affects the IGHID 11802 study, including the study main informed 
consent form.  Submission to the UNC Institutional Review Board (IRB) overseeing this research 
will occur as soon as possible after DAIDS review and approval. The UNC IRB must approve this 
Letter of Amendment before implementation. 
Upon receiving final IRB and any other applicable Regulatory Entity (RE) approval(s) for this LoA, 
UNC will implement per unit SOP. UNC’s Regulatory Department retains a copy of this LoA and 
any associated DAIDS and IRB correspondence in the study’s regulatory file. Any future full 
amendment of the IGHID 11802 protocol will incorporate this Letter of Amendment.  
 
 
Summary of the Revisions and Rationale  
The protocol team is implementing this amendment for the following reasons: 
• 
To relax some of the inclusion and exclusion criteria currently limiting enrollment.   
• 
Suggested changes do not increase the risk to participants. 
• 
To correct the blood volume for Visit 3 (Day 0) in the estimated blood volume table.  
 
 
Implementation  
In changes listed below, additions to current protocol will appear as bolded text while deletions 
to current protocols will appear as crossed out text. 
 
 
Protocol Changes  
1. Section 5.1 Inclusion Criteria (pages 35 - 38)   
Note changes to selected criteria below: 
 


IGHID 11802 – VOR-07      Protocol v4.0 LoA #1 – August 12, 2019 – DAIDS-ES-ID 38536  
Page 2 of 4 
 
#4 - On continuous antiretroviral therapy (ART defined in 5.1.5) for at least 24 months 
prior to screening.  
 
Note: Continuous ART prior to screening is defined as not missing more than 4(four) 9 
total days and never more than 2 consecutive days in the 3 months prior to screening. 
 
2. Section 5.2 Exclusion Criteria (pages 38 – 41)  
Note changes to selected criteria below: 
 
#12 - Prior receipt of use of any HIV immunotherapy within 612 months prior to 
screening. 
 
#13 – Prior use of an HIV vaccine prior to screening. 
 
#15 - Prior receipt of humanized or human mAbs within 2 months prior to screening, 
whether licensed or investigational, will have eligibility determined by the study PI on a 
case-by-case basis.  
 
#27 - Diabetes Mellitus type 1 or type 2  
 
Not exclusionary: type 2 cases controlled with diet alone or a history of isolated 
gestational diabetes 
NOTE: Individuals with type 2 diabetes who meet inclusion criteria for glucose (Section 
5.1.23) are not excluded. 
 
#29 - Hypertension - Exclude for blood pressure consistently >150 mm Hg systolic and 
>100 mm Hg diastolic.  
• If a person has been found to have elevated blood pressure or hypertension 
during screening or previously, exclude for blood pressure that is not well 
controlled. Well-controlled blood pressure is defined as consistently ≤ 140 mm 
Hg systolic and ≤ 90 mm Hg diastolic, with or without medication, with only 
isolated, brief instances of higher readings, which must be ≤ 150 mm Hg systolic 
and ≤ 100 mm Hg diastolic. For these volunteers, blood pressure must be ≤ 140 
mm Hg systolic and ≤ 90 mm Hg diastolic at enrollment. 
• If a person has NOT been found to have elevated blood pressure or hypertension 
during screening or previously, exclude for systolic blood pressure ≥ 150 mm Hg 
at enrollment or diastolic blood pressure ≥ 100 mm Hg at enrollment. 
 
Note: Elevated BP occurring during research leukapheresis procedures completed within 
the past 12 months are excluded from this requirement. Other isolated incidences of 


IGHID 11802 – VOR-07      Protocol v4.0 LoA #1 – August 12, 2019 – DAIDS-ES-ID 38536  
Page 3 of 4 
 
elevated BP should be reviewed by study PI (or designee) to determine whether they are 
exclusionary. Acceptable isolated elevations must be noted as acceptable and signed by 
study PI or designee. 
 
3. Estimated Blood Volumes Associated with the Study Visits (page 64)  
Visit or Week # 
Blood Volume 
(mL)  
Visit or Week 
# 
Blood Volume 
(mL)  
Visit 1  
50 
Visit 8 Day 60 
116 
Visit 2  
153 
Visit 9 Day 67 
18 
Visit 3 Day 0 
61 163 
Visit 10 Day 
74 
18 
Visit 4 Day 7 
15 
Visit 11 Day 
89 
173 
Visit 5 Day 14 
16 
Visit 12 
50 
Visit 6 Day 29 
158 
Visit 13 
135 
 Visit 7  
70 
 
 
 
Informed Consent Changes  
 
1. The Informed Consent Version and Date have been updated from Version 4.0, May 
9, 2019 to Version 4.1, August 12, 2019.  
 
2. Are there any reasons that you should not be in this study? (Page 3) 
a) Deleted the 9th bullet 
• Have previously received an HIV vaccine 
b) Amended text in the 13th bullet  
• Have Type 1 diabetes 
 
3. Study Visits Table (Page 6)  
a) Adjusted volume of blood drawn at Day 0 (Visit 3)  
• ~61163 mL or 411 Tbsp. 
 
 
 
 
 
 


IGHID 11802 – VOR-07      Protocol v4.0 LoA #1 – August 12, 2019 – DAIDS-ES-ID 38536  
Page 4 of 4 
 
Letter of Amendment #1  
IGHID 11802 - Combination Therapy with the Novel Clearance Modality (VRC07-523LS) and 
the Latency Reversal Agent (Vorinostat) to Reduce the Frequency of Latent, Resting CD4+ T 
Cell Infection (The VOR-07 Study), A Phase 1 Study 
Protocol Version 4.0, dated 09 May 2019  
DAIDS-ES Document Number:  DAIDS-ES ID 38536 
IND Number: IND 138852 
Letter of Amendment (LoA) #1 Date: August 12, 2019 
 
 
SIGNATURE PAGE 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable U.S. Food and Drug Administration 
regulations; standards of the International Conference on Harmonization Guideline for Good 
Clinical Practice (E6); Institutional Review Board/Ethics Committee determinations; all applicable in-
country, state, and local laws and regulations; and other applicable requirements (e.g., US National 
Institutes of Health, Division of AIDS) and institutional policies. 
 
 
Protocol Principal Investigator: _______________________________________________  
 Print/Type  
 
 
 
Signed: ___________________________________ Date: __________________________  
 
Title: _____________________________________ 


The VOR-07 Study 
Version 4.0 
Protocol: IGHID 11802 
09 May 2019 
1 
 
 
 
 
 
 
Combination Therapy with the Novel Clearance Modality (VRC07-523LS) and the 
Latency Reversal Agent (Vorinostat) to Reduce the Frequency of Latent, Resting 
CD4+ T Cell Infection (The VOR-07 Study) 
Phase 1 Study 
 
 
 
Protocol Number: IGHID 11802 
National Clinical Trial (NCT) Identified Number: NCT 03803605 
Grant Principal Investigator: David Margolis, MD 
Protocol Principal Investigator: Cynthia Gay, MD, MPH 
University of North Carolina at Chapel Hill 
DAIDS-ES Document Number:  DAIDS-ES ID 38536 
IND Number: IND 138852 
Funded by: National Institutes of Health  
Version Number: v.4.0 
09 May 2019  
 
 
  
 
 
 
 
 
 
 
 
 
 
 


The VOR-07 Study 
Version 4.0 
Protocol: IGHID 11802 
09 May 2019 
2 
 
 
 
IGHID 11802 – Combination Therapy with the Novel Clearance Modality (VRC07-
523LS) and the Latency Reversal Agent (Vorinostat) to Reduce the Frequency of 
Latent, Resting CD4+ T Cell Infection (The VOR-07 Study) 
 
DAIDS-ES ID 38536 
 
 
SIGNATURE PAGE 
 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable U.S. Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
 
 
Investigator of Record: _______________________________________________ 
Print/Type 
 
 
 
 
 
Signed: ___________________________________ Date: ____________________ 
 
 
Title: _____________________________________ 
 
 
 
 
 
 
 
 
 
 


The VOR-07 Study 
Version 4.0 
Protocol: IGHID 11802 
09 May 2019 
3 
 
KEY ROLES AND CONTACT INFORMATION  
 
Grant Principal Investigator 
David M. Margolis, MD 
Professor of Medicine, Microbiology & Immunology 
University of North Carolina at Chapel Hill 
Division of Infectious Diseases 
120 Mason Farm Road, 2016 Genetic Medicine 
Building, CB 7042 
Chapel Hill, NC 27599-7042 
Phone: (919) 966-6388 
Email: dmargo@med.unc.edu 
Protocol Chair/Principal Investigator 
Cynthia Gay, MD, MPH 
Associate Professor 
University of North Carolina at Chapel Hill 
Division of Infectious Diseases 
130 Mason Farm Road, 2nd Floor Bioinformatics 
Building, CB 7030 
Chapel Hill, North Carolina 27599-7030 
Phone: (919) 843-2726 
Fax: (919) 966-8928 
Email: cynthia_gay@med.unc.edu 
Co- Investigators 
Joseph Eron, MD 
Professor of Medicine, School of Medicine,  
Chair Division of Infectious Disease Division,  
Clinical Core, UNC Center for AIDS Research 
University of North Carolina at Chapel Hill 
130 Mason Farm Road, 2nd Floor Bioinformatics, 
CB 7030 
Chapel Hill, North Carolina 27599-7030 
Phone: (919) 843-2722 
Fax: (919) 966-8928 
Email: joseph_eron@med.unc.edu  
 
Michelle Floris-Moore MD, MS 
Associate Professor of Medicine 
Division of Infectious Diseases  
Department of Medicine  
University of North Carolina at Chapel Hill 
130 Mason Farm Road, CB 7030 
Bioinformatics Building, Room 2103  
Chapel Hill, North Carolina 27599-7030 
Phone: (919) 966-4733 
Fax: (919) 966-6714   
Email: michelle_floris-moore@med.unc.edu 
 
Nancie M. Archin, PhD 
Research Assistant Professor 
University of North Carolina at Chapel Hill 
Division of Infectious Diseases 
120 Mason Farm Rd, CB 7042 
Genetic Medicine Building, RM 2049H 
Chapel Hill, NC, 27599-7042 
Phone: (919) 966-6389 
Email: nancie_archin@med.unc.edu 
 
Nilu Goonetilleke, PhD 
Assistant Professor 
Depts. Microbiology & Immunology/Medicine 
University of North Carolina at Chapel Hill 
120 Mason Farm Road, CB 7042 
2023 (Office 2017), Genetic Medicine Building 
Chapel Hill, NC 27599-7264 
Phone: (919) 962-3129 
Email: nilu_goonetilleke@med.unc.edu 
 
Ron Swanstrom, PhD 
Charles P. Postelle, Jr. Distinguished Professorship 
in Biochemistry 
Director, UNC Center for AIDS Research and 
Department of 
Microbiology and Immunology 
University of North Carolina at Chapel Hill 
22-006 Lineberger Cancer Center, CB 7295 
Chapel Hill, NC 27599-7260 
Phone: (919) 966-5710 
Email: risunc@med.unc.edu 
Statistician 
Michael Hudgens, PhD 
Professor 
Department of Biostatistics 
Director, Center for AIDS Research (CFAR) 
Biostatistics Core 
University of North Carolina at Chapel Hill 
Chapel Hill, NC 27599 
Phone: (919) 966-7253 
Email: mhudgens@bios.unc.edu 
 


The VOR-07 Study 
Version 4.0 
Protocol: IGHID 11802 
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Statistician 
Katie Mollan, MS 
Senior Biostatistician 
Center for AIDS Research (CFAR) Biostatistics Core 
3126 McGavran-Greenberg Hall 
University of North Carolina at Chapel Hill 
Chapel Hill, NC 27599 
Phone: (919) 966-8421 
Email: kmollan@unc.edu 
 
 
Clinical Program Manager 
JoAnn Kuruc, MSN, RN 
Clinical Program Director, The UNC Cure Center 
University of North Carolina at Chapel Hill 
Division of Infectious Diseases 
130 Mason Farm Road, 2nd Floor Bioinformatics 
Building, CB 7030 
Chapel Hill, North Carolina 27599-7030 
Phone: (919) 966-8533 
Fax: (919) 843-7625 
E-Mail: joann_kuruc@med.unc.edu 
 
DAIDS Medical Officer  
Lawrence Fox, MD, PhD 
Captain, US Public Health Service 
Senior Medical Officer, HIV Research Branch 
Division of AIDS, NIAID, NIH, DHHS 
Phone: 240-627-3069 
Fax: 240-627-3106 
Email: LFOX@niaid.nih.gov 
DAIDS Program Officer  
Tia Morton, RN, MS 
Nurse Consultant/Program Officer 
DAIDS/TRP 
5601 Fishers Lane, Rm 9E48 
Bethesda, MD 20852 
Phone: 240-627-3073 
Email: fraziert@niaid.nih.gov  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ............................................................................................................................. 6 
1 
PROTOCOL SUMMARY ............................................................................................................................... 7 
1.1 
Synopsis ................................................................................................................................................ 7 
1.2 
Schema ................................................................................................................................................. 9 
1.3 
Schedule of Events............................................................................................................................ 11 
2 
INTRODUCTION .......................................................................................................................................... 13 
2.1 
Study Rationale .................................................................................................................................. 13 
2.2 
Background......................................................................................................................................... 14 
2.3 
Risk/Benefit Assessment .................................................................................................................. 26 
2.3.1 
Known Potential Risks ................................................................................................... 26 
2.3.2 
Known Potential Benefits .............................................................................................. 31 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 31 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 32 
4 
STUDY DESIGN ........................................................................................................................................... 33 
4.1 
Overall Design .................................................................................................................................... 33 
4.2 
Scientific Rationale for Study Design.............................................................................................. 34 
4.3 
Justification for Dose ......................................................................................................................... 34 
4.4 
End of Study Definition ..................................................................................................................... 34 
5 
STUDY POPULATION ................................................................................................................................ 34 
5.1 
Inclusion Criteria ................................................................................................................................ 35 
5.2 
Exclusion Criteria ............................................................................................................................... 38 
5.3 
Lifestyle Considerations .................................................................................................................... 41 
5.4 
Screen Failures .................................................................................................................................. 41 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 42 
6 
STUDY INTERVENTION ............................................................................................................................ 42 
6.1 
Study Intervention(s) Administration ............................................................................................... 42 
6.1.1 
Study Intervention Description ..................................................................................... 42 
6.1.2 
Dosing and Administration ............................................................................................ 43 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 44 
6.2.1 
Acquisition and accountability ...................................................................................... 44 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 44 
6.2.3 
Product Storage and Stability ....................................................................................... 45 
6.2.4 
Preparation ...................................................................................................................... 45 
6.3 
Study Intervention Compliance ........................................................................................................ 49 
6.4 
Concomitant Medications ................................................................................................................. 49 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 49 
7.1 
Discontinuation of Study Intervention ............................................................................................. 49 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 50 
7.3 
Lost to Follow-Up ............................................................................................................................... 52 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 52 
8.1 
Efficacy Assessments ....................................................................................................................... 52 
8.2 
Safety and Other Assessments ....................................................................................................... 59 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 64 
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 64 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 65 
8.3.3 
Classification of an Adverse Event .............................................................................. 65 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 66 
8.3.5 
Adverse Event Reporting .............................................................................................. 68 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 71 
8.3.7 
Reporting Events to Participants ................................................................................. 72 


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8.3.8 
Adverse Events of Special Interest ............................................................................. 72 
8.3.9 
Reporting of Pregnancy ................................................................................................ 73 
8.4 
New Safety Information .................................................................................................................... 74 
8.4.1 
Definition of New Safety Information (NSI) ................................................................ 74 
8.4.2 
New Safety Information Reporting............................................................................... 74 
8.4.3 
Reporting New Safety Information to Participants .................................................... 75 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 75 
9.1 
Statistical Hypotheses ....................................................................................................................... 75 
9.2 
Sample Size Determination .............................................................................................................. 75 
9.3 
Populations for Analyses .................................................................................................................. 76 
9.4 
Statistical Analyses............................................................................................................................ 76 
9.4.1 
General Approach .......................................................................................................... 76 
9.4.2 
Analysis of the Primary safety Endpoint ..................................................................... 77 
9.4.3 
Analysis of the Other Endpoint(s) ................................................................................ 77 
9.4.4 
Safety Analyses .............................................................................................................. 78 
9.4.5 
Tabulation of Individual participant Data .................................................................... 79 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 79 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 79 
10.1.1 
Informed Consent Process ........................................................................................... 79 
10.1.2 
Study Discontinuation and Closure ............................................................................. 80 
10.1.3 
Confidentiality and Privacy ........................................................................................... 80 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 81 
10.1.5 
Key Roles and Study Governance .............................................................................. 81 
10.1.6 
Safety Oversight ............................................................................................................. 82 
10.1.7 
Clinical Monitoring .......................................................................................................... 83 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 84 
10.1.9 
Data Handling and Record Keeping ............................................................................ 84 
10.1.10 
Protocol Deviations ........................................................................................................ 85 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 85 
10.1.12 
Conflict of Interest Policy .............................................................................................. 86 
10.2 
Abbreviations ...................................................................................................................................... 86 
10.3 
Protocol Amendment History ........................................................................................................... 88 
11 
REFERENCES ............................................................................................................................................. 89 
 
STATEMENT OF COMPLIANCE 
 
The trial will be conducted in accordance with International Conference on Harmonization Good Clinical 
Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), and the NIH 
Institute Terms and Conditions of Award. The Principal Investigator will assure that no deviation from, or 
changes to the protocol will take place without prior agreement from the Investigational New Drug 
sponsor, funding agency, and documented approval from the Institutional Review Board (IRB), except 
where necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in 
the conduct of this study have completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval.  Approval of both the protocol and the consent form must 
be obtained before any participant is enrolled.  Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study.  All changes to the consent form 
will be IRB approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent form. 


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1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Phase I Study to Assess the Safety and Activity of Combination Therapy 
using a Novel Monoclonal Antibody, VRC07-523LS, and the Latency 
Reversal Agent, Vorinostat, to Reduce the Frequency of Latent, Resting 
CD4+ T Cell Infection in participants with HIV-1 infection suppressed on 
ART (The VOR-07 Study) 
 
 
 
Study Description: 
Participants with HIV-1 Infection on ART with a CD4 T cell count ≥ 350 
cells/mm3 and viral suppression for ≥ 24 months. Participants will receive 
two series of combination therapy consisting of one (1) intravenous (IV) 
dose of VRC-HIVMAB075-00-AB (VRC07-523LS) followed by 10 oral (PO) 
doses of Vorinostat (VOR) taken every 72 hours. Each series will last 
approximately 1 month and the two series will be separated by at least 
one month. Combination ART is (ART) maintained throughout the study. 
 
 
Objectives: 
Primary Objective:   
1. To evaluate the safety and tolerability of combination therapy 
with VRC07-523LS and VOR in HIV-infected participants on ART. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Endpoints: 
 
Other Objectives:  
1. Explore the effect of two cycles of VRC07-523LS and VOR on the 
frequency of latent, resting CD4+ T cell infection. 
2. Explore the influence of VOR given with VRC07-523LS on low-level 
plasma viremia as measured by low level viremia assay in 
participants who maintain suppression on ART. 
3. Compare HIV RNA expression within resting CD4+ T cells in HIV-
infected participants on stable ART before and after combination 
therapy with VRC07-523LS and VOR measured at baseline (Step 1) 
and after the second series (Step 4). 
4. Explore the impact of combined therapy with VRC07-523LS and 
VOR on the quantity of integrated proviral DNA quantification in T 
cell populations. 
5. Characterize viral envelope sequences detected in plasma or cells 
that are not neutralized by VRC07-523LS from baseline to post- 
treatment with VRC07-523LS and VOR. 
6. Evaluate the pharmacokinetics of VRC07-523LS combined with 
VOR and determine whether anti-drug antibody (ADA) to VRC07-
523LS can be detected in recipients administered VRC07-523LS in 
combination with VOR.  
 
Primary Endpoint: 
1. Safety: Occurrence of at least one ≥ Grade 3 adverse event (AE) 
including signs/symptoms, lab toxicities, and/or clinical events that 
is possibly, probably, or definitely related to VOR or VRC07-523LS 


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from the first day of study treatment through the end of study. 
Safety data will include local and systemic signs and symptoms, 
laboratory measures of safety/toxicity, and all adverse and serious 
adverse events.  
 
Other Endpoints:  
1. Change in the frequency of HIV infection per million resting CD4+ T 
cells (RCI) from baseline to post-treatment with VRC07-523LS 
combined with VOR. 
2. Change in HIV RNA expression within resting CD4+ T cells in HIV-
infected participants on stable ART from baseline to after the 
receipt of two series of VRC07-523LS given with VOR. 
3. Change in HIV-1 RNA by low level viremia assay from baseline to 
post-treatment with VRC07-523LS and VOR. 
4. Change in the chromosomally integrated viral reservoir as 
measured by quantitative-polymerase chain reaction (Q-PCR) from 
baseline to post-treatment with VRC07-523LS and VOR. 
5. Change in frequency of viral envelope sequences detected in 
plasma or cells that are not recognized by VRC07-523LS from 
baseline to post-treatment with VRC07-523LS and VOR. 
6. Pharmacokinetics of VRC07-523LS in combination with VOR. 
 
Population:  
 
Healthy men and women of any race with HIV-1 infection, ages 18 through 
64, suppressed on ART therapy for > 24 months.  
 
Phase:   
 
Phase I 
Description of 
Sites/Facilities Enrolling 
Participants: 
This study will be conducted at a single site, The University of North 
Carolina (UNC) at Chapel Hill (USA). The study will enroll up to12 
participants.  
 
Description of Study 
Intervention: 
 
Participants will receive two treatment interventions (series): 
1. VRC07-523LS – 
a.  40 mg/kg via IV infusion per series 
 (total of 2 infusions) 
2. VOR – 
a. 400 mg PO every 72 hours for 10 doses per series  
(total of 20 doses of VOR 400 mg in the study) 
 
In Step 1, all participants will undergo study screening and enrollment. 
Participants will complete a baseline Leukapheresis (#1). In order to 
advance to Step 2, participants must be found to have a baseline 
measurement of the frequency of resting CD4 T cell infection ≥ 0.3 
infectious units per million (IUPM) determined by Quantitative Viral 
Outgrowth Assay (QVOA) (lower limit of detection is 0.3 IUPM), as a 
further decrease from this low frequency of infection cannot be 
definitively measured given the QVOA assay threshold. 
 


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These criteria assure that eligible enrolled participants will have a 
measurable endpoint, thus decreasing risk of study participation for 
participants who would not have a measurable outcome. 
 
Participants progressing to Steps 2 and 3 will receive two series of a single 
VRC07-523LS infusion followed by multiple doses of VOR. 
 
In the first series (Step 2), participants will receive one VRC07-523LS 40 
mg/kg infusion (infusion #1) on Day 0 followed by the 1st dose of VOR 400 
mg PO taken at home on Day 2. Participants will take VOR 400 mg PO 
every 72 hours for a total of 10 doses.  
 
In the second series (Step 3), participants will receive one VRC07-523LS 40 
mg/kg infusion (infusion #2) on Day 60 followed by the 1st (of the 2nd series 
of VOR) dose of VOR 400 mg PO on Day 62. As in the previous Step, 
participants will take VOR 400 mg PO every 72 hours for a total of 10 
doses. 
 
Step 4 consists of 2 visits. The post-study treatment leukapheresis (#2) will 
be completed 5 – 8 weeks after the 2nd VRC07-523LS infusion. The End of 
Study Visit (EOS) will be scheduled to 2 – 4 weeks following the final 
leukapheresis (#2) visit. 
 
Study Duration: 
The study will take approximately 8 months to enroll up to 12 participants 
and will be completed, inclusive of data analysis within 18 months of the 
enrollment of the last participant.  
 
Participant Duration: 
Each participant will be enrolled on the study for approximately 28 weeks. 
 
1.2 
SCHEMA 
 
This is an open-label study to examine the safety of two series of combination therapy each consisting of 
a single VRC07-523LS 40mg/kg infusion followed by 10 oral doses of VOR taken every 72 hours in 
healthy HIV-infected adults suppressed on ART. 
 
Safety laboratory samples will be collected throughout the study per the Schedule of Evaluations 
(Section 1.3). Participants will keep a daily diary of solicited symptoms for 3 days after each 
administration of VRC07-523LS. 
 


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Step 1 
• 
Consent 
• 
Eligibility confirmed and Enrollment 
• 
Baseline leukapheresis (#1) and research evaluations  
• 
Advancement Criteria Met  
IUPM determined  
 
Step 2  
• 
Day 0 - VRC07-523LS infusion (#1) 
• 
Day 2 - VOR 400 mg PO – 1st dose taken at home  
• 
10 doses of VOR 400 mg PO taken every 72 hours  
• 
Immunology and virology research sample collection 
• 
Safety evaluations  
 
Step 3  
• 
Day 60 - VRC07-523LS infusion (#2) 
• 
Day 62 - VOR 400 mg PO – 1st dose in second series taken at home   
• 
10 doses of VOR 400 mg PO taken every 72 hours  
• 
Immunology and virology research sample collection  
• 
Safety evaluations  
 
Step 4 
• 
Post treatment leukapheresis (#2) 
• 
Safety evaluations 
• 
Immunology and virology research sample collection 
 
 
 
 
 
 
 
 
Screen, Enroll & 
Baseline IUPM 
measurement
Step 2                                       
VRC07-523LS infusion x1            
VOR 400 mg Q 72 hours x 10
Rest
Step 3                                       
VRC07-523LS infusion x1           
VOR 400 mg Q 72 hours x 10
Step 4            
Post TX 
evaluation
4 - 8  Weeks 
4 weeks 
4 weeks 
4 weeks 
5 - 8 weeks 
Leuk
Leuk
VRC07-523LS
VRC07-523LS
Continuous ART Therapy 


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1.3 
SCHEDULE OF EVENTS  
 
Code: d = day 
             h = hour 
Step 1 
Step 2 – Series 1 
Step 3– Series 2 
Step 4 
Screen 
Enroll  
Day 0 
Day 4 - 6 
Day 7 
Day 14 
Day 29 
Pre-Visit 
Day 60 
Day 64- 66 
Day 67 
Day 74    
Day 89 
Evaluation 
† 
End of 
Study ‡ 
Study Visit 
1 
2 
3 
 
4 
5 
6 
7 
8 
 
9 
10 
11 
12 
13 
Study Visit Window 
 
≤ 30d 
of Visit 
1 
≤ 6 wks 
of leuk  
 
+/- 1 
day 
+/- 2 
days 
 
≤ 7d of  
Day 60 
-3d/+ 
14d 
 
+/- 1 
day 
+/- 2 
days 
 
 
 
Clinical Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assign PID 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assign SID 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History and 
Updates  
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X1 
X 
Physical Exam (weight) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Targeted Physical Exam 
(weight) 
 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X1 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medication review 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X1 
X 
ART Medication and 
Adherence Review 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X1 
X 
Vital Signs 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X1 
X 
Adverse Event 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X1 
X 
Assess Venous Access 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
(ECG) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Solicited AE 
Assessment 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Telephone Assessment 
of Solicited AEs  
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Advancement Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-Study treatment 
Safety Assessment 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
VOR 400 mg PO doses 
 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
VRC07-523LS Infusion 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Leukapheresis 
Procedure 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Clinical Laboratory 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differential 
X 
 
X2 
 
X 
X 
X 
X 
 
 
X 
X 
X 
 
X 
CBC for leukapheresis  
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum Chemistry 
(screening)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


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Code: d = day 
             h = hour 
Step 1 
Step 2 – Series 1 
Step 3– Series 2 
Step 4 
Screen 
Enroll  
Day 0 
Day 4 - 6 
Day 7 
Day 14 
Day 29 
Pre-Visit 
Day 60 
Day 64- 66 
Day 67 
Day 74    
Day 89 
Evaluation 
† 
End of 
Study ‡ 
Serum Chemistry 
(safety)  
 
 
X2 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X1 
 
Liver Function Tests 
X 
 
X2 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 1 
X 
Fasting Lipid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/PTT/INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test  
X 
 
X 
X3 
X3 
X3 
X3 
X3 
X 
X3 
X3 
X3 
X3 
X3 
X3 
CD4 T Cell Differential 
Panel 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
HIV-1 RNA PCR 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
HBsAg & HCV Ab 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
RPR 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Interferon-gamma 
release assay (IGRA)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Research Laboratory 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Low level Viremia Assay 
 
X 
X 
 
 
 
X 
X 
 
 
 
 
X 
X1 
 
ADA Analysis 
 
 
X 
 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
Single PK sample (VOR) 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
PK sample 
(VRC07-532LS) 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
HLA Typing  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMV IgG Test  
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
EBV VCA IgG Test 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
caRNA Assay  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acetylation, Virology 
and Viral Sequence 
Analysis 
 
X 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
Resting Cell Assay 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
† Visit to occur 5 – 8 weeks after Day 60. 
‡ Visit to occur 2-4 weeks after Visit 12. 
 
