Conditions: HIV-1 Infection
Keywords: HIV HXTC Antiretroviral Therapy HIV-Infected Vorinostat AIDS
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 17
Healthy volunteers: no

Brief summary:
This is a phase I, single-site, study to evaluate the effects of VOR and HIV-1 Antigen Expanded Specific T Cell Therapy (HXTC) on persistent HIV-1 Infection in HIV-infected individuals suppressed on ART. Twelve participants with durable viral suppression will be enrolled and will complete the study. All participants will receive the same treatment and if eligible, will be dosed with HXTC and VOR. Participants will continue their baseline ART regimen throughout the study.

Detailed description:
Purpose: This study will test the use of special immune system cells called expanded HIV-specific T Cell (HXTC) Therapy to stimulate the immune system to respond better to HIV. HXTC Therapy will be given in combination with the drug Vorinostat (VOR) which has been shown to stimulate some cells infected with HIV to become active and start making HIV virus. The purpose of this study is to:

1. Evaluate the safety of a series of HXTC infusions in combination with serial doses of VOR and
2. Help scientists evaluate ways of re-activating latent (non-active) HIV virus and determine if the immune system can be made stronger to eliminate the activated HIV virus.

Participants: Men and women living with HIV, ≥ 18 and \< 65 years of age, with durable viral suppression for ≥ 24 months as measured on standard HIV RNA assays. Eligible participants must be on stable combination ART (cART) and have a CD4 count ≥ 350 cells/mm3. We plan to enroll up to 12 participants at the University of North Carolina at Chapel Hill (UNC) who complete all 6 Steps of this study.

Procedures (methods):

In Step 1 and prior to initiating the two series of VOR and HXTC combined therapies, all participants will undergo study screening and enrollment where they will be required to: 1. Demonstrate a baseline measurement of the frequency of resting CD4 T cell infection ≥ 0.3 infected cells per million as determined by QVOA, as a further decrease from this low frequency of infection cannot be definitively measured given the quantitative viral outgrowth assay (QVOA) threshold.

Participants with an infectious cells per million (IUPM) measurement \> or equal to 0.3 will provide whole blood cells for the manufacture of their HXTC product (Step 3). Successful manufacturing of the HIV-1 antigen expanded specific T cells will progress participants to combination treatment in Steps 4 and 5. In Steps 4 and Step 5, participants will receive two series of VOR dosing and HXTC infusions, for a total 20 doses of VOR 400 mg and 5 HXTC infusions.

In the first series (Step 4), participants will receive VOR 400 mg PO every 72 hours for 10 doses and 2 infusions of HXTC. The first HXTC infusion will be administered six hours after the first dose of VOR (HXTC #1) and the 2nd HXTC infusion (HXTC #2) will occur 6 hours after the 6th dose of VOR.

In the second series in Step 5, participants will receive an additional 10 doses of VOR 400 mg PO every 72 hours and 3 HXTC infusions. The first HXTC infusion in Step 5 (HXTC #3) will occur 6 hours after the 11th dose of VOR (1st dose in Step 5), the 2nd HXTC infusion (HXTC #4) will occur 6 hours after the 16th dose of VOR, and the 3rd HXTC infusion (HXTC #5) will occur 1 - 3 days after the 20th dose of VOR.

If there are insufficient cells manufactured to allow 5 infusions at 1 x 10-8 cells/m-2 dose, the dose will be adjusted to allow 5 infusions at a dose \> or equal to 5 x 10-7 cells/m-2 but \< 1 x 10-8 cells/m-2 dose.

Following the final HXTC infusion, participants move into Step 6 for a minimum of six additional visits: 21-26. The 2nd leukapheresis will occur at Visit 23 (Week 21), approximately 9 weeks after the last HXTC infusion to evaluate the effect of study treatment on the IUPM by QVOA.

All participants who receive greater than 8 doses of VOR (3200 mg) will be required to enter a study cancer registry where they will be contacted once a year for 5 years after completion of their study participation. The registry was created to monitor participants for the development of future malignancies given concern for genotoxic impact with the use of VOR.

Arms:
arm 1: This is an open label single arm study. All eligible participants receive the following interventions:

* Step 2 - Single dose of Vorinostat (VOR) 400 mg PO
* Step 4 - Vorinostat (VOR) 400 mg PO every 72 hrs x 10 doses and 2 HXTC infusions
* Step 5 - Vorinostat (VOR) 400 mg PO every 72 hrs x 10 doses and 2 HXTC infusions

Interventions: intervention 1: Vorinostat intervention 2: HXTC
Intervention descriptions: intervention 1: Participants meeting criteria for Step 1 (exhibit ex-vivo response to VOR) will progress to Step 2 where they will receive a single dose of VOR 400 mg followed by a leukapheresis. If an increase in cell-associated HIV RNA (ca-RNA) is observed in-vivo following the single VOR dose, they will be eligible to donate cells for the manufacture of HXTC (Step 3). Successful manufacturing of the HIV-1 antigen expanded specific T cells will progress participants to combination treatment in Steps 4 and 5. In Steps 4 and Step 5, participants will receive two series of VOR dosing and HXTC infusions, for a total 20 doses of VOR 400 mg and 5 HXTC infusions. intervention 2: Participants meeting criteria for Step 1 (exhibit ex-vivo response to VOR) will progress to Step 2 where they will receive a single dose of VOR 400 mg followed by a leukapheresis. If an increase in cell-associated HIV RNA (ca-RNA) is observed in-vivo following the single VOR dose, they will be eligible to donate cells for the manufacture of HXTC (Step 3). Successful manufacturing of the HIV-1 antigen expanded specific T cells will progress participants to combination treatment in Steps 4 and 5. In Steps 4 and Step 5, participants will receive two series of VOR dosing and HXTC infusions, for a total 20 doses of VOR 400 mg and 5 HXTC infusions.

Protocol document:
Prot_SAP_000.pdf: 
A Phase I Study to Evaluate the Effects of Vorinostat and HIV-1 
Antigen Expanded Specific T Cell Therapy (HXTC) on Persistent HIV-1 
Infection in HIV-Infected Individuals Started on Antiretroviral Therapy
NCT number NCT03212989 
Document Date 01/31/2022 


 
 
 
Protocol v4.0_31-Jan-2022 
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 A Phase I Study to Evaluate the Effects of Vorinostat and 
HIV-1 Antigen Expanded Specific T Cell Therapy (HXTC) on Persistent HIV-1 Infection 
in HIV-Infected Individuals Started on Antiretroviral Therapy  
 
IGHID 11627 
Grant Number:  1R01HL132791-01 
Principal Investigator:  David M. Margolis, MD 
 
 
Co-Investigators: 
Cynthia Gay, MD, MPH 
Nancie Archin, PhD 
Joseph Eron, MD 
Nilu Goonetilleke, PhD 
Catherine Bollard. MD 
Patrick Hanley, PhD 
C. Russell Y. Cruz, MD, PhD 
Angela Kashuba, BScPhm, PharmD, DABCP 
Ron Swanstrom, PhD 
Susan Pedersen, BSN 
Michael Hudgens, PhD 
Katie Mollan, MS 
Jay Tanna, MS 
Supported by:  
Merck Sharp & Dohme Corp., a Subsidiary of Merck & Co., Inc. 
University of North Carolina at Chapel Hill 
IND # 15984 
National Heart, Lung, and Blood Institute 
Investigational Agents:  
Vorinostat and HIV-1 multi-antigen, expanded specific T-cell Therapy (HXTC Therapy)  
Version 4.0 dated 31-Jan-2022 
 
 
 
 


 
 
 
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TABLE OF CONTENTS 
PAGE 
TABLE OF CONTENTS .............................................................................................................. 2 
LIST OF ABBREVIATIONS ......................................................................................................... 4 
KEY ROLES AND CONTACT INFORMATION……………………………………………………….7 
 
 
1  
PROTOCOL SUMMARY………………………………………………………………………...11 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ....... 12 
2.1 
Background Information ........................................................................................ 12 
2.2 
Vorinostat (VOR) .................................................................................................. 16 
2.3 
HIV-Specific Ex Vivo Expanded T Cell Therapy (HXTC) ....................................... 21 
         2.4       Potential Benefits………………………………………………………………………..26 
3 
OBJECTIVES ................................................................................................................... 26 
3.1 
Study Objectives ................................................................................................... 26 
3.2 
Study Outcome Measures .................................................................................... 27 
3.2.1 Primary ...................................................................................................... 27 
3.2.2 Secondary ................................................................................................. 27 
4 
STUDY DESIGN .............................................................................................................. 27 
5 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................. 29 
5.1 
Participant Inclusion Criteria ................................................................................. 29 
5.2 
Participant Exclusion Criteria ................................................................................ 32 
5.3 
Strategies for Recruitment and Retention ............................................................. 34 
5.4 
Participant Withdrawal .......................................................................................... 35 
Handling of Participant Withdrawals or Participant Discontinuation of Study 
Intervention ............................................................................................... 35 
5.5 
Premature Termination or Suspension of Study .................................................... 36 
6 
STUDY INTERVENTION .................................................................................................. 37 
6.1 
HXTC .................................................................................................................... 37 
6.1.1 Collection of 100 mL of Blood .................................................................... 37 
6.1.2 Study Product Manufacturing .................................................................... 37 
6.2 
Vorinostat (VOR) .................................................................................................. 44 
6.3 
Concomitant Medications/Treatments ................................................................... 47 
            6.3.1 Required Medications  ................................................................................. 47 
            6.3.2 Permitted Medications ................................................................................. 47 
            6.3.3 Prohibited Medications ................................................................................. 48 
7 
STUDY SCHEDULE ......................................................................................................... 48 
7.1 STUDY PROCEDURES ................................................................................................... 48 
7.2 
Co-enrollment ....................................................................................................... 49 
7.3 
Schedule of Events ............................................................................................... 49 
7.4 
Screening Failure and Re-screening Procedures  ................................................. 63 
7.5 
Early Discontinuation Visit .................................................................................... 64 
8 
STUDY PROCEDURES/EVALUATIONS ......................................................................... 65 
8.1 
Decription of Evaluations ...................................................................................... 65 


 
 
 
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8.1.1 Clinical Evaluations and Procedures ......................................................... 65 
8.1.2 Clinical Laboratory Procdures  .................................................................. 65 
8.1.3 Research Laboratory Procedures  ............................................................. 70 
 
         8.1.4   Sample Storage …………………………………...…………………………….72 
9 
CLINICAL MANAGEMENT ISSUES ................................................................................. 74 
9.1 
Toxicity ................................................................................................................. 74 
9.1.1 Grade 1 or 2 Toxicity ................................................................................. 75 
9.1.2 Grade 3 Toxicity ........................................................................................ 75 
9.1.3 Grade 4 Toxicity ........................................................................................ 76 
                     9.1.4   HXTC Infusion- related Toxicities……………………………………...………76 
 
         9.1.5   Systemic Reactions……………………………………………………………..76 
9.2 
Toxicity Managment .............................................................................................. 77 
9.3 
Discontinuation of HXTC and/or VOR ................................................................... 81 
9.4 
Pregnancy ............................................................................................................ 81 
10 
STATISTICAL CONSIDERATIONS .................................................................................. 82 
10.1 
General Design ..................................................................................................... 82 
 
 
 
         10.1.1.  Study Hypothesis………………………………………………………………83 
10.2 
Outcome Measures .............................................................................................. 83 
10.3 
Sample Size Considerations ................................................................................. 84 
10.4 
Safety ................................................................................................................... 84 
         10.5    Monitoring…………………………………………………………………………………84 
         10.6    Efficacy……………………………………………………………………………………85 
         10.7    Analysis……………………………………………………………………………………85 
11 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................. 87 
11.1 
Ethical Standard ................................................................................................... 87 
11.2 
Institutional Review Board .................................................................................... 87 
11.3 
Informed Consent Process ................................................................................... 88 
11.4 
Amendments ........................................................................................................ 88 
11.5 
Participant Confidentiality ..................................................................................... 88 
11.6 
Study Discontinuation  .......................................................................................... 88 
12 
DATA COLLECTION, MONITORING, AND ADVERSE EVENT REPORTING ................. 89 
12.1 
Records to be kept ................................................................................................ 89 
12.2 
Role of the Data Manager ..................................................................................... 89 
12.3 
Clinical Site Monitoring and Record Availability..................................................... 89 
         12.4     Reporting Requirements for this Study………………………………………….........90 
         12.5     Expedited AE Reporting Period………………………………………………………..90 
13 
PUBLICATION/DATA SHARING POLICY ...................................................................... ..90 
14 
REFERENCES ............................................................................................................... ..90 
APPENDIX A: SCHEDULE OF EVENTS .................................................................................. 96 
 
 
 


 
 
 
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LIST OF ABBREVIATIONS 
2 LTR  
2-long terminal repeat  
AE 
Adverse Event/Adverse Experience 
AHI  
acute HIV infection  
ALK PHOS 
alkaline Phosphatase 
ALT 
alanine transaminase 
ANC  
absolute neutrophil count 
APC 
antigen-presenting cell 
ART  
antiretroviral therapy 
ATC 
autologous T cell APCs 
AST 
aspartate transaminase 
AUC  
area under the curve 
BID 
twice a day 
BMT 
bone marrow transplant 
ca-RNA 
cell associated RNA 
CB 
cord blood 
CCIR 
Center for Cancer and Immunology Research  
CETI 
Program for Cell Enhancement and Technologies for Immunotherapy 
CFR 
Code of Federal Regulations 
CHI 
chronic HIV-1 infection 
CRF 
case report form 
CMV 
Cytomegalovirus 
CNH 
Children’s National Hospital 
CTLs 
cytotoxic T cell lymphocytes 
CTRC 
Clinical and Translational Research Center 
DCs 
dendritic cells 
DHHS 
Department of Health and Human Services 
DSMP 
Data Safety and Monitoring Plan  
EBV 
Epstein-Barr virus 
EBNA1 
Epstein-Barr virus nuclear antigen 1 
EBV-LCL 
Epstein-Barr virus-transformed lymphoblastoid cell lines 
FDA 
Food and Drug Administration 
GM-CSF 
granulocyte macrophage colony-stimulating factor 
GLP 
Good Laboratory Practice  
GMP 
Good Manufacturing Practice 


 
 
 
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GVHD 
graft versus host disease 
HBV 
hepatitis B virus 
HBsAg 
hepatitis B virus surface antigen 
HCV 
hepatitis C virus 
HDAC 
histone deacetylase 
HL 
hodgkins lymphoma 
HLA 
human leukocyte antigen 
HPC  
hematopoietic progenitor cell 
HPLC 
high-performance liquid chromatography 
HXTC 
HIV-1 antigen expanded specific T-cell 
ICH 
International Conference on Harmonisation 
IDE 
Investigational Device Exemption 
IFN-γ 
interferon- gamma 
IND 
Investigational New Drug Application 
IL-1β 
interleukin 1, beta 
IL-2 
interleukin-2 
IL-4 
interleukin-4 
IL-6 
interleukin-6 
IL-7 
interleukin-7 
IL-12 
interleukin-12 
IL-15 
interleukin-15 
IR 
immune response 
IRB 
Institutional Review Board 
IUPM  
infectious units per million 
IM 
intramuscular 
IV 
intravenous 
Leuk 
leukapheresis procedure 
LLN                        
LMP 
lower limit of normal 
latent membrane protein 
LMP1 
latent membrane protein 1 
LMP2 
latent membrane protein 2 
LRA 
latency-reversing agent  
MS 
mass spectroscopy 
NHLBI  
National Heart, Lung, and Blood Institute 
NIH 
National Institutes of Health 
NHL  
non-hodgkin’s lymphoma 


 
 
 
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NNRTI 
non-nucleoside reverse transcriptase inhibitor 
NPC 
nasopharyngeal carcinoma 
NRTI 
nucleoside/nucleotide reverse transcriptase inhibitor 
PACT 
Production Assistance for Cellular Therapies 
PBMC 
peripheral blood mononuclear cell 
PGE1 
prostaglandin E1 
PHA 
phytohemagglutinin 
PI 
protease inhibitor 
PLWH                    
PT 
People Living With HIV 
prothrombin time 
PTLD 
post-transplant lymphoproliferative disorder 
QVOA 
quantitative viral outgrowth assay 
rca-RNA 
resting cell associated RNA 
RCI 
resting cell infection 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SCA 
single copy assay 
SFC 
spot forming cell 
SOE 
schedule of events 
SIV 
simian immunodeficiency virus 
SMC 
safety monitoring committee 
T-APC 
T-antigen-presenting cells 
TCR sequencing 
T cell receptor sequencing 
TEAE 
treatment emergent adverse events 
TNF-α  
tumor necrosis factor-alpha 
ULN 
upper limit of normal 
UNC 
University of North Carolina 
US 
United States 
VIA 
viral inhibition assay 
VST 
virus-specific T-cell 
VOR 
vorinostat 
WNL 
within normal limits 
 
 
 
 
 
 


 
 
 
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KEY ROLES AND CONTACT INFORMATION  
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 
 
 
Co- Investigators: 
Catherine Bollard, MD 
Professor of Pediatrics 
Director- Program for Cell Enhancement and Technologies for 
Immunotherapy  
Children's National Hospital  
111 Michigan Avenue, NW 
5th Floor Main, Suite 5200, Room 5207 
Washington, DC 20010 
Phone: 202-476-4776 
Email: cbollard@childrensnational.org 
 
Cynthia Gay, MD, MPH 
Associate Professor 
Medical 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) 843-2726  
Fax: (919) 966-8928 
Email: cynthia_gay@med.unc.edu 
 
Patrick Hanley, PhD 
Assistant Professor of Pediatrics 
Laboratory Facility Director, 
Cellular Therapy and Stem Cell Processing 
Children’s National Hospital 
111 Michigan Ave NW 
Floor 3.5 Main, Room 230 
Washington, DC, 20010 
Phone: 202476-6368 
Email: PHanley@childrensnational.org 


 
 
 
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C. Russell Y. Cruz MD PhD 
Assistant Professor of Pediatrics 
Director, Translational Research Laboratory 
Program for Cell Enhancement and Technologies for Immunotherapy 
(CETI) 
Children’s National Hospital 
111 Michigan Ave NW  
6th Floor Sheikh Zayed Institute M7729 
Washington DC 20010 
Office Phone: 202-476-2046  
 
Joseph Eron, MD 
Professor of Medicine, School of Medicine, Director, Clinical Core, 
UNC Center for AIDS Research 
University of North Carolina at Chapel Hill 
Division of Infectious Diseases  
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 
 
Nancie M. Archin, Ph.D. 
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 
 
 
 
 


 
 
 
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Angela Kashuba, BScPhm, PharmD, DABCP 
John A. and Deborah S. McNeill Jr. Distinguished Professor  
Vice Chair for Research and Graduate Education, Division of 
Pharmacotherapy and Experimental Therapeutics, 
Eshelman School of Pharmacy, 
Adjunct Professor of Medicine, UNC School of Medicine, Division of 
Infectious Diseases, 
University of North Carolina at Chapel Hill  
1094 Genetic Medicine Building, 120 Mason Farm Road 
Eshelman School of Pharmacy, CB 7361 
Chapel Hill, NC 27599-7361 
Phone: (919) 966-9998  
Fax: (919) 966-1020 
E-Mail: akashuba@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 
Associate 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 
 
Katie Mollan, MS 
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 
 


 
 
 
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Jay Tanna, MS, RAC 
Quality Assurance Lead 
Cellular Therapy Laboratory 
Children’s National Hospital 
Office: 202-476-3880 
Email: JTanna@childrensnational.org 
 
Clinical Program Manager 
Susan Pedersen, BSN, 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) 966-6713 
Fax: (919) 966-8928 
E-Mail: susan_pedersen@med.unc.edu 
 
 
 


 
 
 
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1 
PROTOCOL SUMMARY 
 
Title: 
A Phase I Study to Evaluate the Effects of Vorinostat (VOR) and HIV-1 
Antigen Expanded Specific T Cell Therapy (HXTC) on Persistent HIV-1 
Infection in HIV-Infected Individuals Maintained on Suppressive 
Antiretroviral Therapy (XTRA study) 
 
Hypothesis:  
The combination of HXTC therapy and multiple doses of VOR will result 
in depletion of persistent, latent, replication-competent HIV infection. 
 