1 Labs can be collected within 72 hours prior to the leukapheresis procedure    
2 Clinical and research sample drawn pre-dose. Safety Labs at Day 0 must be reviewed by PI prior to VRC07-523LS infusion. Pre-dose 
Safety labs (CBC, chemistries and LFTS) can be obtained within 7 days prior to Day 0.  
3 Serum pregnancy test will be performed at any time, if pregnancy suspected, a serum pregnancy test must be completed on day of intervention to 
confirm pregnancy status. 
 
 
 
 
 
 


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2 
 
INTRODUCTION 
 
The Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID), and 
Division of AIDS (DAIDS) have collaborated to develop and evaluate VRC07-523LS, a highly potent and 
broadly neutralizing HIV-1 human monoclonal antibody (mAb) targeted against the HIV-1 CD4 binding 
site. A similar antibody, VRC01 mAb, is currently in clinical trials under IND 113,611 (prevention 
indication) and IND 126,001 and IND 126,664 (therapeutic indication). The VRC01mAb was originally 
discovered in an HIV-1-infected participant whose immune system controlled the virus without anti-
retroviral therapy (ART) for over 15 years (1, 2). Through advances in B-cell immunology, cloning and 
structure-guided optimization techniques, numerous HIV-1 neutralizing mAbs, including VRC07 (“07” 
denotes sequential numbering when discovered), VRC07-523 (“523” denotes sequential numbering 
when engineered variant generated), and later VRC07-523LS (“LS” denotes 2 amino acid mutations), 
were isolated with potency and breadth greater than those of early antibodies (3).  
 
The VRC07 (wild-type) heavy chain was identified by 454 deep sequencing based on its similarity to the 
VRC01 mAb and paired with the VRC01 (wild-type) light chain. The mutations that together define the 
523 designation are a glycine to histidine mutation at residue 54 of the heavy chain, a deletion of the 
first two amino acids, glutamate and isoleucine, from the light chain, and a valine to serine mutation at 
the third amino acid residue of the light chain. The LS designation specifies methionine to leucine (L) and 
asparagine to serine (S) (M428L/N434S, referred to as LS) changes within the C-terminus of the heavy 
chain constant region. The LS mutation was introduced by site-directed mutagenesis to increase the 
binding affinity for the neonatal Fc-receptor (FcRn), resulting in increased recirculation of functional IgG 
(4, 5), thus increasing plasma half-life.  
 
The resultant molecule, VRC-HIVMAB075-00-AB (VRC07-523LS), is an investigational drug currently 
being evaluated for the prevention of HIV-1 infection in healthy adults. We propose its study herein 
towards future uses to clear established HIV infection.  
 
2.1 
STUDY RATIONALE  
 
The inability to eliminate HIV-1 from quiescent, latently infected reservoirs (6-8) remains the critical 
limitation to HIV eradication. Although combination antiretroviral therapy (cART) effectively suppresses 
viremia, cART drugs do not eliminate the latent viral reservoir. With a half-life of 3.6 years of the latent 
reservoir, over 70 years of suppressive ART would be required to achieve HIV eradication through ART 
alone (9, 10). Given the expanding numbers of HIV-infected individuals on ART, there is a need for 
innovative therapies to eradicate HIV-1 infection (11). One approach to eradicate HIV infection, a ‘kick 
and kill’ strategy, is to 1) expose latent, persistent HIV by interfering with mechanisms that maintain 
latency, and 2) eliminate exposed latently infected cells by an enhanced immune response without 
interrupting ART. Antibodies could be used to enhance HIV-specific immune responses as they can 
mediate effector functions such as antibody-dependent cellular cytotoxicity (ADCC), antibody-
dependent cellular viral inhibition, and phagocytosis through binding of the Fc portion to receptors on 
the surface of cells such as macrophages and natural killer cells. Further, novel and engineered anti-HIV 
antibodies are under study to prevent, treat, and clear infection via these functions (12).  
 
Over the past several years, there has been a successful effort to isolate broadly neutralizing 
antibodies (bNAbs) to HIV-1 from chronically infected individuals (2, 12-26). Studies have provided 
considerable insight into the sites these antibodies target on HIV-1 and the mechanisms by which 


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they neutralize HIV-1 (14, 15, 24, 27). This proposal builds upon the data generated by U01 AI095052, 
which investigated the anti-latency activity of Vorinostat (VOR), defining optimal dosing strategies 
(28-30), resulting in our current optimized strategy of interval dosing with VOR every 3 days.  These 
studies found VOR to be well-tolerated, and optimized dosing intervals result in repeated induction 
of cell-associated HIV RNA expression, potentially allowing clearance of latent infection. Preclinical 
studies with VRC07-523LS to date support the proposed human dose and interval between doses to 
achieve passive immunity. The use of VRC07-523LS, which will provide antibody exposure over the 
period of latency reversal by VOR based on pharmacokinetic data in humans, allows the provision of 
a validated immunotherapy that may direct ADCC to clear reactivated HIV-1. We will assess the 
safety and tolerability, as well as the ability of VRC07-523LS to reduce the frequency of latent, resting 
CD4+ T cell infection in stably treated HIV-infected participants, when combined with pulsatile VOR 
administration. This study will evaluate the safety of the combined treatment and examine the effect 
of VOR and VRC07-523LS on persistent replication-competent HIV within resting CD4+ T cells. 
 
2.2 
BACKGROUND  
 
One approach to eradicate HIV infection, a ‘kick and kill’ strategy, is to 1) expose latent, persistent HIV 
by interfering with mechanisms that maintain latency, and 2) eliminate exposed latently infected cells by 
an enhanced T-cell immune response without interrupting ART. Studies have demonstrated that Histone 
Deacetylase (HDAC) is a critical regulator of HIV latency (28-30). Our own work has shown that the HDAC 
inhibitor, Vorinostat, can induce the expression of latent HIV-1 in vivo (28).  As effective dosing 
strategies for latency reversal agents (LRAs) in vivo are advancing, parallel testing of approaches to 
harness the immune response to clear residual HIV following the disruption of latency are critical. 
Recent work suggests that the antiviral CD8+ T cell response extant in the majority of HIV-1 infected 
individuals is insufficient to clear the latent reservoir.  Attempts to strengthen HIV-specific immune 
responses using a therapeutic vaccine have been disappointing (34-36), likely in part due to the inability 
of the vaccines to produce sustained expansion of HIV specific CD8+ T cells.  Further, archived immune 
escape viral variants within the latent reservoir may present a challenge (37). 
 
Antibodies can mediate effector functions such as ADCC, antibody-dependent cellular viral inhibition, 
and phagocytosis through binding of the Fc portion to receptors on the surface of cells such as 
macrophages and natural killer cells. Novel and engineered anti-HIV antibodies are under study to 
prevent, treat, and clear infection via these functions (38).  
 
VRC01 
VRC01 was a first-in-class broadly neutralizing antibody (bnAb) that targets the same CD4+ binding site 
of the HIV-1 envelope as VRC07-523LS. VRC01 was engineered for increased efficacy using next-
generation sequencing, computational bioinformatics, and structure-guided design. VRC01 has been 
assessed as safe and well tolerated at the 5-40 mg/kg doses administered intravenously (IV) and at 5 
mg/kg subcutaneously (SC) in both HIV-infected and HIV-uninfected adult populations. The 
pharmacokinetic (PK) parameters of passively administered VRC01 were also evaluated. For healthy 
adults who received VRC01 at the 5-40 mg/kg doses administered IV (n=18), the clearance was 
0.016±0.003 L/h and an overall mean value for the elimination half-life was 15.4±3.9 days. At 5 mg/kg SC 
(n=5), the clearance was 0.029±0.007 L/h, and the mean elimination half-life was 16.6 ± 2.9 days. 
Studies are ongoing to further describe the PK and biological activity of VRC01 after repeat dosing in 
HIV-infected and -uninfected adults. VRC01LS is a VRC01 variant with 2 amino acid mutations 
(M428L/N434S, referred to as LS) conferring an increased plasma half-life. 


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VRC07-523 
Numerous HIV-1 neutralizing mAbs from the VRC01 family, including VRC07 (“07” denotes sequential 
numbering when discovered) have been isolated from the same individual (donor 45). The VRC07 (wild-
type) heavy chain was identified by 454 deep sequencing based on its similarity to the VRC01 mAb and 
paired with the VRC01 (wild-type) light chain. The mutations that together define the 523 designation 
are a glycine to histidine mutation at residue 54 of the heavy chain, a deletion of the first two amino 
acids, glutamate and isoleucine, from the light chain, and a valine to serine mutation at the third amino 
acid residue of the light chain. A resulting variant, VRC07-523, was 5- to 8-fold more potent than VRC01, 
neutralized 96% of viruses tested, and displayed minimal autoreactivity.  
 
VRC07-523LS 
VRC07-523LS is an engineered variant of VRC07 that was discovered in the same HIV-1 infected 
participant as VRC01. The LS designation specifies methionine to leucine (L) and asparagine to serine (S) 
(M428L/N434S, referred to as LS) changes within the C-terminus of the heavy chain constant region. The 
LS mutation was introduced by site-directed mutagenesis to increase the binding affinity for the 
neonatal Fc-receptor (FcRn), resulting in increased recirculation of functional IgG (4, 5), thus increasing 
plasma half-life. VRC07-523LS neutralizes more HIV envelope strains than VRC01 at lower 
concentrations. VRC07-523LS was found to be 5-to 8-fold more potent than VRC01, with an inhibitory 
concentration IC50 <50 mcg/mL against 96% of HIV-1 pseudoviruses representing the major circulating 
HIV-1 clades and IC50 <1 mcg/mL against 92% of HIV-1 viruses tested and displayed minimal levels of 
autoreactivity (3). VRC07-523LS was also shown to have a prolonged half-life over VRC07 by about 2-
fold.  In vivo proof-of-concept studies showed that VRC07-523LS is about 5-fold more potent than 
VRC01LS in Rhesus macaques and displays a longer half-life (9.8 days) than VRC07 (4.9 days) after a 
single dose at 10 mg/kg administered IV (3).  
 
Preclinical studies of VRC07-523LS 
The proposed VRC07-523LS dose for this study is based on human studies of VRC01, and preclinical and 
clinical studies of VRC07-523LS.  
 
In nonhuman primate studies, a single dose of VRC07-523LS 10 mg/kg administered IV in cynomolgus 
macaques had a half-life of about 12 days, and persisted at least 28 days (last collection point) in rectal 
and vaginal secretions and tissues. Complete protection from SHIV-SF162P3 challenge was 
demonstrated with a single IV dose of VRC07-523LS at 20 mg/kg.  
 
A repeat dose IV and SC toxicity study with VRC07-523LS was performed in male and female Sprague-
Dawley rats in accordance with “Good Laboratory Practice (GLP) for Nonclinical Laboratory Studies.” 
Treatment with VRC07-523LS at doses up to 400 mg/kg/dose IV or 40 mg/kg/dose SC with three doses 
at 10 day intervals was generally well tolerated as most findings were reversible and no longer seen at 
the end of the recovery period.  
 
Increased neutralization potency in vitro and prolonged half-life of VRC07-523LS correlate with 
improved protection against SHIV infection in vivo in animal studies, suggesting a potential clinical 
application against HIV-1 infection in humans in therapeutic settings.   
 
Several in vitro preclinical safety studies were performed with VRC07-523LS to assess potential off-
target binding. To measure potential anti-phospholipid cross-reactivity, binding of VRC07-523LS to 
cardiolipin was assessed using an enzyme-linked immunosorbent assay (ELISA) and demonstrated 


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minimal binding compared with 4E10, an earlier-generation HIV-1 specific mAb which binds strongly to 
cardiolipin. VRC07-523LS was also tested for cross-reactivity against a panel of various nuclear antigens 
using a licensed systemic lupus erythematosus diagnostic test kit (Luminex AtheNA Multi-Lyte® ANA-II 
test) and did cross-react with a small subset of nuclear antigens consistent with some reactivity with 
nuclear antigens. In addition, VRC07-523LS was assessed for anti-phospholipid properties in a clinical 
activated partial thromboplastin time (aPTT) assay and compared to the anti-HIV mAbs 4E10 and VRC01 
as well as palivizumab; only 4E10 showed evidence of antiphospholipid activity. By 
immunohistochemistry, VRC07-523LS displayed minimal binding to HEp-2 cells at 50 mcg/mL and no 
binding at 25 mcg/mL (3).  
 
A tissue cross-reactivity (TCR) study was performed in accordance with “Good Laboratory Practice (GLP) 
for Nonclinical Laboratory Studies” to determine the potential cross-reactivity of VRC07-523LS with 
cryosections of human and Sprague-Dawley rat tissues. VRC07-523LS staining was similar between the 
human and rat tissues examined, although staining tended to be somewhat more intense and frequent 
in the human tissue compared to the Sprague-Dawley rat tissues. According to ICH S6 (R1), monoclonal 
antibody binding to cytoplasmic sites generally is considered of little to no toxicologic significance. See 
the Investigator’s Brochure (IB) for further details. 
 
Clinical Studies of VRC01 
VRC-07-523LS is a similar product to VRC01 and its variant VRC01LS, and there is substantial clinical 
experience with both VRC01 and VRC01LS mAbs as described below.  
 
VRC 601 
VRC 601 (NCT01950325) was the first study of the VRC01 mAb in HIV-infected participants (31). It was 
a dose-escalation study to examine safety, tolerability, dose, PK, and anti- antibody immune responses. 
VRC 601 opened in September 2013 as a single site study at the NIH Clinical Center, Bethesda, 
Maryland and in total, 23 HIV-infected participants, including 15 aviremic ARV-treated participants and 
8 viremic non-ARV treated participants, were infused with one or two doses of VRC01 at doses up to 40 
mg/kg IV. 
 
All IV infusions and SC injections were well tolerated with no serious adverse events (SAEs) or dose 
limiting toxicity (DLT). VRC 601 demonstrated evidence of VRC01-mediated antiviral effect. Analysis of 
the VRC 601 viral load data obtained from 8 viremic adults shows that VRC01 has a statistically 
significant in vivo virological effect on HIV viral load when administered as a single 40 mg/kg IV dose 
(Figure 1; (31)). None of 
these adults were taking 
ART when enrolled into the 
study and had not started 
ART during the time period 
when the viral load data 
were collected. Six of the 
eight adult participants had 
≥1 log10 copies/mL decrease 
in viral load and two 
participants had a viral load 
drop of 0.26 and 0.18 log10 
copies/mL respectively. 
Figure 1. The effect of VRC01 on plasma viral load after infusion. Plasma virus load 
over time for eight viremic participants before and after infusion with VRC01 (day 0, 
indicated by arrow). Limit of detection of the assay is indicated with a tick at 20 
copies/mL.


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These interim data indicate the following for a single dose of VRC01 at 40 mg/kg IV: a statistically 
significant decline in viral load after infusion at days 5 to 16; a median time of 5 days to reach ≥ 0.5 
log10 decrease in viral load; and a median time of 7 days to greatest decrease in viral load post 
infusion. 
 
In VRC 601, participants were administered a single dose of 
VRC01 at 40 mg/kg and, therefore, a sustained effect on 
viral load was not expected. However, data demonstrated 
an anti-viral effect and led to the hypothesis that repetitive 
VRCO1 dosing could have a beneficial clinical effect. This 
hypothesis was tested in two clinical trials, AIDS Clinical 
Trials Group (ACTG) A5340 and NIH 15-I-0140, in which ART 
suppressed participants underwent an analytical treatment 
interruption (ATI) after receiving VRC01 40 mg/kg (32). No 
product-related safety concerns were identified in the 24 
participants enrolled. Viral rebound occurred despite VRC01 
serum concentrations well above 50 mcg/mL with a mean 
time to rebound of 4 to 6 weeks (32). While the mean time 
to rebound was statistically significantly different from 
historical controls in previous ACTG ATI studies at 4 weeks, 
there was no difference at 8 weeks. VRC01 was also found 
to exert selection pressure on emergent viruses (Figure 2, 
(32)). 
 
VRC 602 
VRC 602 was a dose-escalation study of the VRC01 mAb in HIV-uninfected adults to examine safety, 
tolerability, dose, and PK of VRC01 (1). There were 3 open-label, dose escalation groups for IV 
administration and 1 double-blinded, placebo-controlled group for SC administration. All IV infusions 
and SC injections were well tolerated with no SAEs or DLTs. PK analysis from VRC 602 revealed a 
VRC01 terminal half-life of 15 days across all IV infused dose groups. After the first infusion, 28-day 
trough levels were 35 mcg/mL and 57 mcg/mL for the 20 mg/kg and 40 mg/kg dose groups, 
respectively. Following the second infusion, the 28-day trough values rose to 57 mcg/mL and 89 
mcg/mL for the 20 mg/kg and 40 mg/kg dose groups, respectively. In addition, post infusion VRC01 
retained the expected neutralizing activity in serum and no anti-VRC01 antibodies were detected (1). 
 
HVTN 104  
HVTN 104 was a phase 1 clinical trial designed to evaluate the safety and drug levels of VRC01 
administered in multiple IV or SC doses and different dosing schedules to 88 healthy, HIV-uninfected 
adults at six HIV Vaccine Trials Network (HVTN) CRSs in four US cities: Boston, New York, Philadelphia, 
and Cleveland. The first participant enrolled in HVTN 104 on September 9, 2014 and study product 
administration for all participants was complete as of November 30, 2015. The study had 5 arms: 
Group 1 evaluated the IV administration of a 40 mg/kg loading dose, with 2 subsequent 20 mg/kg 
doses given at 8 week intervals. Groups 2, 4, and 5 evaluated 3 infusions of 40 mg/kg, 10 mg/kg, or 30 
mg/kg, respectively, given 8 weeks apart. Group 3 evaluated 5 mg/kg given every 2 weeks 
subcutaneously for 24 weeks after an initial IV administration at 40 mg/kg in order to inform the 
design of perinatal prophylaxis studies. 
 
 
Figure 2. Viral suppression mediated by 
VRC01. Kaplan-Meier curve of plasma viremia 
suppression (< 200 copies/mL) after VRC01 
administration in A5340 and NIH trial 
participants as compared with historical ACTG 
trials who underwent interruption of therapy 
without other immunotherapeutic 
interventions (40). 


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A total of 249 IV infusions and 208 SC injections of VRC01 were administered in HVTN 104. The 
infusions and injections were well tolerated, with 28% of infusions and 14% of injections associated 
with mild pain and/or tenderness. 55% of VRC01 and 50% of placebo recipients experienced mild pain 
and/or tenderness at the infusion or injection site sometime during the trial. One participant 
experienced moderate pain and/or tenderness following an SC injection of VRC01. Mild infusion site 
erythema/induration reactions were reported for 2 VRC01 participants and 1 placebo recipient. Two 
moderate erythema/induration reactions were reported, 1 following IV VRC01 and 1 following VRC01 
SC injection. For 76% of the infusions and injections administered in the trial, no systemic 
reactogenicity symptoms were reported. 56% of VRC01 and 75% of placebo recipients experienced 
systemic reactogenicity symptoms following at least one study product administration. These were all 
graded as mild in the placebo recipients. Among VRC01 recipients with any systemic symptom, the 
maximum severity was mild in 70%, moderate in 23%, and severe in 6% (3 participants). The most 
commonly reported symptoms were malaise/fatigue (30%), headaches (32%), and myalgias (26%). 
 
The severe systemic reactogenicity symptoms reported in 3 VRC01 recipients in HVTN 104 are detailed 
as follows: 
 One participant developed severe malaise, myalgia, headache and chills, mild nausea, and 
moderate arthralgia symptoms within 3 days after the first infusion of study product. The 
participant had a concomitant AE of laboratory confirmed influenza A infection diagnosed on Day 
2 treated with ibuprofen. Symptoms resolved by Day 7.  
 One participant reported a viral illness adverse event (AE) of moderate intensity beginning 3 days 
prior to the 9th SC injection (10th study product administration), characterized by nausea and 
vomiting, sore throat, runny nose but no fevers; a household contact was also ill. At baseline on 
Day 0 of the 9th SC injection, mild malaise/fatigue was still present. At the early assessment time 
point on Day 0, mild malaise/fatigue was still present and was accompanied by grade 1 nausea. 
Within 3 days of the injection, the participant developed severe malaise, myalgia, headache, chills, 
and arthralgia; these all resolved on Day 6, which was the date the AE for viral illness resolved. 
There was no reported use of concomitant medications for these symptoms. 
 One participant reported severe malaise/fatigue on the day of the first infusion, resolving 
spontaneously the next day. During this reactogenicity period, this participant also reported a 
grade 1 headache on Day 1, resolving the next day.  
 
There were no study product discontinuations due to reactogenicity symptoms. There were 235 AEs 
occurring in 70 participants (79.5%), with similar rates of occurrence across all treatment groups (81% 
among VRC01 recipients; 75% in placebo recipients). 74% of AEs were graded as mild, 22.5% as 
moderate, and 3.4% as severe. Only 9 AEs (3.8% of all AEs) occurring in 8 participants were deemed 
product-related by the investigators; all were mild and transient. Those occurring following VRC01 
administration included elevations of hepatic transaminases (aspartate aminotransferase [AST] and 
alanine aminotransferase [ALT] in 1 individual), elevated creatinine, neutropenia, localized injection 
site pruritus, diarrhea, generalized rash, and Varicella zoster infection. No VRC01- related 
hypersensitivity reactions or Cytokine Release Syndrome symptoms were observed during the study. 
Study product administration was discontinued in 8 participants.  Reasons for discontinuing study 
product included: AEs (3 participants), relocation from study site (2), unable to adhere to visit 
schedule (1), unable to contact (1), and pregnancy (1).  
 
 
 
 


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Safety summary of VRC01 
In summary, VRC01 has been well-tolerated when administered IV or SC.  As of February 22, 2018, more 
than 2600 HIV-uninfected adult participants, approximately 88 HIV-infected adult participants and 40 
HIV-exposed infants, have received one or more VRC01 administrations in unblinded VRC01 studies. 
There have been no SAEs assessed as related to VRC01 and no study safety pauses for AEs (Investigator’s 
Brochure (IB), version 4.0, February 26, 2018). 
 
VRC01 SC or IV administrations are generally associated with mild or moderate local reactions of 
pruritus, redness, and pain/tenderness, which resolve within a few minutes to a few hours after the 
administration is completed. When present, most systemic reactions after administration of VRC01 SC or 
IV are mild and include: malaise, myalgia, headache, chills, nausea, and joint pain. Unsolicited AEs of 
grade 3 or higher severity and deemed related to study product were not reported in these trials. 
 
Other AEs attributed to study product administration have included mild or moderate AST elevation, ALT 
elevation, creatinine elevation, and decreased neutrophil count. Mild or moderate elevated 
transaminases were reported in 4 of 21 (19%) HIV-infected participants in VRC 601 (all of whom were 
taking ARVs). These laboratory changes resolved spontaneously and did not require discontinuation of 
study product administration. Among HIV-uninfected participants in VRC 602 or HVTN 104, 1 participant 
had grade 1 (mild) transiently elevated ALT assessed as possibly attributed to VRC01 in the VRC 602 
study and 2 participants had grade 1 (mild) transiently elevated ALT/AST values assessed as related to 
VRC01 in HVTN 104. These 3 participants all received VRC01. 
 
In HVTN 104, there were 3 product discontinuations for AEs, 2 of which were deemed related to study 
product infusion or injection. One discontinuation was for a 20-minute episode of chest tightness 
occurring approximately 25 minutes after SC injection of placebo in a participant who is a chronic 
smoker on nicotine replacement while continuing to smoke. One discontinuation was in a participant 
who reported a generalized rash that began three days after SC injection of VRC01, and resolved within 
4 hours with ibuprofen and the application of an inert cream. The third discontinuation was in a young, 
otherwise healthy participant who experienced a brief episode of syncope, deemed not related to study 
product, approximately 4 hours after IV infusion of VRC01. In addition, one person in HVTN 104 had 
study product discontinued due to pregnancy occurring during the trial.  Of note, the safety experience 
with VRC01 has remained consistent whether 1 or 2 doses were administered, as in VRC 601 and 602, or 
multiple doses were administered, as in HVTN 104. There were no observed trends toward recurrence 
of lab abnormalities or AEs deemed related to study product, nor observed increases in frequency or 
severity of local or systemic reactogenicity symptoms with multiple administrations of VRC01 in these 
trials.  
 