Objectives: 
Primary:  
1. Evaluate the safety of serial administration of VOR followed by 
autologous ex vivo expanded HIV-1 specific T-cells (HXTC) therapy 
in participants maintained on suppressive combination antiretroviral 
therapy (ART). 
 
2. Evaluate the association of serial VOR dosing and serial HXTC 
therapy on the frequency of resting CD4 T cell infection (IUPM) via 
quantitative viral outgrowth (QVOA) in participants who complete 
the leukapheresis procedure (#2) in Step 6, Visit 23. 
 
 
Secondary:   
1. Explore the ability of combination VOR and HXTC therapy to 
increase HIV-1 specific immune responses in participants 
maintained on suppressive ART. 
 
Other Outcome Measures: 
1. Explore the influence of HXTC therapy combined with serial 
VOR doses on low-level plasma viremia as measured by single 
copy assay (SCA) in participants who maintained suppression 
on ART. 
2. Explore the impact of VOR and HXTC therapy on the ability of 
CD8 T cells to enhance clearance of latently infected cells as 
they emerge from latency in a latency clearance assay. 
3. Explore the impact of VOR and HXTC therapy on integrated 
proviral DNA quantification. 
4. Explore the impact of VOR and HXTC therapy on the presence 
and persistence of T cell escape variants within the latent 
reservoir 
 
Population: 
Men and women living with HIV, ≥ 18 and < 65 years of age, with 
durable viral suppression for ≥ 24 months as measured on standard HIV 
RNA assays.  Eligible participants must be on stable ART and have a 
CD4 count ≥ 350 cells/mm3. 
Phase: 
Phase 1    
Number of Sites: 
Single site – University of North Carolina at Chapel Hill  
Description of 
Intervention: 
In Step 1 and prior to initiating the two series of VOR and HXTC combined 
therapies, all participants will undergo study screening and enrollment 
where they will be required to:  


 
 
 
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1. Demonstrate a baseline measurement of the frequency of resting 
CD4 T cell infection ≥ 0.3 infected cells per million as determined 
by QVOA, as a further decrease from this low frequency of 
infection cannot be definitively measured given the QVOA assay 
threshold  
Participants with an IUPM measurement ≥ 0.3 will provide whole blood 
cells for the manufacture of their HXTC product (Step 3). Successful 
manufacturing of the HIV-1 antigen expanded specific T cells will 
progress participants to combination treatment in Steps 4 and 5. In Steps 
4 and Step 5, participants will receive two series of VOR dosing and 
HXTC infusions, for a total 20 doses of VOR 400 mg and 5 HXTC 
infusions.  
In the first series (Step 4), participants will receive VOR 400 mg PO every 
72 hours for 10 doses and 2 infusions of HXTC. The first HXTC infusion 
will be administered six hours after the first dose of VOR (HXTC #1) and 
the 2nd HXTC infusion (HXTC #2) will occur 6 hours after the 6th dose of 
VOR.  
In the second series in Step 5, participants will receive an additional 10 
doses of VOR 400 mg PO every 72 hours and 3 HXTC infusions. The 
first HXTC infusion in Step 5 (HXTC #3) will occur 6 hours after the 11th 
dose of VOR (1st dose in Step 5), the 2nd HXTC infusion (HXTC #4) will 
occur 6 hours after the 16th dose of VOR, and the 3rd HXTC infusion 
(HXTC #5) will occur 1 – 3 days after the 20th dose of VOR.  
If there are insufficient cells manufactured to allow 5 infusions at 1 x 108 
cells/m2 dose, the dose will be adjusted to allow 5 infusions at a dose ≥ 
5 x 107 cells/m2 but < 1 x 108 cells/m2 dose.  
Study Duration: 
48 months 
Subject Participation 
Duration: 
Up to 12 people living with HIV (PLWH) on ART will be followed for 
approximately 52 weeks after the last HXTC infusion. Up to 6 of these 
participants will have started ART during acute HIV infection.  
Estimated Time to 
Complete Enrollment: 
36 months 
NOTE: THE PROTOCOL AMENDMENT FOR VERSION 3.0, DATED 20 DECEMBER 2019 
ELIMINATED STEP 2 OF THE PROTOCOL. IN ADDITION, THE PROTOCOL AMENDMENT 
FOR VERSION 4.0 DATED 31 JANUARY 2022 ELIMINATED VISITS 22, 25, AND 26.  TO 
AVOID DATA AND PROTOCOL IMPLEMENTATION ISSUES RELATED TO 
RENUMBERING ALL STUDY VISITS AND STEPS, WE OPTED TO REMOVE STEP 2 AND 
VISIT NUMBERS 3, 4, 22, 25, AND 26 FROM THE PROTOCOL. 
 
2. INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
 
2.1. BACKGROUND INFORMATION 
 
HIV INFECTION AND THE NEED FOR ALTERNATIVE THERAPIES: There are still over 37 
million PLWH worldwide, 1 million of which reside in the United States (US).  Despite 
educational and medical resources, the number of new infections far outpaces the number of 


 
 
 
Protocol v4.0_31-Jan-2022 
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those starting on combination antiretroviral therapy (ART) [1].  Over 50% of the affected 
individuals in the US are minorities, with the African American population most affected. 
Despite the success of ART in suppressing HIV viral load, it cannot eradicate established HIV 
infection due to the presence of persistent HIV infection in the form of latent, transcriptionally 
silent but inducible replication-competent virus that is impervious to ART, which only blocks 
spread of actively replicating virus [2-4]. Latent HIV infection can, however, reactivate, 
necessitating lifelong ART adherence to prevent viral rebound and, in some cases, the 
emergence of drug resistance. However, treatment of HIV-1 infection remains a significant 
financial burden in the US, at an estimated $379,668 life time cost/patient [5], and daily ART 
adherence is challenging. The Center for Disease Control estimates that only 28 out of every 
100 HIV-infected individuals in the US are engaged in care and adherent with ART [6].  Even 
for those who do successfully adhere to ART, the long-term use of ART has side effects and 
does not completely eliminate the effects of persistent low level inflammation, reflected by an 
increased risk of neurologic and cardiovascular disease as well as malignancies [6-8]. 
Innovative therapies to purge the latent reservoir, thereby eradicating HIV-1 infection, are 
urgently needed [4, 9]. 
 
ELIMINATING THE LATENT RESERVOIR: Induction of Viral Expression.  
Eradication of HIV will require elimination of the latent reservoir. Resting CD4+ T cells are the 
most well characterized contributor to the latent HIV reservoir [4]. Host cell molecular 
mechanisms maintain the quiescence of HIV gene expression in infected resting CD4+ 
lymphocytes, and could therefore serve as therapeutic targets for disrupting latency. One well 
defined mechanism contributing to maintenance of latency is the recruitment of histone 
deacetylases (HDACs) to the HIV long terminal repeat (LTR) promoter, mediating the 
formation of a repressive chromatin environment that inhibits LTR expression and viral 
production [10-13]. The relevance of this mechanism has been validated in the resting CD4+ 
T cells of ART-treated, aviremic, PLWH [11, 12, 14], and extended by several research groups 
[15-18]. Our group has attempted to translate these discoveries into anti-latency therapy, and 
while the task has been challenging we have made steady progress.  An initial study 
demonstrated a depletion of resting cell infection (RCI) in three of four ART-treated PLWH 
receiving intensified ART and the weak HDAC inhibitor (HDACi), valproic acid (VPA) [19]. 
However, further studies by our group and others found infrequent or modest depletion of RCI 
in participants treated with VPA [20-23]. 
 
In pre-clinical studies, we and others found that the more potent HDACi, Vorinostat (VOR), 
which is 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 PLWH on suppressive ART [24, 25].  This effect was 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 [10]. 
 


 
 
 
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However, administration of a latency reversing agent (LRA) alone would not be expected to 
deplete the latent reservoir, as viral cytopathic effects do not appear prominent in the absence 
of full T cell activation and high-level virus production [26].  An effective HIV-specific immune 
response will be necessary to clear latently infected cells following induction of viral 
expression [4, 26-28]. Further, it is not yet clear that the induction of cell-associated HIV RNA 
expression observed in several studies leads to the expression of viral antigens that could 
mark the infected cell for clearance.  By combining the most well characterized latency 
reactivating agent, VOR, with a powerful and precisely controlled immune augmenting tool, 
this study may provide definitive evidence that a latency reversing agent can induce clinically 
relevant HIV antigen expression, and allow depletion of the latent reservoir. 
 
ELIMINATING THE LATENT RESERVOIR: Enhancing the HIV-specific T cell Response.  
Recent work suggests that in most individuals the existing low frequency CD8+ T cell 
responses are insufficient to clear the latent reservoir [26], in part because of CD8+ T cell 
escape mutations which arise within weeks of HIV-1 infection and are archived in the latent 
reservoir [28-31]. Strategies to eliminate the need for ART by strengthening HIV-specific T 
cell immune responses using a therapeutic vaccine have been attempted, but with 
disappointing results [27, 32-34]. Most notably, only a small number of vaccine trials have 
reported the impact of vaccines on the size of the latent reservoir; finding either no sustained 
impact [35] or, at best, a small, transient decline in the frequency of replication competent 
latent infection [52] that was below the threshold of what our group has found to be  significant  
[36]. These failures in part can be attributed to the poor immunogenicity of vaccine regimens 
employed that failed to produce sustained expansion of HIV-specific CD8+ T cells in the time 
frame studied, as well as due to a lack of viral expression in latently infected cells [4]. 
 
 
Adoptive T cell therapy has proved very successful in certain oncology settings [37-39]. In this 
strategy, T cells are isolated from patients, expanded, and then reinfused into the patient. The 
Bollard group has successfully employed this strategy against reactivated EBV, CMV, and 
adenovirus in hematopoietic stem cell transplant recipients [37, 39, 40], as well as against 
EBV mediated malignancies [38, 41, 42]. The infused T cells are highly potent, including, in 
the cancer setting, inducing sustained complete responses in >50% of patients with high risk 
or multiply relapsed EBV related lymphoma [38]. Further, gene marking studies have 
confirmed that adoptively transferred donor-derived EBV specific T cells can be detected at 
least as far out as ten years post infusion [38]. The benefit to cost ratio is quite favorable, with 
a cost of about $6,000 per patient to manufacture and infuse virus specific T cells once a 
program is established [42]. This is in contrast to the estimated annual cost of HIV care of 
$23,000 (in 2010 dollars) [5, 43]. 
 
 
Adoptive T cell therapy for PLWH was first tested over a decade ago (reviewed in [44]). While 
these studies established the safety of adoptive transfer of HIV-specific T cells, antiviral 
efficacy was transient [45, 46]. This was due in part to a reliance on monoclonal T cells, 
extensive in vitro expansion resulting in a potentially exhausted phenotype, and the infusion 
of T cells into actively viremic, untreated patients [44]. More recently, HIV-specific T cell 
therapy was applied in the setting of ART suppression; these T cells persisted in blood and 


 
 
 
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were capable of homing to rectal tissue following infusion, but virologic outcomes were not 
reported [47]. Previous studies have also examined the utility of infusing T cells specific for a 
single HLA-restricted epitope, either by clonal selection or introducing an artificial, high-affinity 
T cell receptor for the HLA-A2 gag epitope SL9 [48]. Infused T cell clones showed little 
persistence and no clear long-term reduction in viral load. While high-affinity T cell receptor 
technology has promising preclinical data, it is not currently feasible to rapidly generate such 
T cell receptors against a well-conserved epitope for every patient’s HLA-type.  
 
In contrast, the advanced manufacturing approach the Bollard group has developed for cancer 
immunotherapy is more feasible than prior techniques used to generate a Good 
Manufacturing Practice (GMP) grade T cell product. Within one month it provides a product 
for any participant, independent of HLA type. We adopted this strategy to the HIV setting, and 
validated the generation of HIV-1 antigen-specific T-cells in a GMP compliant manner [49]. 
The advantage of this novel approach for HIV is that T cells may be primed against epitopes 
that are not immunodominant in vivo [44], thus expanding the breadth of the T cell responses 
to potentially include putative beneficial, subdominant responses [28, 50]. T cells were 
stimulated ex vivo with autologous dendritic cells pulsed with overlapping peptides (Pepmixes) 
spanning both early and late HIV proteins, Gag, Pol, and Nef to elicit a range of HIV-1 specific 
T cells that detect HIV-1 infected cells at different stages of the virus life cycle and have been 
associated with delayed disease progression and in vivo viral control [51-56].  
 
 
The HXTCs generated detect endogenously processed and presented HIV-1 epitopes as 
demonstrated by specific inhibition of HIV-infected CD4 T cells, are not restricted to a single 
T cell receptor clonotype (are polyclonal), elicit multiple anti-viral cytokines and lytic molecules 
(polyfunctional), and can clear HIV latently infected cells following ex vivo exposure to VOR 
[49, 57]. This study aims to establish that HIV-1 antigen-specific expanded T-cells (HXTC) 
activated and expanded ex vivo can produce improved in vivo HIV-1 specific T cell responses 
in PLWH who remain on suppressive ART, and combine HXTCs with VOR to achieve 
clearance of the latent reservoir in vivo. HXTCs are an attractive tool for this proof-of-concept 
study, as their dose and time of administration can be controlled, allowing the precise delivery 
of immune effectors following the administration and clearance of VOR. 
 
Dose Rationale 
In versions 1 and 2 of this protocol, we infused 2x107 cells/m2 of HXTC based on doses of T 
cell therapy that had been effective in the treatment of EBV-related lymphoma. However, 
higher doses of CTL therapy for lymphoma have subsequently been found to be well-tolerated 
and feasible from a production standpoint. The experience treating oncology patients with up 
to twelve doses of up to 1.5 x 108 cells/m2 per dose suggests that this increase will be safe 
and rational [80-82]. Given the need to target the rare T cell population with latent HIV infection 
as compared to tumor cells expressing EBV-related proteins, we propose to increase the dose 
of HXTCs infused in version 3. 
 
As of 01 December 2019, we have studied individuals under Version 2 of the protocol for this 
pilot study, with the administration of Vorinostat and five infusions of 2 x 107 cells/m2 of HXTCs. 


 
 
 
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There have been no study treatment-related AEs. All observed AEs have been ≤ Grade 1, 
transient, and judged to be related to the apheresis procedure. However, no significant decline 
in the primary endpoint of the frequency of persistent HIV infection within circulating resting 
CD4+ T cells has yet been observed. Two additional individuals will receive HXTCs under 
Version 2. If no unexpected AEs are observed, under Version 3 of this protocol we will 
administer an increased number of HXTCs with 5 infusions up to 1.0 x 108 cells/m2 per dose,  
to an additional six participants. 
 
Rationale: Elimination of latent HIV infection will require 1) induction of viral expression by a 
LRA and 2) enhancement of the existing HIV-specific immune response to clear the infected 
cells as they emerge from latency.  
 
We hypothesize that induction of viral antigen expression by administration of VOR to PLWH 
while maintaining suppressive ART followed by HXTC therapy to recognize and clear the 
infected cells as they emerge from latency will be 1) safe, 2) increase in vivo, HIV-1 antigen 
specific T-cell immune responses that circumvent archived viral escape variants and 3) 
decrease resting cell infection. 
 
2.2. 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) [58-60]. Concentrations of VOR that 
cause the accumulation of acetylated histones also induce cell cycle arrest, differentiation, or 
apoptosis of transformed cells [59]. 
 
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 [58, 59, 61-68]. 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 [69]. 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 [70-72]. 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. 


 
 
 
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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 RT-
PCR, 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 [25].   
 
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, ART-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.   
 
2.2.1. 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. 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 


 
 
 
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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. 
 
2.2.2. 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 
dose), 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. 
 
2.2.3. 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 through metabolism with less than 
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). 


 
 
 
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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. 
 
2.2.4. 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. 
 
2.2.5. Risks Associated with VOR   
 
The types of adverse experiences observed in clinical trials of VOR in the oncology 
setting were those usually associated with chemotherapy, such as nausea, fatigue, 
diarrhea, constipation, and cytopenias. The three major clinical categories of adverse 
experiences attributable to VOR include a constellation of gastrointestinal symptoms, 
constitutional complaints, and cytopenias. All adverse experiences were 
manageable using conventional supportive care for chemotherapy. On the whole, 
treatment with oral VOR was well tolerated for use in the outpatient setting. 
 
Merck & Co., Inc. sponsored VOR clinical studies showed that adverse experiences 
considered by the Investigators to be at least possibly related to VOR in ≥10 % of 
participants included (in descending frequency): nausea, fatigue, diarrhea, anorexia, 
vomiting, thrombocytopenia, anemia, weight decreased, blood creatinine increased, 
dysgeusia, hyperglycemia, neutropenia, constipation. The total daily doses studied 
ranged from 200 mg to 900 mg.  The tolerability of oral VOR appears to be 
determined by total daily dose and the length of consecutive days of dosing.  The 
maximum tolerated dose (MTD) for continuous daily dosing without a rest period is 
400 mg daily or 200 mg BID.  The MTD for intermittent dosing is 300 mg BID x 3 
consecutive days per week, or 250 mg TID x 14 consecutive days followed by a 7-
day rest. Dose-limiting toxicities (DLTs) of single agent VOR were mainly non-
hematologic (anorexia, dehydration, diarrhea, and fatigue); hematologic toxicities are 
primarily anemia and thrombocytopenia, most of which were mild to moderate.  The 
majority of these DLTs occurred within the first month on oral VOR.  The DLTs were 
manageable because the toxicities resolved quickly after drug administration was 
interrupted. 
 


 
 
 
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Dose-limiting toxicities (DLTs) have been mainly non-hematologic. The majority of 
these DLTs occurred within the first month on VOR. At continuous daily dosing of 
600 mg QD, 300 mg BID, and 400 mg BID, doses that exceeded the established 
MTD, the pattern and severity of DLTs were similar. The DLTs were manageable 
because these toxicities resolved quickly after drug administration was interrupted. 
Hematologic events were primarily anemia, leukopenia, and thrombocytopenia. 
Generally, these events were rapidly reversible after study drug interruption. 
 
Clinical serious adverse experiences (SAEs) regardless of causality have been 
reported in approximately 39% of the first 350 participants treated with VOR in Merck 
& Co., Inc. sponsored studies. This overall high incidence may reflect the underlying 
conditions of participants in this group. Of the participants who had a serious adverse 
experience, approximately 16% were considered by the Investigator to be related to 
study medication. Serious laboratory adverse experiences were uncommon, 
occurring in 3% or fewer of patients in the various populations. By contrast to patients 
with solid tumors, the incidence of SAEs was higher in patients with hematologic 
malignancies. Pulmonary embolism and deep vein thrombosis have been reported.  
 
In prior studies, we assessed the intermittent administration of VOR to PLWH 
suppressed on ART. Thirty-two individuals received at least one 400 mg dose and 
thirteen received at least 10 doses of  400 mg (with up to 11 doses in one month), 
and we observed minimal side effects attributed to VOR. We observed no adverse 
events (AEs) exceeding Grade 1, but for a single episode of Grade 2 fatigue in one 
participant that resolved after 24 hours without intervention. No AEs led to the 
interruption of VOR dosing. We observed no new or unique AEs other than those 
commonly reported. Participants completing the combination VOR and HIV-specific 
ex vivo expanded T cells (HXTC) protocol will receive no more than a total of 4000 
mg (2 cycles of 10 doses) of VOR. For reference, participants who completed our 
prior multi-dose studies under NIH U01 AI095052 received a total of 10,000 mg and 
5200 mg of Vorinostat, respectively, without clear evidence of any durable drug-
associated toxicity, and no AE greater than Grade 1.  
 
In this proposed study, participants will receive 10 doses of 400 mg VOR over a 30 
day period, then no VOR for 4 weeks. They will then receive a second cycle of 10 
doses of 400mg VOR over another 30 day period, for a total of 20 doses. Each 
participant will receive a total of 5 HXTC infusions; 2 infusions will be administered 
in the first 4 week cycle and 3 administered in the second 4 week cycle. In our 
previous study with VOR, most participants exhibited a 15%–35% transient decline 
in platelet count after 4 weeks of 3 daily doses each week. However, only one 
participant’s platelet count reached grade 1 toxicity level. No other clinical events or 
drug-related AEs were observed. Given we now propose to administer fewer doses, 
over a shorter time (20 doses over 3 months), significant toxicity seems unlikely. 
 
 


 
 
 
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2.2.6. Risk Associated with “unmasking” HIV  
 
The HDAC inhibitors that “unmask” HIV in latent cells could cause other cells to 
become infected. However, we have not detected any evidence of this in the 
participants who received VOR thus far [73, 74]. We have observed a rare “blip” of 
low-level viremia; however, we have not observed any drug-resistance and/or failure 
of ongoing ART. Should we observe any instances of detectable HIV-1 RNA (> 50 
copies/mL), we would repeat testing to confirm the result and inform all participants 
of the reason for re-testing. For those with confirmed viremia, we would notify the 
participant and their primary care provider for management per standard of care. If 
clinically indicated, blood samples would be obtained to measure antiretroviral serum 
drug levels and/or HIV phenotype and genotype to measure for the development of 
resistance. Participants with confirmed viremia > 150 copies/mL will be discontinued 
from the study. 
 
2.2.7. Reproductive Toxicity 
 
VOR rapidly crossed the placenta in both the rat and rabbit, following administration 
of a dose of 15 mg/kg/day and 150 mg/kg/day, respectively (<1 times the human 
exposure based on AUC0-24) and reached transplacental equilibrium within 30 
minutes post-dose.  
 
Reproductive toxicity studies were conducted in male and female rats to determine 
potential effects of dosing with VOR for more than 20 days, and up to 26 weeks, on 
fertility and reproduction. In male rats, there were no treatment-related effects on 
mating performance, fertility, embryonic/fetal survival, sperm count and motility, 
testicular weight, or testicular and epididymal histomorphology in any drug-treated 
group. The NOEL for effects on female fertility was ≥150 mg/kg/day (≥900 
mg/m2/day). The NOEL for effects on female reproductive performance, however, 
as determined by increases in the number of corpora lutea, was <15 mg/kg/day (<90 
mg/m2/day), which is below the equivalent human dose expressed on an equivalent 
surface area basis (250 mg/m2/day).  
 
VOR was evaluated in a panel of genetic toxicity assays; in vitro assays were found 
to be positive. No human safety data for the use of VOR during pregnancy are 
available. 
 
2.3. HIV-SPECIFIC EX VIVO EXPANDED T CELL THERAPY (HXTC)   
 
2.3.1. T cell Therapy in HIV-Infected Individuals    
  
Support for this phase I study is derived from studies demonstrating the feasibility 
and safety of infusing PLWH with ex vivo-expanded HIV-specific CTLs that were 
specific for 1-3 epitopes of Gag, Pol, or Nef [45-47, 75, 76]. The earliest study of 


 
 
 
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expanded HXTCs in actively viremic participants found that infusion with up to 1010 
non-specifically activated, expanded autologous CD8+ T cells was safe and tolerable 
with no CTL related adverse events in 5 participants with AIDS, but enhancement of 
HIV specific cytotoxicity post-infusion was transient and no impact on virologic 
outcome was found [77, 78]. In another pilot study of actively viremic participants 
with CHI, autologous administration of CD8+ CTLs primed to express cytotoxicity 
against HIV-1 epitopes gp120, gag p17, p24m, and nef produced no toxicity or 
clinical deterioration over six months of follow-up [46]. Three of six participants 
showed improvements in plasma HIV RNA levels or CD4+ count at six months 
despite low enrollment CD4+ counts (100-400 c/mm3). Two additional studies of one 
patient each who received an infusion of CTL clones against Gag and Nef, 
respectively, did not find any impact on viremia due to the short lived nature of the 
Gag clone and development of HIV escape variants to the Nef clone, but did find that 
the infusion was safe and well-tolerated [75, 79]. Another small study in three 
participants on ART but with low level viremia established the safety and tolerability 
of escalating doses of gag-specific CTL clones of up to 3.3 x 109/m2 [45]. Transferred 
HIV-specific CTLs migrated to lymph nodes where they co-localized with HIV RNA+ 
cells in the parafollicular regions.  The presence of CTL clones in the peripheral blood 
correlated with a significant but transient reduction in the number of HIV-infected 
peripheral CD4+ T cells. In all of these studies, the only adverse event reported was 
mild and transient chills and rigors following infusion. These studies established the 
feasibility and safety of adoptive transfer of HIV-specific CTL clones, but showed only 
modest results. Notably, these studies were performed in actively viremic HIV-
infected participants, and infused cells were generally monoclonal and had been 
expanded extensively in vitro, hence were likely highly differentiated. In a more 
recent study, HIV-specific CD8+ T cell clones derived from the central memory 
population of chronically HIV-infected participants on suppressive ART were 
expanded in vitro, and following autologous re-infusion could be detected for up to 
84 days in blood and rectal tissue and retained or re-expressed memory markers 
(CD28+, CD62L+) and function (secretion of IL-2 and proliferation on cognate Ag 
exposure) [47]. Virologic outcomes were not assessed in this study, however. In 
contrast to the latter study, we will break new ground by generating polyclonal CD4+ 
and CD8+ T cells specific for multiple HIV epitopes in multiple antigens.   
 
Among these studies and others with HIV-specific T cells, the only adverse events 
reported were mild and transient fever, arthralgias, myalgias, chills, and rigors 
following the infusions [45-47, 75-79]. Some of these events were associated with 
the administration of exogenous IL-2 given in conjunction with T cell infusion. This 
suggests that it will be safe and perhaps more effective to target these three antigens 
simultaneously in one T cell product, as proposed with this study. Furthermore, we 
hypothesize that our HXTCs will be safely tolerated in participants that have been on 
stable ART with undetectable viral load based on the rationale that these early 
studies demonstrated the safety of infusing CTLs in higher risk groups including 
viremic and HIV-infected participants with advanced immunosuppression.  


 
 
 
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Despite infusing T cells with very limited specificity in order to target a highly mutable 
virus, only one study showed a single instance of the emergence of escape variants 
in a severely immunocompromised AIDS patient [79]. Though this demonstrates that 
escape variants are a low risk, we are further lessening this risk by proposing to 
infuse broadly-specific T cells. Importantly, not all previous studies excluded the 
presence of CD4+ T cells in the product and this did not result in increased HIV RNA 
levels post-infusion. Although CD4+ HIV-specific T cells may be subject to 
elimination by HIV infection, this risk is lessened by administration only to participants 
with durable viral suppression on ART, and if functionality and persistence is 
observed in this phase I study, HIV-specific T cells could be rendered resistant to 
HIV infection prior to infusion in subsequent trials. The fact that almost all participants 
who are suppressed on ART have low level (and stable) detectable viremia gives us 
a quantifiable endpoint following autologous T cell infusion without having to stop 
therapy in these participants. An impact on low level viremia as measured by a single 
copy assay (SCA) would be the first signal that these ex vivo enhanced and 
expanded T cells are having an effect. Taken altogether, the previous human 
experience with the infusion HIV-specific T cells supports the feasibility and of our 
novel strategy of polyclonal CD4+ and CD8+ T cells specific for multiple HIV epitopes 
in multiple antigens in participants with viral suppression on ART.   
 
2.3.2. Safety and Efficacy of antigen specific HIV-specific T cell (HXTC) therapy in 
humans  
 
Under IND 15984 (HXTC study), we have successfully infused HIV-specific ex-vivo 
expanded T cells (HXTCs) in four PLWH on suppressive ART to date. The HXTCs 
were well tolerated with no SAEs reported in any of the participants, with the most 
common non-serious AE being a transient altered taste during HXTC infusion 
(expected with DMSO-containing infusions).  
 
Our group has over a decade of experience with safely and effectively treating 
immunocompromised patients post-transplant with virus-specific T cells and tumor-
specific T cells that are manufactured using similar protocols to the HXTC product. 
Prior work by several groups has demonstrated that CMV, EBV, and adenovirus-
specific T cells, including T cells generated using overlapping peptide pools, provide 
a safe and effective treatment and prophylaxis for viral infections and post-transplant 
lymphoproliferative disorder (PTLD) in immunocompromised patients post-transplant 
(Table 1).   
 
Table 1: 
Human Experience–Related INDs, and protocols from co-investigator 
Catherine Bollard and colleagues. 
 
IND 5049 - Administration of EBV specific cytotoxic T lymphocytes to recipients of mismatched-
related or phenotypically similar unrelated donor marrow grafts (ETNA). 


 
 
 
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IND 6387 – Administration of neomycin resistance gene marked EBV specific cytotoxic T-
lymphocytes to patients with relapsed EBV- positive Hodgkin disease (ANGEL). 
 
IND 11186 - Virus specific cytotoxic T-lymphocytes for the prophylaxis of CMV after allogeneic 
stem cell transplant: a dose-finding trial (VICTA). 
 
IND 12830 – Administration of TGF-β resistant LMP2a-specific cytotoxic T-lymphocytes to 
patients with relapsed EBV-positive lymphoma (TGFb). 
 
IND 11835 - Administration of virus-specific cytotoxic T-lymphocytes for the prophylaxis and 
therapy of adenovirus infection post allogeneic stem cell transplant (LYPTAIST). 
 
IND 13958 - Phase I/II study of the administration of multi-virus-specific cytotoxic T lymphocytes 
(CTLS) expressing CD19 chimeric receptors for prophylaxis of therapy of relapse of acute 
lymphoblastic leukemia post hemopoietic stem cell transplantation (MULTIPRAT). 
 
IND 14714 - Administration of Tumor-Associated Antigen (TAA)-specific Cytotoxic T-
lymphocytes to patients with active or relapsed Hodgkin or non-Hodgkin Lymphoma (TACTAL) 
 
IND 15086 - Administration of rapidly generated LMP, BARF1 and EBNA1 specific Cytotoxic 
T-lymphocytes to patients with EBV+ Lymphoma (GRALE) 
 
IND 15092 - Administration of Rapidly Generated Multivirus-Specific Cytotoxic T-Lymphocytes 
for the Prophylaxis and Treatment of EBV, CMV, Adenovirus, HHV6, and BK virus infections 
post Allogeneic Stem Cell Transplant (ARMS) 
 
IND 15714 - Adoptive Transfer of Cord Blood T cells to Prevent and Treat CMV, EBV, and 
Adenovirus Infections after Transplantation (ACTCAT2) 
 
IND 15779 - Multivirus-Specific Cytotoxic T-Lymphocytes for the Prophylaxis and Treatment of 
EBV, CMV, and Adenovirus Infections post Allogeneic Stem Cell Transplant (MUSTAT) 
 
IND 15779 - Administration of Most Closely HLA-matched Multivirus-specific Cytotoxic T-
Lymphocytes for the Treatment of EBV, CMV, Adenovirus Infections Post Allogeneic Stem Cell 
Transplant (CHAPS) 
 
IND 15779 - Treatment of EBV, CMV, and Adenovirus Infections in Primary Immunodeficiency 
Disorders with Viral-specific Cytotoxic T-Lymphocytes (TREPID) 
 
IND 15772 – Administration of LMP-Specific Cytotoxic T-Lymphocytes to Patients with 
Relapsed EBV-Positive Lymphoma (ALC12) 
 
 


 
 
 
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2.3.3. Virus specific Cytotoxic T Lymphocytes after allogeneic hematopoietic 
stem cell transplantation  
 
At St. Jude Children’s Research Hospital and Baylor College of Medicine (IND 5049), 
more than 100 allogeneic HSCT recipients received donor-derived ex vivo expanded 
EBV-CTLs. The only agent-related adverse events were inflammatory reactions at 
tumor sites; this was marked in one bone marrow transplant (BMT) recipient with 
bulky disease at the time of CTL administration and milder in three BMT recipients 
with subclinical disease (IND 5049). 
 
Subsequently, allogeneic trivirus-(BCM IND 11186), and bivirus-specific (BCM IND 
11835) CTL derived from HLA-matched related, HLA-mismatched related and HLA-
matched unrelated donors (NHLBI-PACT project 00014) were administered to over 
40 patients both as prophylaxis and as treatment of viral infections. No adverse 
events were attributable to the T-cell infusions. None developed more than grade 2 
GVHD or other toxicities over the 3 months of safety monitoring after infusion. This 
study demonstrated that multi-virus-specific T-cells derived from the peripheral blood 
of seropositive donors were able to expand in vivo and mediate activity against 
multiple viral reactivations from a single product. 
 
To increase the safety and decrease the manufacturing time of virus-specific T-cells, 
Bollard and colleagues while at Baylor replaced EBV-transformed B-cell lines and 
adenoviral vectors as a source of viral antigens with overlapping peptide libraries 
(pepmixes) spanning the entire protein sequence of protective antigens (those that 
induce T-cells with protective capacity) from viruses including EBV, CMV, 
adenoviruses, BK, and HHV6. Large numbers of multi-virus-specific T-cells can be 
produced after a single stimulation of peripheral blood mononuclear cells (PBMCs) 
with combined pepmixes. These have been infused in >20 allogeneic HSCT 
recipients (IND 15092 (Baylor) and IND 15779 (CNMC)). There were no immediate 
infusion-related toxicities with one incidence of grade 2 GVHD. The polyspecific 
VSTs expanded in vivo and produced clinical responses in all patients. 
 
2.3.4. Safety and Efficacy of Autologous T-cell therapies for EBV positive 
Lymphoma 
 
Under IND 6387, the Bollard group at the Center for Cell and Gene Therapy (CAGT) 
at Baylor College of Medicine generated CTL enriched for effector cells specifically 
targeting LMP antigens (LMP2 +/- LMP1) and administered them to patients with 
EBV+ lymphoma. No immediate toxicity was observed. After CTL infusion, increased 
numbers of LMP-specific T-cells were detected in the blood, (range 2 to 70 fold) 
persisting for up to 3 months. In conclusion, immunotherapy with CTL targeting LMP 
antigens is well tolerated in patients with EBV+ lymphoma, and can induce complete 
and sustained clinical responses in 62% of patients. This demonstrated that the anti-


 
 
 
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tumor activity of ineffective circulating tumor-specific T cells could be restored by ex 
vivo activation and expansion. 
 
Bollard and colleagues have also modified T cell manufacturing for EBV-positive 
lymphoma patients. Dendritic cells loaded with overlapping peptide libraries 
spanning 4 EBV antigens were used for the first stimulation of T-cells in the presence 
of cytokines, and pepmix-pulsed, autologous activated T-cells combined with K562 
cells expressing co-stimulatory molecules as transgenes were used for a second 
stimulation. Such T cells have been used safely in >9 individuals with multiple 
relapsed lymphoma, resulting in increases in the frequency of EBV-specific T-cells, 
producing tumor responses and no adverse events. This manufacturing protocol is 
similar to the manufacturing of HXTCs proposed here, suggesting that the adoptive 
transfer of HXTCs in patients with HIV should also have an excellent safety profile. 
 