The ongoing efficacy trials (HVTN 704/HPTN 085 and HVTN 703/HPTN 081) have accumulated significant 
additional VRC01 clinical experience; but these trials remain blinded and, thus, do not yet contribute to 
the unblinded VRC01 safety profile. However, in the ongoing blinded phase of these trials, urticaria or 
similar reactions have been reported at an overall frequency of about 1%. These reactions have been 
treated by stopping the infusion and providing supportive care, including anti-histamine and steroid 
therapy, as indicated, and no serious health consequences have been reported. No participants who 
experienced urticaria have been re-challenged with VRC01. Overall, VRC01 administration in the dose 
range from 10 to 40 mg/kg IV and at 5 mg/kg SC has been assessed as well-tolerated and safe for further 
evaluation. 
 


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Clinical Studies of VRC01LS 
 
VRC 606 
VRC01LS began evaluation in the VRC 606 study in November 2015. VRC 606 is a dose-escalation study 
to examine safety, tolerability, dose, and pharmacokinetics of VRC01LS. There were 4 open-label, dose 
escalation groups (Groups 1-4) to assess VRC01LS administered IV and SC once per participant and 2 
open-label groups (Groups 5 and 6) to assess VRC01LS at 5 mg/kg SC or at 20 mg/kg IV administered 
every 12 weeks for a total of 3 administrations per participant. At 4 weeks post administration, serum 
concentrations of VRC01LS were approximately 5-fold higher than corresponding levels of VRC01. The 
half-life of VRC01LS in healthy HIV-uninfected adults was also approximately 4-fold longer than VRC01 
with the maximal concentration observed 1-5 hours following IV administration (33). 
 
The safety and PK data for the first 37 subjects who received administrations of VRC01LS have been 
published in 2018 (33). In summary, VRC01LS has been generally well tolerated when delivered IV or SC 
and there were no SAEs or dose-limiting toxicity (Investigator’s Brochure, version 4.0, February 26, 
2018). 
The solicited local and systemic signs and symptoms following administration of VRC01LS were mild or 
moderate for local and systemic reactogenicity. Mild malaise and myalgia were the most common 
solicited AEs reported by 10 and 6 participants, respectively. The most frequent local reaction was 
pain/tenderness at injection site reported by 14 participants, but which occurred in only 2 participants 
by the IV route and which were mild in both cases; the remainder occurred with SC administration). No 
systemic symptoms were reported during product administration.  
Six AEs were assessed as possibly related to VRC01LS administration and all were mild in severity. Only 
one of the treatment-related AEs occurred in one participant receiving VRC01LS via the IV route and 
included diarrhea (in the 5 mg/kg, IV group) and which resolved the same day. The remainder of the AEs 
possibly related to VRC01LS SC administration included diarrhea on the day of administration and which 
resolved the same day, lightheadedness on the day following administration and symptoms resolved 
within 24 hours, an injection site reaction which resolved 14 days post administration and elevated 
aminotransferase levels (56 and 69 IU/L) on Day 14 post injection and which both resolved within 15 
days of onset. No volunteer had a positive HIV enzyme immunoassay (EIA) response during the study. 
VRC 607 
Evaluation of VRC01LS in HIV-infected adults in the VRC 607 study was initiated in April 2017. As of 
01/17/2018, 7 participants have been enrolled and received VRC01LS at 40 mg/kg IV. No local or 
systemic reactogenicity were reported during VRC01LS administrations in VRC 607. None of the 7 
participants reported any local reactogenicity on a 3-day diary card. As to systemic solicited 
reactogenicity, one participant reported mild symptoms of headache, chills, and nausea that resolved 
within 7-11 days after product administration. One SAE of gout was assessed as not related to study 
product administration. All other unsolicited AEs were Grade 1 (mild) or Grade 2 (moderate) and 
assessed as unrelated to study product. 
HVTN 116 
An additional study of VRC01LS, HVTN 116 [NCT02797171], is currently recruiting with 19 of 101 
participants enrolled as of July 31, 2017. Serum VRC01LS concentrations as high as 20 mcg/mL were 
observed in VRC 606 at 165 days (approximately 24 weeks) after a 5 mg/kg IV infusion and were, on 
average, over 65 mcg/mL at 165 days after a 20 mg/kg IV infusion (Figure 3).  


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VRC01LS concentration on Day 84 after a single 5mg/kg SC administration was, on average, over 10 
times greater than VRC01 concentration on Day 84 after a single 5mg/kg SC VRC01 administration. 
VRC01LS concentrations were over 40 times higher than those of VRC01 when comparing VRC01 
concentrations on Day 84 after a single 20 mg/kg IV infusion to VRC01LS concentrations on Day 84 after 
a single 20 mg/kg IV infusion.  
Overall, VRC01LS administration in the dose range from 1 to 40 mg/kg IV and at 5 mg/kg SC have been 
assessed as well-tolerated and safe for further evaluation. 
 
Figure 3. VRC01LS serum concentrations in VRC 606 compared to VRC01 serum concentrations with IV 
and SC administration. 
Clinical Studies of VRC07-523LS 
 
VRC 605 
A phase 1, open-label, dose-escalation study of VRC07-523LS, VRC 605 (NCT03015181), is 
underway in healthy, HIV-uninfected adults to evaluate the safety and pharmacokinetics of 1 to 3 
administrations of the antibody. The doses being evaluated are a single administration of 1 mg/kg 
and 5 mg/kg IV and SC, and 20 mg/kg and 40 mg/kg IV, and three administrations (q 12 weeks) of 5 
mg/kg SC and 20 mg/kg IV VRC07-523LS. Study objectives include evaluating the safety and 
tolerability of the study regimen and the pharmacokinetics of each dose level; determining the 
presence or absence of detectable ADA to VRC07-523LS; and evaluating for evidence of functional 
activity of VRC07-523LS.  


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PK results following 
VRC07-523LS infusion 
of 40mg/kg (the dose 
proposed in this 
protocol) are shown in 
Figure 4, showing 
serum concentrations 
>10 mcg/mL beyond 30 
days. In addition, serum 
concentrations of 
VRC07-523LS have 
been found to be 
comparable to VRC01 
40mg/kg IV and 
VRC01LS 40mg/kg IV.  
 
Additional interim PK 
results for VRC07-
523LS 5 mg/kg dose by 
IV and SC routes as 
compared with 
VRC01LS are shown in 
Figure 5.   
 
As of January 15, 2018, 
the VRC 605 study is 
fully enrolled. Twenty-
five (25) of 26 
participants have 
received at least 1 dose 
of VRC07-523LS (25 IV 
and 12 SC). One 
participant withdrew prior to receiving study product. There have been no SAEs and no safety pauses for 
AEs. Overall, 15 and 25 participants (60%) have had at least one AE, with the maximum severity being 
Grade 1 for 7 participants, Grade 2 for 6 participants, Grade 3 for 1 participant, and Grade 4 for 1 
participant. The grade 3 AE was for an elevated creatinine 56 days after last product administration 
based on an increase of 1.5 to 2 times the baseline value but still within the normal range, felt most 
likely related to dehydration following exercise. The Grade 4 AE was for elevated liver enzymes likely 
caused by concomitant initiation of fluoxetine, known to cause hepatoxicity and not related to VRC07-
523LS. This event was independently evaluated by the NIH hepatology consult service. The product 
 
Figure 4: Group 5 received a 40mg/kg IV dose of VRC07-523LS and demonstrated 
serum concentrations >10 mcg/mL beyond 30 days and serum concentrations 
comparable to VRC01 40mg/kg IV and VRC01LS 40mg/kg IV. 


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administrations were discontinued for this participant 
due to the concomitant illness. While the participant 
was followed for safety, her liver enzymes decreased, 
but then increased again after starting on citalopram, 
which reinforced that the original event was likely 
incited by an underlying sensitivity to selective 
serotonin reuptake inhibitor (SSRI) medications.  
 
Six mild of moderate AEs were assessed as related to 
study product, including mild dizziness, 4 occasions of 
infusion reactions (1 mild and 3 moderate, reported for 
2 participants), and mild abdominal pain. All AEs 
assessed as related to the study product have resolved 
without residual effects.  
 
Two participants developed infusion reactions shortly 
after IV product administration. Symptoms were 
typical of infusion reactions observed with other 
monoclonal antibodies. No atypical symptoms or 
delayed symptoms were seen. One participant 
enrolled in the 40 mg/kg IV group experienced a 
moderate infusion reaction with chills, rigors, fever, 
myalgia, and headache beginning 15 minutes after 
completion of the infusion. The participant was treated 
with acetaminophen and ibuprofen. All symptoms 
resolved within 12 hours. A separate participant in the 
20 mg/kg IV group experienced 3 separate infusion 
reactions (n = 2 moderate, n = 1 mild) after each 
product infusion. The participant experienced nausea, 
chills, rigors, malaise, tachycardia, headache, myalgia 
(mostly back), and arthralgia (mostly hips and knees). 
Symptoms began 15 minutes to 1 hour after 
completion of each product administration and 
completely resolved within 12 hours. The participant 
was treated with acetaminophen and ibuprofen.  
 
Overall, product administrations have been generally well tolerated with no unexpected reactions. For 
solicited local reactions in the week after VRC07-523LS administrations, one of 17 participants (5.9%) 
who received the product by IV administration reported mild bruising at administration site. For 
solicited systemic adverse events reported 3 days after product administration, 4 of 17 participants 
(25%) receiving VRC07-523LS IV reported mild or moderate systemic reactogenicity symptoms. The 
reported symptoms were malaise (n = 2 mild, n=1 moderate), myalgia (n = 2 mild, n = 1 moderate), mild 
headache (n = 2), and moderate chills (n = 2). Five of 8 participants (62.5%) receiving VRC07-523LS SC 
reported mild systemic reactogenicity symptoms: malaise (n = 3), myalgia (n = 2), headache (n = 3), chills 
(n = 1), nausea (n = 1), and joint pain (n = 2).  
 
As of February 15, 2018, preliminary interim PK results are insufficient to determine the clearance rate 
or half-life for each dose. Based on interim data, the overall average compartmental half-life is currently 
 
Figure 5. Interim VRC 605 PK results for VRC07-
523LS. (A) 5 mg/kg IV (Group 2) shown with VRC01LS 
comparator (administrations completed). (B) 5 mg/kg 
SC (Group 5, no VRC01LS comparator 
(administrations ongoing). 


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estimated to be 33 ± 10 days. The 28 day trough following one dose of VRC07-523LS 40 mg/kg IV was 
272 (53 mcg/mL) (n=3) (IB, version 4.0, February 26, 2018). 
 
Vorinostat (VOR) 
VOR is a potent inhibitor of HDAC activity and binds directly to the catalytic pocket of HDAC enzymes. 
VOR, at low nanomolar concentrations, inhibits the enzymatic activity of HDAC1, HDAC2, and HDAC3 
(Class I) and HDAC6 (Class II) (34-36). Concentrations of VOR that cause the accumulation of acetylated 
histones also induce cell cycle arrest, differentiation, or apoptosis of transformed cells (35). VOR induces 
apoptosis in a wide variety of transformed cells in culture, including cutaneous T-cell lymphoma (CTCL) 
cell lines, circulating atypical T-cells derived from patients with CTCL, human lymphoma cell lines and 
murine erythroleukemia (MEL) cells. VOR also inhibits proliferation of cultured transformed human cells 
derived from leukemias, non-small cell lung carcinomas, colon carcinomas, central nervous system 
tumors, melanomas, ovarian carcinomas, renal cell carcinomas, prostate and breast cancers. In cultured 
human transformed cell lines, VOR has synergistic or additive activity in combination with other cancer 
therapies, including radiation, kinase inhibitors, cytotoxic agents, and differentiating agents (34, 35, 37-
44). In vivo, VOR demonstrates anti-neoplastic activity in a variety of rodent tumor models including 
xenograft models of human prostate, breast, and colon carcinoma. While it has been assumed that the 
effects of VOR on histone acetylation underpin its biological activities, a number of other proteins are 
regulated by histone acetyltransferases (HATs) and HDACs and may be targeted by VOR (45). Several 
non-histone proteins, (e.g., tubulin, Hsp90, and p53) are known to be reversibly acetylated on lysine 
residues and undergo hyperacetylation following exposure to VOR (46-48). Acetylation of these proteins 
may also contribute to the antitumor activity of VOR. Please refer to the VOR Clinical Investigator’s 
Brochure (CIB), edition 8, 8/1/2013, for detailed information. 
 
VOR and HIV 
The U.S. Food and Drug Administration has approved Vorinostat (VOR) for the treatment of cutaneous 
manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent, or 
recurrent disease on or following two systemic therapies. Due to its potency as an HDAC inhibitor, its 
effect on HIV infection within resting CD4+ T cells might be more profound than VPA. The effect of VOR 
was compared to VPA in J89, a Jurkat T cell line infected with a single HIV genome encoding the 
enhanced green fluorescence protein (EGFP) within the HIV genome. Histone acetylation at nucleosome 
1 of the HIV promoter was assayed by chromatin immunoprecipitation. EGFP mRNA expression was 
monitored by flow cytometry and RTPCR, and p24 antigen production by ELISA. Both VPA and VOR 
induced chromatin remodeling at nucleosome 1, HIV transcription, and virus production in the J89 cell 
line (49). Limiting-dilution outgrowth assays compared the ability of VOR, VPA, and maximal mitogen 
stimulation to induce virus expression from the resting CD4+ T cells obtained at four occasions from 
three aviremic, cART-treated HIV-infected participants. HIV p24 capsid antigen was measured by ELISA, 
and infectious units per billion (IUPB) calculated by a maximum likelihood method. Comparable and 
clinically relevant concentrations of both compounds also induced virus outgrowth ex vivo from 
participants’ cells at similar frequencies. 
 
Nonclinical Pharmacology of VOR 
VOR is approximately 71% bound to human plasma proteins over the range of concentrations 0.5 to 50 
μg/mL. VOR has a low propensity to cause or be affected by drug-drug interactions. In animal models 
and in vitro human systems, the major pathways of metabolism of VOR involve glucuronidation and 
hydrolysis followed by β-oxidation. Additionally, the glucuronidation of VOR is mediated by multiple 
uridine diphosphate glucuronosyltransferase isozymes (UGTs), making it less susceptible to drug 
interactions through modulation of UGTs. VOR is not recovered intact in urine to any appreciable extent. 


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Therefore, compounds known to affect renal elimination are not expected to affect the 
pharmacokinetics of VOR. VOR is not an inhibitor of CYP drug metabolizing enzymes in human liver 
microsomes at steady state Cmax of the 400 mg dose (Cmax of 1.2 μM vs. IC50 of >75 μM). Gene 
expression studies in human hepatocytes detected some potential for suppression of CYP2C9 and 
CYP3A4 activities by VOR at concentrations higher (≥ 10 μM) than pharmacologically relevant. Thus, VOR 
is not expected to affect the pharmacokinetics of other agents metabolized by CYP enzymes. As VOR is 
not eliminated via the CYP pathways, it is anticipated that VOR will not be subject to drug-drug 
interactions when co-administered with drugs that are known CYP inhibitors or inducers. However, no 
formal clinical studies have been conducted to evaluate drug interactions with VOR. 
 
Nonclinical Toxicology of VOR 
VOR has been investigated in nonclinical acute and oral repeated-dose toxicity studies, reproductive, 
developmental toxicity studies, and genetic toxicity studies to support oral administration of this 
compound to humans. The main toxicities observed in animal models were weight loss and loss of 
appetite, apparent hemolytic anemia (rats only at 3.8 times the equivalent 400 mg human leukopenia 
(rats only at 1.3 times the equivalent 400 mg human dose), thrombocytopenia (male rats only, 
statistically significant change at 0.5 times the equivalent 400 mg clinically effective human dose, but 
within normal range at all doses), and gastrointestinal tract irritation (dogs only, at 8.5 times the 
equivalent 400 mg human dose). Although statistically significant and dose-dependent, many of the 
clinical pathology findings were within normal historical ranges indicating that they should not have 
major toxicological consequences. The toxicities appeared to be rapidly reversible within 12 to 14 days. 
There has been no evidence of cardiac toxicity based on electrocardiogram (ECG, dogs only), blood 
pressure (dogs only), heart rate (dogs only), creatinine kinase, organ weight, gross pathology, or 
histopathology assessments in studies up to one month duration. No serious, irreversible damage to any 
vital organ has been observed. Importantly, toxicities in rats and dogs were predictive of adverse effects 
in humans (anorexia, weight loss, fatigue). Toxicities present in animals would be manageable in the 
clinic, and the onset of serious toxicity is readily forecasted by prodromal symptoms. The nonclinical 
toxicity profile of VOR is acceptable for an oncology drug. 
 
Clinical Pharmacokinetics of VOR 
The pharmacokinetics of VOR following 400 mg single-dose in a fasted state; and 400 mg single- and 
multiple-doses in a fed (high-fat meal) state were evaluated in 23 participants in a Phase I study with 
relapsed or refractory advanced cancer using a validated assay. VOR is eliminated predominantly 1% of 
the dose recovered as unchanged drug in urine, indicating that renal excretion does not play a role in 
the elimination of VOR. Recovery of two pharmacologically inactive metabolites, O glucuronide of VOR 
(OG-V) and 4 anilino-4 oxobutanoic acid (4A4OA), in urine was more substantial. A population 
pharmacokinetic model using nonlinear mixed effects (NONMEM, ICON plc) demonstrated that a first 
order, transit-compartment absorption and linear elimination best described VOR concentration data. 
The structural model was: (1) dXa/dt = -Ka x Xa, (2) dXb/dt = Ka x Xa – Kt x Xb, (3) dXc = Kt x Xb – (CLt/Vc 
x Xc). Fixed effects: CLt (731 L/h), Vc (5.21 L), Ka (1.35 1/h), Kt (0.7 1/h). Random effects: CLt (26% CV), 
Vc (76.8%), Ka (73%). Residual error was: 0.0001 ng/mL (additive), 73.6% (proportional). An exponential 
model was used for inter-individual variability; and a heteroscedastic model was used for residual 
variability. Weight (power model, Vctyp=Vcwt x Weight (kg)θ, θ=1.17) was found to be a significant 
covariate on Vc. 
 
In pre-clinical studies, we and others found that VOR, already licensed for use in patients with cancer, 
induces HIV chromatin acetylation and promoter expression in cell lines, and virus production ex vivo 
from the resting CD4+ T cells of HIV-infected participants on suppressive ART (49, 50). This effect was 


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achieved without upregulation of cell surface markers of activation, HIV co-receptors, or de novo HIV 
infection. We then demonstrated a significant increase in cell-associated RNA production following in 
vivo administration of VOR to ART suppressed individuals, the first direct proof-of-concept of latency 
reversal (29). In subsequent work, our group demonstrated that serial VOR doses for up to 4 weeks were 
well-tolerated and that a dosing interval of 72 hours resulted in a significant increase in in rca-HIV RNA 
levels within circulating resting CD4+ T cells (51).  
 
Summary of Clinical Experience with VOR 
VOR has been studied in Merck Research Labs (MRL) sponsored studies, Investigator Initiated Study 
Protocols (IISP) and National Cancer Institute (NCI) sponsored studies. VOR has been orally administered 
in Phase I, Phase II, and Phase III clinical studies in participants with advanced solid tumors and 
hematologic malignancies. VOR has been studied both alone and in combination with other 
chemotherapy agents. As of 02-Jul-2012, over 5,000 participants have received at least one dose of VOR 
in studies sponsored by Merck and Co., Inc., the NCI, or independent Investigators. 
 
The above studies have found VRC-523LS and similar mAbs as well as VOR to be safe and well-tolerated. 
Based on our prior work to define optimized VOR dosing intervals and pharmacokinetic data for 
VRC01LS in humans, the proposed study design will provide antibody exposure over the approximate 
four week period of latency reversal by VOR.  We propose to evaluate the safety of combining VRC523-
LS 40 mg/kg infusion followed by oral VOR and to explore the impact of this combined immunotherapy 
to direct ADCC to clear reactivated HIV-1. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 
KNOWN POTENTIAL RISKS  
 
Risk of VRC07-523LS  
There is limited human experience with administration of VRC07-523LS in HIV infected and uninfected 
persons. VRC 605 is evaluating VRC07-523LS prior to the start of this study, and thus far, there have 
been no SAEs or Grade 3 or higher AEs. Two participants developed infusion reactions shortly after 
VRC01-523LS administration by IV, with symptoms typical for infusion reactions observed with other 
monoclonal antibodies. 
 
In addition, the similar CD4-binding site mAb VRC01 has been given to over 2600 participants in several 
phase 1 and phase 2 clinical trials. More than 8,000 infusions of 10 mg/kg and 30 mg/kg VRC01 have 
been given to HIV-uninfected adults in HVTN 704/HPTN 085 and HVTN 703/HPTN 081. Both VRC01 and 
VRC01LS are being tested in an ongoing phase 1 study (HVTN 116). 
 
Standard infusion reactions to mAb administration are typically mild but may include fever, flushing, 
chills, rigors, nausea, vomiting, pain, headache, dizziness, shortness of breath, hypertension, pruritus, 
rash, urticaria, diarrhea, tachycardia, or chest pain (52). Most infusion reactions appear to result from 
antibody-antigen interactions resulting in cytokine release (52). Administration of mAbs may have a risk 
of severe reactions, such as acute anaphylaxis, serum sickness, angioedema, bronchospasm, 
hypotension, and hypoxia, the generation of anti-drug antibodies; they may also be associated with an 
increased risk of infections. However, these reactions are rare and more often associated with mAbs 
targeted to human proteins (52) or with the use of murine mAbs, which have a risk of eliciting human 
anti-mouse antibodies (53). Infusion of mAbs directed against cell surface targets on lymphocytes may 


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cause a reaction known as “cytokine release syndrome,” with clinical manifestations including fatigue, 
headache, urticaria, pruritus, bronchospasm, dyspnea, sensation of tongue or throat swelling, rhinitis, 
nausea, vomiting, flushing, fever, chills, hypotension, tachycardia, and asthenia (54). Cases of cytokine 
release syndrome occur most often in the first few hours after the first mAb dose, because the cytokine 
release is associated with lysis of the cells targeted by the mAb and the burden of target cells is greatest 
at the time of the first mAb treatment (54). 
 
Since VRC07-523LS targets a viral antigen rather than human cell surface antigens and is a human mAb, 
severe infusion reactions are expected to be rare. Most infusion-related events occur within the first 24 
hours after beginning administration. 
 
1. Mild Reaction to mAb Administration:  
 
Standard infusion reactions can occur and most appear to result from antibody-antigen 
interactions resulting in cytokine release (53, 54).  These reactions include:  
 
• 
fever 
 
pain  
• 
flushing 
 
headaches 
• 
chills 
 
dizziness 
• 
rigors  
 
tachycardia 
• 
nausea 
 
chest pain 
• 
vomiting 
 
 
2. Severe Reaction mAb Administration:  
 
These reactions are rare and more often associated with mAbs targeted to human proteins or 
with the use of murine mAbs, which have a risk of eliciting human anti-mouse antibodies (42) 
and include: 
a) acute anaphylaxis 
b) serum sickness –this type of reaction is usually delayed and these symptoms are may 
not appear until several days after the exposure to the mAb. This type of reaction is 
more common with chimeric types of mAb (43). 
a. Symptoms include urticaria, fever, lymph node enlargement, and joint pains. 
These symptoms may not appear until several days after the exposure to the 
mAb and are noted to be more common with chimeric types of mAb (43). 
c) angioedema 
d) bronchospasm  
e) hypotension  
f) hypoxia  
g) the generation of anti-drug antibodies (ADA) 
h) increased risk of infections 
 
3. Cytokine Release Syndrome  
 
These symptoms occur most often in the first few hours after the first mAb dose, because the 
cytokine release is associated with lysis of the cells targeted by the mAb and the burden of 
target cells is greatest at the time of the first mAb treatment (54). 


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• 
fever 
 
rhinitis 
• 
urticaria 
 
headaches 
• 
pruritus 
 
nausea 
• 
bronchospasm 
 
vomiting 
• 
dyspnea 
 
flushing 
• 
fatigue 
 
sensation of the tongue or throat swelling 
• 
chills  
 
hypotension 
• 
tachycardia 
 
asthenia 
 
4. Reactions related to the rate of infusion: 
 
These reactions have been described for several FDA- licensed mAbs. With licensed therapeutic 
mAbs, cytokine-mediated infusion reactions, including cytokine release syndrome, are typically 
managed by temporarily stopping the infusion, administering histamine blockers, and restarting 
the infusion at a slower rate (55). Supportive treatment may also be indicated for some signs 
and symptoms. 
 
To date, the clinical trial safety experience with VRC01-class mAbs has been reassuring. 
a) In HVTN 104, IV administration of VRC01 was generally well-tolerated with mild pain 
and/or tenderness commonly reported at the site of the IV infusion. Mild to moderate 
systemic reactogenicity symptoms were reported by VRC01 recipients following at least 
one of the infusions, but there was no clear relationship with frequency or severity to 
the dose of VRC01 (56). 
b) No hypersensitivity reactions or cytokine release syndrome symptoms were reported in 
HVTN 104 (56). 
c) The ongoing blinded HVTN 704/HPTN 085 and HVTN 703/HPTN 081 trials have reported 
an approximately 1% rate of urticaria or similar reactions. 
d) In the ongoing VRC 605 trial of VRC07-523LS, there have been no SAEs and no safety 
pauses.  
e) Severe reactions associated with mAb administration, such as acute anaphylaxis, serum 
sickness, anti-drug antibodies, and increased risk of infections have not been observed 
to date in trials of VRC01-class mAbs. 
 
Risks Associated with Vorinostat 
1. Reaction to VOR administration: 
The three major clinical categories of adverse experiences attributable to VOR include a 
constellation of gastrointestinal symptoms, constitutional complaints, and cytopenias. Most of 
the adverse experiences were manageable. In fact, most of the very common adverse 
experiences were reversible and could be managed using conventional supportive care for 
chemotherapy. On the whole, treatment with oral VOR was well tolerated for use in the 
outpatient oncology setting. 
 
Adverse experiences considered by the Investigators to be at least possibly related to VOR in 
≥10 % of participants across all Merck & Co., Inc. sponsored VOR clinical studies include (in 
descending frequency): nausea, fatigue, diarrhea, anorexia, vomiting, thrombocytopenia, 


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anemia, weight decreased, blood creatinine increased, dysgeusia, hyperglycemia, neutropenia, 
and constipation. 
 
 UNC has studied the effect of VOR on latent HIV virus. Other research institutions (both in the 
U.S. and internationally) also used the drug for this purpose. In UNC studies, approximately 23 
different participants, have received up to 47 doses of 400 mg VOR, with most people taking an 
average of 14 doses. Several of these participants took VOR in different studies. We have 
observed only mild toxicities that we felt were related to VOR. In all, we have seen very few side 
effects, and none of the side effects or abnormal labs observed were significant or required 
medical attention. 
 