2.4. POTENTIAL BENEFITS   
 
The addition of VOR and HIV-specific ex vivo expanded T cells (HXTCs) to a person’s 
ART regimen or the donation of one’s blood cells to this research project provide no direct 
medical benefits to participants. However, participation makes it possible to continue 
research on HIV, potentially resulting in new treatments for HIV infection. Due to the 
intensive, demanding nature of study follow-up, administration of experimental product 
and multiple leukapheresis time points, we will provide an IRB-approved compensation to 
participants.  
 
3. OBJECTIVES 
 
3.1. Study Objectives 
3.1.1. Primary Objectives 
3.1.1.1. 
Evaluate the safety of serial administration of VOR followed by 
autologous ex vivo expanded HIV-1 specific T-cells (HXTC) therapy in 
participants maintained on suppressive combination antiretroviral therapy 
(ART) 
3.1.1.2. 
Evaluate the association of serial VOR dosing and serial HXTC therapy on 
the frequency of resting CD4 T cell infection (IUPM) via quantitative viral 
outgrowth (QVOA) in participants who complete the leukapheresis 
procedure (#2) in Step 6. 
 
3.1.2. Secondary Objectives 
3.1.2.1. 
Explore the ability of combination VOR and HXTC therapy to increase 
HIV-1 specific immune responses in participants maintained on 
suppressive ART. 
  
3.1.3. Other Outcome Measures 


 
 
 
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3.1.3.1. 
Explore the influence of HXTC therapy combined with serial VOR doses 
on low-level plasma viremia as measured by single copy assay (SCA) in 
participants who maintained suppression on ART.  
3.1.3.2. 
Explore the impact of VOR and HXTC therapy on the ability of CD8 T 
cells to enhance clearance of latently infected cells as they emerge from 
latency in a latency clearance assay. 
3.1.3.3. 
Explore the impact of VOR and HXTC therapy on integrated proviral 
DNA quantification. 
3.1.3.4. 
Explore the impact of VOR and HXTC therapy on the presence and 
persistence of T cell escape variants within the latent reservoir 
 
3.2. Study Outcome Measures 
3.2.1. Primary  
The primary outcome will be safety and tolerability of administration of VOR 
combined with HXTC therapy.  
3.2.2. Secondary 
The secondary outcome will be the impact of VOR and HXTC therapy on the 
HIV-specific immune response and on the frequency of latent HIV infection, as 
measured by a QVOA and plasma HIV-1 RNA viremia measured by SCA, an 
assay with a limit of quantitation of 1 copy/mL. 
 
4. STUDY DESIGN 
 
This is a phase I, single-site, study to evaluate the effects of VOR and HIV-1 Antigen Expanded 
Specific T Cell Therapy (HXTC) on persistent HIV-1 Infection in HIV-infected individuals 
suppressed on ART. Overall, twelve participants with durable viral suppression will be enrolled 
and will complete the study. All participants will be dosed with HXTC and VOR. Participants will 
continue their baseline ART regimen throughout the study.  
 
4.1. Step 1 (Visits 1 and 2) – Screening, Enrollment, and Baseline Leukapheresis 
procedure (Leuk #1)   
During the screening visit, all participants will have the study explained and the informed 
consent signed. After the informed consent process is completed, participants will be 
screened for the study and those who meet eligibility requirements will enroll (Visit 2) and 
have their white blood cells collected via a leukapheresis procedure (Leuk #1). A baseline 
measurement for the frequency of HIV-1 infection per million resting CD4+ cells (IUPM) 
of ≥ 0.3 by QVOA allows participants to progress to Step 3, Visit 5.  
 
Note: Participants who exhibited an IUPM ≥ 0.3 in prior UNC IRB-
approved studies, will be required to complete the baseline 
leukapheresis after meeting the eligibility criteria and enrolling. 
However, they will not be required to wait for results of the baseline 
leukapheresis IUPM measurement to move to Step 3 for collection of 
blood samples for the manufacturing of HXTCs. 


 
 
 
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4.2. Step 2 (Visits 3 and 4) – Omitted from Version 3 of the protocol (V3.0) 
 
4.3. Step 3 (Visits 5 and 6) – Production of HXTC Therapy and Pre-Dose Safety 
Assessment for Initiation of Combination Therapy 
 
At Step 3, Visit 5, collect up to 245 mL of blood and send ambient temperature overnight 
to the Program for Cell Enhancement and Technologies for Immunotherapy (CETI) at 
Children’s National Hospital (CNH) in Washington, DC for the manufacturing of HXTCs 
and HLA testing. This manufacturing process takes approximately 8 weeks.  
 
Participants who participated in studies conducted under IND 15984 (IRB# 17-0468 and 
IRB# 14-0741) with HXTC cells already produced and stored at CNH, with documentation 
that adequate cells are available for infusions, can bypass Step 3, Visits 5 and 6 and 
progress directly to Step 4.  
 
4.4. Step 4 (Visits 7 – 13) – 1st Series of 10 Doses of VOR with 2 Infusions of HXTCs.  
 
Successful manufacturing of HXTC cells and acceptable clinical findings during the pre-
dose safety assessment at Step 3, Visit 6 determine advancement to Step 4. 
 
Participants receive 10 doses of VOR 400 mg PO every 72 hours. At study Visits 7 and 
10, approximately 6 hours after their VOR dose, they will receive an HXTC infusion of up 
to 1 x 108 cells/m2. Thus, each participant receives ten VOR 400 mg doses and two HXTC 
infusions (HXTC #1 and #2) in Step 4.  
 
4.5. Step 5 (Visits 14 – 20) - 2nd Series of 10 Doses of VOR with 3 Infusions of HXTCs.  
 
Approximately 4 – 5 weeks after the 10th dose of VOR 400 mg (Visit 12), if participants 
meet the pre-dose safety assessment requirements at Step 4, Visit 13, participants return 
for their first Step 5 visit (Visit 14).  
 
Participants receive 10 doses of VOR 400 mg PO every 72 hours (total VOR dose #11 – 
20). At Visits 14, 16, and 19, participants receive HXTC infusions of up to 1 x 108 cells/m2 
each (HXTC #3, #4, and #5). The first 2 HXTC infusions occur approximately 6 hours 
after their VOR dose; however, the last HXTC infusion (HXTC #5) will occur 1 – 3 days 
after the last VOR 400 mg dose (Dose #20).   
 
If there are insufficient cells manufactured to allow five HXTC infusions at 1 x 108 
cell/m2 each, the study team will review the amount of cells manufactured and change 
the HXTC dose to be less than 1 x 108 cells/m2 but ≥ 5 x 107 cells/m2 each. 
 
Monitoring for toxicity occurs throughout Steps 4 and 5. 
 


 
 
 
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4.6. Step 6 (Visits 21, 23, 24) – Immune Monitoring and Leuk #2 
Following the final HXTC infusion, participants move into Step 6 for a minimum of three 
additional visits. The 2nd leukapheresis will occur at Visit 23 (Week 16), approximately 5 
weeks after the last HXTC infusion to evaluate the effect of study treatment on the 
IUPM by QVOA.   
 
All participants who receive greater than 8 doses of VOR (3200 mg) will be required to 
enter a study cancer registry where they will be contacted once a year for 5 years after 
completion of their study participation. The registry was created to monitor participants 
for the development of future malignancies given concern for genotoxic impact with the 
use of VOR. 
 
NOTE: THE PROTOCOL AMENDMENT FOR VERSION 4.0 DATED 31 JANUARY 
2022 ELIMINATED VISITS 22, 25, AND 26 FROM STEP 6 OF THE PROTOCOL. 
 
 
4.7. Figure 1: Study Schema 
 
 
 
 
5. STUDY ENROLLMENT AND WITHDRAWAL 
 
5.1. Participant Inclusion Criteria 
5.1.1. ≥ 18 years and < 65 years of age at screening 
 
5.1.2. Ability and willingness of participant to give written informed consent.  
NOTE: Due to the lack of foreseeable benefit to study volunteers, the study will not 
enroll illiterate or mentally incompetent volunteers. 
 
5.1.3. Confirmation of HIV-1 infection  
Rest 
Period
2 - 4 
Week 
Period
Visits 1
2
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
23
24
Immune Response Assays
HXTC Infusion
Leukapheresis
Single Copy Assay
Other Research Assays
Step 5 
2nd Series Combination Treatment
VOR every 72 hours & 3 HXTC Infusions
4 Week Period
Step 6
Immune Response 
Monitoring
Approx. 9 Week Period
Step 3
Product Manufacturing 
Phase
Approx. 8 Week Period
Step 1
Pre-Treatment Phase
Screen and Enroll
Approx. 4 - 8 Week Period
Step 4 
1st Series Combination Treatment
VOR every 72 hours & 2 HXTC Infusions
4 Week Period
Continuous ART
Vorinostat 400 mg PO 
every 72 hours x 10 doses
Vorinostat 400 mg PO 
every 72 hours x 10 doses


 
 
 
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HIV infection is defined as documentation 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 load. 
 
NOTE: The term “licensed” refers to a US FDA-approved kit. 
 
WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) 
guidelines mandate that confirmation of the initial test result must use a test that is different 
from the one used for the initial assessment. 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. 
 
5.1.4. On antiretroviral therapy for at least 24 months and on potent antiretroviral therapy 
for ≥ 6 months prior to Screening (Visit 1). 
 
Potent ART is defined by current treatment guidelines and consists of at least 
nucleoside/nucleotide reverse transcriptase inhibitors plus a non-nucleoside 
reverse transcriptase inhibitor, integrase inhibitor, or a protease inhibitor without 
interruption (defined as missing more than 9 total days in the 12 weeks prior to 
Screening). 
 
Other potent fully suppressive antiretroviral combinations will be considered on a 
case-by-case basis. Prior changes in or elimination of medications for easier 
dosing schedule, intolerance, toxicity, or other reasons are permitted if an 
alternative suppressive regimen was maintained. 
 
5.1.5. Ability and willingness of participant to continue ART throughout the study. 
 
5.1.6. Able and willing to adhere to protocol therapy, schedule, and judged adherent to 
antiretroviral therapy (adherence defined in 5.1.4.) 
 
5.1.7. Plasma HIV-1 RNA < 50 copies/mL at two time points in the previous 12 months 
prior to study screening (one time point can be at screening) and never ≥ 50 
copies/mL on two consecutive time points in the last 24 months. 
 
NOTE: A single unconfirmed plasma HIV RNA ≥ 50 copies/mL but < 1000 c/mL is allowed 
if a subsequent assay was <50 copies/mL; but none in the 6 months preceding the study 
screening visit.   
 
5.1.8. Plasma HIV-1 RNA < 50 copies/mL at screening. 
 
5.1.9. CD4+ cell count ≥ 350 cells/mm3 at screening. 
 
5.1.10. No active HCV infection at or within 90 days of screening. 
Note: NO active HCV defined as negative HCVAb or if HCVAb is positive, reflex HCV RNA 
is negative. 


 
 
 
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5.1.11. No active HBV infection (measurable HBV DNA or HBsAg+) at or within 90 days 
of screening. 
 
5.1.12. Women with written documentation of any of the following: 
a) prior hysterectomy OR bilateral oophorectomy (removal of both ovaries)  
b) bilateral tubal ligation or non-surgical permanent sterilization   
c) Women with intact uterus and ovaries who have not had a period for ≥ one year 
AND have a documented FSH level indicating postmenopausal status. 
 
5.1.13. All male study volunteers must agree not to participate in a conception process 
(e.g. active attempt to impregnate, sperm donation, in vitro fertilization) and, if 
participating in sexual activity that could lead to pregnancy, the male study 
volunteer and his female partner must use two reliable methods of contraception 
(condoms, with or without a spermicidal agent; a diaphragm or cervical cap with 
spermicide; an IUD; or hormonal-based contraception) simultaneously while 
receiving the protocol-specified study products and for 6 weeks after stopping the 
study products. Participants must use a reliable barrier method of contraception 
(condom, cervical cap) along with another form of contraception.   
 
NOTE: For female partners receiving ritonavir, estrogen-based contraceptives are not 
reliable and an alternative method should be suggested. 
 
5.1.14. Ability and willingness to provide adequate locator information.  
 
5.1.15. Ability and willingness to communicate effectively with study personnel. 
  
5.1.16. Adequate vascular access for HXTC infusion and leukapheresis.  
 
5.1.17. Able to swallow pills without difficulty. 
 
5.1.18. Potential participant must have 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 
≥ 12 g/dL (male) and ≥ 11.0 g/dL (females) 
System 
Laboratory Value 
Coagulation  
Prothrombin Time (PT) or INR 
<1.1 x ULN  
 
 
Chemistry 


 
 
 
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K+ levels 
WNL 
Mg++ levels1 
WNL  
Glucose  
Screening serum glucose ≤ Grade 1 (fasting or 
non- fasting)  
Albumin  
≥ 3.5 g/dL or ≥ LLN  
Renal 
Creatinine clearance determined by the 
CKD-Epi equation found at: 
https://www.qxmd.com/calculate/calcula
tor_251/egfr-using-ckd-epi 
eGFR > 60mL/min 
Hepatic 
Serum total bilirubin 
Total bilirubin < 1.1 times the ULN range. 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  
< 1.25 X ULN 
Lipase  
< 1.1 X ULN 
1 LLN for Mg++ per the clinical laboratory’s normal range used for this study is a grade 1 event per 
DAIDS Toxicity Table and is allowed for eligibility 
 
ULN = upper limit of normal     LLN = lower limit of normal     WNL = within normal limits 
 
5.2. Participant Exclusion Criteria  
5.2.1. Known allergy or sensitivity to components of VOR and its analog or to 
components in the HXTC product.  
 
5.2.2. Women without written documentation of menopause (absence of a period for ≥ 
one year and FSH level indicating menopause), hysterectomy or bilateral 
oophorectomy, non-surgical permanent sterilization, or bilateral tubal ligation. 
  
5.2.3. Untreated syphilis infection (defined as a positive rapid plasma reagin (RPR) 
without clear documentation of treatment).  
 
Note: In cases of untreated syphilis, participant may re-screen following documentation of 
adequate treatment of syphilis  
 
5.2.4. All male participants expecting to father children within the projected duration of 
the study.  
 


 
 
 
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5.2.5. Receipt of compounds with HDAC inhibitor-like activity, such as valproic acid 
within 30 days prior to screening.  
 
5.2.6. Use of any investigational antiretroviral agents within 30 days prior to screening. 
 
5.2.7. If the study PI (or designee) is unable to construct a fully active alternative ART 
regimen based on previous resistance testing and/or treatment history.  
 
5.2.8. Use of the following medications that carry risk of torsade des pointes: 
amiodarone, arsenic trioxide, astemizole, bepridil, chloroquine, chlorpromazine, 
cisapride, clarithromycin, diopyramide, dofetilide, domperidone, droperidol, 
erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, 
methadone, pentamidine, pimozidine, probucol, procanimide, quinidine, sotalol, 
sparfloxacxin, terfenadine, thioridizine. 
 
5.2.9. Use of any of the following within 90 days prior to screening: immunomodulatory, 
cytokine, or growth stimulating factors such as systemic corticosteroids, 
cyclosporine, methotrexate, azathioprine, anti-CD25 antibody, IFN, interleukin-2 
(IL-2), coumadin, warfarin, or other Coumadin derivative anticoagulants. 
 
5.2.10. Prior use of any HIV immunotherapy or HIV vaccine within 6 months prior to 
Screening, except for prior HXTC infusions. 
 
5.2.11. Received any infusion blood product, immune globulin, or hematopoietic growth 
factors within 90 days prior to study screening.   
 
5.2.12. Pregnancy or breast-feeding. 
 
5.2.13. History or other clinical 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 (or designee).  
 
5.2.14. Use of topical steroids over a total area exceeding 15 cm2  within 30 days prior to 
Screening. 
 
5.2.15. Treatment for an active AIDS-defining opportunistic infection within 90 days prior 
to Screening.  
 
5.2.16. Any active malignancy that may require chemotherapy or radiation therapy. 
 
5.2.17. Compulsorily detained (involuntarily incarcerated) for treatment of either a 
psychiatric illness or a physical illness, e.g., infectious disease. Prisoner 
recruitment and participation is not permitted.  
 


 
 
 
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5.2.18. Known psychiatric 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).  
 
5.2.19. History or other clinical evidence, as assessed by the study PI (or designee), of 
significant or unstable cardiac disease (e.g., angina, congestive heart failure, 
recent myocardial infarction, significant arrhythmia requiring medical or surgical 
therapy) or clinically significant electrocardiogram (ECG) abnormalities.  
 
 
5.2.20. Participation in another investigational clinical research study (with the exception 
of an antiretroviral treatment trial that uses FDA approved antiretroviral agents) 
or use of investigational agents within 30 days prior to screening. 
 
NOTE: Co-enrollment in observational only studies is permitted. 
 
NOTE: Co-enrollment in the ACTG 5332 REPRIEVE study (NCT023442900) and 
using FDA approved pitavastatin is permitted provided participant enrolled on 
ACTG 5332 and has taken the study provided medication ≥ 4 months. 
 
5.3 Strategies for Recruitment and Retention 
 
There are several venues for recruitment available to the study team: 
 
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 research studies in the past. These individuals will be 
provided with the opportunity to discuss this study with their provider and the study 
coordinator.  
 
The UNC acute HIV program actively enrolls persons diagnosed with AHI into treatment 
protocols and also follows persons off treatment studies in a longitudinal cohort protocol. 
Currently there are at least 65 active participants who were seen and treated in AHI in 
the UNC cohort.   
 
Individuals who have signed the UNC CFAR (Center for AIDS Research) database 
consent as well as those who have signed the consent for the PHI (Primary HIV Infection) 
studies/database will be identified and approached about the study by either their primary 
care provider or the study coordinator, after consultation with their primary care provider.  
 