Participants are permitted to receive appropriate supportive care measures as considered 
appropriate by the Study PI (or designee) including: 
a) Diarrhea: Diarrhea should be treated promptly with appropriate supportive care per 
guidelines. Supportive care should begin at the first sign of poorly formed or loose stool, 
occurrence of more bowel movements than usual in one day or unusually high volume 
of stool. Supportive care should be deferred if blood or mucus is present in the stool or 
if diarrhea is accompanied by fever. 
b) Dehydration: Altered taste and decreased food and liquid intake are associated with 
VOR administration. Participants should also be advised to drink a lot of clear fluids (at 
least 2 liters/day) to help prevent dehydration. 
c) Nausea and Vomiting: Nausea and vomiting should be managed according to standard 
practice. 
d) Anemia: Treatment with VOR can cause dose-related anemia that may result in fatigue, 
lethargy, or shortness of breath. If hemoglobin is reduced during treatment with VOR, 
the incident will be evaluated and the dose will either be maintained or terminated in 
the case of toxicity. 
e) Thrombocytopenia: Treatment with VOR can cause dose-related thrombocytopenia. If 
platelet counts are reduced during treatment with VOR, this incident will be evaluated 
and dosing will either be maintained or terminated in the case of toxicity. 
f) Hyperglycemia has been observed. Serum glucose should be monitored. Adjustment of 
diet and/or therapy for increased glucose may be necessary. 
g) Hypokalemia or hypomagnesemia should be corrected prior to administration of VOR, 
and monitoring potassium and magnesium in symptomatic participants (e.g., 
participants with nausea, vomiting, diarrhea, fluid imbalance, or cardiac symptoms.) 
h) Unknown effects, such as detectable HIV RNA (viral load) and other factors related to 
HIV infection, with this participant population, since there is limited data on the use of 
VOR in this particular population. 
 
2. Overdose 
We include this section for completeness. A person who takes any dose of VOR more than 
prescribed will be considered to have taken an overdose. Specific information is not available on 
the treatment of an overdose. There are no noted adverse experiences reported when a person 
took an overdose of VOR. No specific antidote has been identified for an overdose of VOR. 
 
Participants should be advised not to make up missed doses. If a participant has an episode of 
emesis after taking VOR, the participant should be instructed not to take an additional dose. If a 


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participant on this study takes more than the prescribed dose of VOR, he/she will be observed 
closely for signs of toxicity. Supportive treatment will be provided, as clinically indicated.  
 
3. Pregnancy  
No human safety data for the use of Vorinostat during pregnancy are available. Vorinostat has 
been assigned to pregnancy category D by the FDA based on a study in animals which found that 
Vorinostat crosses the placenta and may harm the developing fetus. 
 
Risks Associated with Leukapheresis  
These include common side effects due to blood drawing. However, more serious side effects could 
occur such as flushing, infection due to contaminated equipment, and damage to red blood cells. These 
serious side effects occur in less than 1 in 10,000 procedures. No such adverse events have occurred in 
our prior studies. 
 
The following are the most common: 
a) Pain or bruising at the site of needle sticks 
b) Phlebitis - Formation of a blood clot at the blood draw site 
c) Citrate toxicity (10%) 
a. Oral paresthesia (tingling around the mouth)  
b. Paresthesia (tingling/cramping in hands, fingertips, and feet) 
d) Stiffness in the arms due to the immobilization during donation 
e) Fatigue or tiredness 
f) Fluctuations in blood pressure or heart rate 
 
Less common: 
a) Infiltration – the needle dislodges and comes out of the vein causing the fluid to go into the 
tissue, 
b) Muscle aches or cramps 
c) Chills 
d) Fever 
e) Nausea or vomiting 
f) Lightheadedness or headache 
g) Vasovagal reaction resulting in decrease in BP and heart rate  
 
Rare: 
a) Seizures or fainting 
b) Transient weight gain, ankle swelling, or increased urination for 24 hours due to fluid retention 
c) Infection due to contamination of equipment 
d) Skin rashes, flushing, or other allergic responses 
e) Damage to or loss of red blood cells due to machine malfunction 
f) Possibility of air entering the vein and causing chest pains, shortness of breath, or shock or 
death 
 
Risks of Blood Drawing  
Blood drawing may cause pain, and bruising and may infrequently cause a feeling of lightheadedness or 
fainting. Rarely, it may cause infection at the site where the blood is taken. Problems from use of an IV 
for blood drawing are generally mild and may include pain, bruising, minor swelling or bleeding at the IV 


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site, and rarely, infection, vein irritation (called phlebitis), or blood clot. Risk will be minimized by using 
sterile technique and universal precautions. 
 
Risks of Intravenous Infusion 
Problems from use of an IV are generally mild and may include pain, bruising, minor swelling or bleeding 
at the IV site, and rarely, infection, vein irritation (called phlebitis), or blood clot. Risk will be minimized 
by using sterile technique and universal precautions. 
 
The placement of an intravenous catheter can allow for the development of bacteremia because of the 
contact between the catheter and unsterile skin when it is inserted. This will be prevented through 
careful decontamination of local skin prior to catheter placement and through the use of infection 
control practices during infusion. Product contamination will be prevented by the use of aseptic 
technique in the pharmacy and universal precautions during product administration. 
Unknown Risks  
New therapies can lead to unexpected, incidental findings that could have a potential effect on the 
participant’s health. Upon confirmation of a potential health or reproductive effect, the study team will 
notify participants impacted by the new information and will advise proper medical follow-up when 
indicated. If findings require more immediate medical attention, the study PI in conjunction with the 
study coordinators will assist participants in getting an appropriate care appointment.  
 
Study participation 
Participation in this study may make participants ineligible for other clinical trials for a period of time or 
indefinitely after completing this protocol. Participation in this study may make participants ineligible for 
future clinical trials with vorinostat. 
 
2.3.2 
KNOWN POTENTIAL BENEFITS  
 
The addition of VOR and VRC07-523LS to a person’s ART regimen or the donation of one’s blood cells to 
this research study provides no direct medical benefits to participants. However, participation 
contributes to ongoing HIV research, potentially resulting in new treatments for HIV infection.  
 
2.3.3 
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Given that most HIV-1-infected patients on effective ART have persistent low-level viremia and despite 
this viremia have blunted HIV-1 specific immune responses, interventions with the potential to improve 
HIV-specific immune clearance and limit viremia should be tested. Therapies that improve clearance of 
persistently HIV-1-infected cells will likely be a necessary component of any HIV remission or eradication 
strategy. Based on the data outlined above, there is sufficient expectation that the proposed treatment 
interventions will be safe and well-tolerated. This study seeks to evaluate whether a combination 
treatment will result in a reduction in the frequency of resting cell infection such that this result would 
advance the field. Although participants in this early phase study will most likely receive no direct 
benefit for their participation in this study, there remains a strong desire among HIV-infected 
individuals, and the HIV community at-large, to pursue HIV cure and remission strategies. The potential 
adverse effects, stigmatization, and financial costs encountered by HIV-infected persons receiving life-
long antiretroviral therapy along with the potential harm of persistent immune activation/inflammation 
are strong reasons to pursue HIV cure and remission research. In short, an HIV cure or sustained 


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remission in the absence of ART remain desirable goals that would have substantial benefits for many 
individuals if achieved. 
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
 
To evaluate the safety and 
tolerability of combination 
therapy with VRC07-523LS 
and VOR in HIV-infected 
participants on ART. 
 
 
Safety 
Occurrence of at least one ≥ Grade 3 
adverse event including signs/symptoms, 
lab toxicities, and/or clinical events that 
is possibly, probably, or definitely related 
to VOR or VRC07-523LS any time from 
the first day of study treatment through 
Step 4.  
 
Safety data will include local and systemic 
signs and symptoms, laboratory 
measures of safety/toxicity, and all AEs 
and SAEs. Safety data will be routinely 
collected throughout the duration of the 
study. 
 
 
The study will use standard 
safety grades used in HIV 
clinical trials. Should these 
grades be exceeded, it is 
currently felt that such 
risks would be 
unacceptable in a research 
study of this nature. 
Tertiary/Exploratory  
 
 
 
1. Explore the effect of two 
cycles of VRC07-523LS and 
VOR on the frequency of 
latent, resting CD4+ T cell 
infection. 
 
 
2. Compare HIV RNA 
expression within resting 
CD4+ cells in HIV-infected 
participants on stable ART 
before and after VRC07-
523LS given with VOR at 
leukapheresis #1 (Step 1) 
and leukapheresis #2 (Step 
4). 
 
3. Explore the influence of 
VOR given with VRC07-
523LS on low-level plasma 
 
1. Change in QVOA from resting CD4+ 
cells in HIV-infected participants on 
stable ART before and after VRC07-
523LS given with VOR from baseline to 
post-VRC07-523LS/VOR. 
 
 
2. Change in HIV RNA expression within 
resting CD4+ cells in HIV-infected 
participants on stable ART before and 
after VRC07-523LS given with VOR 
from baseline to post-VRC07-
523LS/VOR.  
 
 
 
 
3. Change in HIV-1 RNA by SCA from 
baseline to post-VRC07-523LS/VOR. 
 
 
These various measures of 
persistent HIV infection will 
allow us to detect an effect 
of VOR and VRC07-523LS (if 
any), validate expected 
exposures to these agents, 
and seek evidence of 
selective pressure exerted 
by VRC07-523LS on 
persistent HIV. 


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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
viremia as measured by 
single copy assay (SCA) in 
participants who maintain 
suppression on ART. 
 
4. Explore the impact of VOR 
and VRC07-523LS therapy 
on the quantity of 
integrated proviral DNA in 
T cell populations. 
 
 
5. Characterize viral 
envelope sequences 
detected in plasma or cells 
that are not recognized by 
VRC07-523LS from 
baseline to post-VRC07-
523LS/VOR. 
 
6. Evaluate the 
pharmacokinetics of 
VRC07-523LS and VOR and 
determine whether anti-
drug antibody (ADA) to 
VRC07-523LS can be 
detected in recipients 
administered VRC07-
523LS in combination with 
VOR.  
 
 
 
 
 
4. Change in the chromosomally 
integrated viral reservoir as 
measured by quantitative-
polymerase chain reaction (Q-PCR) 
from baseline to post-VRC07-
523LS/VOR. 
 
5. Change in diversity of viral envelope 
sequences detected in plasma or cells 
that are not recognized by VRC07-
523LS from baseline to post-VRC07-
523LS/VOR. 
 
 
 
6. Serum concentrations of VRC07-
523LS in combination with VOR. 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
This is a phase I, single-site study to evaluate the effects of VOR given in combination with VRC07-523LS 
on persistent HIV-1 Infection in HIV-infected individuals suppressed on ART.  
 
We hypothesize that combination therapy with VRC07-523LS and VOR will be safe and well-tolerated by 
HIV-1-infected participants suppressed on ART. 
 
This study will also explore the ability of a novel clearance modality (VRC07-523LS) to reduce the 
frequency of latent, resting CD4+ T cell infection when combined with a latency reversal agent (VOR). 
 


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This study will enroll up to twelve evaluable participants with durable viral suppression to complete all 4 
Steps.  We estimate that it will take approximately 8 months to complete enrollment.  
 
All eligible participants will receive the same treatment. Each participant will receive a total of two (2) 
infusions of VRC07-523LS at 40mg/kg/dose and twenty (20) PO doses of VOR 400 mg. Participants will 
continue their baseline ART regimen throughout the study. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
This is an open label, non-randomized study to validate the safety of VRC07-523LS when given with 
Vorinostat. For scientific aims, assays are performed before and after intervention.  
 
4.3 
JUSTIFICATION FOR DOSE 
 
The dose of VOR (400 mg every (q) 72 hours) has been validated (51). The dose of VRC07-523LS has 
been validated at 40 mg/kg in study VRC 605 (see above). 
 
The VRC07-523LS dose and timing of administration with combination with VOR is based on human 
studies of VRC01, preclinical and clinical studies of VRC01LS, preclinical and clinical studies of VRC07-
523LS, and PK data for VOR in humans. PK results following VRC07-523LS infusion of 40mg/kg (the dose 
proposed in this protocol) are shown in Figure 4 (above), showing serum concentrations >10 mcg/mL 
beyond 30 days which encompasses the duration of VOR dosing on the study. 
 
In addition, serum concentrations of VRC07-523LS are comparable to VRC01 40mg/kg IV and VRC01LS 
40mg/kg IV. Additional interim PK results for VRC07-523LS 5 mg/kg dose by IV route as compared with 
VRC01LS are shown in Figure 5 (above).  Panel A of Figure 5 shows serum concentrations >10 mcg/mL 
through day 40 following infusion.  
 
4.4 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all Steps of the study 
including the last visit shown in the Schedule of Events in Section 1.3. 
 
5 
STUDY POPULATION 
 
The study will enroll healthy, HIV-infected adults on ART and durably suppressed (HIV-1 RNA PCR <50 
copies/mL for ≥ 24 months) who verbalize comprehension of the purpose of the study and provide 
written informed consent. Potential participants will be recruited and screened; those determined 
eligible, based on the inclusion and exclusion criteria, will be enrolled in the study. Final eligibility 
determination will depend on information available at the time of enrollment, including results of 
screening laboratory tests, medical history, and physical examinations. 
 
Determination of eligibility, taking into account all inclusion and exclusion criteria, must be made within 
30 days prior to enrollment unless otherwise noted in Sections 5.1 and 5.2. 
 


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5.1 
INCLUSION CRITERIA 
 
1. 
≥ 18 years and < 65 years of age 
 
2. 
Ability and willingness of participant to give written informed consent.  
Note: Due to the lack of foreseeable benefit to study participants, mentally incompetent 
participants will not be enrolled. 
 
3. 
HIV infection documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence 
immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed 
Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, 
or by HIV-1 antigen, plasma HIV-1 RNA viral assay.  
 
A reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA 
that is based on a different antigen preparation and/or different test principle (e.g., indirect 
versus competitive), or a Western blot or a plasma HIV-1 RNA viral load. 
 
4. 
On continuous antiretroviral therapy (ART defined in 5.1.5) for at least 24 months prior to 
screening.  
 
Note: Continuous ART prior to screening is defined as not missing more than 4 total days and 
never more than 2 consecutive days in the 3 months prior to screening. 
 
5. 
Permitted  ART regimens include:        
 
a) At least 3 ART agents (not counting ritonavir if less than a 200mg total daily dose or 
cobicistat as one of the agents).  
 
NOTE: One of the agents must include an integrase inhibitor, NNRTI (Non-Nucleoside 
Reverse Transcriptase Inhibitors), or a boosted-PI (protease inhibitor).  
 
OR 
 
Two (2) ART agents in which one of the agents is either a boosted PI or an integrase 
inhibitor. 
 
NOTE: Other fully suppressive antiretroviral combinations will be considered on a case-by-
case basis.  
 
NOTE: Prior changes in, or elimination of, medications for easier dosing schedule, 
intolerance, toxicity, improved side effect profile or within a drug class are permitted if an 
alternative suppressive regimen was maintained but not within 30 days prior to screening. 
 
NOTE: Changes in drug formulation or dose are allowed (e.g., TDF to TAF, ritonavir to 
cobicistat, or separate ART agent dosing to fixed-dose combination), but none within 30 
days prior to screening.  
 


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6. 
Ability and willingness of participant to continue ART throughout the study. 
 
7. 
Able and willing to adhere to protocol therapy, schedule, and is judged adherent to antiretroviral 
therapy. 
 
8. 
Plasma HIV-1 RNA <50 copies/mL at 3 time points in the previous 24 months prior to screening 
and never ≥50 copies/mL on 2 consecutive time points in the last 24 months. 
 
NOTE: The documented plasma HIV-1 RNA must be performed by any US laboratory that has a 
Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent. 
 
9. 
At least 1 documented plasma HIV-1 RNA result <50 copies/mL ≥24 months but ≤ 36 months prior 
to screening. 
 
10. 
Plasma HIV-1 RNA level <50 copies/mL on an FDA-approved HIV RNA assay at screening, 
performed at US CLIA Certified Laboratory (or its equivalent).  
 
11. 
CD4 cell count ≥ 350 cells/mm3 obtained within 90 days prior to study entry, performed at any US 
CLIA Certified Laboratory (or its equivalent).  
 
12. 
Hepatitis C (HCV) antibody negative result within 60 days prior to study entry or, if the participant 
is HCV antibody positive, a negative HCV RNA within 60 days prior to study entry. 
 
13. 
Hepatitis B surface antigen (HBsAg) negative within 60 days prior to study entry. 
 
14. 
Interferon-gamma release assay (IGRA) for tuberculosis (TB) with negative results within 60 days 
prior to study entry. 
 
NOTE: Participants with a prior positive TB IGRA and documented evidence of completed 
prophylaxis treatment may enroll in the study and do not need to undergo IGRA at screening. 
Participants with a prior positive IGRA who have not completed prophylaxis treatment will be 
excluded. 
 
15. 
Men and women who are not of reproductive potential (see below) are eligible without requiring 
the use of contraceptives. Acceptable documentation of sterilization and menopause is specified 
below. 
a) Written or oral documentation communicated by clinician or clinician’s staff of one of the 
following: 
a. Physician report/letter 
b. Operative report or other source documentation in the patient record (a 
laboratory report of azoospermia is required to document successful vasectomy 
in any partner assigned male sex at birth, hysterectomy, oophorectomy, non-
surgical permanent sterilization, or tubal ligation.) 
c. Discharge summary 
b) Documented or participant-reported absence of a period for ≥ one year must be 
confirmed with Follicle stimulating hormone-release factor (FSH) measurement elevated 
into the menopausal range as established by the reporting laboratory.  


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16. 
All participants must agree not to participate in a conception process (e.g., active attempt to 
become pregnant or to impregnate, sperm donation, in vitro fertilization, egg donation) while on 
study and for 4 months after their last infusion.   
 
17. 
All men participating in sexual activity that could lead to pregnancy must agree to consistently use 
at least one of the following forms of birth control for at least 21 days prior to Visit 3 and for 4 
months after their last infusion: 
a) Condoms (male or female) with or without a spermicidal agent  
b) Diaphragm or cervical cap with spermicide 
c) Intrauterine device (IUD) 
d) Tubal ligation 
e) Hormone-based contraceptive 
f) Successful vasectomy 
 
NOTE: For female partners who are receiving ritonavir or cobicistat, estrogen-based 
contraceptives are not reliable and an alternative method should be suggested. 
 
18. 
Ability and willingness to provide adequate locator information.  
 
19. 
Ability and willingness to communicate effectively with study personnel; considered reliable, 
willing, and cooperative in terms of compliance with the protocol requirements. 
 
20. 
Adequate vascular access for infusion and leukapheresis.  
 
21. 
Able to swallow pills without difficulty. 
 
22. 
Agrees not to enroll on another study of an investigational research agent during the study 
period. 
 
NOTE: Investigational research agent is defined as any unlicensed investigational drug not yet 
approved by the FDA for intended use in humans.  
 
23. 
Adequate organ function as indicated by the following laboratory values:  
 
System  
Laboratory Value  
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥125,000 / mcL 
Hemoglobin 
≥ 13 g/dL (male) and ≥ 11 g/dL (females) 
Coagulation  
 
Prothrombin Time or INR 
≤1.5x upper limit of normal (ULN)  
Chemistries  
 
K+ levels 
Within normal limits 
Mg++ levels  
≥ 1.2 mEq/L but <1.5 x ULN 
Glucose  
Screening serum glucose ≤ Grade 1 (fasting or non- 
fasting)  


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Albumin  
≥ 3.3 g/dL 
Renal  
 
Creatinine clearance determined by the 
CKD-Epi equation found at: 
https://www.qxmd.com/calculate/calcul
ator_251/egfr-using-ckd-epi 
eGFR > 60mL/min 
Hepatic 
 
Serum total bilirubin 
Total bilirubin < 1.5 X ULN. If total bilirubin is 
elevated, direct bilirubin must be < 2 times the 
ULN range. 
NOTE: If participant is on an atazanavir-containing 
therapy, then a direct bilirubin should be measured 
instead of the total bilirubin and must be ≤ 1.0 
mg/dL.  
AST (SGOT) and ALT (SGPT) 
≤ 1.25 X ULN 
Alkaline Phosphatase  
≤ 2.0 X ULN 
Lipase  
< 1.6 X ULN 
Urinalysis  
 
Urine Protein  
Negative or trace allowed  
 ULN = upper limit of normal 
 
5.2 
EXCLUSION CRITERIA 
 
1. 
Known allergy or sensitivity to components of VOR 
 
2. 
Serious adverse reactions to VRC07-523LS formulation components, VRC01 or VRC01LS, 
including history of anaphylaxis and related symptoms such as hives, respiratory difficulties, 
angioedema, and/or abdominal pain.  
 
3. 
Women without documentation of an FSH level indicating menopause, hysterectomy or bilateral 
oophorectomy, bilateral tubal ligation, or non-surgical sterilization.  
 
4. 
Receipt of compounds with HDAC inhibitor-like activity, such as valproic acid within 30 days 
prior to screening. Potential participants may screen after a 30-day washout period.  
 
5. 
Any investigational research agent within 30 days before study entry. 
 
NOTE: Co-enrollment in observational only studies is permitted. 
NOTE: Co-enrollment in other studies using FDA approved medication that are not otherwise 
listed as prohibited will be evaluated by the study PI and permitted on a case-by-case basis.   
 
6. 
Plasma HIV RNA ≥150 copies/mL in the 6 months prior to screening. 
 
7. 
Weight > 115 kg 
 
 


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8. 
Untreated syphilis infection (defined as a positive rapid plasma reagin (RPR) without clear 
documentation of treatment). 
 
NOTE: In cases of untreated syphilis, participant may rescreen following documentation of 
adequate treatment of syphilis 
 
9. 
Current treatment for HCV with antiviral therapy or participants who have received HCV 
treatment within 6 months prior to screening. 
 
10. 
Use of any of the following within 90 days prior to entry: immunosuppressive, 
immunomodulatory, cytokine, or growth stimulating factors such as systemic corticosteroids, 
cyclosporine, methotrexate, azathioprine, anti-CD25 antibody, IFN, interleukin-2 (IL-2). 
 
Not Exclusionary: [1] corticosteroid nasal spray; [2] inhaled corticosteroids; [3] topical steroids 
for mild, uncomplicated dermatitis (see 5.2.20 below); or [4] a single course of oral /parental 
prednisone or equivalent at doses <2mg/kg/day and length of therapy <11 days with completion 
at least 30 days prior to enrollment.  
 
11. 
Current use of Coumadin, warfarin, or other Coumadin derivative anticoagulants. 
 
12. 
Prior use of any HIV immunotherapy within 12 months prior to screening. 
 
13. 
Prior use of an HIV vaccine prior to screening. 
 
14. 
Prior receipt of more than three doses of Vorinostat. 
 
15. 
Prior receipt of humanized or human mAbs, whether licensed or investigational, will have 
eligibility determined by the study PI on a case-by-case basis.  
 
16. 
Received any infusion blood product, immune globulin, or hematopoietic growth factors within 
90 days prior to study entry.   
 
17. 
Pregnancy or breast-feeding. 
 
18. 
History or other evidence of severe illness, malignancy, immunodeficiency other than HIV, or 
any other condition that would make the participant unsuitable for the study in the opinion of 
the investigator, for at least 90 days prior to screening. 
 
19. 
History of autoimmune disease  
 
Not exclusionary: Persons with mild, stable, and uncomplicated autoimmune disease that do not 
require immunosuppressive medication and that, in the judgement of the site investigator (or 
designee), is likely not subject to exacerbation and likely not to complicate AE assessments.   
 
20. 
Use of topical steroids over a total area exceeding 15 cm2 within 30 days prior to Screening. 
 
21. 
Treatment for an active AIDS-defining opportunistic infection within 90 days prior to Screening.  
 


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22. 
History of malignancy within the last 5 years. 
 
NOTE: A history of non-melanoma skin cancer (e.g., basal cell carcinoma or squamous cell skin 
cancer) is not exclusionary with documentation of complete resection at least 3 months prior to 
enrollment). 
 
23. 
Compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric illness or 
a physical illness, e.g., infectious disease.  
 
24. 
Known psychiatric, medical, occupational, or substance abuse disorders that would interfere 
with participant’s ability to fully cooperate with the requirements of the trial as assessed by the 
study investigator (or designee).  
 
Specifically exclusionary: [1] recent psychosis; [2] ongoing risk for suicide; or [3] recent history of 
suicide attempt or gesture.  
 
25. 
History or other clinical evidence of a significant medical condition that includes but is not 
limited to: 
a) A process that would affect the immune response 
b) A process that would require medication that affects the immune response 
c) Any contraindication to repeated injections, infusions, or blood draws  
d) A condition or process (e.g., chronic urticarial or recent injection or infusion with 
evidence of residual inflammation) for which signs and symptoms could be confused 
with reactions to the study product  
 
26. 
Current anti-tuberculosis therapy  
 
27. 
Diabetes Mellitus type 1 or type 2  
 
Not exclusionary: type 2 cases controlled with diet alone or a history of isolated gestational 
diabetes 
 
28. 
History of coronary artery disease, congestive heart failure, or cardiac arrhythmia requiring 
current treatment prior to study screening. 
 
29. 
Hypertension  
 
If a person has been found to have elevated blood pressure or hypertension during 
screening or previously, exclude for blood pressure that is not well controlled. Well-
controlled blood pressure is defined as consistently ≤ 140 mm Hg systolic and ≤ 90 mm Hg 
diastolic, with or without medication, with only isolated, brief instances of higher readings, 
which must be ≤ 150 mm Hg systolic and ≤ 100 mm Hg diastolic. For these volunteers, blood 
pressure must be ≤ 140 mm Hg systolic and ≤ 90 mm Hg diastolic at enrollment. 
 
If a person has NOT been found to have elevated blood pressure or hypertension during 
screening or previously, exclude for systolic blood pressure ≥ 150 mm Hg at enrollment or 
diastolic blood pressure ≥ 100 mm Hg at enrollment. 
 
Note: Elevated BP occurring during research leukapheresis procedures completed within 
the past 12 months are excluded from this requirement. Other isolated incidences of 


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elevated BP should be reviewed by study PI (or designee) to determine whether they are 
exclusionary. Acceptable isolated elevations must be noted as acceptable and signed by 
study PI or designee.  
 
30. 
Unstable asthma (e.g., sudden acute attacks occurring without an obvious trigger) or either of 
the following in the past 12 months: 
a) >1 exacerbation of symptoms treated with oral/parenteral corticosteroids; 
b) Emergency care, urgent care, hospitalization, or intubation for asthma.  
 
31. 
Bleeding disorder diagnosed by a doctor (e.g., factor deficiency, coagulopathy, or platelet 
disorder requiring special precautions).  
 
32. 
Seizure disorder: History of seizure(s) within past three years or use of medications used to 
prevent or treat seizure(s) at any time within the past 3 years. 
 
33. 
History of asplenia – absence of normal spleen function as indicated by: 
a) Splenectomy 
b) Sickle cell disease 
 
34. 
History of hereditary angioedema, acquired angioedema, or idiopathic angioedema. 
 
35. 
Prisoner recruitment and participation is not permitted.  
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
Each dose of VOR should be taken with food. 
 
5.4 
SCREEN FAILURES 
 
Screening takes place in a step-wise manner and includes the completion of the following prior to 
enrollment:  
1. 
Determination of HIV infection status 
2. 
Documentation of stable continuous ART  
3. 
Documentation of HIV RNA values below limit of quantitation for eligibility  
4. 
Participant locator information  
5. 
Assessment of baseline laboratory testing for continued safety monitoring 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently entered in the study. Minimal information required to be maintained with screen failure 
includes but is not limited to demography, screen failure details, eligibility criteria, and any SAE as well 
as clinical and laboratory data collected on persons at screening. The information collected on persons 
who fail screening and do not enroll will be retained in the screen failure section of the study file.  
 
Potential participants who are unable to meet protocol-defined eligibility criteria at the Screening Visit 
may be eligible to re-screen again at the investigator’s discretion.  
 


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If a screen failure or the failure to move to Visit 2 is due to the inability to meet one of the laboratory 
parameters (hematology, chemistry, HIV RNA level, or CD4+ T cell count), a retest of the failed criteria 
may be performed one time only. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Recruitment venues - There are several venues for recruitment available to the study team: 
 
1. In the UNC ID Clinic and/or other local HIV clinics, there is a large pool of patients with long-term 
viral suppression on ART interested in participating in research.  Many have previously 
participated in clinical studies. These individuals will be provided with the opportunity to discuss 
this study with their provider and the study coordinator.  
 
2. Individuals who signed the UNC CFAR database consent, as well as those who signed the 
consent for the UNC Cure and PHI studies/database, will be identified and approached about 
the study. Primary care providers or the study coordinator, after consultation with their primary 
care provider, will provide information about the study and participation.  
 
3. Individuals interested in participating in the study will be provided with appropriate study 
information and the opportunity to screen. All potential participants will be informed that:  
b) On rare occasions some of the serious side effects described in this protocol as well as 
other unpredicted adverse events can occur.  
c) Their participation in this study will allow researchers the opportunity to collect valuable 
information about the use of VRC07-523LS in individuals with durable viral suppression 
and its ability to improve immune responses.  
d) There will be no direct and immediate benefits to participants in this study, but 
information learned from this study may be of value to the participant and other people 
with HIV disease. 
 
4. Targeted study demographics will be addressed. Recruitment for this study will largely be clinic-
based, but participant advocacy groups will assist us, and local media may be used if needed. 
Our studies routinely enroll a representative sample of under-represented populations and 
women. We will also use recruitment materials such as flyers, palm cards, and posters and use 
social media websites and employ a community engagement plan.   
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 
STUDY INTERVENTION DESCRIPTION 
 
Vorinostat:  
The oral formulation of vorinostat is available as a 100 mg capsule. The 100 mg dose of vorinostat is 
provided in white opaque gelatin capsules (size 3). The capsules are supplied in HDPE (high-density 
polyethylene) bottles. Each bottle contains the protocol-specified count of vorinostat capsules. 
 


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VRC07-523LS  
VRC07-523LS will be supplied as 10 mL glass vials with a 6.25 ± 0.1 mL fill volume and 3 mL glass vials 
with a 2.25 mL ± 0.1 mL fill volume, at a concentration of 100 ± 10 mg/mL. Each vial contains a clear, 
colorless to yellow isotonic, sterile solution essentially free of visible particles; some opaque or 
translucent particles may be present. The formulation buffer is composed of 50 mM histidine, 50 mM 
sodium chloride, 5% sucrose, and 2.5% sorbitol at pH 6.8.  
6.1.2 
DOSING AND ADMINISTRATION 
 
Vorinostat  
The study provides the Vorinostat 400 mg to the participants. In Step2 and Step 3, participants will take 
their first dose of VOR 400 mg PO at home two (2) days after the VRC07-523LS infusion. All participants 
will be dispensed 5 doses of VOR 400 mg at the infusion visits on Day 0 and Day 60. All participants will 
be provided with instructions for the safe administration of VOR at home. Participants will return to the 
CTRC on the day of their 5th dose (Day 14 and Day 74) for safety labs and evaluations and to receive their 
last 5 doses of VOR 400 mg.  
 
Participants will return to the CTRC for safety assessments as per the SOE (Section 1.3). Participants will 
be monitored for the development of toxicities. 
 
VRC07-523LS 
VRC07-523LS will be administered as an IV infusion at the dose of 40 mg/kg in the CTRC. Participants will 
be monitored and observed for at least 60 minutes after the first infusion and for at least 30 – 60 
minutes after the second infusion. 
 
Reference Study Specific SOP entitled ‘Infusion Guidelines and Emergency Management Plan’ for details. 
 
The following is performed prior to each administration of VRC07-523LS: 
1. Initiate, maintain, and verify IV access.  
2. Pre-dose assessments and Blood Sampling completed as listed in the SOE (Section 1.3). 
3. The calculated dose will be administered based on the participant’s weight obtained at Step 1, 
Visit 1 (baseline). Significant (≥ 10%) change in body weight from baseline should prompt 
recalculation of dose. 
 
 
Administration of VRC07-523LS: 
1. VRC07-523LS will be administered as an IV infusion: 
a. Day 0 (1st infusion) VRC07-523LS will be infused over 60 minutes using a volumetric 
pump  
b. Day 60 (2nd infusion) will be infused over 60 minutes using a volumetric pump 
2. Vital Signs: Taken immediately before infusion (up to 3 minutes before the infusion); at 15, 30, 
45, and 60 minutes after the start of infusion; and at the end of infusion 
3. An in-line filter infusion set must be used for all VRC07-523LS administrations (Reference SOP). 
The pharmacist will supply the in-line filter and the infusion tubing set for delivery to the clinical 
setting. 
4. The infusion rate may vary based on the total volume needed to administer the full dose. The 
total time needed to administer the dose may be longer than 60 minutes based on factors such 
as participant tolerance, but should be completed no more than 4 hours after the product is 
prepared. Infusion access should be maintained and the participant observed for a minimum of 


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60 minutes following completion of the first infusion and at least 30 – 60 minutes following the 
completion of the 2nd infusion.  
 
Post Infusion Monitoring: 
Each participant will be monitored for a minimum of 60 minutes on site following receipt of their 1st 
VRC07-523LS infusion. Post infusion monitoring for the 2nd infusion will be at least 30 – 60 minutes. 
Monitoring will occur in the CTRC. During the monitoring period, participants are observed for clinical 
AEs and the following procedures are performed: 
1. Vital Signs: Following the infusion: every 15 minutes up to 60 minutes after the completion of 1st 
infusion and every 15 minutes up to 30 - 60 minutes after completion of the 2nd infusion. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 
ACQUISITION AND ACCOUNTABILITY 
 
Study products will be provided directly to the UNC Investigational Drug Services (IDS) by Merck (VOR) 
and the VRC (VRC07-523LS). The primary IDS pharmacist will be responsible to the study PI for 
maintaining study drug accountability, reconciliation, and record maintenance during the study, 
including documentation of the amount of both study treatments (VRC07-523LS and VOR) received in 
IDS and the amount administered to each participant. 
 
VRC07-523LS and VOR will be stored and dispensed by the UNC Hospitals IDS Pharmacy by prescription 
on a participant-specific basis. The IDS clinical supplies storage area will be monitored by the IDS staff 
for temperature consistency. 
 
Vials containing VRC07-523LS and VOR will be stored in an appropriate, locked room accessible only to 
IDS pharmacy personnel, the Investigators, or designated study personnel. The IDS staff’s responsibilities 
include maintaining, monitoring, and documenting the temperature in the pharmacy supply storage 
area per institutional guidelines.  
 
6.2.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Vorinostat 
VOR (N-hydroxy-N’-phenyl-octane-18-diotic acid diamide, N hydroxy-N’-phenyl (9CI) octanediamide, 
suberoylanilide hydroxamic acid, also known as SAHA, or MK- 0683) is an orally available HDAC inhibitor. 
The physical and chemical properties of VOR are listed in the table below.  
 
Properties of VOR 
 
Molecular Formula  
C14H20N2O3 
Molecular Weight  
264.32 
Physical Appearance  
White to light orange powder 
Solubility  
Water (pH = 11.2) ≤5 mg/mL 
Moisture (Karl Fischer)  
≤1% 
Melting Point  
159.5 to 160.5°C 
pKa  
8.5 and 11.1 
Hygroscopicity  
None 


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Hydrates  
None 
Chirality  
None 
 
The oral formulation of VOR is available as a 100-mg capsule. Each 100 mg ZOLINZA capsule for oral 
administration contains 100 mg Vorinostat and the following inactive ingredients: microcrystalline 
cellulose, sodium croscarmellose and magnesium stearate. The capsule shell excipients are titanium 
dioxide, gelatin, and may contain sodium lauryl sulfate. 
 
VRC07-523LS (Labeled as VRC07-523LS HIV mAb Drug Product VRC- HIVMAB075-00-AB) 
VRC07-523LS will be supplied as 10 mL glass vials with a 6.25 ± 0.1 mL fill volume and 3 mL glass vials 
with a 2.25 mL ± 0.1 mL fill volume, at a concentration of 100 ± 10 mg/mL. Each vial contains a clear, 
colorless to yellow isotonic, sterile solution essentially free of visible particles; some opaque or 
translucent particles may be present. The formulation buffer is composed of 50 mM histidine, 50 mM 
sodium chloride, 5% sucrose, and 2.5% sorbitol at pH 6.8. 
 
Vials are intended for single use only and thus do not contain a preservative. 
 
6.2.3 
PRODUCT STORAGE AND STABILITY 
 
Vorinostat:  
Vorinostat capsules should be stored at room temperature (do not store above 30°C) in a dry, limited-
access area. Care should be taken to maintain acceptable storage temperature. Vorinostat capsules 
should not be opened or crushed and must be administered whole. 
 
VRC07-523LS:  
VRC07-523LS product label designates the long-term storage as -35°C to -15°C (-31°F to 5°F). Clinical site 
storage in a qualified, continuously monitored, temperature-controlled freezer with temperatures from 
-45°C to -10°C (-49°F to 14°F) is acceptable. 
 
After thaw, VRC07-523LS vials may be stored for up to 24 hours at room temperature (maximum 27°C). 
If vials are not used within that time, they may then be refrigerated for up to 14 days at 2-8°C. If stored 
at 2-8°C, vials must be equilibrated at controlled room temperature (maximum 27°C) for a 
minimum of 30 minutes and may be held at room temperature for up to 8 hours prior to product 
preparation. Product may not be stored in direct sunlight. 
 
6.2.4 
PREPARATION 
 
Both VRC07-523LS and VOR will be stored and prepared in the UNC IDS Pharmacy.  
 
The clean-up and disposal of spilled, wasted, or unused medication and used syringes must be 
documented appropriately (i.e., witnessed) in accordance with applicable federal regulations, Good 
Clinical Practice (GCP) procedures, and the procedures for handling biohazardous substances.  
 
Vorinostat 
There is no preparation for the administration of VOR.  
 
 


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VRC07-523LS  
In this trial, the dose is limited or established based on the participant’s weight. In calculating the dose 
to administer and the number of vials to thaw, it should be assumed that the concentration is 100 
mg/mL and that a volume of at least 6 mL can be withdrawn from a vial. Preparation of VRC07-523LS for 
IV administration will require a 100 mL bag of 0.9% sodium chloride, USP (normal saline). Note that the 
normal saline bags referred to as “100 mL bags” in the IV administration instructions will typically have 
103 mL volume before any VRC07-523LS is added and this is acceptable in context of the instructions 
below. 
 
1. Preparation of study product  
Prior to preparation of the first infusion (Day 0), a new prescription will be sent to the IDS 
pharmacy. The prescription MUST contain the participant’s weight based upon the participant’s 
weight at Step 1 Visit 1.  
 
Any changes in weight of more than 10% (between the weight obtained at Step 1 Visit 1 and the 
weight on the day of the first infusion or between the weight used at the 1st infusion visit and 
the weight on the day of the 2nd infusion visit) will require a new prescription, which includes 
the new weight, and written so that product can be prepared based on that weight change. 
 
Pharmacists should keep in mind that the preparation instructions below are considered 
medium risk per USP 38 General Chapter Physical Tests / <797> Pharmaceutical Compounding - 
Sterile, and should follow the requirements of their country, their institution, and their 
pharmacy regulatory authority regarding these procedures.  
 
VRC07-523LS is a highly concentrated protein solution and may develop white, opaque to 
translucent particles after thawing. When particles are observed, they may disappear after a few 
hours at room temperature or storage at 2°C to 8°C. 
 
Ensure that only the required vials are present in the preparation unit during dilution and that 
medication labels are strictly segregated to avoid mix-ups. 
 
2. Thawing  
 
a) Thaw vial(s) for a minimum of 1 hour at controlled room temperature (maximum 27°C) 
after removing from the freezer. 
 
Following thaw, unopened vials of VRC07-523LS may be stored for up to 24 hours at 
controlled room temperature (maximum 27°C) and/or up to 2 weeks (14 days) at 2°C to 
8°C. 
 
b) Keep the material at room temperature during the entire preparation period until use, 
up to the maximum storage times described in section 6.2.3.  
 
c) Prior to preparation for administration, vials should be swirled for 30 seconds with 
sufficient force to re-suspend any visible particles, yet avoiding foaming. DO NOT SHAKE 
THE VIALS. If particles are observed, return the vials to 2°C to 8°C storage. If the particles 
re-dissolve within the maximum storage times, described in section 6.2.3 for 2°C to 8°C 


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storage, the vials may be used for product preparation. If particles continue to be 
observed, do not use the vialed product for IV administration. 
 
Refrigerated product must be equilibrated at controlled room temperature (maximum 
27°C/80.6°F) for a minimum of 30 minutes before preparation and must be used within 
4 hours of any subsequent return to room temperature. 
 
d) If the thawed material is not administered within 24 hours of thawing, do not use for 
another participant.  
• 
Any empty vials, unused portion of entered vials, or unused IV solution which 
contains VRC07-523LS should be discarded in a biohazard containment bag and 
incinerated or autoclaved in accordance with institutional or pharmacy policy. 
 
e) Preparation is to be done using aseptic technique, in a limited access, laminar flow 
biosafety cabinet. Ensure that only the required vials are present in the preparation unit 
during dilution and that medication labels are strictly segregated to avoid mix-ups. 
 
3. Intravenous Infusion Preparation Instructions: 
 
a) After thawing, if product was refrigerated again at 2-8°C, vials of VRC07-523LS should be 
equilibrated to controlled room temperature (maximum 27°C) for a minimum of 30 
minutes and may be held at room temperature for up to 8 hours prior to product 
preparation. 
 
b) Calculate the total milligrams of VRC07-523LS required based on the participant’s 
weight and 40 mg/kg.  
• 
Remove the total number of vials required from storage based on a 6 mL or 2 
mL withdrawal volume containing 600 mg or 200 mg of VRC07-523LS, 
respectively. 
 
c) Gently swirl thawed vials for 30 seconds to avoid foaming. DO NOT SHAKE VIALS. Keep 
the vials upright at all times until ready to withdraw the contents. Do not invert the vial 
during inspection. 
 
d) Observe vials for particles. If particles are observed, refer to the thawing instructions for 
further information, section 6.2.4.2. 
 
e) Using aseptic technique, add the calculated volume of VRC07-523LS (total calculated 
milligrams of VRC07-523LS) to 100 mL IV bag of Sodium Chloride Injection, USP 0.9% 
that will also permit the addition of the required calculated volume of VRC07-523LS. 
Alternatively, if the full VRC07-523LS dose volume cannot be accommodated in IV bag 
containing the 100 mL of Sodium Chloride Injection, USP 0.9%, please refer to the -
Pharmacy Manual for further preparation instructions. 
 
The thawed VRC07-523LS product will be added to Sodium Chloride Injection, USP 0.9% 
100 mL IV solution bag using aseptic technique. The 100 mL bag of normal saline has the 
capacity to accept up to 50 mL of added product and this should be sufficient to 
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f) After preparation for administration in IV bags, VRC07-523LS must be completely 
administered within 4 hours of preparation, including infusion time, when stored at 
room temperature (maximum 27°C/80.6°F).  
 
Additionally, after product preparation in IV bags, the prepared VRC07-523LS may be 
stored at 2°C to 8°C up to 48 hours including the infusion time. Product may not be 
stored in direct sunlight. If stored at 2°C to 8°C, prepared product must be equilibrated 
at room temperature (maximum 30°C) for a minimum of 30 minutes prior to product 
administration. 
 
g) Label the IV bag with: 
• 
the participant name,  
• 
DOB,  
• 
participant identifier,  
• 
participant weight, 
• 
the dose of VRC07- 523LS at 40 mg/kg,   
• 
the total amount (mg) of VRC07-523LS added to the 100 mL bag of normal 
saline,  
• 
the final volume of the bag, and  
• 
lot number 
 
The prepared IV label should also be labeled with DO NOT INFUSE after date and time 
as follows:  
• 
48 hours if stored at 2°C to 8°C  
• 
4 hours, including completion of infusion, if stored at controlled room 
temperature (not to exceed 27°C/80.6°F) 
• 
Product may not be stored in direct sunlight 
 
h) Any unused portion of a VRC07-523LS vial will not be used for another participant. Any 
empty vials, unused portion of entered vials, or unused IV solution which contains study 
product should be discarded in a biohazard containment bag and incinerated or 
autoclaved in accordance with institutional or pharmacy policy. 
 
4. VRC07-523LS Disposition  
 
a) The empty vials and the unused portion of a vial will be discarded in a biohazard 
containment bag and incinerated or autoclaved.  
 
b) Any unopened vials that remain at the end of the study will be returned to the 
production facility or discarded at the discretion of the sponsor in accordance with 
policies that apply to investigational products.  
 
c) Partially used vials will not be administered to other participants or used for in vitro 
experimental studies. These vials will be disposed of in accordance with institutional or 
pharmacy policy. 
 


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6.3 
STUDY INTERVENTION COMPLIANCE 
 
Participants will keep a daily diary of solicited AEs for both local and systemic symptoms for 3 days after 
each administration of VRC07-523LS. 
 
6.4 
CONCOMITANT MEDICATIONS 
 
Medications to be reported are prescription medications, over-the-counter medications, and 
supplements. 
 
All routine prescription medications, over-the-counter medications, supplements, and study provided 
medications and investigational products will be entered in the study-specific database, starting at the 
time of enrollment through the EOS.  
 
Whenever a concomitant medication is initiated or a dose changed, investigators must be informed. The 
study PI as well as all other investigators and clinical personnel on this study are responsible for 
reviewing  the concomitant medications’ and study agents’ most recent package inserts, investigator’s 
brochures, or updated information from DAIDS to obtain the most current information on drug 
interactions, contraindications, and precautions. 
 
Prohibited Medications  
1. Prohibited HIV ART: Ongoing use of investigational ART. Prior use of investigational ART is 
permitted, provided it has been replaced with another class of ART and last dose was taken >90 
days prior to study screening visit; 
2. Concomitant use with oral or parenteral corticosteroids, immunosuppressive agents (including 
but not limited to azathioprine, and cyclosporine) or any immunotherapy or immunomodulatory 
agents; 
3. Use of any agent that suppresses lymphocytes or monocyte function; 
4. Use of chemotherapeutic agents, growth factors, cytokines, or chemokines, white lineage colony 
stimulating factors (e.g., granulocyte-colony stimulating factor [G-CSF] and GM-CSF);  
5. Chronic use of topical corticosteroids that are applied to large areas of the skin (exceeding the 
cumulative area of the palm of the participant’s hand) or any corticosteroids or antihistamines 
used on or near the infusion site. 
6. Standard and live vaccinations (e.g., varicella, measles, mumps, rubella, MMR; yellow fever, oral 
polio) are permitted but timing of vaccine must be discussed and approved by the study PI or 
designee.  
7. Antihistamine can be administered only if needed to treat an anaphylactic reaction. 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
Participants for whom study interventions are discontinued should be counseled on the importance of 
continuing with the study and strongly encouraged to participate in follow-up visits and protocol- 
specified procedures. 


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The study will replace all participants who withdraw for reasons unrelated to drug toxicity. If participant 
withdrawal occurs prior to the initiation of the VRC07-523LS infusions (Step 2), the participant will have 
inadequate data, and therefore “new” replacement participants can be enrolled.  These participants will 
not be required to return for additional study visits.  
 
Participants who are withdrawn for safety or drug toxicity reasons will continue on study but off study 
treatment for safety assessments per the end of treatment study visit (see SOE in Section 1.3).  Analyses 
will be completed on all participant samples, including blood, collected at the end of treatment study 
visit. The data may or may not be included in the final analyses but all clinical safety data will be 
included in the final Clinical Study Report (CSR). 
 
Participants who are no longer on treatment but are still followed on the study (with safety evaluations 
obtained per the SOE in Section 1.3) can be terminated from the study for the following reasons: 
• 
Uncontrolled intercurrent illness that prevents continuing study follow-up or regular study visits. 
• 
Noncompliance with protocol-required evaluations. 
• 
Participant request for discontinuation from the study, i.e., withdrawal of consent. 
• 
The Sponsor, Investigator, or regulatory agency terminates the study. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Study Treatment Discontinuation 
Under certain circumstances, an individual participant’s receipt of study product will be prematurely or 
permanently discontinued. Specific events that will result in stopping a participant’s infusions or VOR 
dosing in this study include: 
• 
Failure to meet requirements established for safety assessment 
• 
Withdrawal from the study  
• 
Pregnancy  
• 
Grade 3 AE assessed as related to the study products (with the exception that self-limited Grade 
3 solicited reactogenicity does not require discontinuation from VRC07-523LS administration). 
• 
Grade 4 AE assessed as related to the study products 
• 
Intercurrent illness that is not expected to resolve prior to the next scheduled VRC07-523LS 
administration which is assessed by the study PI (or designee) to require withdrawal from the 
administration of VRC07-523LS 
• 
Repeated failure to comply with protocol requirements  
• 
Co-enrollment into a study in which other investigational research agents will be administered 
before the participants has completed the follow-up visits after receiving the last study product  
• 
Investigator discretion 
• 
Clinically significant hypersensitivity or infusion-related reaction including but not limited to 
type 1 hypersensitivity reaction, urticaria, or serum sickness associated with study treatment.  
 
If the study Principal Investigator (or designee) decides that a participant should be withdrawn from 
study treatment, the protocol team must be alerted within 24 hours. All participants who discontinue 
treatments should comply with protocol-specified visits and follow-up as required by the protocol and 
evaluation by the study PI (or designee). The only exception to this requirement is when a participant 
withdraws consent for all study procedures or loses the ability to consent freely (i.e., is imprisoned or 
involuntarily incarcerated for the treatment of either a psychiatric or physical illness). 


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If a participant is withdrawn before completing the study, the reason for withdrawal must be 
documented appropriately in the study documents. 
 
Early Study Discontinuation 
A participant may withdraw or be withdrawn from the study if any of the following occurs: 
• 
Failure by the participant to attend multiple clinic visits. 
• 
Failure to receive the first VRC07-523LS infusion.  
• 
Development of an illness that requires treatment with medications prohibited in this study. 
• 
Poor adherence to ART as judged by the site Principal Investigator or designee. 
• 
Request by the participant to withdraw from the study and study procedures. 
• 
Request of the participant’s primary care provider if she/he thinks the study is no longer in the 
best interest of the participant. 
• 
Participant judged by the study Principal Investigator to be at significant risk of failing to comply 
with the provisions of the protocol, as to cause harm to self or seriously interfere with the 
validity of the study results. 
• 
At the discretion of the IRB/Ethics Committee, FDA, NIH, and other government agencies as part 
of their duties, Principal Investigator, or industry supporter. 
 
Premature Treatment Discontinuation Evaluations 
Participants who begin but do not complete all doses of VRC07-523LS and VOR will be replaced. The 
collection of virologic, immunologic, and 2nd leukapheresis samples following premature discontinuation 
will be determined on a case-by-case basis in discussion with the protocol team. 
 
Participants who complete Steps 2 and 3 but are unable to complete the leukapheresis (#2) in Step 4 will 
contribute to safety analyses and complete an end of study visit. The ability to complete virologic and 
immunologic endpoint analysis will be determined on a case-by-case basis in discussion with the 
protocol team. Replacement will be determined by the protocol team based on the ability to complete 
endpoint analysis.  
 
Delaying VRC07-523LS administration 
Under certain circumstances, a participant’s scheduled VRC07-523LS infusion may be delayed. The 
factors to be considered in such a decision include but are not limited to the following: 
 
Within 7 days prior to any study product administration 
• 
Receipt of systemic glucocorticoids (e.g., prednisone or other glucocorticoids) or other 
immunomodulators (other than nonsteroidal anti- inflammatory drugs [NSAIDs]) – Please 
reference paragraph below as these medications are prohibited on study.  
• 
Pre-infusion abnormal vital signs or clinical symptoms that may mask assessment of study 
product reaction. 
• 
Inability to dose with VOR due to clinical symptom or laboratory value. 
• 
Intercurrent illness that is not expected to resolve prior to the VRC07-523LS infusion which is 
assessed by the site principal investigator (or designee) to require delay or withdrawal from the 
study product administration schedule.  
 
Infusions should not be administered outside the visit window periods.  
 


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Participants who take systemic glucocorticoids or other immunomodulators will be followed for safety by 
completing all the study visits and evaluations associated with the Step they are in when the study team 
learns of the need for a prohibited medication. If this occurs prior to completing all doses of VRC07-
523LS and VOR, DO NOT give any more VRC07-523LS infusions or VOR. Collection of research labs for 
the time points thereafter will be considered on a case-by-case basis. These participants will be 
replaced.  
 
Discontinuation of Antiretroviral Therapy  
Participants who discontinue ART for any reason will be followed for safety by completing all the study 
visits and evaluations associated with the Step they are in when the study team learns of the 
interruption of ART. If the participant discontinues ART prior to completing all doses of VRC07-523LS and 
VOR, DO NOT give any more VRC07-523LS infusions or VOR. Collection of research labs for the time 
points thereafter will be considered on a case-by-case basis in discussion with the protocol team. This 
participant will be replaced.  
 
If the participant discontinues ART before administration of the first dose of VOR and 1st VRC07-523LS 
infusion, the first VOR dose should not be given and the participant terminates from the study at this 
time. 
 