If individuals are interested in participating in the study, they will be provided with 
appropriate study information and the opportunity to screen. All potential participants will 
be informed that on rare occasions some of the serious side effects described in this 
protocol as well as other unpredicted adverse events can occur. They will be told that 


 
 
 
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their participation in this study will allow researchers the opportunity to collect valuable 
information about the use of HXTC in individuals with durable viral suppression and its 
ability to improve immune responses. Potential participants will be informed that there 
may be no direct and immediate benefits to them as volunteers in this study, but 
information learned from this study may be of value to the participant and other people 
with HIV disease.  
 
Participants will be screened and recruited in the Infectious Diseases (ID) Clinic and the 
Clinical and Translational Research Center (CTRC) of the University of North Carolina 
(UNC) at Chapel Hill. Study activities can take place in the CTRC unit, the Apheresis Lab, 
the American Red Cross (ARC) in Durham, NC, and/or the UNC ID Clinic, located in the 
University of North Carolina Memorial Hospital.   
 
Screening will take place in a step-wise manner. Screening procedures and assessments 
will include the following: completion of informed consent process, determination of HIV 
infection status, documentation of stable ART and HIV RNA < 50 copies for ≥ 2 years, 
locator information, and screening safety laboratory testing and safety procedures.  
 
Screening and enrollment occur in Step 1. After establishment of the baseline safety (Visit 
1) parameters and qualifying for the study per the Inclusion and Exclusion Criteria, the 
participant is enrolled (Visit 2) and completes the baseline leukapheresis.  The IUPM 
measurement of ≥ 0.3 obtained from samples collected during the baseline leukapheresis 
determine whether the participant moves to Step 3.   
 
5.4. Participant Withdrawal 
 
Handling of Participant Withdrawals or Participant Discontinuation of Study Intervention 
 
Participants failing to meet criteria to advance to Step 4 are not required to complete an 
end of study visit (Step 6, Visit 23). Reasons for not progressing to Step 4 include: 
• 
Inability to manufacture HXTC product in Step 3  
• 
Failure to meet requirements established for the pre-dose safety assessment for 
Step 4 at Visit 6. 
 
If the participant withdraws, discontinues, or fails to advance in the study for any reason 
after initiating VOR dosing and HXTC infusions in Step 4, the participant would be 
asked to complete an Early Discontinuation Study Visit (Step 6, Visit 23). This visit will 
occur ≥ 4 weeks but ≤ 8 weeks after the last documented visit or study treatment, 
whichever occurred last. Participants would then proceed to complete Visit 24. 
 
In scenarios where participants are discontinued or withdrawn after receiving VOR 
doses in combinations with HXTC infusions, the study PI (or designee) will make every 
effort to complete the Early Discontinuation Study Visit/End of Study Intervention (Step 
6, Visit 23) evaluations. 


 
 
 
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The Early Discontinuation or End of Study Interventions Visit will include the clinical 
assessments and required labs per the SOE. The completion of the Leukapheresis 
procedure at this visit will be determined on a case-by-case basis by the study PI (or 
designee). 
 
UNC reserves the right to discontinue the study for any reason at any time. The study 
may also be stopped if, in the opinion of the principal investigator and/or protocol team, 
the continuation of the study represents an unwarranted medical risk to the participants.   
 
5.5. Premature Termination or Suspension of Study  
 
5.5.1. Study Treatment Stopping Rules or Permanent Treatment Discontinuation 
 
A participant will not receive VOR and/or HXTC infusions if any of the following 
occurs: 
• 
Pregnancy of study participant 
• 
Treatment related ≥ Grade 3 adverse event 
• 
Requirement for prohibited concomitant medications 
• 
Inability to complete treatments as defined in the protocol 
• 
Request by participant to terminate study treatments 
• 
Clinical reasons believed life-threatening by the PI or designee 
• 
Hematologic dose-limiting toxicity defined as any confirmed toxicity ≥ 
Grade 2, that cannot clearly be attributed to another reversible cause other 
than VOR 
• 
Development of a dose-limiting toxicity  
• 
HIV RNA > 150 copies/mL on two consecutive determinations.  
 
Participants who prematurely discontinue study treatment will move to Step 6, Visit 
23 and will be followed through Visit 24. See section 5.4, Participant Withdrawal, for 
details on study procedures to be completed.  
 
5.5.2. Premature Study Discontinuation  
 
A participant may withdraw or be withdrawn from the study if any of the following 
occurs: 
• 
Pregnancy of study participant 
• 
Failure by the participant to attend multiple clinic visits 
• 
Failure to receive the first HXTC infusion  
• 
Failure to continue to meet pre-dose safety assessment requirements 
• 
Failure to meet baseline IUPM measurement criteria 
• 
Development of an illness that requires treatment with certain medications 
not allowed in this study 
• 
Inability to manufacture HXTC product for infusion  


 
 
 
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• 
Poor adherence to ART as judged by the PI (or designee) 
• 
Request by the participant to withdraw 
• 
Request of the participant’s primary care provider if s/he thinks the study is 
no longer in the best interest of the participant 
• 
Participant judged by the PI (or designee) 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, Food and Drug 
Administration (FDA), NHLBI, Office for Human Research Protections 
(OHRP), other government agencies as part of their duties, PI, or industry 
supporter  
 
6. STUDY INTERVENTION 
 
6.1 HXTC 
6.1.1. Collection of 100 mL of Blood 
 
Participants will have 100 mL of blood drawn at Step 3, Visit 5 to make the study 
product. These whole blood samples are shipped ambient temperature overnight to 
the CETI Processing Facility at CNH in Washington, DC. This shipment also includes 
an additional sample for HLA analysis.  
 
If the participant previously participated in another study protocol at UNC and has 
sufficient product already manufactured under IND 15984, the study will not require 
an additional blood sample and will use the previously manufactured and stored 
HXTCs. 
 
6.1.2. Study Product Manufacturing 
 
The study product will be made at an established GMP facility at CNH in Washington, 
DC.  A description of the facilities and their operation can be found in the IND 15984 
application under IND Section 7.0 – Product Manufacturing & Characterization 
Manufacturing Environment. 
 
6.1.2.1. 
Manufacture of HXTC 
 
Cells.  
The cell therapy product for infusion consists of autologous HXTCs targeting 
the gag, pol, and nef antigens of HIV-1. Blood will be collected by 
venipuncture and processed according to UNC Clinical and Translational 
Research Center (CTRC) and shipped ambient to CNH per SOP. Blood will 
be processed into peripheral blood mononuclear cells (PBMCs) and then 
used to manufacture three different components: (1) Dendritic cells (DCs) 
that will be loaded with pepmixes spanning the three target antigens, 


 
 
 
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irradiated and used as antigen-presenting cells (APCs) for the first 
stimulation of PBMCs, (2) peptide pulsed autologous T- cell PHA blasts and 
K562 that will be irradiated and used for the second and subsequent 
stimulations of HXTCs, and (3) HXTCs generated by stimulation with 
peptide-pulsed PHA blasts and K562 and which will comprise the final T-cell 
product. 
 
The flow chart for these procedures is shown in Figure 2 of the protocol.  
 
Overlapping Peptide Libraries (pepmixes). PepMixes HIV Ultra produced 
by JPT Peptide Technologies will be used as an antigen source. These 
pepmixes include a pool of 150 15meric peptides derived from Gag, Pol, 
and Nef polyprotein designed to cover the high sequence diversity of the 
HIV-1 virus. The pepmixes were derived from protein sequences of all 
subtypes of HIV-1/SIVcpz based on the HIV sequence database of the Los 
Alamos National Lab. The end product pool will be cryopreserved prior to 
infusion. 
 
Cell Bank System. A formal cell bank system will not be used for the cell 
therapy product. Back-up cells will be frozen down at various stages during 
the manufacturing process. Each final product, however, will consist of a 
single lot of cells designated for a specific participant.  
 
Manufacturing Environment. The cell therapy product described in this 
section will be manufactured by the Cell Processing Facility (CPF) staff in 
the Program for CETI at CNH in Washington, DC. These are ISO 7 and ISO 
8 manufacturing environments that operate in compliance with current Good 
Manufacturing Practices as applicable to products intended for Phase I/II 
clinical trials.  
 
Dendritic Cell Generation. The generation and maturation of DCs is 
accomplished when peripheral blood mononuclear cells are isolated from 
whole blood and separated by adherence. Monocytes contained in the 
adherent fraction are cultured in DC skewing conditions for 4- 5 days. They 
are then matured with an established cytokine cocktail before use as an 
antigen presenting cell.   
 
Loading Dendritic Cells With Pepmixes. Mature DCs are pelleted and 
pulsed with pepmixes using a proprietary algorithm to provide broad 
coverage of gag, pol, and nef across all clades. 
 
HXTC generation. HXTCs are derived from the non-adherent fraction of 
PBMCs. T cells are stimulated a minimum of two times using Gag, Pol, and 
Nef pepmix-pulsed DCs for the first stimulation and pepmix-pulsed, 


 
 
 
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irradiated PHA blast for the second and any subsequent stimulations, if 
required for HXTC expansion. Genetically-modified co-stimulatory K562 
cells (GM-K562) will be incorporated into the co-culture during the second 
stimulation, if needed based on insufficient expansion.  
 
Culture of DCs and T cells will be performed in the presence of Atazanavir 
(AZT) and Enfuvirtide (T20) to inhibit potential HIV replication in cultures. At 
the end of the culture period, HXTCs will be cryopreserved for infusion and 
submitted for release testing. For information purposes only, additional 
assays such as ICS, elispot, and pentamer analysis will be performed based 
on cell availability and HLA.   
 
Each product will have 4 identifying IDs. All labeling will conform to the 
labeling procedures required by CETI. All cultureware is labeled with the 
UNC participant ID (PID) and Study ID (SID) as well as the unique CETI-
assigned donor identification number (DIN) and unique product number (P 
number). Only one participant cell line is ever processed at any one time. 
Medium prepared and labeled specifically for each participant’s cells is 
always used.  
 
Figure 2: Summary of Manufacturing Process 
 
 
6.1.3. Cryopreservation of Products  
 
When sufficient cells for participant infusion are obtained, they are characterized and 
frozen. The number of cells required for five participant doses is based on the 
participant’s body surface area. Sufficient cells to allow for loss during 


 
 
 
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cryopreservation (+ up to 20%) and for samples required for characterization and 
safety testing are processed. The product’s cells and supernatant will be tested for 
mycoplasma testing and microbiological testing. Final product will be tested for HLA-
typing, and phenotyping, and viability. The final cell suspension will also undergo 
endotoxin testing. Cryovials or cryocyte bags are labeled with participant’s PID, SID, 
CETI DIN, and P number, type of component, number of cells, and date of freezing. 
Cryovials or bags are then cryopreserved in a controlled rate freezer and transferred 
to storage in the Central Processing Facility liquid nitrogen freezer under the 
auspices of QC (quality control). The storage facility is within clean room space and 
is fully monitored 24/365. 
 
6.1.4. Study Product Manufacturing Process 
 
Reagents. Certificates of analysis for all reagents, materials, and supplies are kept 
on file indefinitely and the lot numbers, manufacturer, and expiration date of each is 
captured at each use by means of our inventory control system where only released 
supplies and reagents are available in the GMP facility, and all supplies and reagents 
are tracked on the worksheet.  
 
Reagent Qualification. Pepmixes are a mixture of peptides chosen by a proprietary 
algorithm developed by JPT Peptide Technologies to provide broad coverage of HIV 
antigens Gag, Pol, and Nef across many clades of HIV. JPT Peptide Technologies 
will provide these clinical grade pepmixes freeze-dried. One mg of each individual 
peptide was synthesized and purified by HPLC to a purity of ≥ 90% measured at 
220nm using a linear gradient system. The purity and identity of the peptides was 
confirmed by high-performance liquid chromatography (HPLC) and mass 
spectroscopy (LC-MS). For pooling, sub-pools of 10-25 peptides were generated. 
The presence of all peptides within sub-pools was proven by LC-MS analysis of each 
sub-pool. From each sub-pool at least one peptide was defined as a "marker-
peptide" having a unique molecular weight and HPLC retention behavior. Sub-pools 
were combined and the generated final pool applied to LC-MS. LC-MS data were 
tracked to show the presence of at least one "marker-peptide" per sub-pool within 
the final pool confirming that all individual peptides are present in the final pool. The 
pepmixes are sterile, and endotoxin-free.  
 
Materials and reagents in contact with the product during manufacturing are sterile 
and pyrogen-free as determined from the manufacturer’s certificate of analysis.  No 
antibiotics are used during manufacturing. Records of all testing are kept on file. 
 
Removal of Reagents from Final Product. Cytokines, antiretrovirals, and culture 
medium are removed by extensive washing of the cells. The final cells are washed 
four times and re-suspended in balanced salt solution or plasmaLyte containing US 
Pharmacopeia (USP) human serum albumin and USP dimethyl sulfoxide (DMSO) 
for cryopreservation. 


 
 
 
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Antibiotics: Antibiotics are not used during manufacturing. 
 
6.1.5. Product Testing and Release 
 
Test Methods 
The following tests are performed by the CETI QC laboratory or a CNH facility per 
standard operating procedures. 
 
Sterility Testing 
The BacT/Alert blood culture system and Fungal Isolator tubes are used to test 
sterility of the final product, and samples are inoculated into culture medium in 
anaerobic, aerobic, and fungal culture bottles. Bottles are incubated for 14 days 
(bacterial) or 21 days (Fungal) with ongoing assessment for contamination.  
 
Mycoplasma 
Mycoplasma testing of the final product uses a commercially available MycoAlert 
(Lonza) by the CETI Quality Control Laboratory. This assay uses the MycoAlert kit, 
which detects the presence of mycoplasmal enzymes, which catalyze the conversion 
ADP to ATP and is detectable using luciferase. It is used for in-process testing and 
to obtain rapid results while results of the culture assays are pending. Data from this 
test method will be accumulated in preparation for validation against the Points to 
Consider method.  
 
Endotoxin 
Endotoxin levels in the final product will be assayed using the Limulus Amebocyte 
Lysate assay. For release testing, the Endosafe PTS system will be used. This test 
is a miniaturized version of the standard LAL assay and the cartridges employed 
have received FDA approval. The limit of quantitation of the assay is approximately 
0.05 EU/mL. 
 
Identity 
The identity of the cells will be determined by HLA typing. The final product consists 
of participant-derived HIV-specific T cells. Therefore, the HLA type of the final 
product should be identical to that of the participant blood. 
 
Potency 
For this phase I study, potency is not a release criterion. However, for safety 
purposes we will ensure that the immunophenotype excludes the presence of 
dendritic cells (CD3-CD83+) and GM-K562 cells (CD3-, CD16/56-, CD32+, CD83+) 
in the product. For informational purposes, the potency of all HXTCs will be 
evaluated using cytotoxicity and or Elispot assays.  
 
 


 
 
 
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Viability 
Viability of the final cell product will be assessed for release using trypan blue 
exclusion. 
 
Notification of Physician in Case of Positive Sterility Report 
The final cell product will be tested for sterility using a BacT/Alert test but will not be 
available at the time the product is released. Should the BacT/Alert or fungal 
sterilities be reported as positive after product administration, the UNC Principal 
Investigator and study team will be immediately notified. CETI will obtain and inform 
him/her of the identity and antibiotic sensitivity of the organism. CETI will generate a 
Variance to document and determine corrective actions and their efficacy.  
 
Table 2. Final product testing 
Testing 
Test to be 
used 
Specificity/ 
Sensitivity 
Criteria for Acceptance 
Results 
Available Before 
Administration 
Viability 
Trypan Blue 
Live cells 
>70% 
Yes 
Sterility 
BacT/Alert 
Bacteria 
Negative at 4 days 
(cultured for up to 14 days) 
Yes 
Sterility 
Isolator tubes 
Fungal 
Culture 
Fungus 
Negative at 4 days (cultured up 
to 21 days) 
Yes 
Mycoplasma 
MycoAlert 
12 most 
common 
species 
Negative 
Yes 
Purity 
Endotoxin 
Endosafe 
PTS (LAL) 
<5.0 EU/kg 
<5.0 EU/mL 
Yes 
Identity 
HLA Typing 
N/A 
Identical to participant 
Yes 
Phenotype 
Flow 
Cytometry 
Cell type 
<0.1% CD3-, CD16/56-, CD32+, 
CD83+ (GM-K562 cells); <2% 
CD3-/CD83+(DCs) 
Yes 
 
6.1.6. HXTC Storage and Stability 
 
The samples collected at UNC for product manufacturing are kept in a temperature-
controlled storage area of the UNC CFAR HIV and STD Laboratory Core (CHSLC) 
Lab located in the CTRC Unit in the Burnett-Womack Building next to UNC Hospitals. 
These samples will be packaged per International Air Transport Association (IATA) 
regulations, and picked up in the later part of the same day of collection, and sent 
overnight, delivered at approximately 10 AM the next day at CNH. The shipment of 
the samples occurs Monday – Thursday to assure that a person is on site at CETI 
(CNH) to receive the package. The UNC CHSLC Lab communicates with the CETI 


 
 
 
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site via email, notifying them of shipment, and receipt of package is then verified by 
CNH. Samples are shipped ambient temperature.   
 
The HXTC final cellular product is cryopreserved and shipped in a liquid nitrogen-
charged cryogenic shipper from the manufacturing site in Washington, DC to the 
Hematopoietic Progenitor Cell (HPC) Lab located in UNC Memorial Hospital in 
Chapel Hill, NC. The CNH group has extensive experience with the shipping of virus-
specific T-cells to distant sites. 
6.1.7. Dosage, Preparation, and Administration of HXTC 
Each dose of HXTC is 1 x 108 cells/m2 and each participant will receive five infusions 
at this dose, provided there are enough manufactured T-cells. If unable to 
manufacture enough cells for five infusions at 1 x 108 cells/m2 participants will receive 
five infusions at a dose ≥ 5 x 107 cells/m2 up to 1 x 108 cells/m2 as determined by the 
protocol team.  
 
The first HXTC infusion (HXTC #1) will be infused approximately 6 hours after the 1st 
dose of VOR (Step 4, Visit 7) and the 2nd HXTC infusion (HXTC #2) after the 6th dose 
of VOR (Visit 10) in Step 4. In Step 5 each participant will receive the next three 
HXTC infusions. The 3rd HXTC infusion (HXTC #3) will be infused approximately 6 
hours after the 11th dose of VOR 400 mg (Step 5, Visit 14) and HXTC infusion #4 will 
occur approximately 6 hours after the 16th dose (Step 5, Visit 16). The 5th or last 
HXTC infusion (HXTC #5) occurs 1 to 3 days after the 20th dose of VOR (Visit 19).  
 