If the participant discontinues ART after the first infusion (Day 0) and multiple doses of VOR but before 
the 2nd VRC07-523LS infusion (Day 60) or prior to completing the second series of multiple VOR doses, 
study treatment should be discontinued and the participant should continue on study for safety follow-
up as noted in the SOE or per the study PI (or designee). Collection of virologic, immunologic, and the 2nd 
leukapheresis samples following premature discontinuation will be determined on a case-by-case basis 
in discussion with the protocol team. This participant will be replaced. 
 
 
7.3 
LOST TO FOLLOW-UP 
 
Participants classified as lost to follow-up (LTFU) need to meet both of the following criteria:  
• 
a) Failure to respond or reply to 3 documented phone contact attempts followed by  
• 
b) Failure to respond to a certified letter sent to the address provided by the participant.  
 
Only after documentation of these failed attempts to connect with the participant, will they be 
determined to be LTFU. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
 
This section provides a general description of the procedures and assessments associated with this 
study. 
 
Informed Consent 
Prior to performing any study-related procedures or assessments, the study coordinator discusses the 
study with the potential participant and obtains signed informed consent. This communication will be 


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documented. Labs/procedures completed during a routine clinical care appointment that are the same 
as the study screening labs and/or procedures and completed within the 14 days preceding the 
screening visit can be used to qualify the participant upon approval by the study PI or designee. 
 
Screening  
At the screening visit, participants will screen for the study. Only those participants who meet all 
eligibility criteria specified in Section 5.1 Inclusion Criteria and Section 5.2 Exclusion Criteria will be 
enrolled. A unique PID will be assigned during the screening visit.  
 
Participants who are unable to meet protocol-defined eligibility criteria at the Screening Visit (Step 1, 
Visit 1) may be eligible to re-screen again at the study PI (or designee)’s discretion. In such cases, the 
same PID will be used. If a screen failure or the failure to move to the next Step is due to the inability to 
meet one of the laboratory parameters (hematology, chemistry, HIV RNA, or CD4 T cell count), a 
laboratory retest of the failed criteria may be performed one time only. If the repeat value is within 
eligibility requirements, the participant can enroll on the study. 
 
Enrollment  
Step 1 Visit 1 determines eligibility and enrollment occurs at Visit 2.  
 
Advancement to Step 2  
 
Step 2  
Participants enrolled on the study will advance to Step 2 of the protocol based upon the following 
criteria: 
1. A frequency of resting CD4 T cell infection of ≥ 0.3 IUPM as determined by QVOA in Step 1 Visit 2 
 
Note: Participants with prior participation in one of the following UNC protocols in which they 
had an IUPM measurement ≥0.3, will be able to use this previous measurement for 
advancement: 
 
IRB 08-1575 (CID 0819) - Apheresis Procedures to Obtain Leukocytes for Research Studies 
from HIV Positive Subjects; 
 
IRB 11-0228 (CID 0807) - NCT01319383; 
 
IRB 13-3613 (IGHID 1309) - NCT02042248;  
 
IRB 14-0741 (IGHID 1320) - NCT02208167; 
 
IRB 15-1626 (IGHID 11424) - NCT02707900;    
 
IRB 17-0468 (IGHID 11627) - NCT03212989  
 
IRB 18-0608 (CP-MGD014-01) – NCT 03570918 
 
IRB 18-0944 (IGHID 1801) -The HIV Reservoir In Women: Implication For HIV Cure 
Strategies    
 
Note: Participants with these results and measurements from one of the above listed studies, would be 
able to use these results for advancement to Step 2, but would need to repeat the leukapheresis at Visit 
2 to be used as a baseline for this study.  
 
Failure to advance to Step 2 will result in discontinuation from study. Further follow-up is not required 
as no doses of VRC07-523LS will have been administered. 
 
 


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Medical History 
Significant medical history should be obtained during the screening visit. All concurrent medical 
conditions in the last 30 days and any significant medical conditions (e.g., hospitalizations, surgeries, 
prior medical history) should be collected. Medical history obtained at Screening will include 
demographic information (e.g., date of birth, gender, race, and ethnicity, etc.), participant’s medical 
history, and HIV medication history.  
 
Prior and Concomitant Medications 
All concomitant medications administered from screening until the end-of-study visit must be recorded 
in the source documents. Prescription and non-prescription medications taken within 4 weeks prior to 
screening must be recorded on the source document. 
 
All routine prescription medications, over-the-counter medications, supplements, and study provided 
medications and investigational products will be entered in the study-specific database, starting at the 
time of enrollment through the EOS.  
 
Antiretroviral (ART) Medication Assessment 
During the study, all modifications to the participant’s ART regimen, including any ARV interruptions, 
dose modifications, formulations modifications, starts, and permanent discontinuations since the last 
study visit or at the study visit must be recorded. 
 
ART Adherence 
ART adherence will be reviewed at every visit. Non-adherence will be defined as missing doses for more 
than 2 consecutive days or more than 4 cumulative days during the study. Assess any missed doses 
while on study and discuss with Study PI (or designee). Continuance on study will be contingent on 
adherence.  
 
Physical Examination 
Complete physical examination will include examination of skin, head, eyes, ears, nose, throat, lymph 
nodes, heart, chest, lungs, abdomen, extremities, and neurologic system according to schedule specified 
in the SOE in section 1.3.  
 
A directed physical exam will be performed at all clinical visits where a complete physical examination is 
not performed, according to the SOE in section 1.3.  A directed physical examination includes vital signs 
and addresses any previously identified or new event that the participant experiences since the last 
study visit or any unresolved signs or symptoms previously experienced. This assessment includes 
updates to signs and symptoms, and clinical assessment of HIV disease. 
 
Signs and Symptoms Assessments  
At entry, all signs and symptoms, regardless of grade, that occurred within the 30 days before entry 
must be recorded.  
 
Active solicitation of AEs will be done at every study visit. Post-entry signs and symptoms, Grade ≥ 2, will 
be recorded. All signs or symptoms, definitely, possibly, or probably related to study interventions, will 
be recorded, regardless of grade. Additionally, all signs and symptoms that lead to a change in study 
treatment or change in ART, regardless of grade, must be recorded. 
 
 


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Treatment Emergent Adverse Events  
An event that first appears during treatment, which was absent before or which worsens relative to the 
pre-treatment state.  
 
Vital Signs 
Vital signs (weight, body temperature, pulse or heart rate, respiratory rate, and seated blood pressure) 
will be recorded according to the SOE in section 1.3. Vital sign measurements will be conducted after 
resting 5 minutes in the sitting position. Height is only required at Step 1, Visit 1.  
 
Repeat vital signs may also be captured as necessary to elucidate the course of any untoward event or 
AE. 
 
Electrocardiogram 
ECG will be performed at screening and should be read per institutional protocol within 72 hours to 
establish baseline for further evaluation as clinically indicated. 
 
VRC07-523LS Infusions  
All study product administrations will be completed per the SOE, section 1.3. Prior to each infusion, 
temperature (T), blood pressure (BP), heart rate or pulse (P), respiratory rate (RR), and weight will be 
collected and a targeted PE (based on signs, reported symptoms, or interim medical history) conducted. 
The participant will be observed for at least 60 minutes following the 1st infusion of VRC07-523LS and at 
least 30 – 60 minutes after the 2nd VRC07-523LS infusion.  
 
Solicited AE Assessments 
For all participants, baseline assessments will be performed before each infusion and assessments for 
Solicited AEs will be performed after each infusion. All Solicited AEs are graded according to the Division 
of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1 
dated July 2017. 
 
The Solicited AE assessment period is 3 full days following each infusion per the SOE in Section 1.3. 
Participants are instructed to record symptoms using a daily symptom tool. The study coordinator and 
the participant will be in contact after the 3-day Solicited AE assessment period, or sooner if indicated. 
In general, a participant who self-reports any reaction following an infusion that is greater than mild is 
seen by a clinician within 48 hours after onset, unless the reaction is improving and/or has completely 
resolved. Clinic study staff will follow new or unresolved Solicited AEs present at day 3 to resolution. 
 
Solicited AE assessments include assessments of systemic and local symptoms, and study product-
related lesions.  
 
Assessment of Systemic and Local Symptoms 
Systemic symptoms to be assessed as solicited AEs include increased body temperature, chills, malaise 
and/or fatigue, headache, myalgia, arthralgia, nausea, urticaria, non-exertional dyspnea, non-exertional 
tachycardia (assessed by CRS staff, not by the participant), generalized pruritus, facial flushing, and 
unexplained diaphoresis.  
 
Local symptoms include pain or tenderness at the infusion site. The daily maximum severity reached for 
each symptom during the assessment period is reported. 
 


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Body temperature is measured by oral or infrared thermometry and is reported in degrees Celsius. If 
temperature is measured in Fahrenheit, the conversion to Celsius should be documented in the 
participant’s chart note. A measurement is taken once daily during the assessment period and should be 
repeated if participant is feeling feverish. 
 
Assessment of Infusion Site 
Typical infusion site reactions are erythema/redness and induration/swelling. The maximum horizontal 
and maximum vertical measurements for all infusion site reactions are recorded.  
 
All infusion/injection site reactions are monitored until resolution. Areas greater than 25 cm2 are 
followed daily; otherwise, the frequency of follow-up is based on clinician judgment. 
 
VRC07-523LS Post Infusion Telephone Follow-Up 
Participants will have a telephone interview with a study coordinator 4 -6 days following each infusion to 
review the solicited AE assessment tool. Any incidents or events identified that could be related to the 
infusion and are still unresolved at Day 3, will require participants to come into clinic for clinical 
assessment.  
 
Leukapheresis 
Participants will undergo 2 leukapheresis procedures. The baseline leukapheresis will be completed at 
Visit 2. Participants will advance to Step 2 based on the attainment of an IUPM measurement ≥ 0.3. The 
second leukapheresis will occur 5 – 8 weeks after the 2nd series of a VRC-07 infusion followed by VOR 
dosing.  
 
All protocol-required leukapheresis product will be transported on the day of collection to the Margolis 
Laboratory on the UNC campus. 
 
NOTE: Refer to the UNC Apheresis SOP and Study Specific Lab Manual for procedures specific to this 
study.  
 
If participants experience a Grade 3 or higher toxicity before completing the screening leukapheresis, 
they will be discontinued from study, as completing the leukapheresis procedures is a requirement of 
the study. Participants who experience a Grade 3 or higher toxicity during the leukapheresis will be 
evaluated on a case-by-case basis to understand the cause of the Grade 3 event. If the clinical situations 
(i.e., vasovagal response) that lead to the discontinuation of the leukapheresis procedure is determined 
by the study PI in collaboration with the Apheresis Medical Director to be situational and poses no 
apparent harm to the participant, the leukapheresis procedure may be repeated. However, if 
determined by the study PI, Apheresis Medical Director, and/or the Medical Monitor that repeated 
leukapheresis would be harmful to the participant, then he/she will be terminated from the study. 
The only exception to this discontinuation policy will be related to elevations in blood pressure (BP). 
Transiently elevated BPs to Grades 2 and 3 are frequently observed during this procedure, secondary to 
the BP cuff placement and nervousness of the participant. Elevated BP observed during the 
leukapheresis procedure will be monitored via Apheresis Lab policies. These will be noted and 
documented but will not be used to discontinue study participation.  
 
Clinical Laboratory Tests 
Blood and urine specimens will be collected according to the SOE in section 1.3. Safety laboratory tests 
should be performed and reviewed before study drug administration. 


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Laboratory Assays 
Study specific safety and research assays will be collected at the research visits. Safety and clinically 
relevant labs will be performed at UNC McLendon Laboratories or LabCorp. Research assays will be 
processed and stored in associated research laboratories. Additional details on collection, processing, 
storage, and shipping of laboratory samples will be provided in the Study Specific Laboratory Manual. 
 
End of Treatment/End of Study Visit 
An End of Study (EOS) visit should occur approximately 2 - 4 weeks after Visit 12 depending on ability to 
follow the participant and duration and severity of ongoing AEs. An individual participant will be 
considered to have completed the study if the participant was followed through their last protocol-
specified visit/assessment (EOS). Participants who have treatment discontinued due to a DLT or other 
clinical event will be followed on study until the clinical event is resolved or deemed stable and 
irreversible. Participants will complete the EOS visit per the SOE (section 1.3) but will be followed as 
necessary for acceptable resolution of the clinical event.    
 
Participants will be considered not to have completed the study if consent was withdrawn, the study 
Principal Investigator discontinues the participant from study for severe lack of compliance, or the 
participant was lost to follow-up. 
 
A list of evaluations to be performed for the EOS visit is provided in the SOE in section 1.3. The EOS Visit 
should be performed after the participant has met off-study criteria, or has been followed for at least 7 
weeks after the last VRC07-523LS dose. Participants experiencing an unresolved AE will be followed until 
the AE is either resolved or deemed stable and irreversible. 
 
Research Laboratory Assays  
 
The ability of VRC07-523LS infusion in combination with multiple doses of VOR to alter markers of 
persistent HIV-1 infection in individuals on suppressive ART will be evaluated by measurement of: a) the 
frequency of resting CD4 T cell infection by QVOA and b) levels of plasma HIV-1 RNA, as measured by 
low levels of an HIV-1 RNA assay. 
 
Resting CD4 T Cell Infection (RCI) 
Lymphocytes are obtained by continuous-flow leukapheresis (samples obtained as per the SOE, section 
1.3) and resting CD4 T cells are isolated as previously described (57).  
 
QVOA measurements will be conducted with the leukapheresis samples collected prior to and following 
combined VOR/VRC07-523LS administration to determine if the frequency of resting CD4 T cell 
infection, expressed as IUPM, has declined. Since RCI frequency is a definitive measure of the minimum 
size of the HIV reservoir, a statistically significant decline in response to VRC07-523LS in combination 
with VOR treatment would be definitive evidence of a reduction in the HIV reservoir. 
 
Plasma for Assays that measure low levels of RNA   
Residual low-level viremia will be measured, as evidence suggests that such viremia originates in 
persistently infected cells, and low-level viremia might be reduced by an augmented antiviral immune 
response. Plasma for HIV-1 RNA will be obtained as required per the SOE in section 1.3 and stored for 
batched analyses. Two baseline sample determinations will be obtained during Steps 1 and 2 of the 


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protocol and 2-4 low level viremia assay measurements after combination therapy with VOR and VRC07-
523LS will allow a robust evaluation of changes in plasma levels of cell-free HIV RNA.  
 
Human Leukocyte Antigen (HLA) Typing  
HLA testing will be performed at one time point in the study; however, if HLA type is already available in 
the medical record, it does not need to be repeated. The result will be used for research purposes.  
 
Cytomegalovirus (CMV) IgG Testing  
We will perform CMV testing for research purposes only  at baseline (Visit 2) and after the 10th dose of 
VOR in Steps 2 and 3.  If positive CMV testing results are available in the medical record, these results 
will be used for the baseline result. If the previous CMV IgG result in the medical record is negative, the 
test will be repeated at Visit 2.  The 2nd and 3rd tests performed in the research lab will determine 
whether Vorinostat reactivates CMV enough to detect it in the plasma. The results will not be placed in 
the participant’s medical record.  
 
Epstein-Barr Virus (EBV) Viral Capsid Antigen (VCA) IgG Testing 
We will perform EBV testing for research purposes only at baseline (Visit 2) and after the 10th dose of 
VOR in Step 2 or 3. If positive EBV testing results are available in the medical record, we will use these 
results for the baseline result. The 2nd and 3rd test performed in the research lab will determine whether 
Vorinostat reactivates EBV enough to detect it in the plasma. The results will not be placed in the 
participant’s medical record 
 
Vorinostat PK samples 
Pharmacokinetic samples will be collected at 3 time points in the study. These will be processed and 
stored for testing as required.  
 
VRC07-523LS PK samples  
Pharmacokinetic samples will be collected at 3 time points: at baseline and after antibody 
administration at Days 29 (Visit 6) and 89 (Visit 11). These will be processed, stored, and shipped for 
testing as required. 
 
Anti-Drug Antibody (ADA) Detection Assay 
ADA will be measured by using the Meso Scale Discovery (MSD) platform with VRC07-523LS as the 
target antigen. Anti-VRC07-523LS antibody assays will be performed on serum samples collected at 
baseline and after antibody administration at Days 29 (Visit 6) and 89 (Visit 11). Serum will be stored at 
other visits per the SOE. Additional ADA testing may be performed on participants if indicated.  
 
Virology and Viral Sequence Analysis  
Samples will be collected per the SOE. Samples will be processed, stored, and analyzed as required.  
 
Cell associated RNA Assay (caRNA)  
Samples collected to isolate resting CD4 T cells and run the caRNA assay to have an additional baseline 
point. It will provide an idea of the baseline variation in caRNA of a given participant. This is important in 
trying to measure a change in caRNA after the intervention.  
 
 
 


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8.2 
SAFETY AND OTHER ASSESSMENTS 
 
All clinical and laboratory information required by this protocol is to be present in the source 
documents. Reference the Source Document Guidelines on the DAIDS web site for information about 
what must be included in the source document.  
http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/documents/sourcedocappndx.pdf 
 
All stated evaluations are to be recorded unless otherwise specified. This includes events that meet the 
International Conference on Harmonisation (ICH) definitions for a serious adverse event. 
 
• 
Results in death 
• 
Life-threatening 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity  
• 
Congenital anomaly/birth defect 
• 
Other important medical event that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the participant or may require intervention to prevent one 
of the other outcomes listed in the definition above.  
 
To grade diagnosis, signs and symptoms, and laboratory results, reference the DAIDS Table for Grading 
the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 
2017, on the DAIDS RSC website at http://rsc.tech-res.com/clinical-research-sites/safety-
reporting/daids-grading-tables 
 
Medical History and Medical History Updates  
The medical history must include all signs and symptoms and all diagnoses regardless of grade within 
the past 30 days prior to entry.  
 
Document: 
• 
all allergies to any medications and their formulations 
• 
date of birth, gender at birth, race and ethnicity of participant   
• 
nadir CD4 and pre-ART HIV-1 RNA level, if available (if nadir documentation is not available, then 
collect and record participant recall) 
 
The medical history evaluation will be assessed and recorded at the screening visit. Updates to medical 
history will occur at all clinical study visits. Any reported sign, symptom, and/or new diagnoses occurring 
after the participant signs the study consent but prior to the administration of the first dose of study 
product will be recorded in the medical history (pre-existing condition) unless the reported event is 
related to a protocol procedure. 
 
Clinical Laboratory Testing for Safety 
 
Hematology  
Hemoglobin, hematocrit, white blood cell count (WBC), differential WBC, absolute neutrophil count 
(ANC), and platelet count will be performed in real time at the local laboratory. 
 


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STAT CBC with differential is required prior to each leukapheresis procedure done at UNC unless 
completed within 24 hours of the procedure and the results of that test are available to the Apheresis 
Lab. Apheresis collections completed at the American Red Cross require a CBC within the 30 days prior 
to the procedure. 
 
Liver Function Tests  
Total bilirubin, AST (SGOT), ALT (SGPT), and alkaline phosphatase will be performed in real time at the 
local laboratory.  
 
NOTE: For participants on ritonavir boosted atazanavir, total and direct bilirubin should be measured. 
 
Blood Chemistries  
Screening lab evaluation are done fasting and includes electrolytes (sodium, chloride, potassium, 
CO2/bicarbonate), glucose, blood urea nitrogen (BUN), creatinine, calcium, albumin, magnesium, lipase, 
and total protein in real time at the local laboratory.  
 
Safety lab evaluations throughout the study include electrolytes (sodium, potassium, chloride, 
CO2/bicarbonate), BUN, creatinine, calcium, magnesium, and glucose (also reference Pre-Infusion Safety 
Lab Assessment).  
 
Creatinine and Creatinine Clearance  
Creatinine clearance (eGFR) calculations will use the CKD-EPI equation. This calculation can be found at 
https://www.qxmd.com/calculate/calculator_251/egfr-using-ckd-epi 
 
The creatinine clearance (eGFR) will be required for study enrollment eligibility. The study assesses 
serum creatinine level at all of the safety lab checks and uses the serum creatinine value for toxicity 
grading.  
 
The creatinine clearance (eGFR) value reported as part of the lab report of serum creatinine level will be 
re-assessed and re-calculated if incidental finding indicates a value ≥ Grade 3. The re-calculated value 
using the CKD-EPI equation will be used to determine the severity of the lab abnormality. 
 
Pre-Study Treatment Safety Lab Assessments 
Participants will have a Pre-Study Treatment Safety Lab Assessment prior to receipt of  VRC07-523LS 
infusions at Day 0 and Day 60. The safety lab results obtained in this assessment must be within the 
eligibility criteria parameters established for this study. Labs that fall outside the parameters can be 
repeated one time only to qualify the participant to proceed on study.  
 
After repeat testing, any lab value that remains outside the guidelines but considered clinically non-
significant and documented as such by the study clinical PI (or designee), must be reviewed and 
approved by the protocol team and/or safety committee prior to the infusion. 
 
Time points for the Pre-Study Treatment Safety Lab Assessment are: 
• 
Step 2, Day 0 – prior to the administration of the first infusion. These labs can be performed up 
to 7 days prior to the infusion.  
• 
Step 3, Visit 7, Pre-Visit – prior to the administration of the 2nd VRC07-523LS infusion  
 
 


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Follicle Stimulating Hormone (FSH) Test 
This test is done at screening to document menopause in women who have been without a period for > 
12 months. 
 
Serum Pregnancy Test  
A negative serum pregnancy test (to rule out pregnancy) is required on all women at screening.  
 
A negative serum pregnancy test is required at each visit prior to VRC07-523LS infusion, and within 72 
hours of the first VOR dose in Step 2 and Step 3 regardless of documented procedures that prohibit 
pregnancy.  
 
In addition, a serum pregnancy test should be performed at any time if pregnancy is suspected. Because 
the study has no direct clinical benefit, this added protection is warranted. 
 
Hepatitis Screen 
Both hepatitis tests (HCV AB and HBsAg) must be negative or non-detected to be included on the study. 
A positive HCV AB test reflexed to Hepatitis C RNA revealing a negative result is acceptable. 
 
Eligibility will be determined based on negative testing, per above definition at screening and prior to 
the Day 60 visit.  
 
RPR 
This test is done to rule out clinically active untreated syphilis at screening. 
 
Participant may participate on study following documentation of adequate treatment of syphilis at 
screening (Visit 1). Participants diagnosed with syphilis while on study, will be referred for and require 
documentation of treatment prior to the 2nd infusion at Day 60. These infusions can be delayed until a 
minimum of 14 days post treatment for syphilis per recommendation by the study PI (or designee). 
 
Fasting Lipid Panel   
Total cholesterol, HDL, LDL calculation, VLDL calculations and triglycerides are obtained at screening.   
 
Prothrombin Time (PT), INR, and APTT  
Evaluated at the Screening Visit.  
 
CD4+/CD8+ 
All study required absolute CD4+/CD8+ count and percentages must be obtained from a laboratory that 
possesses a CLIA certification or equivalent.  
 
Eligibility will be determined based on a CD4+ cell count ≥ 350 at screening and at Visit 7 (within 7 days 
prior to Day 60 Visit).  
 
Plasma HIV-1 RNA 
All study-required HIV-1 RNA must be performed by a laboratory that possesses a CLIA certification or 
equivalent.  
 
Eligibility will be determined based on an HIV-1 RNA value <50 copies/mL at screening and at Visit 7 
(within 7 days prior to Day 60 Visit). 


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Urinalysis   
A full urinalysis with microscopic evaluation will be performed at screening. 
 
Dipstick testing (including protein, glucose, hemoglobin, pH, and ketone) will be done at select visits. 
After screening, microscopic analysis will only be done in the event of abnormal results from dipstick 
testing. 
 
Clinical Procedures for Safety  
 
VRC07-523LS Administration  
Record the infusion, including dose, and time of the study treatment administration. Record where the 
IV was inserted (location). If entire dose is not administered for any reason, notify the study PI and 
document the reason. 
 
The following will be completed at each infusion administration visit: 
• 
Confirm participant name and DOB with study treatment label, research chart, and verbal 
confirmation of same from participant with a second licensed provider. 
• 
Participant must be seated in a secure chair or lying in a bed for the infusion. 
• 
Document time of administration. 
• 
Have emergency kit at bedside. 
 
Post-Infusion Management  
Observe participant and infusion site for a minimum of 60 minutes following the first infusion and a 
minimum of 30 - 60 minutes following the second infusion. 
• 
Assess for site for a reaction every 15 minutes X 4, document observed reactions for 60 minutes 
following the first infusion and for every 15 minutes X 2 (at minimum) following the second 
infusion.  
• 
Assess participant for local and systemic reactions every 15 minutes x 4, document observed 
reactions for 60 minutes following the first infusion and for every 15 minutes X 2 (at minimum) 
following the second infusion. 
• 
Observe and assist participant when coming to a standing position for the first time following 
each infusion  
• 
Obtain vital signs (BP, P, RR, and T) every 15 minutes for 60 minutes following the first infusion 
and every 15 minute for at least 30 minutes – 60 minutes following the second infusion. 
Document VS prior to discharge home.  
 
Instruct participant to contact the study coordinator immediately with any concerns after leaving the 
clinic. 
 
Provide participant post-infusion symptom log and instructions for completion prior to leaving the clinic. 
Post-infusion assessment includes the following: 
• 
Contact participant between Days 4 and 6 post-infusion in the manner pre-determined by study 
coordinator and participant 
• 
Review the symptom log at Days 4-6 with participant 
• 
Collect and reconcile the symptom log with the participant at the Day 7 visit following each 
infusion 


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Solicited AE Assessments 
Participants will be given a “Post-infusion AE Assessment” tool to use as a memory aid for tracking AEs 
that occur during the 3 days following the infusion. Participants will record daily temperature and 
symptoms.  
 
For this study, solicited AEs occurring during the 3 days after receipt of study agent will include:  
 
Localized  Symptoms  
Systemic Symptoms  
• Erythema (redness) 
•  Fatigue  
• Local pain/tenderness 
•  Headache 
• Warmth at infusion site 
•  Fever >37.7°C or 99.9°F 
• Induration (hardening or formation of a crust or scab) 
•  Chills  
• Itching (generalized and local)  
• Rashes 
• Swelling 
•  Myalgia  
• Skin discoloration 
•  Arthralgia  
• Skin damage (vesiculation or ulceration) 
•  Nausea 
• Vomiting 
• Malaise  
• Urticaria 
• Non-exertional dyspnea 
• Facial flushing 
• Non-exertional tachycardia 
• Unexplained diaphoresis 
 
 
Participants will also record the highest measured temperature daily. Participants should be instructed 
to take their temperature at least once daily, starting with the day of infusion (day 0), after leaving the 
clinic and through day 3 post-infusion. 
 