In preparation of each HXTC dose of 1 x 108 cells/m2, an extra - volume (1 – 20%) is 
added to account for cell loss. When possible, CETI will cryopreserved the cells at 1 
x 108 T cells per mL, allowing the cells to be thawed and injected directly. However, 
the cell concentrations can vary from time to time; therefore, dosage calculations and 
body surface area (BSA) are calculated both at CETI (prior to shipment) and then by 
two independent licensed practitioners at the UNC site prior to administration to 
confirm accurate dose delivery.  
 
The required amount of HXTCs for the infusions are shipped to the UNC HPC Lab, 
where they are stored and maintained in in biological safety cabinets (BSC). If extra 
cells are produced, CETI archives these aliquots at their manufacturing site. These 
stored aliquots are accessible for additional infusions under IND 15984 or research 
analysis. 
 
All study HXTC infusion visits occur in the UNC CTRC. After completion of all 
required clinical assessments prior to the infusion, the HXTC product is thawed, 
delivered and verified with the study coordinator. Review of the HXTC product occurs 
prior to administration per the UNC HIV Cure Center SOP entitled Cellular Product 
Infusion Guidelines and Emergency Management Plan.  
  
Participants are pre-medicated with cetirizine (Zyrtec)  and acetaminophen (Tylenol). 


 
 
 
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• 
Cetirizine 
o All infusions – administer 10 mg PO 
• 
Acetaminophen 
o All infusions – administer 500 mg PO (weight <65 kg) or 650 mg PO 
(weight ≥65 kg). 
 
Cell Administration:  HXTC will be given by IV infusion at a rate of 4-6 mL/min through 
a peripheral line.  
 
Post infusion monitoring lasting at least 60 minutes follows each infusion.  
 
Participants will receive supportive care for acute toxicity directly attributable to 
HXTC, as appropriate. 
 
All treatments will be given at the University of North Carolina at Chapel Hill.  
 
The grading system for drug toxicities is located in the Division of AIDS (DAIDS) 
Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1. 
[July 2017], which can be found on the DAIDS RSC Web site:  
http://rsc.tech-res.com/safetyandpharmacovigilance/ 
 
A period of six weeks following the completion of the last infusion will constitute the 
time required for clinical safety monitoring and reporting of adverse events related to 
infusions.  
 
6.2. VORINOSTAT (VOR) 
 
6.2.1. Formulation, Packaging, and Labeling   
 
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 Table 3. 
 
Table 3: 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 160.5oC 
pKa 
8.5 and 11.1 
Hygroscopicity 
None 


 
 
 
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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% 
Hydrates 
None 
Chirality 
None 
 
The oral formulation of VOR is available as a 100-mg capsule. Earlier studies of VOR 
were performed with formulation strengths of 50 mg and 200 mg. Currently no 
additional dose images other than the 100 mg strength is manufactured. Each 100 
mg ZOLINZA capsule for oral administration contains 100 mg VORINSTAT 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. 
 
6.2.2. VOR Storage and Stability 
 
VOR will be stored and dispensed by the UNC Hospitals Investigational Drug 
Services (IDS) Pharmacy. VOR will be dispensed by prescription on a participant 
specific basis. 
 
Store at 20-25°C (68-77°F), excursions permitted between 15-30°C (59-86°F) [See 
USP Controlled Room Temperature.] The IDS staff’s responsibilities include 
maintaining, monitoring and documenting the temperature in the pharmacy supply 
storage area per institutional guidelines. 
 
Proper Disposal of VOR 
 
The IDS Pharmacy follows the guidance established in their SOP for the disposal of 
non-hazardous investigational drug.   
 
VOR is an anti-cancer drug. Procedures for proper handling and disposal of anti-
cancer drugs are established in the UNC Hospital Policy (Policy Stat ID 4734545) 
called “Handling and Disposal of Hazardous Drugs (Antineoplastic, Biologic, 
Cytotoxic, and Immunosuppressant Drugs) dated February 2018. 
 
VOR in capsule form is a low-risk hazardous drug. Gloves must be worn when 
handling VOR. VOR capsules should not be opened or crushed. Direct contact of 
the powder in VOR capsules with the skin or mucous membranes should be avoided. 
If such contact occurs, wash thoroughly. Your supervisor and employee health 
should be notified immediately. Personnel should avoid exposure to crushed and/or 
broken capsules. 
 


 
 
 
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Procedures for proper handling and disposal of anti-cancer drugs follow the UNC 
Hospital Policy Stat ID 4734545. Spills of powder from VOR capsules due to 
damaged or broken capsules should be cleaned up carefully to minimize inhalation 
of VOR. The affected area must be washed at least 3 times with ethyl alcohol, 
followed by water. Direct contact of the powder in VOR capsules with the skin or 
mucous membranes should be avoided. If such contact occurs, wash thoroughly. 
 
For the most part, the techniques are merely an extension of good work practices by 
health-care and similar in principle and practice to Universal Precautions (Centers 
for Disease Control. 1988. Update: Universal Precautions for Prevention of 
Transmission of Human Immunodeficiency Virus, Hepatitis B Virus, and Other 
Bloodborne Pathogens in Health-Care Settings. Morbidity and Mortality Weekly 
Report, 37(24):377-382, 387-388.). 
 
The cleanup and disposal of spilled, wasted, or unused medication as well as 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. 
 
6.2.3. Dosage, Preparation, and Administration of VOR 
 
The UNC IDS Pharmacy stores, distributes, and maintains accountability for VOR.  
The dispensing of each dose will be participant specific and by signed prescription. 
Upon receipt of the VOR doses from IDS, the study coordinator dispenses VOR to 
the participant in the research clinic according to the dose, schedule, and supportive 
care guidelines.   
 
Take each VOR dose with food.  
 
The primary IDS pharmacist will be responsible to the principal investigator for 
maintaining study drug accountability, reconciliation, and record maintenance during 
the study, including documentation of the amount of study treatments (VOR) 
received in IDS and the amount administered to each participant.  
  
 
Participants will be provided their first dose of VOR 400 mg in Step 3, Visit 6 to take 
4 in Step 4, Visit 7.  Participants will take this dose at home in the morning prior to 
coming for Visit 7.  The study coordinator will provide participants with individualized 
dosing instructions, clearly identifying the days they are required to take VOR. The 
study coordinator will contact participants on each dosing day. Participants will be 
instructed to contact the study coordinator and be prepared to return to the clinic 
should any adverse event evolve. Participants will be monitored for the development 
of toxicities. Participants will take the doses approximately 72 hours apart.  
 
6.3. Concomitant Medications/Treatments 


 
 
 
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Once a participant enrolls in the study, all medications will be monitored. Participants 
must report whenever they start a new medication or have changes to their existing 
medications. This applies to both prescription and over-the-counter medications. 
Document the initiation and administration of the study agents. The study PI or co-
investigators reviews the concomitant medications’ and study agents’ most recent 
package inserts and investigator’s brochures to obtain the most current information on 
drug interactions, contraindications, and precautions. 
 
6.3.1. Required Medications  
 
All participants must be on ART as specified in the inclusion criteria (Section 5.1). 
The study does not provide ART medications.   
 
Changes to the participants’ ART during the study are permitted for dosing 
simplification, tolerability issues, or at the investigator’s discretion. If the participant 
develops toxicity related to his/her previously stable ART, then the principal 
investigator (PI) or protocol team should be consulted and preferably before 
appropriate therapy modification. 
 
6.3.2. Permitted Medications  
 
Regularly prescribed medications such as antipyretics, analgesics, antidepressants, 
sleep medications, oral contraceptives, megestrol acetate, testosterone, and other 
medications for chronic conditions that do not interact with VOR or HXTC Therapy; 
 
Antibiotics for bacterial infections;  
 
Maintenance therapy for opportunistic infections that develop while on study 
according to standards of medical care; 
 
Standard vaccinations (e.g., flu) with the exception of live vaccines are permitted any 
time; 
 
Intermittent use of inhaled corticosteroids (e.g., for chronic obstructive pulmonary 
disease [COPD], asthma) is only permitted for participants not receiving ritonavir or 
cobicistat as part of their current ART regimen and after consultation with the study 
PI or designee); 
 
Sporadic topical use of corticosteroids (e.g., creams) to small areas of the skin (15 
cm2) after consultation with the PI (or designee) is only permitted for participants who 
are not receiving ritonavir or cobicistat as part of their current ART regimen; and  
 


 
 
 
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For treatment of infusion reactions (Grade 1 and Grade 2) flu-like symptoms, non-
steroidal anti-inflammatory drugs (NSAIDs) may be used to alleviate symptoms 
under a physician’s guidance and for a limited period of time.   
 
6.3.3. Prohibited Medications 
 
Prohibited HIV ART: Any investigational ART.  
 
Live vaccines after enrollment and for the duration of the study.  
 
Concomitant immunosuppressive, immunomodulatory, or neoplastic agents; 
 
Use of growth factors, cytokines, or white lineage colony stimulating factors (e.g., 
granulocyte-colony stimulating factor [G-CSF] and GN-CSF); 
 
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;  
 
Note: Refer to exclusion criteria in section 5.2.  
 
7. STUDY SCHEDULE 
 
7.1. Study Procedures 
 
Participant study screening, eligibility, enrollment, baseline leukapheresis, and IUPM 
measurement are all completed and assessed during Step 1.  
 
Study eligibility is determined at screening.  Enrollment (Visit 2) occurs prior to or at the 
baseline leukapheresis procedure (leuk#1).  
 
Enrolled participants advance to Step 3 if the baseline IUPM measurement is ≥ 0.3.   
    
Study Visit Windows 
 
Study enrollment is within 30 days of screening. The baseline leukapheresis can be 
performed at enrollment or within 45 days of screening. 
 
While on study, all study windows are in the schedule of events (SOE) and section 7.3.3 
(Step 4) and 7.3.4 (Step 5). 
 
7.2. Co-enrollment 
 


 
 
 
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Co-enrollment on other studies will be addressed on a case-by-case basis with the study 
team. Due to the potential interference with the monitoring of the effects of this study’s 
treatments, participants will not be able to be enrolled on other studies of investigational 
treatment, unless pre-determined by PI (or designee) that investigational treatment on 
another study is allowed. 
 
7.3. Schedule of Events  
 
A detailed Schedule of Events (SOE) is in Appendix A. 
 
The SOE represents all possible study visits through the last study visit.  Exceptions to 
specific events are noted. 
 
7.3.1. Step 1 – Screening and Enrollment  
 
Screening occurs at Visit 1, with potential participants evaluated for eligibility per the 
inclusion and exclusion criteria. Eligible participants are enrolled at Visit 2. 
 
7.3.1.1. 
Visit 1 – Screening 
 
Includes informed consent, inclusion/exclusion criteria, demographics, and 
other procedures per SOE.  
 
Estimated Blood Volume: up to 45 mL 
 
7.3.1.2. 
Visit 2 – Enrollment and Baseline Leukapheresis 
 
The leukapheresis procedure will follow institutional guidelines for safety 
and monitoring procedures including CBC with differential prior to the 
leukapheresis (UNC Apheresis lab) or within 30 days (ARC), and blood 
pressure and pulse monitoring before, during, and after the procedure. 
 
Estimated Blood Volume: up to 145 mL 
 
Advancement Criteria for Step 3:  
1) Participants with IUPM of ≥ 0.3 as determined by QVOA assay  
 
NOTE: THE PROTOCOL AMENDMENT FOR VERSION 3.0, DATED 20 DECEMBER 2019 ELIMINATED STEP 
2 (VISITS 3 AND 4) OF THE PROTOCOL.  
 
 
7.3.2. Step 3 (Visits 5 and 6) – HXTC Manufacturing and Eligibility Visit for Step 4 
 
Schedule Visit 5 once participant meets advancement criteria for Step 3.  


 
 
 
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7.3.2.1. 
Visit 5 – HXTC Manufacturing 
 
The following events occur at this visit: 
Clinical assessments per SOE 
Blood collection for HXTC manufacturing, HLA typing and Donor ID 
panel 
 
Estimated Blood Volume: up to 245 mL 
 
Ship samples ambient, overnight to CNH. Upon receipt, CNH sends 
confirmation and assigns the two unique CNH product IDs. (Reference 
XTRA Lab Manual and XTRA SOP #3.)  
 
7.3.2.2. 
Visit 6 – Pre-Dose Safety Assessment Visit for Step 4 
 
Schedule Visit 6 after CNH verifies that product manufacturing is complete. 
The pre-dose visit will be ≤ 21 days prior to Step 4, Visit 7 (Study Week 0).  
The pre-dose safety labs must be reviewed and signed off by the study PI 
or designee prior to Visit 7. If the participant does not meet one or more of 
the pre-dose safety lab assessments, repeat of the abnormal lab values 
can occur one time only. If repeat values are within the pre-dose safety 
lab assessment criteria, participants receive VOR and HXTC infusions at 
Visit 7.  
After repeat testing, participants with any lab values that remain outside 
the guidelines below but are considered clinically non-significant and 
documented as such by the study PI (or designee), may proceed to the 
dosing/infusion visit after review and approval of the case by the protocol 
and/or safety committee.  
Please reference the SOE for clinical and research procedures done at 
this visit.    
Hematology 
Laboratory Value 
ANC 
≥1,500 /mcL 
Platelets 
≥125,000 / mcL  
Hemoglobin 
≥ 12 g/dL (male) and ≥ 11.0 g/dL (females) 
Chemistry 
K+ levels 
WNL 
Mg++ levels 
WNL 
Glucose 
≤ Grade 1 (fasting or non-fasting) 
Renal 
Creatinine 
<1.3 X ULN 
Hepatic 


 
 
 
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Total bilirubin 
< 1.1 times the ULN range. If total bilirubin is 
elevated, direct bilirubin must be < 2 times the ULN 
range. 
AST (SGOT) and ALT 
(SGPT) 
< 1.25 X ULN 
Alkaline Phosphatase 
<1.25 X ULN 
Other Testing  
 
Serum pregnancy test 
(all females)  
Negative  
RPR  
No active infection  
HIV RNA  
<50 copies/ml   
CD4  
≥350 
HBsAg and HCV Ab 
Negative or not detectable  
Note: positive HCV Ab will reflex to an HCV RNA. 
In this scenario, a negative HCV RNA will qualify 
participant. 
 
Estimated Blood Volume: up to 120 mL 
 
At this visit, participants will be given 1 dose of VOR 400 mg to take 
home. Upon verification of acceptable labs, participants will be contacted 
to verify date and time of Visit 7 and also to verify the time participant is to 
take the first dose of VOR that morning. Plans will be made for 
participants to return the dose of VOR 400 mg to the study coordinator 
should the participant fail to have acceptable pre-dose labs for Step 4. 
 
The study coordinator and participant will also discuss the Step 4 visits and 
VOR dosing schedule. Participants will be given a VOR dosing schedule 
illustrating the 72-hour dosing schedule (inclusive of date and time) and 
dates of the HXTC infusions. Participants will be provided with information 
about VOR as well as information regarding the storage and handling of 
VOR at home. All of this information will be reviewed prior to sending 
participants home with the first VOR dose.  
 
Steps 4 and 5   
Combined therapy occurs in Steps 4 and 5 – Each participant will receive doses of 
VOR 400 mg with scheduled HXTC infusions.  
 
In Steps 4 and 5, participants receive a combined total of 20 doses of Vorinostat 400 mg 
over the course of 3 months with five (5) intermittent scheduled HXTC infusions up to 1 X 
108 cell/m2 per dose. Following completion of Step 5, participants will complete 6 additional 
visits in Step 6 for immune response monitoring. 
 
7.3.3. Step 4 (Visits 7 – 13) - First Series of VOR 400 mg x 10 doses and 2 HXTC 
infusions 


 
 
 
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Visit Windows for Step 4  
 
Visit # 
Visit Evaluations  
Visit Window  
Visit 7 
VOR Dose 1 and HXTC Infusion #1 
≤ 21 days after Visit 6 
Visit 8 
Safety check and Research Labs 
1 - 3 days after Visit 7 
 
VOR Dose #2 
3 days after Visit 7 (Dose 1 + 3 days) 
Visit 9 
VOR Dose #3 
6 days after Visit 7 (Dose 1 + 6 days) 
 
VOR Dose #4 
3 days after Visit 9 (Dose 1 + 9 days) 
 
VOR Dose #5 
6 days after Visit 9 (Dose 1 + 12 days) 
Visit 10 
VOR Dose #6 and HXTC Infusion #2 
9 days after Visit 9 (Dose 1 + 15 days) 
Visit 11 
Safety Check and Research Lab 
1 - 3 days after Visit 10 
 
VOR Dose #7 
3 days after Visit 10 (Dose 1 + 18 days) 
 
VOR Dose #8 
6 days after Visit 10 (Dose 1 + 21 days) 
 
VOR Dose #9 
9 days after Visit 10 (Dose 1 + 24 days) 
Visit 12 
VOR Dose #10 
12 days after Visit 10 (Dose 1 + 27 days) 
Visit 13 
Safety F/U & Step 5 Pre-Dose Clinical 
Assessment  
7-14 days after Visit 12 
 
7.3.3.1. 
Visit 7 (Week 0) 
 
All female participants require a negative POC urine pregnancy test within 48 hours 
of Visit 7. If, despite the documentation of infertility, a female participant has a 
positive pregnancy test at this visit, they will be discontinued from the study and not 
receive the HXTC infusion or additional doses of VOR.  
 
Estimated Blood Volume: up to 60 ml 
 
7.3.3.1.1. 
VORINOSTAT 400 mg 
 
Participants take one dose of VOR 400 mg PO the morning of this visit and 
document the time of the dose. VOR dosing will be approximately 6 hours (give or 
take approximately 30 minutes) prior to scheduled HXTC infusion. Participants will 
contact the study coordinator to inform them of the time that they took the dose of 
VOR.  
 
If the participant experiences any abnormality, sign, or symptom after taking the 
dose of VOR, they will contact the study coordinator immediately and, if necessary, 
come to the clinic for evaluation prior to their infusion time.  
 