Temperature should be taken orally or via infrared thermometry and in the evening whenever possible. 
If more than one measurement is made in a day (for example, due to feeling unwell), then the highest 
temperature taken that day should be recorded.  
 
Participants will have a telephone interview with a study coordinator 4 -6 days following each VRC07-
523LS infusion to review the solicited AE assessment tool. Any incidents or events identified that could 
be related to the infusion and are still unresolved after Day 3, will require participants to come into clinic 
for clinical assessment. Telephone conversation will be documented and signed off by the study PI. 
 
Events occurring during the Solicited AE Assessment period that may require a clinic visit based on the 
judgment of a study clinician include: 
• 
Rash,  
• 
Urticaria,  
• 
Fever of 38.6˚C (Grade 2) or higher lasting greater than 24 hours,  
• 
A significant impairment in the activities of daily living (such as those consistent with Grade 2 or 
higher impairment),  
• 
Arthralgia or other clinical concerns  
 
The study coordinator reviews symptom logs for accuracy and completeness and will collect log at the 
Day 7 and Day 67 visits. Additionally, participants will undergo clinical laboratory assays and clinical 


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evaluations to assess safety at every visit. Participants will also be asked to contact the study 
coordinator, or study PI or designee should they experience any adverse events at any time points 
during the study.   
 
Reactogenicity Assessment 
The participant will assess for reactogenicity (expected) symptoms from days 0 to 3 following each 
infusion on their post-infusion symptom card.  
 
The daily maximum severity reached for each symptom during the 3-day assessment period will be 
reported. Study staff will follow new or unresolved reactogenicity symptoms to resolution. In general, 
participants self-reporting any post-infusion reaction greater than mild are to be evaluated by Study PI (or 
designee) within 48 hours after onset, unless the reaction is improving and/or has completely resolved. 
Institute appropriate countermeasures, including medical intervention or procedures, if clinically 
indicated. 
 
Estimated Blood Volumes Associated with the Study Visits  
 
Visit or Week # 
Blood Volume 
(mL)  
Visit or Week # 
Blood Volume 
(mL)  
Visit 1  
50 
Visit 8 Day 60 
116 
Visit 2  
153 
Visit 9 Day 67 
18 
Visit 3 Day 0 
61 
Visit 10 Day 74 18 
Visit 4 Day 7 
15 
Visit 11 Day 89 173 
Visit 5 Day 14 
16 
Visit 12 
50 
Visit 6 Day 29 
158 
Visit 13 
135 
 Visit 7  
70 
 
 
 
Cancer Registry  
All participants who receive greater than 8 doses of VOR in a study are asked to enter a study cancer 
registry. The registry is maintained by the clinical program director of the UNC HIV Cure Center.  
Participants willing to participate in the registry are contacted annually for 5 years following the 
completion of their VOR dosing regimen. The UNC Cancer Registry is searched annually for new cancer 
diagnoses registered to any of the VOR recipients. Data on participants included in this registry will be 
provided in the Annual Reports to the FDA for this study. 
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 
DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
An adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. This includes any occurrence that 
is new in onset or aggravated in severity or frequency from the baseline condition, or abnormal results 
of diagnostic procedures, including laboratory test abnormalities. 


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8.3.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes:  
• 
death,  
• 
a life-threatening adverse event,  
• 
inpatient hospitalization or prolongation of existing hospitalization,  
• 
a persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or  
• 
a congenital anomaly/birth defect.  
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias, or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
8.3.3 
CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 
SEVERITY OF EVENT 
 
Event severity will be assigned according to the Investigator’s assessment.  
 
Severity Grade for Parameters Not Identified in the Grading Table:  
The functional table below should be used to grade the severity of an AE that is not specifically 
identified in the grading table. In addition, all deaths related to an AE are to be classified as Grade 5. 
 
PARAMETER  
GRADE 1 MILD  
GRADE 2 
MODERATE  
GRADE 3 SEVERE  
GRADE 4 POTENTIALLY 
LIFE-THREATENING  
Clinical adverse 
event NOT 
identified 
elsewhere in 
the grading 
table  
Mild symptoms 
causing no or 
minimal interference 
with usual social & 
functional activities 
with intervention not 
indicated  
Moderate 
symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
with intervention 
indicated  
Severe symptoms 
causing inability to 
perform usual social 
& functional 
activities with 
intervention or 
hospitalization 
indicated  
Potentially life-
threatening symptoms 
causing inability to 
perform basic self-care 
functions with 
intervention indicated to 
prevent permanent 
impairment, persistent 
disability, or death  
 
8.3.3.2 
RELATIONSHIP TO STUDY INTERVENTION 
 
Attribution/Assessment of Causality is a determination that describes the relationship or association of 
the study product with an adverse event.  
 


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This assessment of causality or relationship of AEs to the study drug is provided by the Investigator and 
is determined by 1) temporal relationship of the event to the administration of study drug; 2) whether 
an alternative etiology has been identified, and 3) biological plausibility. Causality must be assessed 
separately for each study drug.  
 
The causality assessment categories that will be used for this study are described below.  
 
1. Causality assessments that are considered not related to study drug: 
a. Not related: 
 
The event is related to an etiology other than the study drug (the alternative etiology 
must be documented in the participant’s medical record). 
 
If an SAE is considered "unrelated" to study drug, the Investigator should offer his/her clinical 
opinion as to what factor(s), agent(s), or process(s) were the likely causative mechanism for the 
event.  
 
2. Causality assessments that are considered related to study drug: 
a. Possible: 
 
There is an association between the event and the administration of the study drug and 
there is a plausible mechanism for the event to be related to study drug; but there may 
also be alternative etiology, such as characteristics of the participant’s clinical status or 
underlying disease. 
 
b. Probable: 
 
There is an association between the event and the administration of study drug, a 
plausible mechanism for the event to be related to the study drug, and the event could 
not be reasonably explained by known characteristics of the participant’s clinical status 
or an alternative etiology is not apparent. 
 
c. Definite: 
There is an association between the event and the administration of study drug; a 
plausible mechanism for the event to be related to the study drug, causes other than 
the study drug have been ruled out, and/or the event re-appeared on re-exposure to 
the study drug. 
 
8.3.3.3 
EXPECTEDNESS  
 
The study PI (or designee) will be responsible for determining whether an adverse event (AE) is expected 
or unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the study intervention or is not listed in 
the most current IBs for the study intervention. 
8.3.4 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review of medical record. 


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The study unsolicited AE reporting period will be from enrollment (Day 0) through the end of study visit.   
During Step 1 (period between consent and Day 0), any AE that occurs will be collected as concurrent 
medical history (pre-existing condition) and not as an AE, unless it is due to a protocol–related 
procedure (leukapheresis).  
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured in the 
research record on the appropriate form. Information collected includes:  
• 
Event description,  
• 
Time of onset,  
• 
Study PI’s (or designee’s) assessment of severity, relationship to study product and 
expectedness,  
• 
Time of resolution/stabilization of the event.  
 
All AEs occurring while on study must be documented appropriately regardless of relationship. All AEs 
will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The study  research coordinator will record all reportable events with start dates occurring any time on 
or after the enrollment visit until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation.  At each study visit, the research coordinator will inquire about the occurrence of AE/SAEs 
since the last visit.  Events will be followed for outcome information until resolution or stabilization. 
 
Clinical Laboratory Changes:  
 
Safety laboratory assessments will be carried out locally at UNC and evaluated by the Investigator (or 
designee) to ensure participant safety. The Investigator (or designee) is responsible for reviewing the 
results of all laboratory tests as they become available.  
• 
Laboratory values that fall outside of a clinically accepted reference range or differ significantly 
from previous values must be evaluated for clinical significance by the Investigator (or 
designee). The Investigator (or designee) may repeat the laboratory test or request additional 
tests to verify the results of the original laboratory tests.  
• 
If the Investigator (or designee) determines the laboratory value is an abnormal change from 
baseline and is of clinical significance for that participant, it is considered an AE.  
• 
Generally, Grade 1 and Grade 2 laboratory findings need not be reported as AEs unless deemed 
clinically significant by the Investigator (or designee).  
• 
Consistent with the DAIDS designation of Grade 3 events as severe or medically significant and 
Grade 4 events as life-threatening, Grade 3 and Grade 4 laboratory findings should be reported 
as AEs or SAEs, as appropriate.  


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• 
The test result or finding should be reported as the AE. Such laboratory values should generally 
be recorded as “increased” or “decreased” (e.g., change from baseline potassium of 5.0 to 3.5 
mEq/L = potassium decreased). 
 
The study PI (or designee) is responsible for appropriate reporting of adverse events to the regulatory 
authorities. The study PI (or designee) will also report all suspected unexpected serious adverse 
reactions. The study PI (or designee) must report suspected unexpected serious adverse reactions to the 
UNC IRB, unless otherwise required and documented by the UNC IRB. 
 
8.3.5 
ADVERSE EVENT REPORTING  
 
Adverse events will be graded according to the DAIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017, on the DAIDS RSC 
website at http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables 
 
Participants will be monitored for adverse events. Toxicities will be characterized in terms including 
duration, intensity, and time to onset. Safety endpoints will include all adverse experiences, in addition 
to laboratory safety assessments, and vital signs. All AEs will be recorded on the appropriate study form. 
All AEs will be recorded in the database if any of the following criteria have been met:   
• 
Study-related grade ≥ 1 AEs 
• 
Grade ≥ 3 AEs  
• 
Autoimmune-related AEs regardless of grade 
• 
HIV viral loads ≥ 50 copies/mL 
• 
Infusion reactions regardless of grade  
• 
AEs that led to a change in study intervention regardless of grade 
• 
AEs meeting SAE definition or EAE (Expedited Adverse Event) reporting requirement 
 
Grade 1 or 2 Toxicity  
 
Participants who develop a Grade 1 or 2 AE or lab toxicity that occurs following a VRC07 infusion  or 
dose of VOR dosing that is thought to be possibly, probably, or definitely related to study treatment 
should be discussed with the study team. Grade 1 or 2 AEs that may be related to the VRC07-523LS or 
VOR should be handled according to standard clinical practice and documented. Participants who 
experience a Grade 1 or 2 AE that is judged related to the study treatments by the study PI (or 
designee), may continue study treatment at the discretion of the study PI (or designee). 
 
Participants who experience a Grade 1 or 2 AE that is judged not to be related to the study drug/product 
by the study PI (or designee), may continue study treatment at the discretion of the study PI (or 
designee).   
 
Grade 3 Toxicity 
 
For participants who develop a Grade 3 AE following administration of VRC07-523LS or VOR that is 
judged by the study PI (or designee) to be at least possibly study treatment-related, the protocol team, 
inclusive of the DAIDS Medical Officer, must be notified within 24 hours. Participants experiencing Grade 
3 AEs should be followed closely and if the AE does not return to Grade ≤ 2 within 2 weeks, the study 
team should again be notified within 24 hours and the SMC will be notified. Continued receipt of study 


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products is at the discretion of the study PI (or designee) in consultation with the protocol team and the 
SMC.  
 
For participants who experience a Grade 3 AE that is judged not related to the study treatment by the 
investigator, continued study participation is at the discretion of the study PI (or designee) in 
consultation with the protocol team and SMC.  
 
Grade 4 Toxicity   
 
For participants who develop a Grade 4 AE following administration of VRC06-523LS or VOR that is 
judged by the study PI (or designee) to be at least possibly study treatment-related, the protocol team, 
the DIADS Medical Officer and SMC must be notified within 24 hours. Participants experiencing Grade 4 
AEs should be followed closely with additional clinical assessments and laboratory testing as clinically 
indicated. If the AE does not return to Grade ≤ 2 within 2 weeks, the protocol team and SMC should 
again be notified within 24 hours. 
 
All study treatments will be discontinued in the event of Grade 4 AEs possibly related to study 
treatment. 
 
Local or Systemic Reactions to VRC07-523LS 
 
Grade 1 or 2  
Local reactions of mild (Grade 1) or moderate (Grade 2) severity will usually resolve spontaneously. If 
needed, they may be managed with local application of cold packs, oral acetaminophen, oral non-
steroidal anti-inflammatory agents, or a combination of these measures as appropriate. 
 
NOTE: Topical steroids should not be applied to the infusion site. 
 
Grade 3 or 4  
For severe (Grade 3) or potentially life-threatening (Grade 4) local reactions, the protocol team, inclusive 
of the DAIDS Medical Officer, must be notified within 24 hours. For Grade 4 local reactions, definitive 
medical and/or surgical intervention should be undertaken as appropriate. Further infusions will not be 
administered. 
 
Systemic Reactions  
The protocol team, inclusive of the DAIDS Medical Officer, must be contacted within 24 hours for any 
non-local Grade 3 or 4 systemic reactions thought definitely, possibly, or probably related to the VRC07-
523LS infusion or the administration of VOR doses. Further infusions and VOR doses will not be 
administered. 
 
If an adverse event of special interest (AESI) occurs (see section 8.3.8), the study coordinator, in 
collaboration with the study PI (or designee), will evaluate the severity and seriousness of the AE and 
the relationship to the study treatment, and will document the findings. 
 
The protocol team, inclusive of the DAIDS Medical Officer, should be contacted within 24 hours of 
notification of any reactions thought definitely, possibly, or probably related to the VRC07-523LS 
infusion. 
 


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Infusion Site reaction 
Infusion Site Erythema or Redness and Infusion Site Induration or Swelling will not be considered 
interference with usual social and functional activities such that:  
• 
Grade 1 is: 2.5 to < 5 cm in diameter OR 6.25 to < 25 cm2 surface area;  
• 
Grade 2 is: ≥ 5 to < 10 cm in diameter OR ≥ 25 to < 100 cm2 surface area;  
• 
Grade 3 is: ≥ 10 cm in diameter OR ≥ 100 cm2 surface area OR Ulceration OR Secondary infection 
OR Phlebitis OR Sterile abscess OR Drainage;  
• 
Grade 4 is: Potentially life-threatening consequences (e.g., abscess, exfoliative dermatitis, 
necrosis involving dermis or deeper tissue) 
 
Allergic or Hypersensitivity Reactions 
Record all allergic and hypersensitivity reactions with both grade severity and attribution.   
Serious allergic or hypersensitivity reactions (≥ Grade 3) that are deemed possibly related to the study 
treatment by the study PI (or designee) will be reported to the protocol team and SMC within 24 hours 
of notification and to the NIH, UNC IRB, FDA, and study product sponsors within 48 hours per their 
reporting requirements. 
 
Dose Limiting Toxicity (DLT)  
• 
Hematologic dose-limiting toxicity will be defined as any confirmed toxicity ≥ Grade 2, that 
cannot clearly be attributed to another reversible cause. These participants will not receive 
further doses of VOR or VRC07-523LS.  
 
• 
Follow participants per protocol schedule of events until the lab abnormality or toxicity resolves 
to ≤ Grade 1 or the participant’s baseline.  
 
• 
Non-hematologic dose-limiting toxicity will be defined as any confirmed symptomatic ≥ Grade 3, 
if related (definitely, probably, or possibly) to VOR or VRC07-523LS 
 
Monitoring HIV RNA levels 
In the event of viremia of ≥ 50 copies/mL the following should occur per standard of care: 
• 
Adherence to ART should be carefully assessed and documented.  
• 
A standard HIV RNA assay should be repeated within 1-4 weeks. 
• 
HIV resistance testing will be performed at the time of drawing a confirmatory sample. 
• 
HIV RNA will be repeated every 2 weeks, or sooner as clinically indicated, until <50 copies/mL 
and the participant can continue on study. 
• 
If persistent viremia is documented, ongoing administration of study treatment will be reviewed 
on a case-by-case basis with the participant, their HIV provider, and the study team.   
 
In the event of confirmed viremia and documented adherence to ART, ART should be managed by the 
primary care provider in discussion with the study team. The results of the HIV resistance tests will be 
shared with the participants and their care providers. 
 
Immediately Reportable Events 
Immediately Reportable Events (IREs) are events that must be reported immediately to the sponsor 
within 24 hours of the study site’s awareness of the event: 
• 
All SAEs  
• 
Pregnancy in a study participant or partner of a study participant  


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• 
All ≥ Grade 2 Cytokine Release Syndrome/Infusion-Related Reactions 
• 
Administration of a dose significantly greater (specifically, + 20 % or higher) than the planned 
dose, and results in an event of clinical consequence  
• 
AEs leading to permanent discontinuation of study drug in an individual participant 
• 
Withdrawal of the participant from study drug administration during or after receipt of any 
doses of VRC07-523LS or VRC07-523LS in combination with VOR  for any reason 
• 
Product quality issues with an associated clinical consequence.  
 
In those cases, in which the IRE is considered related to study drug, the study drug may be discontinued 
and the participant will continue participation in the study for observational safety and analysis (except 
for cases where the participant is withdrawn from the study by the study PI (or designee) or withdrew 
their consent). At any time after completion of the study, if an Investigator becomes aware of a serious 
adverse event that s/he suspects is related to study drug, the study PI (or designee) should report the 
event to NIH, VRC, Merck, FDA, and the UNC IRB, if applicable. 
 
The study PI (or designee) is responsible for appropriate reporting of AEs to the regulatory authorities.  
 
The Protocol Core Team will monitor the conduct and safety of the study via monthly meetings and 
regular summaries. Accrual, baseline characteristics, conduct of the study (including premature study 
discontinuations), any interruptions of ART, virologic failures, and all reported toxicities and events will 
be monitored during the study and discussed with the protocol team on a monthly basis or more 
frequently, if needed.  
 
The study protocol team will review the individual safety data monthly to assess relation of all reported 
toxicities and AEs to the study treatment. A study unique independent Safety Monitoring Committee 
(SMC) will receive monthly study progress and safety monitoring reports. Study feasibility and the 
achievement of study milestones will be assessed in these reports. 
 
The DAIDS program and medical officers will review and assess the monthly safety reports, as well as 
EAE reports for potential impact on the study participant safety and protocol conduct as per DAIDS 
policies, guidance documents, and SOPs, as applicable. 
 
8.3.6 
SERIOUS ADVERSE EVENT REPORTING  
 
All SAEs occurring during the study must be reported to the UNC IRB per the UNC IRB reporting 
requirements. A written report (Serious Adverse Event Report Form) will be submitted to DAIDS and 
DAIDS MO within 24 hours of site becoming aware of the SAE. Additional information will be supplied as 
requested. All SAEs occurring during the study will be reported to DAIDS following guidelines for 
expedited AE reporting and to the FDA according to their regulatory guidelines. 
 
After 30 days following the last dose of study drug administration, only SAEs the study PI (or designee) 
considers related to study drug or a protocol procedure, should be reported. Information regarding SAEs 
will be submitted to the DAIDS on required SAE reporting forms, which must be completed and signed 
by the study PI or designee, and sent within 24 hours of the site becoming aware of the SAE.  
 
All Grade 3 or Grade 4 AE/SAEs considered related to study drug must be followed until recovery to 
baseline or Grade 1 with the date of resolution recorded in the source documents. In addition, the 


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investigator should report all follow-up for reportable Grade 3 or Grade 4 AE/SAEs to the UNC IRB. 
Resolution of an event is defined as the return to pre-treatment status or stabilization of the condition 
with the expectation that it will remain chronic. 
 
All SAEs that have not resolved by the end of the study, or that have not resolved upon discontinuation 
of the participant's participation in the study, must be followed until any of the following occurs: 
• 
The event resolves. 
• 
The event stabilizes. 
• 
The event returns to baseline, if a baseline value/status is available. 
• 
The event can be attributed to etiology other than the study drug or to factors unrelated to 
study conduct.  
• 
It becomes unlikely that any additional information can be obtained (participant’s or health care 
practitioner’s refusal to provide additional information, or lost to follow-up after demonstration 
of due diligence with follow-up efforts).  
 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the course of a 
participant's participation in a study must be reported as an SAE, except hospitalizations for the 
following: 
• 
Hospitalizations not intended to treat an acute illness or adverse event (e.g., social reasons such 
as pending placement in long-term facility). 
• 
Surgery or procedure planned before entry into the study (must be documented in the source 
document). 
 
The study PI (or designee) will be responsible for notifying the FDA, VRC, and Merck, Inc. of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later 
than 7 calendar days after the sponsor's initial receipt of the information.  In addition, the sponsor must 
notify FDA in an IND safety report of potential serious risks, from clinical trials or any other source, as 
soon as possible, but in no case later than 15 calendar days after the sponsor determines that the 
information qualifies for reporting. 
 
8.3.7 
REPORTING EVENTS TO PARTICIPANTS  
 
We are engaged in a number of similar studies of persistent HIV infection, using VOR and other 
interventions. We report the scientific findings of our work in the literature, and have regular (annual or 
more frequent) presentations with the local and national HIV+ and affected community. Due to the lack 
of evidence thus far that our studies have a clinical impact, we discuss the scientific findings in a general 
way with each participant after EOS visits. Our studies have extremely stringent stopping criteria, and 
thus far we have had no relevant or study-related SAEs to report. We would inform all study participants 
by letter or electronic messaging of any AEs determined by the External Study Safety Monitoring 
Committee to merit such notice.  
 
8.3.8 
ADVERSE EVENTS OF SPECIAL INTEREST  
 
An adverse event of special interest (AESI; serious or non-serious) is one of scientific and medical 
concern specific to the protocol team, for which ongoing monitoring and rapid communication to the 
protocol team is required. These events might warrant further investigation in order to characterize and 


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understand it. Depending on the nature of the event, rapid communication by the protocol team to the 
UNC IRB, FDA, NIH, and product manufacturers (i.e., regulators) might also be warranted. 
 
AESI for this protocol include those listed below. Updates to AESI will be added as an amendment to this 
protocol.  
• 
Systemic lupus erythematosus (SLE) 
• 
Systemic scleroderma (SSD) (Systemic sclerosis [SSc]), including diffuse systemic form and CREST 
syndrome 
• 
Sjogren’s syndrome (SS) 
• 
Polymyositis/Dermatomyositis syndrome (PM/DM) 
• 
Raynaud’s syndrome 
• 
Antiphospholipid antibody syndrome (APS) 
• 
Idiopathic thrombocytopenic purpura (ITP) 
• 
Crohn’s disease 
• 
Ulcerative colitis 
 
8.3.9 
REPORTING OF PREGNANCY  
 
We do not anticipate women participants becoming pregnant as we exclude women of child bearing 
potential from study participation. However, we will do the following should a pregnancy occur on 
study.  
 
If the participant becomes pregnant during the study, all study treatment must be discontinued 
immediately. Although not considered an adverse experience, it is the responsibility of investigators or 
their designees to report any pregnancy in a participant or participant’s partner (spontaneously 
reported to them) that occurs during the study or within 6 weeks of completing the study. All 
participants or their partners who become pregnant must be followed to the completion/termination of 
the pregnancy. If the pregnancy continues to term, the outcome (health of infant) must also be reported 
the UNC IRB, the DAIDS Medical Officer, and the FDA (US Food and Drug Administration). 
 
If a male participant impregnates his partner while he is participating in this study, the pregnancy must 
be reported and the study PI (or designee) should make a concerted effort to follow the pregnancy and 
outcome. The study PI (or designee) will make every effort to obtain a medical release and a separate 
pregnancy outcome consent from the pregnant partner granting permission to follow the health of both 
the pregnant partner and her unborn child to the UNC IRB, DAIDS, VRC, Merck and FDA without delay 
and within 24 hours if the outcome is an SAE (e.g. death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn). 
 
Pregnancy and pregnancy outcome will be recorded. Pregnancies that occur on study should be 
reported prospectively to The Antiretroviral Pregnancy Registry. More information is available at 
www.apregistry.com. Telephone: 800-258-4263; Fax: 800-800-1052.  
 
Pregnancy Outcomes and Reporting 
If a woman has completed the study or chooses to discontinue from the study before the end of the 
pregnancy, then site study staff should request permission via a separate pregnancy outcome consent to 
contact her regarding pregnancy outcomes at the end of pregnancy. If the information is obtained, 
pregnancy outcomes will be submitted at the end of the pregnancy. 


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Pregnant women will discontinue study treatment and will be encouraged to continue on study and 
complete the evaluations included in the post-treatment evaluation section. At the end of the 
pregnancy, outcome and adverse events for participant and infant will be recorded. If pregnancy is 
suspected in a woman on study after study treatment, then a pregnancy test should be obtained. If 
pregnancy is confirmed, then further study treatment will be discontinued and the woman should 
continue on study (off study medication) safety follow-up visits as noted in the SOE. Stored 
plasma/PBMC for stored plasma for virologic studies should not be obtained to minimize blood volume. 
The site study staff should request permission via a separate pregnancy outcome consent to contact her 
regarding pregnancy outcomes at the end of pregnancy. A visit 6 months following the end of pregnancy 
will be conducted to assess for evidence of adverse events (AEs) in the participant and infant and 
documented. 
 
8.4 
NEW SAFETY INFORMATION 
 
8.4.1 
DEFINITION OF NEW SAFETY INFORMATION (NSI) 
 
The Office for Human Research Protections (OHRP) considers new safety information involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures/study 
treatment that are described in the protocol-related documents, such as the Institutional 
Review Board (IRB)-approved research protocol, the informed consent document and 
Investigator’s Brochure (IB); and (b) the characteristics of the participant population being 
studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures/treatment involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2 
 NEW SAFETY INFORMATION REPORTING 
 
The investigator will report NSI to the UNC IRB. The NSI report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents the NSI;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the NSI. 
 
To satisfy the requirement for prompt reporting, NSIs will be reported using the following timeline:   
 


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• 
NSIs that are serious adverse events (SAEs) will be reported to the IRB and the DAIDS MO within 
3 business days of the investigator becoming aware of the event.  
• 
Any other NSIs will be reported to the IRB and to the DAIDS MO within 7 business days of the 
investigator becoming aware of the event.  
• 
All NSIs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the NIH MO (or designee), and the Office for Human Research 
Protections (OHRP) within 30 business days of the IRB’s review and determination that the 
report of the problem from the investigator imposed a safety risk. 
 
8.4.3 
REPORTING NEW SAFETY INFORMATION TO PARTICIPANTS  
 
We would inform all study participants by letter or electronic messaging of any NSI if it is determined by 
the UNC IRB to merit such notice.  
 
9 
STATISTICAL CONSIDERATIONS  
 
This is a phase I, single-site study to evaluate the safety of VRC07-523LS combined with VOR in HIV-
infected individuals suppressed on ART.  There are secondary analyses to measure the effect of this 
therapy on persistent HIV-1 infection. All eligible participants will receive the same treatment which 
includes two (2) VRC07-523LS infusions and twenty (20) doses of VOR 400 mg. Participants will 
continue their baseline ART regimen throughout the study.  
 