7.3.3.1.2. 
Pre – HXTC INFUSION 
The participant will come to the CTRC research clinic approximately 3.5 - 4 hours 
after taking their dose of VOR for pre-infusion evaluations, which includes:  
• 
Review participant allergies  


 
 
 
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• 
Establish IV access 
• 
Collect research samples approximately 4 hours after AM VOR 
dose. Collection can be +/- one hour of the 4-hour time point. 
• 
Clinical assessments per SOE 
• 
Documented PI review of clinical labs from Visit 6 as well as 
review of clinical assessments done at this visit are required 
prior to the thawing and infusion of HXTC study product. 
 
Note: Administration of HXTC can be delayed up to 1 week pending resolution of 
physical findings or lab abnormalities.  
 
7.3.3.1.3. 
Administration of HXTCs 
• 
Verify IV access 
• 
Pre-medicate approximately 30 minutes prior to infusion with: 
o Cetirizine 10 mg PO   
o Acetaminophen 500 mg PO (weight < 65 kg) or 650 mg 
PO (weight ≥ 65 kg) 
• 
Administer cells per UNC HIV Cure Center SOP for HXTC 
Infusion and the SOP for Cellular Product Infusion Guidelines 
and Emergency Management Plan. 
o Administer HXTC dose up to 1 x 108 cells/m2 by IV 
infusion at a rate of 4-6 mL/min.  
• 
Provide supportive care for acute toxicity as appropriate. 
• 
Assess participant for infusion reaction for 60 minutes post 
infusion. Monitor the infusion site and vital signs. Document the 
assessments every 15 minutes for 60 minutes, and then 
discharge home.  
 
7.3.3.1.4. 
Post Infusion 
 
Provide the participants with the 2nd and 3rd doses of VOR 
400 mg to take home.   
 
The study coordinator will contact participants via their preferred 
way of communication approximately 2 to 3 days after this visit to 
inquire about any reactions or potential treatment emergent 
adverse events (TEAE). Instruct the participant to contact the study 
coordinator or investigator if any adverse events occur not only after 
the infusions but at any time during the study. Coordinator can 
combine this assessment with VOR dosing reminder when these 
events overlap.  
 
7.3.3.2. 
Visit 8 
 


 
 
 
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Participants will have a post HXTC infusion follow-up visit per SOE with 
labs drawn 1 – 3 days post infusion.  
 
Estimated Blood Volume: up to 105 mL 
 
7.3.3.3. 
Visit 9 - Administration 3rd Dose of VOR 400 mg  
 
• 
Participants will take VOR 400 mg PO the morning of this visit and 
document the time taken.  
• 
Participants will contact the study coordinator to inform him/her of the 
time that they took the dose of VOR.  
• 
Participants will come to study visit after taking their dose.  
• 
Refer to SOE for visit procedures and lab collections.  
• 
Dispense 3 doses of VOR 400 mg for self-administration every 72 hours 
at home (Doses # 4, 5, and 6). 
 
Estimated Blood Volume: up to 45 mL 
 
7.3.3.4. 
Visit 10 (VOR Dose #6 and HCTX Infusion #2)  
 
All female participants require a negative POC urine pregnancy test within 
48 hours of infusion visit. If, despite the documentation of infertility, a 
female participant has a positive pregnancy test at this visit, they will be 
discontinued from the study and not receive the HXTC infusion or additional 
doses of VOR.  
 
Estimated Total Blood Volume: up to 45 mL 
 
7.3.3.4.1. 
Administration of the 6th dose of VOR 400 mg 
 
Participants takes VOR 400 mg PO the morning of this visit and 
document the time. This is the 6th dose in the series of 10 doses.  
 
Reference section 7.3.3.1.1. for dosing time and process prior to 
infusion.  
 
7.3.3.4.2. 
Pre – HXTC Infusion  
 
The participant will come to the clinic approximately 3.5 - 4 hours 
after taking their VOR dose.  
 
Reference section 7.3.3.1.2. and SOE for visit procedures and 
processes.  
 


 
 
 
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Safety evaluations and research lab collection:  
• 
Collect safety labs (STAT) or within 48 hours of the visit. 
• 
Collect research labs on the day of visit only.  
o Collect approximately 4 hours after AM VOR dose. 
Collection can be +/- one hour of the 4-hour time 
point. 
 
Documented PI review of clinical labs as well as review of clinical 
assessments done at this visit are required prior to the thawing and 
infusion of HXTC study product. 
 
Administration of HXTC can be delayed up to 1 week, pending 
resolution of physical findings or lab abnormalities.  
 
7.3.3.4.3. 
Administration of HXTC Therapy  
 
Reference section 7.3.3.1.3 for infusion guidelines. 
 
7.3.3.4.4. 
Post infusion  
 
Provide participant with the 7th, 8th, 9th, and 10th doses of VOR 
400 mg to take home.   
 
The study coordinator will contact participants via their preferred 
way of communication approximately 2 to 3 days after study product 
administration to inquire about any reactions or potential TEAEs. 
Instruct the participant to contact the study coordinator or 
investigator of any adverse events after this infusion or at any point 
time during the study. Study coordinator can combine this 
assessment with VOR dosing reminder when these events overlap. 
 
7.3.3.5. 
Visit 11  
 
The study participant will have a post HXTC infusion follow-up visit per SOE 
with labs drawn 1 – 3 days post infusion.  
 
Estimated Total Blood Volume: up to 25 mL 
 
7.3.3.6. 
Visit 12 
 
Participants take their last dose in this series (Dose #10) of VOR 400 mg 
PO in the morning and document the time of the dose. Participants will 
come to research clinic approximately 4 – 6 hours after this dose. 
 


 
 
 
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Participant dose management and coordination with study coordinator will 
be conducted as described in section 7.3.3.1.1. 
 
Clinical assessments and sample collections will be performed per SOE.  
 
Estimated Blood Volume: up to 60 mL 
 
7.3.3.7. 
Visit 13 - Safety Follow-Up and Step 5 Pre-Dose Safety Assessment 
Occurs between 7 and 14 days after Visit 12 and within 21 days of Step 
5, Visit 14.  
The pre-dose safety labs must be reviewed and signed off by the study PI 
or designee prior to Visit 14. If the participant does not meet one or more 
of the requirements of the pre-dose safety lab assessments, repeat of the 
abnormal lab/s can occur one time only. 
After repeat testing, any lab values that remain outside the guidelines 
listed below but are considered clinically non-significant and documented 
as such by the study PI (or designee), may proceed to the dosing/infusion 
visit after review and approval of the case by the protocol and/or safety 
committee.  
Please reference the SOE for clinical and research procedures 
done at this visit.  
Hematology 
Laboratory Value 
ANC 
≥1,500 /mcL 
Platelets 
≥125,000 /mcL  
Hemoglobin 
≥ 12 g/dL (male) and ≥ 11.0 g/dL (females) 
Chemistry 
K+ levels 
WNL 
Mg++ levels 
WNL  
Glucose 
≤ Grade 1 (fasting or non- fasting) 
Renal 
Creatinine 
<1.3 X ULN 
Hepatic 
Total bilirubin 
< 1.6 times the ULN range. If total bilirubin is 
elevated, direct bilirubin must be < 2 times the 
ULN range. 
AST (SGOT) and ALT 
(SGPT) 
≤ 2.5 X ULN 
Alkaline Phosphatase 
≤ 2.5 X ULN 
Other Testing  
 
Serum pregnancy test 
(all females)  
Negative  
RPR  
No active infection  
HIV RNA  
< 50 copies   


 
 
 
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CD4  
≥350 
 
Estimated Blood Volume: up to 60 mL 
Participants will be given 1 dose of VOR 400 mg to take home. Upon 
verification of acceptable labs, participants will be contacted to verify date 
and time of Visit 14 and also to verify the time participant is to take the 11th 
dose of VOR that morning. Plans will be made for participants to return the 
dose of VOR 400 mg to the study coordinator should the participant fail to 
have acceptable pre-dose labs for Step 5. 
The study coordinator and the participant will discuss Step 5 visit schedule 
and VOR dosing schedule. Participant will be given a VOR dosing 
schedule/calendar illustrating the 72-hour dosing schedule (inclusive of 
date and time) and the dates of the HXTC infusions. Participants will be 
provided with information about VOR as well as information regarding the 
storage and handling of VOR at home. All of this information will be 
reviewed prior to sending participant home with the 11th VOR dose.  
7.3.4. Step 5 (Visits 14 – 20) Second Series of VOR 400 mg x 10 doses and three 
HXTC Infusions 
Participants with acceptable pre-dose safety labs as determined in Visit 13 are 
eligible to start dosing with VOR and receive their 3rd HXTC infusion in Step 5, Visit 
14. 
 
Visit Windows for Step 5  
 
Visit # 
Visit Evaluations  
Visit Window  
Visit 14 
VOR Dose #11 and HXTC Infusion 
#3 
≤ 21 days after Visit 13 
Visit 15 
Safety check and Research Labs 
1 - 3 days after Visit 14 
 
VOR Dose #12 
3 days after Visit 14 (Dose 11 + 3 days) 
 
VOR Dose #13 
6 days after Visit 14 (Dose 11 + 6 days) 
 
VOR Dose #14 
9 days after Visit 14 (Dose 11 + 9 days) 
 
VOR Dose #15 
12 days after Visit 14 (Dose 11 + 12 days) 
Visit 16 
VOR Dose #16 and HXTC Infusion 
#4 
15 days after Visit 14 (Dose 11 + 15 days) 
Visit 17 
Safety Check and Research Lab 
1 - 3 days after Visit 16 
 
VOR Dose #17 
3 days after Visit 16 (Dose 11 + 18 days) 
 
VOR Dose #18 
6 days after Visit 16 (Dose 11 + 21 days) 
 
VOR Dose #19 
9 days after Visit 16 (Dose 11 + 24 days) 
Visit 18 
VOR Dose #20 
12 days after Visit 16 (Dose 11 + 27 days) 
Visit 19 
HXTC Infusion #5 
1-3 days after Visit 18 
Visit 20  
Safety Check and Research Lab 
1-3 days after Visit 19 


 
 
 
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7.3.4.1. Visit 14 – 1st Visit of 2nd series 
 
All female participants will be required to have a negative POC urine 
pregnancy test within 48 hours of Visit 14. If, despite the documentation of 
infertility, a female participant has a positive pregnancy test at this visit, she 
will be discontinued from the study and not receive any additional VOR doses 
or HXTC infusions. 
 
Estimated Blood Volume: up to 25 mL 
 
7.3.4.1.1. 
VORINOSTAT 400 mg   
 
Participants take one dose of VOR 400 mg PO the morning of this 
visit and document the time of the dose. This is the first dose (Dose 
#11) in the 2nd series of 10 doses.  
 
Reference section 7.3.3.1.1 for dosing time and process prior to 
infusion.  
 
7.3.4.1.2. 
Pre - 3rd HXTC Infusion  
 
The participant will come to the clinic approximately 3.5 - 4 hours 
after taking their VOR dose for pre-infusion evaluations.  
 
Reference section 7.3.3.1.2. and SOE for visit procedures and 
processes.  
 
Documented PI review of clinical labs from Visit 13 as well as review 
of clinical assessments done at this visit are required prior to the 
thawing and infusion of HXTC study product. 
 
Note: Administration of HXTC can be delayed up to 1 week pending 
resolution of physical findings or lab abnormalities.  
 
7.3.4.1.3. 
Administration of HXTC 
 
Reference section 7.3.3.1.3 for infusion guidelines. 
 
7.3.4.1.4. 
Post Infusion  
 
Provide participant with doses #12 – #16 of VOR 400 mg to take 
home.   
 


 
 
 
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The study coordinator will contact participants via their preferred 
way of communication approximately 2 to 3 days after study product 
administration to inquire about any reactions or potential TEAEs. 
Instruct the participant to contact the study coordinator or 
investigator if such any adverse events occur after this infusion or 
at any point during the study. The study coordinator can combine 
this assessment with VOR dosing reminder when these events 
overlap. 
 
7.3.4.2. 
Visit 15 – Safety Follow-Up Visit  
 
The study participant will have a post HXTC infusion follow-up visit per SOE 
with labs drawn 1 – 3 days post infusion.  
 
Estimated Blood Volume: up to 55 mL 
 
7.3.4.3. 
Visit 16 - Dose #6 of VOR and 4th HXTC Infusion  
 
All female participants require a negative POC urine pregnancy test within 
48 hours of infusion visit. If, despite the documentation of infertility, a 
female participant has a positive pregnancy test at this visit, they will be 
discontinued from the study and not receive the HXTC infusion or additional 
doses of VOR. 
 
Estimated Total Blood Volume: up to 45 mL 
 
7.3.4.3.1. 
VORINOSTAT 400 mg  
 
Participants take VOR 400 mg PO the morning of this visit and 
document the time. This is the 6th dose in the series of 10 doses.  
 
Reference section 7.3.3.1.1. for dosing time and process prior to 
infusion.  
 
7.3.4.3.2. 
Pre – HXTC Infusion  
 
Safety evaluations and research lab collection:  
• Collect safety labs (STAT) or within 48 hours of the visit. 
• Collect research labs on the day of visit only.  
o Collect approximately 4 hours after AM VOR dose. 
Collection can be +/- one hour of the 4-hour time point. 
 


 
 
 
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Documented PI review of clinical labs as well as review of clinical 
assessments done at this visit are required prior to the thawing and 
infusion of HXTC study product. 
 
Administration of HXTC can be delayed up to 1 week, pending 
resolution of physical findings or lab abnormalities.  
 
7.3.4.3.3. 
Administration of HXTC Therapy 
 
Reference section 7.3.3.1.3 for infusion guidelines. 
 
7.3.4.3.4. 
Post Infusion  
 
Provide participant with the last four (4) doses of VOR 400 mg to 
take home.   
 
The study coordinator will contact participants via their preferred 
way of communication approximately 2 to 3 days after study product 
administration to inquire about any reactions or potential TEAEs. 
Instruct the participant to contact the study coordinator or 
investigator if any adverse events occur after this infusion or at any 
point during the study. Study coordinator can combine this 
assessment with VOR dosing reminder when these events overlap. 
 
7.3.4.4. 
Visit 17 – Safety follow-up   
 
The study participant will have a post HXTC infusion follow-up visit per SOE 
with labs drawn 1 – 3 days post infusion.  
 
Estimated Total Blood Volume: up to 25 mL 
 
7.3.4.5. 
Visit 18 – Last dose of VOR 400mg - Dose #20 ) 
Participants take their last dose (Dose #20) of VOR 400 mg PO in the 
morning and document the time of the dose. Participants will come to 
research clinic approximately 4 – 6 hours after this dose.  
Clinical assessments and sample collections will be performed per SOE.  
 
Estimated Blood Volume: up to 35 mL 
 
7.3.4.6. 
Visit 19 – 5th and final HXTC Infusion 
 
All female participants require a negative POC urine pregnancy test within 
48 hours of infusion visit. If, despite the documentation of infertility, a 
female participant has a positive pregnancy test at this visit, they will be 


 
 
 
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discontinued from the study and not receive the HXTC infusion or additional 
doses of VOR.  
 
Estimated Blood Volume: up to 25 mL 
 
7.3.4.6.1. 
Pre – HXTC Infusion 
 
Reference section 7.3.3.1.2. and SOE for visit procedures and 
processes.  
 
Safety evaluations and research lab collection:  
• 
Collect safety labs (STAT) or within 48 hours of the visit. 
• 
Collect research labs on the day of visit only.  
 
Documented PI review of clinical labs as well as review of clinical 
assessments done at Visit 18 as well clinical assessments from this 
visit are required prior to the thawing and infusion of HXTC study 
product. 
 
Administration of HXTC can be delayed up to 1 week, pending 
resolution of physical findings or lab abnormalities.  
 
7.3.4.6.2. 
Administration of HXTC Infusion 
 
Please reference section 7.3.3.1.3. for infusion guidelines. 
 
7.3.4.6.3. 
Post Infusion  
 
The study coordinator will contact participants via their preferred 
way of communication approximately 2 to 3 days after this visit to 
inquire about any reactions or potential TEAEs. Instruct the 
participant to contact the study coordinator or investigator if any 
such adverse events occur after this infusion or at any point during 
the study.  
 
7.3.4.7. 
Visit 20 - Safety Follow-up  
 
The study participant will have a follow-up visit per SOE with labs drawn 1 
– 3 days post infusion.  
 
Estimated Total Blood Volume: up to 25 mL 
 
7.3.5. Step 6 (Visits 21, 23 and 24) Immune Monitoring Follow-up  


 
 
 
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These last three visits (Visits 21, 23 and 24) are longitudinal follow-up to evaluate 
for a sustained immune response. There is a leukapheresis at Visit 23 to 
measure the effect on the frequency of resting cell infection by QVOA.   
NOTE: THE PROTOCOL AMENDMENT FOR VERSION 4.0 DATED 31 
JANUARY 2022 ELIMINATED STEP 6 VISITS 22, 25, AND 26 OF THE 
PROTOCOL. 
7.3.5.1. 
Visit 21  
 
The clinical and research assessments and procedures occur per SOE at 
Visit 21. 
 
Estimated Blood Volume: up to 50 mL 
 
7.3.5.2. 
Visit 23 and End of Study Intervention Visit 
 
The clinical and research assessments and procedures occur per SOE at 
Visit 23. 
 
A leukapheresis is performed at this visit.  
 
Estimated Total Blood Volume: up to 70 mL 
 
7.3.5.3. 
Visit 24 
  
In addition to the participants completing all study visits, participants 
terminated, at any time point after initiating Step 4, will complete this visit 
after completing Visit 23.  
 
The clinical and research assessments and procedures occur per SOE at 
Visits 24. 
 
Estimated Blood Volume:  up to 55mL 
 
Visit 24 will be the last study visit and the end of study.  
 
7.4. Screening Failure and Re-screening Procedures 
 
Participants unable to meet laboratory values as defined in the protocol and defined 
inclusion/exclusion criteria may repeat the disqualifying lab/s once to meet eligibility 
prior to enrolling at Visit 2.  
 
Participants unable to meet protocol defined eligibility criteria at the Screening Visit 
after repeating disqualifying labs per protocol, can re-screen again at the Principal 


 
 
 
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Investigator’s (or designee) discretion. In such cases, the participant keeps the same 
PID.  
 
7.4.1. Failure of the frequency of resting CD4+ T cell infection to be ≥ 0.3 infected cells 
per million as determined by QVOA assay at baseline evaluation. 
 