 
9.1 
STATISTICAL HYPOTHESES 
 
Hypothesis 
Combination therapy with VRC07-523LS administered by IV infusion in combination with multiple doses 
of VOR 400mg orally will be safe and well tolerated. 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
We will enroll up to 12 fully evaluable participants (who receive two cycles of VRC07-523LS and VOR) 
to examine the effect of adding VOR and VRC07-523LS to ART on persistent replication-competent 
HIV within resting CD4+ T cells. 
 
Any participant who does not complete both series of VRC07-523LS and VOR and the leukapheresis in 
Step 4 for reasons other than a grade 3 or higher AE will be replaced, to ensure up to 12 evaluable 
participants for safety. 
 
Since the trial will be stopped if two participants experience a study treatment-related toxicity of Grade 
3 or higher, the criterion for safety is grade 3 or higher toxicity in no more than 1 of 12 participants in 
the study. 
 
For n=12 participants, if there are no primary AEs, then the exact 95% 1-sided upper confidence limit 
(UCL) for the true AE rate will be 0.22. Thus, if no AEs are observed, one can confidently rule out event 
rates greater than 22%.  


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All other analyses are therefore equally exploratory. 
 
Because a focus of the study is on safety and potential AEs, accrual will be staggered such that 
enrollment and treatment administration will include a maximum of 1 participant per week. 
 
9.3 
POPULATIONS FOR ANALYSES 
 
All participants who receive at least one dose of study therapy will contribute to the safety analysis of 
this study. 
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 
GENERAL APPROACH 
 
We plan a phase I, single-center study in participants with HIV-1 infection who are receiving ART. 
Baseline ART will be maintained throughout the study. HIV-1 infected participants with plasma HIV RNA 
stably below the limit of quantitation will be screened. After meeting all eligibility criteria and 
enrollment, all participants will undergo an initial evaluation of resting CD4+T cells obtained via 
leukapheresis. A baseline measurement of the frequency of HIV-1 infection per million units (IUPM) in 
resting CD4+ cells will be performed by QVOA.  
 
In Step 2, all participants will receive one (1) IV infusion of VRC07-523LS 40mg/kg, followed by ten (10) 
doses of VOR 400 mg PO every 72 hours. This exact cycle of a single VRC07-523LS 40mg/kg infusion 
followed by ten (10) doses of VOR 400 mg PO every 72 hours is repeated in Step 3.  Therefore all 
participants will receive a total of 2 IV infusions of VRC07-523LS and 20 doses of VOR 400mg PO over a 3 
month period.  Participants completing this protocol will receive no more than a total of 8,000 mg of 
VOR. For reference, participants who completed a prior multi-dose study (58) received a total of 10,000 
mg of VOR without clear evidence of any durable drug-associated toxicity, and no AEs greater than 
Grade 1.  
 
Following Step 3, a leukapheresis will be performed approximately 1- 4 weeks after the last dose of VOR 
to measure the frequency of HIV-1 infection (IUPM) by QVOA. 
 
Each participant will be followed for approximately 26 weeks once Step 2 begins. 
 
Formal interim analyses will be performed at 6 month intervals during the conduct of this study, and will 
be reviewed by an independent Safety Monitoring Committee (SMC). If an interim analysis has not yet 
been performed, the Committee will perform a preliminary review of accumulated safety data after 4 
participants have completed the first series of combined treatment with VRC07-523LS and 10 doses of 
VOR. This review will be based on assessment of participant safety, and will serve as a basis for allowing 
enrollment to continue. The Committee also will oversee all subsequent analyses.  
 
 
 
 


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9.4.2 
ANALYSIS OF THE PRIMARY SAFETY ENDPOINT 
 
Safety:  
For the primary safety analysis, AEs attributed to study treatment will be described through the end of 
study visit approximately 20 weeks after getting their first infusion at Day 0. All participants who have 
been exposed to at least one dose of study treatment will be included in this analysis.  
 
Since the trial will be paused for SMC review if two participants experience a study treatment-related 
toxicity of Grade 3 or higher, the criterion for safety of this study is grade 3 or 4 toxicity in no more than 
1 of 12 participants. 
 
 
9.4.3 
ANALYSIS OF THE OTHER ENDPOINT(S) 
 
Other Activity Endpoints: 
• 
Change in the frequency of HIV infection per million resting CD4+T cells (RCI) from baseline to 
after treatment with VRC07-523LS and VOR 
 
We will analyze pre-VOR/VRC07-523LS and post- VOR/VRC07-523LS frequency of HIV infection 
per million resting CD4+T cells using a non-parametric 2-sided sign test (supplemented by 
longitudinal regression modeling to estimate the magnitude of changes) to determine whether 
or not a significant decrease of IUPM is observed. With 12 participants, there will be 80% power 
to reject H0 (change expected with ART alone) in favor of HA (greater change than expected with 
ART) if the true probability of observing a decrease in IUPM in a participant after VOR/VRC07-
523LS is 0.93.   
 
This is based on a 2-sided alpha = 0.05 and the assumption that observed HIV infection 
frequency would decrease with probability 0.54 on ART alone after 6 months without 
intervention, based on the decay of IUPM seen on ART alone [Crooks 2015, Siliciano 2003]. 
 
In addition to summarizing the number and proportion of participants who show decrease in 
IUPM after VOR/VRC07-523LS, we will describe the magnitude of the changes in decrease in 
IUPM after VOR/VRC07-523LS via the median fold-change and corresponding 95% confidence 
interval. We will also summarize the proportion of participants with >6-fold decreases; this 
magnitude change is rarely seen in participants on stable ART [9].  
 
 
Other Endpoints: Activity 
• 
HIV-1 RNA by low level viremia assay measurement at baseline and after treatment with 
VRC07-523LS and VOR 
 
The virologic analysis will include estimation of the low level viremia levels at pre-treatment 
(screening and entry) and separately at post-treatment. We assume that the probability would 
be 0.10 (10%) for a baseline (pre-entry, entry) detectable low level viremia ≥ 1 copy. The 
assumption that 10% of participants with a quantifiable low level viremia at screening will have 
low level viremia assay below the limit of detection at a pre-treatment measure is an estimate 
based on data from A5244 in which 6 of 50 (12%) enrolled participants had undetectable low 


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level of viremia at pre-entry and 5 of 51 (10%) at entry after having a screening low level of 
viremia ≥ 1 copy (59).   
 
Other Exploratory Analyses: 
• 
Following VOR/VRC07-523LS we will also explore whether there is a depletion of rc-RNA using 
the same statistical tests in the reverse (compare baseline rc-RNA to after two cycles of 
VOR/VRC07-523LS). 
 
• 
To assess these within each individual participant (n of 1 analyses), we will use the non-
parametric 2-sided Wilcoxon rank sum test to determine whether or not a statistically significant 
change in rc-RNA expression is observed, comparing rc-RNA levels measured in each of 24-36 
replicate pools of 1 million resting CD4+ cells.  Pools with undetectable RNA will be considered as 
0 copies and analyzed as the lowest rank in this rank-based statistical test.  
 
The pre-VOR rc-RNA expression will be determined as the median RNA copies over the 
individual pools of one million participant cells tested prior to VOR (setting undetectable RNA 
pools as 0 copies), and the post-VOR RNA expression level will be similarly determined. Changes 
in RNA expression will be evaluated by the exact sign test and the proportion of participants 
with increases versus decreases. Summaries of the magnitude of changes will be examined in 
terms of median fold-changes.  
 
• 
We will also explore changes in the chromosomally integrated viral reservoir as measured by Q-
PCR from baseline to post VOR/VRC07-523LS. 
 
• 
We will also explore the change in frequency of viral envelope sequences detected in plasma or 
cells that are not recognized by VRC07-523LS from baseline to post VOR/VRC07-523LS. 
 
• 
A 0.05 significance level will be used throughout, with no adjustment for multiple testing given 
the proof of concept nature of this study. Emphasis will be put on estimation with 
corresponding 95% confidence intervals to evaluate the scientific and biologic effect size. 
Individual-level data will be visualized in plots. Given the small sample size, exploratory analyses 
will have limited or no statistical power and findings should be interpreted with caution and 
assessed in a subsequent, larger study if the combined treatment is found to be safe and 
potentially efficacious. If the study is stopped at n=12 participants, statistical analyses will be 
limited to descriptive summaries and n of 1 analyses within each participant.  
 
9.4.4 
SAFETY ANALYSES 
 
For the safety endpoint, we will describe all study treatment-related AEs through the end of study 
approximately 20 weeks after getting their first infusion at Day 0. AEs will be coded to the Medical 
Dictionary for Regulatory Activities (MedDRA). Events prior to treatment (e.g., due to study-related 
procedure) will be listed separately in an appendix to the final clinical study report. The following tables 
of AE data will be created to summarize the number and percent of participants who experience at least 
one event of each of the following types: 
• 
All AEs 
• 
Drug-related AEs by severity grade 
• 
AEs by severity grade 


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• 
All SAEs (this may be a listing if there are few events) 
• 
Drug-related SAEs 
• 
Fatal AEs (this may be a listing if there are few events) 
• 
AEs that result in study discontinuation 
• 
AEs that lead to withdrawal of study drug 
• 
AEs categorized as AESI and/or IREs 
• 
AEs with severity grade 3 or greater 
• 
Drug-related AEs with severity grade 3 or greater 
 
All of these tables will display the number and percent of participants that experience the given event 
and will display events by System Organ Class (SOC) and Preferred Term (PT). Events will be displayed 
alphabetically for SOC and in descending order of overall PT incidence within each SOC. 
 
9.4.5 
TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Individual participant data will be listed by measure and time point. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PARTICIPANTS 
 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.   
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. The consent forms are UNC IRB -
approved and the participant will be asked to read and review the document. The study investigator (or 
designee) and/or study coordinator will explain the research study to the participant and answer any 
questions that may arise. A verbal explanation will be provided in terms suited to the participant’s 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
research participants. Participants will have the opportunity to carefully review the written consent 
form and ask questions prior to signing. The participants are provided the opportunity to discuss the 
study with their family, primary care provider, or significant other or to just think about the study and its 
requirements prior to agreeing to participate. The participant signs the informed consent document 
prior to any procedures being done specifically for the study. Participants are informed that 
participation is voluntary and that they may withdraw from the study at any time, without prejudice. A 
copy of the informed consent document will be given to the participants.  
 


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The informed consent process will be conducted and documented in the source document, and the 
consent form signed, before the participant undergoes any study-specific procedures. The study PI (or 
designee) or the research coordinator will inform participants that the quality of their medical care will 
not be adversely affected if they decline to participate in this study, thus emphasizing the protection of 
the rights and welfare of the participants.   
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided to the study participants, funding agency (NIH), the FDA (IND), the VRC (VRC07-523LS), Merck 
(Vorinostat) and UNC IRB.  If the study is prematurely terminated or suspended, the study PI (or 
designee) will promptly inform study participants, the UNC IRB, and DAIDS and will provide the reason(s) 
for the termination or suspension.  Study participants will be contacted, as applicable, and be informed 
of changes to the study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy DAIDS, UNC IRB, and/or FDA. 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the UNC IRB, 
regulatory agencies or pharmaceutical company supplying study product may inspect all documents and 
records required to be maintained by the study PI, including but not limited to, medical records and 
pharmacy records for the participants in this study. The clinical study site will permit access to such 
records. 
 
The study participants’ contact information will be securely stored at the clinical study site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location for 
as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 


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Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be stored at the UNC HIV Cure Center. This will not include the participants’ contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique study 
identification number. The study data entry and study management systems used by the clinical staff of 
the UNC HIV Cure Center and by research staff will be secured and password protected. At the end of 
the study, all study databases will be de-identified and archived.  
 
Certificate of Confidentiality  
 
To further protect the privacy of study participants, a Certificate of Confidentiality will be issued by the 
National Institutes of Health (NIH). This certificate protects identifiable research information from 
forced disclosure. It allows the investigator and others who have access to research records to refuse to 
disclose identifying information on research participation in any civil, criminal, administrative, legislative, 
or other proceeding, whether at the federal, state, or local level. By protecting researchers and 
institutions from being compelled to disclose information that would identify research participants, 
Certificates of Confidentiality help achieve the research objectives and promote participation in studies 
by helping assure confidentiality and privacy to participants. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored at the UNC HIV Cure Center. After the study is 
completed, the de-identified, archived data will be stored in the UNC Cure Center Database, for use by 
the UNC HIV Cure Center researchers. Permission to transmit data to researchers outside the UNC HIV 
Cure Center Collaboratory will require review and approval by the UNC IRB. In some circumstances, we 
will need to obtain additional consent from participants to share samples collected for the purpose of 
this study.   
 
With the participant’s approval and as approved by the UNC IRB, de-identified biological samples will be 
stored at the UNC HIV Cure Center and/or the UNC Chapel Hill HIV/STD Laboratory Core. These samples 
could be used to research the causes of HIV cure for which individuals with HIV infection can greatly 
benefit.  The UNC HIV Cure Research Laboratories will also be provided with a code-link that will allow 
linking the biological specimens with the phenotypic data from each participant, maintaining the 
blinding of the identity of the participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage may not be possible after the study is completed.  
 
When the study is completed, access to study data and/or samples will be provided through the UNC 
HIV Cure Center Laboratory.  
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Protocol Principal Investigator 
 Grant Principal Investigator 
Cynthia Gay, MD, MPH 
David Margolis, MD 


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Associate Professor, Medical Director HIV 
Cure Center 
Professor of Medicine, Microbiology & 
Immunology, and Epidemiology 
University of North Carolina at Chapel Hill  
University of North Carolina at Chapel Hill  
130 Mason Farm Road, Suite 2112 
Bioinformatics Building, Campus Box 7030  
120 Mason Farm Road, 2060 Genetic Medicine 
Building, Campus Box 7042 
Chapel Hill, NC 27599-7030 
Chapel Hill, NC 27599-7042 
919-843-2726 
919-966-6388 
cynthia_gay@med.unc.edu 
dmargo@med.unc.edu  
 
10.1.6 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of a Safety Monitoring Committee (SMC) composed of 
individuals with the appropriate expertise, including a Biostatistician and an HIV Therapy clinician. 
Members of the SMC are independent from the study conduct and free of conflict of interest.   
 
The SMC advises the study PI and protocol team for this Phase I study. The primary responsibility of the 
SMC is to monitor human subject safety. The SMC considers study-specific data as well as relevant 
background information about the disease, test agents, and target population under study. 
 
During the trial the SMC will review:   
• 
Real-time and cumulative safety data for evidence of study-related adverse events;   
• 
Adherence to the protocol;  
• 
Factors that might affect the study outcome or compromise the trial data (such as protocol 
violations, losses to follow-up, etc.). 
• 
Review the achievement of enrollment benchmarks  
 
The SMC will receive monthly reports via email for review and comments. The SMC will be contacted 
directly via email (and possibly via teleconferencing) for any event or situation that impacts participant 
safety throughout the study and specified interventions or study participation will be suspended or 
terminated dependent on the response of the SMC. 
Safety Pause 
Administration of the study products and new enrollments will be paused by the PI according to the 
criteria noted below if any of the following occur: 
 
a) Two or more participants experience a primary safety outcome measure that is a Grade ≥3 
AE possibly related to study treatment (other than self-limited Grade 3 solicited 
reactogenicity AEs); or  
 
b) One (or more) participant experiences a Serious Adverse Event (SAE) that is assessed as 
related to study product. 
 
In the event of a pause, the Study Monitoring Committee (SMC) will be asked to review all safety data.  
Review will include the relation to study treatment of the event(s) thought by the core team to be a 
primary safety outcome. In the event of a pause, the FDA (IND) and the DAIDS Medical Officer (MO) will 
be promptly notified.  
 


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Criteria for Resuming the Study  
Study product administration and enrollments would resume only if review of the AEs that caused the 
pause results in a recommendation to permit further study product administrations and study 
enrollments. The reviews to make this decision will occur as follows: 
• 
Pauses for treatment-related SAEs: The DAIDS MO and the PI will consult with the FDA to 
conduct the review and make the decision to resume, amend, or close the study and will notify 
the IRB accordingly. 
• 
Pauses for Grade 3 or higher treatment-related AEs: The DAIDS MO, with the PI and the Safety 
Monitoring Committee (SMC), will conduct the review and make the decision to resume, amend, 
or close the study for the Grade 3 or higher AEs that meet criteria for pausing the study. As part 
of the pause review, the reviewers will also advise on whether the study needs to be paused 
again for any subsequent events of the same type. The FDA and the IRB will be notified of Grade 
3 or higher pause reviews and of the study protocol team decision. 
 
 
10.1.7 CLINICAL MONITORING 
 
To ensure the safety of participants in the study, compliance with applicable regulations, and to ensure 
accurate, complete, and reliable data, the study PI will keep records of laboratory tests, clinical notes, 
and participant medical records in the participant files as source documents for the study. 
 
An independent study monitor will monitor the study on a regular basis throughout the study period 
according to the study monitoring plan. The study PI (or designee) will allocate adequate time for such 
monitoring activities. The study monitor periodically will conduct a review of a sample of the participant 
data recorded on source documents at the study site. The study PI (or designee) will also ensure that the 
monitor is given access to all the above noted study-related documents, source documents (regardless 
of media), and study-related facilities (e.g., IDS pharmacy, etc.), and has adequate space to conduct the 
monitoring visit. Queries may be raised if any datum is unclear or contradictory. The study PI and site 
study personnel must address all queries in a timely manner. 
 
Participation as an Investigator in this study implies acceptance of the potential for inspection by the 
study Sponsor/Funder and its Representatives, US or non-US government regulatory authorities, IRB, 
and applicable compliance and quality assurance offices. The study PI (or designee) will permit study-
related audits and inspections and will provide access to all study-related documents (e.g., source 
documents, regulatory documents, data collection instruments, study data, etc.). The study PI will 
ensure the capability for inspections of applicable study-related facilities (e.g., IDS pharmacy, CTRC, 
etc.). 
 
Minimizing risk to participants 
 
Procedures to minimize risk to participants in the conduct of this study include: 1) informing participants 
about risks so they can recognize and report harms in partnership with the study team; 2) respecting 
local/national blood draw limits; 3) direct observation of participants after study treatment 
administration with VRC07-523LS and collection of information regarding side effects for several days 
post product administration; 4) having study staff properly trained in administering study procedures 
that may cause physical harm or psychologic distress, such as blood draws and infusions; and 5) 
providing study monitoring. 


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10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
UNC will perform internal quality management of study conduct, data and biological specimen 
collection, documentation, and completion.  A quality management plan was developed to describe the 
quality management program. 
 
UNC follows Standard Operating Procedures (SOPs) for quality management. Clinical research files verify 
and insure that the clinical trial is conducted per protocol and that data is generated and biological 
specimens collected, documented (recorded), and reported in compliance with the protocol, 
International Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory 
requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). Data 
Quality is monitored per the data quality management plan with routine and specific research chart 
review. 
 
The study staff will be educated on the protocol and training will be provided as needed to implement 
protocol procedures. The study data management team will be responsible for addressing QA issues 
(e.g., correcting procedures that are not in compliance with the protocol) and QC issues (e.g., correcting 
errors in data entry). Documentation, as required, will be maintained in the regulatory files. 
 
UNC will provide direct access to all trial-related sites, source data/documents, and reports for the 
purpose of monitoring and auditing by the funding sponsor, and inspection by local and regulatory 
authorities. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
The clinical research staff is responsible for data collection under the supervision of the site principal 
investigator (or designee). The study PI (or designee) is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   
 
Hard copies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report 
form derived from source documents should be consistent with the data recorded on the source 
documents.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into a UNC School of Medicine Database, a 21 CFR Part 
11-compliant data capture system. The data system includes password protection and external quality 
checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered 
directly from the source documents. 
 
 


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10.1.9.2 STUDY RECORDS RETENTION  
 
Per ICH guidelines, all essential documents, including source documents (regardless of media), signed 
ICFs, and laboratory test results, should be retained by the study PI (or designee) for at least 2 years 
after last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed since formal 
discontinuation of clinical development of the investigational products.  
 
10.1.10 PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigators, or the study site staff. As 
a result of deviations, corrective actions will be developed and implemented promptly, when necessary.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, 4.5.3, and 4.5.4  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1 and 5.20.2.  
 
It is the responsibility of the site PI (or designee) to use continuous vigilance to identify and report 
deviations at the annual renewal of the protocol, provided there is not impact on participant safety as a 
result of the deviation. All deviations must be addressed in study source documents. Protocol deviations 
are sent to the UNC IRB per their policies. The site PI is responsible for knowing and adhering to 
reviewing the IRB requirements. Further details about the handling of protocol deviations will be 
included in the MOP.  
 
10.1.11 PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
• 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access 
to the published results of NIH-funded research. It requires scientists to submit final peer-
reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central 
upon acceptance for publication. 
• 
NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information 
and the Clinical Trials Registration and Results Information Submission rule. As such, this trial 
will be registered at ClinicalTrials.gov, and results information from this trial will be submitted to 
ClinicalTrials.gov, if required.  
• 
NIH Genomic Data Sharing Policy, which applies to all NIH-funded research that generates large-
scale human or non-human genomic data, as well as the use of these data for subsequent 
research. Large-scale data include genome-wide association studies (GWAS), single nucleotide 
polymorphisms (SNP) arrays, and genome sequence, transcriptomic, epigenomic, and gene 
expression data. 
 
 
 


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10.1.12 CONFLICT OF INTEREST POLICY 
 
The University of North Carolina at Chapel Hill recognizes that conflicts of interest will arise from the 
research enterprise, from technology transfer activities, and from the many facets of our investigators’ 
professional activities. UNC seeks to identify and manage these conflicting relationships, restricting 
activities where necessary, to preserve transparency, independent decision-making, protection of 
research participants, and integrity of the educational experience. UNC’s Conflict of Interest Program 
will have oversight over this study.  
 
10.2 ABBREVIATIONS 
 
ACTG 
AIDS Clinical Trials Group 
ADA 
Anti-Drug Antibody 
ADCC 
Antibody-Dependent Cell-Mediated Cytotoxicity  
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
AIA  
Anti-Idiotypic Antibody 
ALT 
Alanine Aminotransferase 
ANC  
Absolute Neutrophil Count 
ANCOVA 
Analysis of Covariance 
ART 
Antiretroviral Therapy or combination ART 
AST 
Aspartate Aminotransferase 
ATI  
Analytical Treatment Interruption  
BMI 
Body Mass Index 
Boosted-PI 
Boosted Protease Inhibitor  
BP 
Blood Pressure 
bNAbs 
Broadly Neutralizing Antibodies 
ca-RNA 
CD4 T Cell-Associated HIV RNA 
CFAR 
Center for AIDS Research  
CFR 
Code of Federal Regulations 
CKD-EPI 
Chronic Kidney Disease - Epidemiology Collaboration Equation  
CI  
Confidence Interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CRS 
Clinical Research Sites  
DAIDS 
Division of AIDS 
DHHS 
Department of Health and Human Services 
DLT 
Dose Limiting Toxicity 
DOB 
Date of Birth 
DRE 
Disease-Related Event 
E/CIA 
Enzyme Chemiluminescence Immunoassay 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
eGFR 
estimated Glomerular Filtration Rate 
EOS 
End of Study  
Fc-Rn 
Fc-Receptor 


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FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
FSH 
Follicle Stimulating Hormone  
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HBsAg 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HDAC 
Histone Deactylase 
HIPAA 
Health Insurance Portability and Accountability Act  
HIV 
Human Immunodeficiency Virus 
HPTN 
HIV Prevention Trials Network  
HSP 
Human Subjects Protection  
HVTN 
HIV Vaccine Trials Network  
IB 
Investigator’s Brochure 
IC (F)  
Informed Consent (Form) 
ICH 
International Conference on Harmonisation  
ID 
Infectious Diseases  
IDS 
Investigational Drug Services 
IFN 
Interferon 
IGHID 
International Global Health and Infectious Diseases  
IL-2 
Interleukin 2 
IND 
Investigational New Drug Application 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRE 
Immediate Reportable Events 
ISO 
International Organization for Standardization 
IUD 
Intrauterine Device 
IUPM 
Infectious Units per Million 
IV 
Intravenous 
K+ 
Potassium 
kg/m2 
Kilogram per square meter 
LDL 
Low Density Lipoprotein 
LRA 
Latency Reversal Agent  
LTFU 
Lost To Follow Up 
mAbs 
Monoclonal Antibodies  
MedDRA 
Medical Dictionary for Regulatory Activities 
meq 
milliequivalents 
Mg++ 
Magnesium 
mm Hg 
Millimeter of mercury 
mg/kg 
Milligram per kilogram 
MOP 
Manual of Procedures 
MRN 
Medical Record Number 
NCT 
National Clinical Trial 
NIAID 
National Institutes of Allergy & Infectious Diseases 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 


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nm 
Nanometer 
NNRTI 
Non-Nucleoside Reverse Transcriptase Inhibitor 
NSI  
New Safety Information 
OHRP 
Office for Human Research Protections 
PHI Studies  
Primary HIV Infections Studies  
P 
Pulse or heart rate 
PI 
Principal Investigator 
PID 
Participant Identifier Code 
PK 
Pharmacokinetic 
PO  
By mouth  
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
“q” or Q 
every 
Q-PCR 
Quantitative–Polymerase Chain Reaction  
QA 
Quality Assurance 
QC 
Quality Control 
QVOA 
Quantitative Viral Outgrowth Assay 
RNA 
Ribonucleic Acid 
RPR 
Rapid Plasma Reagin 
RR 
Respiratory Rate 
RSC 
Regulatory Support Center  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SCA 
Single Copy Assay 
SID 
Study Specific Identifier Code 
SMC 
Safety Monitoring Committee 
SOE 
Schedule of Events 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
T 
Temperature 
TAF 
Tenofovir Alafenamide 
TCR 
Tissue Cross Reactivity  
TDF 
Tenofovir Disoproxil Fumarate 
TEAE 
Treatment Emergent Adverse Event  
ULN 
Upper Limit of Normal  
UNC 
University of North Carolina at Chapel Hill  
US 
United States 
VOR 
Vorinostat 
VRC 
Vaccine Research Center 
VRC07-523LS 
VRC-HIVMAB075-00-AB 
 
10.3 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
Version 1.0 
13 February 2018 
Initial Protocol  
CSRC Review  
Version 2.0  
4 May 2018 
Amendments following the CSRC, FDA 
and UNC IRB reviews 
UNC IRB approved on 
5/29/18   


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Version 3.0  
08 November 2018  
Increase in # participants to be 
enrolled (n=12); modification to 
Inclusion/Exclusion Criteria   
Change in NIH funding; 
clarification of 
eligibility requirements 
Version 4.0 
09 May 2019 
Removed ex vivo and in vivo cell 
associated RNA response to Vorinostat  
Advance of assay 
methodology to 
measure resting cell 
infection 
 
 
 
 
 
 
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