If a participant fails to have a frequency of resting CD4+ T cell infection to be ≥ 0.3 
infected cells per million as determined by QVOA assay at the baseline 
leukapheresis in Step 1, study participation is terminated.  The SID for this 
participant will be retired and will not be used again. These participants will be 
replaced in the study. 
 
7.4.2. Inability to manufacture HXTC therapy or failure to meet release criteria  
 
In the unlikely event that product or sufficient product is not successfully 
manufactured for participants, these participants would not proceed to Step 4 and 
would not undergo any further study procedures.   
 
These participants may undergo a single repeat blood draw of 100mL to allow a 
second attempt at manufacturing product. 
 
If the participant refuses to repeat the blood draw or the product cannot be 
manufactured after receipt of the 2nd 100 mL sample, the participant will be 
terminated from the study. The SID for this participant will be retired and will not 
be used again. These participants will be replaced in the study. 
 
7.4.3. Inability to meet the pre-dose lab guidelines for study progression based on clinical 
evaluations at Step 3, Visit 7 and at Step 4, Visit 13. 
 
If a participant’s failure to move to Step 4 or Step 5 is due to an inability to meet 
one of the pre-dose safety laboratory assessments parameters, repeat the failed 
criteria one time only.  
 
Participants failing to advance to Step 4, without receiving any combination 
treatment of VOR and HXTC, will terminate from the study. The SID for this 
participant will be retired and will not be used again. These participants will be 
replaced in the study. 
 
Participants completing combination dosing in Step 4 and/or Step 5 who then fail 
to meet safety assessment requirements, will not receive further doses of VOR or 
HXTC. Participants will proceed to complete the early discontinuation visit per Step 
6, Visit 23 (when clinically acceptable, per PI assessment) and continue to 
complete the longitudinal assessment at Visit 24.  
 


 
 
 
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7.5. Early Discontinuation Visit (Step 6, Visit 23)  
 
Complete this visit any time a participant discontinues early from the study. This is 
the End of Study Intervention Visit and completed when participants complete study 
interventions, whether pre-maturely (as with an early discontinuation or upon 
successful completion of the study.   
 
Perform the Early Discontinuation or End of Study Intervention Visit assessments 
and procedures per the SOE. 
 
The Leukapheresis is completed on all participants who have completed all dosing 
visits. If a participant terminates early, completion of the leukapheresis at Visit 23 
will be determined by study PI or the study team. 
 
Estimated Blood Volume: up to 65 mL  
 
8. STUDY PROCEDURES/EVALUATIONS 
 
8.1. Description of Evaluations 
 
Evaluation of participants occur by physical examinations, medical history, clinical 
laboratory tests, research lab assay results, vital sign measurements, and adverse 
event evaluations. Safety assessments will include grading of the frequency and 
severity of adverse events associated with study treatment including, but not limited 
to, clinical laboratory values, physical examination and evaluations of infusion site 
reactions. 
 
8.1.1. Clinical Evaluations and Procedures 
 
8.1.1.1. 
Informed Consent  
Prior to performing any study-related procedure or assessments, the study 
coordinator discusses the study with the potential participant and obtains 
signed informed consent. This communication will be 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.  
 
8.1.1.2. 
Study Eligibility  
Determination of study eligibility by the Inclusion and Exclusion criteria 
occurs at Screening and prior to enrollment at Step 1, Visit 2. Potential 
participants failing eligibility will be considered a screen failure. (Please 
reference section 7.4.),  
 


 
 
 
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8.1.1.3. 
Advancement Criteria  
There is one time point when participants are required to meet 
Advancement Criteria to continue on study: 
 
Step 1 to Step 3 
The leukapheresis procedure performed at or after enrollment in Step 1, 
Visit 2 determines the criteria required to advance to Step 3. Failure to meet 
the criteria results in participant’s termination from the study. 
 
Advancement Criteria for Step 3  
• 
Participants with frequency of resting CD4+ T cell infection of < 0.3 
IUPM by QVOA will not progress to Step 3, as a further decrease 
from this low frequency of infection cannot be definitively measured 
given the QVOA assay threshold.  
 
8.1.1.4. 
Pre-Dose Lab Assessments 
There are two time points in the study when the participant completes Pre-
Dose Safety Lab Assessments. The lab results obtained in these 
assessments must be within the study established parameters for the 
administration of VOR to occur. Labs that fall outside the parameters can 
be repeated one time only to qualify participants to proceed. 
 
After repeat testing, any lab values that remain outside the guidelines but 
considered clinically non-significant and documented as such by the study 
PI (or designee), must be reviewed and approved by the protocol and/or 
safety committee prior to dosing/infusion visit. 
 
The time points of Pre-Dose Lab Assessments are: 
1. Step 3, Visit 6 (1st Series of VOR doses (10) and two HXTC 
infusions)  
2. Step 4, Visit 13 (2nd Series of VOR doses (10) and three HXTC 
infusions) 
 
8.1.1.5. 
Complete Medical Histories  
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 history.   
  
8.1.1.6. 
Update Medical History at all clinical visits 
Any reported signs and symptoms or new diagnoses occurring after the 
participant signs the study consent but prior to the administration of the first 


 
 
 
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study dose will be recorded in the medical history (pre-existing condition) 
unless reported event is related to a protocol-related procedure. 
 
8.1.1.7. 
Complete Physical Exams  
A complete physical examination (PE) is done at the following visits:  
• 
Step 1, Visit 1 - Screening  
• 
Step 3, Visit 6  
• 
Step 4, Visit 13 (Study Week 6) 
• 
Step 6, Visit 23 (Study Week 16) 
• 
Early Discontinuation Visit (same as End of Study Intervention Visit 
in SOE - Step 6, Visit 23 (Study Week 16) 
 
The PE will include a complete review of systems, vital signs, and weight. 
Measure Height at the Screening Visit only. The complete physical 
examination will include examination of skin, head, eyes, ears, nose, throat, 
lymph nodes, heart, chest, lungs, abdomen, extremities, psychological and 
neurologic systems. 
 
8.1.1.8. 
Directed or Targeted Physical Exams 
A targeted PE is done at all other visits where a complete PE is not 
performed, per the SOE. 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. 
 
8.1.1.9. 
Vital Signs  
Temperature, respiration, pulse, blood pressure, and weight (without 
shoes) at each study visit. Complete vital sign measurements after 5 
minutes in the sitting position. Repeat vital signs may also be captured as 
necessary to elucidate the course of any untoward event or AE. 
 
8.1.1.10. Height – required at study screening visit only without shoes.  
 
8.1.1.11. ART History  
May consist of a combination of participant report and clinical records 
where available. 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.  
 
8.1.1.12. ART Adherence 


 
 
 
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ART adherence will be reviewed at every visit. Any missed doses while on 
study should be discussed with Study PI (or designee). Continuance on 
study will be contingent on adherence. 
 
8.1.1.13. Concomitant Medication History  
Include all current medications and any PRN medications used within the 
past 30 days.  
• 
All medication taken within 30 days of study screening.  
• 
After study entry, record only new and discontinued over-the-
counter, herbal, dietary and vitamin supplements, and prescription 
medications.  
• 
Document all doses of VOR and HXTC therapy and permanent 
discontinuation.  
 
8.1.1.14. Signs, Symptoms, and Diagnosis of Illnesses and Diseases 
At screening, all signs and symptoms, regardless of grade, that occurred 
within the 30 days before entry must be recorded. After study entry, record 
any new diagnosis or illnesses that develop. 
 
After study entry, grade ≥3 signs and symptoms must be recorded. Record 
only signs and symptoms that are related to VOR or HXTC therapy and all 
signs and symptoms that lead to a change in treatment, regardless of 
grade. 
 
8.1.1.15. Blood collection  
Please reference SOE in Appendix A 
 
8.1.1.16. Urine Collection 
Please reference SOE in Appendix A 
 
8.1.1.17. Assessment of adverse events  
Please reference protocol section 9.1 
 
8.1.1.18. Leukapheresis 
Participants will undergo two Leukapheresis procedures. The baseline 
leukapheresis will be completed at or after Visit 2. Participants will advance 
to Step 3 based on an IUPM measurement ≥ 0.3. The 2nd leukapheresis 
will take place at the End of Study Intervention visit in Step 6, Visit 23.  
 
All protocol required leukapheresis products will be transported on the 
day of collection to the Margolis Laboratory on the UNC campus.  
 
All leukapheresis procedures will occur at the UNC Apheresis Lab located 
in the UNC Blood Bank or at a local contracted blood collection center.  


 
 
 
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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 in the screening 
leukapheresis, they will be discontinued from study, as completing the 
leukapheresis procedures is a requirement of the study screening process. 
Participants who experience a Grade 3 or higher toxicity related to any 
additional 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 includes 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.   
 
8.1.1.19. Pre-HXTC Infusion Medications (cetirizine and acetaminophen) and other 
Medications for Administration in the Advent of a Hypersensitivity or 
Anaphylactic Reaction  
o Licensed study staff will administer cetirizine (PO) and the 
acetaminophen (PO). 
o Administration of medications for treatment of adverse reactions to 
the HXTC will follow hospital policy and the UNC HIV Cure Center 
SOP entitled Cellular Product Infusion Guidelines and Emergency 
Management Plan. 
 
8.1.1.20. HXTC Infusion  
The HXTC will be administered by staff competent in cellular product 
infusion; the study PI (or designee) or a licensed physician assistant 
(PA)/nurse practitioner (NP) or RN.  A research assistant (RA) may obtain 
and record vital signs and provide other participant care necessary during 
the HXTC infusion.  
 
8.1.1.21. Product Infusion Reaction Evaluations  


 
 
 
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Participants will be monitored for up to 1 hour following treatment while the 
participant remains in the clinic. Participants will be instructed to contact 
study staff about any reactions that occur after receipt of the HXTC therapy. 
The study staff will contact the participants via telephone or their preferred 
way of communication approximately 2 to 3 days after the study product 
administration to inquire about reactions or any potential TEAEs. Infusion 
reactions will be graded according to the DAIDS toxicity grading table. 
 
8.1.2. Clinical Laboratory Procedures 
These laboratory evaluations will be conducted primarily at one of the clinical site 
laboratories available to the research team. Details of specimen collection are 
found in the Lab Procedures Manual for this study. 
 
At designated visits, the study PI (or designee) assesses the clinical events and 
the laboratory test results and determines whether the participant can receive 
VOR doses or HXTC infusions.  If values are outside the study reference range, 
the PI (or designee) determines if the abnormal value is clinically significant and 
if study treatments can continue. Report all abnormal laboratory values that the 
investigator deems clinically significant as AEs.   
 
All participants will have safety labs (CBC with differential and chemistries) done 
throughout the study to monitor for any adverse events due to the administration 
of VOR and HXTC therapy. Labs that are abnormal and meet grading standards 
per Division of AIDS (DAIDS) Table for Grading the Severity of Adult and 
Pediatric Adverse Events, Version 2.1. [July 2017], will be re-assessed based on 
these initial parameters. 
 
Blood specimens will be collected and evaluated at either UNC McLendon 
Hospital Lab or LabCorp.  
 
8.1.2.1. 
HIV -1 Infection Documentation  
 
8.1.2.2. 
Donor ID Panel Testing  
The following tests will be performed on samples collected at Step 3, Visit 
4. These samples will either be sent to HPC Lab or LabCorp for testing. 
Test kits, tubes, and sample processing is done in the HPC lab. 
 
• 
AbO/Rh  
• 
HBsAg 
• 
HB Core antibody  
• 
HIV1/2 plus O  
• 
Syphilis (T. Pallidum IgG)   
 
• 
HTLV I/II  
• 
CMV total  
• 
HIV-1/HBV/HCV Ulrio NAT  
• 
West Nile Virus NAT  
• 
T. Cruz (Chagas) antibody 
 
8.1.2.3. 
Clinical Chemistry  


 
 
 
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Assessments include Sodium (Na), potassium (K), chloride (Cl), 
bicarbonate (CO2), glucose, blood urea nitrogen (BUN), creatinine, 
calcium (Ca), magnesium (Mg), ALT, AST, alkaline phosphatase, total 
bilirubin.  
 
In addition to the labs listed above, the following labs will be done at 
screening and Visit 23 only:  
o Direct bilirubin will be obtained if participant is on atazanavir.  
o Lipase, albumin, total protein, cholesterol, and triglycerides  
 
8.1.2.4. 
Hematology – All assessments include CBC with WBC differential  
 
8.1.2.5. 
Safety Labs  
All participants will have safety labs (CBC with differential and chemistries) 
done at protocol required visits. Labs from the screening visit will be 
considered baseline. All lab values obtained pre- and post-dosing that are 
abnormal and meet grading standards per the DAIDS Table for Grading 
the Severity of Adult and Pediatric Adverse Events, version 2.1, July 2017 
will be re-assessed based on these initial parameters.  
 
Creatinine clearance 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 will be required for study enrollment eligibility. The 
study assesses serum creatinine level at all the safety lab checks and uses 
the serum creatinine value for toxicity grading and as confirmation to 
progress to each dosing Step. Grade the serum creatinine per the DAIDS 
Table for Grading the Severity of Adult and Pediatric Adverse Events, 
version 2.1, July 2017.  
 
8.1.2.6. 
Prothrombin time (PT), INR, and APTT - at Screening Visit only. 
 
8.1.2.7. 
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. 
 
8.1.2.8. 
HBsAg and Hep C Antibody Both hepatitis tests 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. 
 
8.1.2.9. 
RPR  


 
 
 
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If positive and participant has documentation of recent appropriate 
treatment, they may continue in study. Completion of RPR testing occurs 
again at Step 3, Visit 6 and Step 4, Visit 13. 
 
8.1.2.10. HIV-1 RNA  
The definition for the HIV-1 RNA quantitative PCR “less than (<) level/limit 
of detection” or “undetectable per institutional standard” for the purpose of 
this study will be <50 copies/mL. 
 
8.1.2.11. CD4+ T cell differential panel   
 
8.1.2.12. Serum and Point of Care (POCT) Urine Pregnancy test  
A negative serum pregnancy test (to rule out pregnancy) is required on all 
women at screening and VOR pre-dose assessment visits, regardless of 
documented procedures that prohibit pregnancy. The use of the POCT 
urine pregnancy test as confirmation of negative pregnancy status is 
acceptable at all visits except screening.  
 
All women regardless of child bearing potential will have a pregnancy test 
prior to the first VOR dose, prior to the first dose in subsequent series of 
dosing, as well as at each HXTC infusion.  The test must be negative within 
48 hours of the dose. Because the study has no direct clinical benefit, this 
added protection is warranted. 
 
8.1.2.13. Urinalysis  
Perform this test at Screening and the End of Study Intervention (Visit 23) 
to establish baseline and evaluate if any changes occurred post therapeutic 
interventions. Dipstick testing (including protein, glucose, hemoglobin, pH, 
and ketone) will be done. Microscopic analysis will only be done in the 
event of abnormal results from dipstick testing. 
 
8.1.3. Research Laboratory Procedures  
 
8.1.3.1. 
Research analysis to be performed per the SOE 
 
8.1.3.2. 
Immune Response Assay   
Immune responses are assessed using IFNγ ELispot response to individual 
epitopes. Changes in the magnitude of response to any single epitope 
reflects immune responses induced as a consequence of dosing with VOR-
HXTC.  T cell phenotype and markers of exhaustion pre and post VOR-
HXTC administration will also be evaluated. Tetramer staining and Vβ 
usage analysis will also be performed in order to track the fate of the 
infused HXTCs.  
  


 
 
 
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8.1.3.3. 
Stored Plasma for Single Copy Assay    
Plasma for HIV-1 RNA SCA will be obtained as required per the SOE and 
stored for batched analyses. PBMCs will be processed off these samples 
and stored for future study analysis.  
 
8.1.3.4. 
PBMCs for HDAC Responsive Gene Measurement 
PBMCs will be used to confirm pharmacologic effect of VOR on cellular 
targets in vivo. We will isolate total RNA from PBMCs and evaluate the 
expression of several genes with predictable behavior in response to 
HDAC inhibition in vitro and in vivo.  
 
8.1.3.5. 
Limiting Dilution Cultures of Resting CD4+ T Cells to Quantify Resting 
Cell Infection  
Lymphocytes are obtained by continuous-flow leukapheresis and resting 
CD4 positive T-cells are isolated as previously described [51]. A maximum 
likelihood method will be used to calculate the infectious units per million 
of resting CD4+ T-cells. Exploratory assays for quantitation of resting cell 
infection may include digital droplet PCR of resting cell associated RNA. 
 
8.1.3.6. 
Clinical Pharmacokinetics   
We will collect a PK sample at designated time points throughout the study. 
Please reference SOE for exact time points.  
 
8.1.3.7. 
Ex-vivo Latent Clearance Assay 
Resting CD4 cells are isolated via negative selection from a leukapheresis 
product and then activated. After 15 days of culture, each well is assessed 
for the presence of residual HIV infection with an HIV-1 gag p24 ELISA 
performed on supernatant. 
 
8.1.3.8. 
Epitope Mapping  
If sufficient cells are available we will perform Epitope mapping of the 
HXTC product and compare circulating HIV-1 reactive T cell frequencies 
pre- and post- VOR administration and HXTC infusions. We will also 
conduct mapping of individual HIV-1 reactivated T cell epitopes targeted 
by T cell populations and their dominance hierarchies pre- and post- 
administration of VOR doses and HXTC infusions in Steps 4 and 5. 
 
8.1.3.9. 
HLA Typing  
HLA typing is performed on participant peripheral blood at the time of blood 
collection for HXTC manufacture. For product release, HLA typing will also 
be performed on the final product to confirm identity. In addition, HLA typing 
results will be used to inform epitope specific responses as part of the 
HXTC product characterization.  
 


 
 
 
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8.1.3.10. Specimen Preparation, Handling, and Shipping  
Specimen processing and shipment will follow the Study SOPs and Lab 
Procedures Manual. 
 
8.1.4. Sample Storage 
Participants sign a separate consent for the use and storage of these blood 
samples for research analysis associated with this study. The research analysis 
includes genetic testing, and this information will be included in the blood storage 
consent reviewed with the participants. Participants can opt out of genetic testing. 
 
Any remaining specimens that will be stored for future research will be stored 
safely and securely in a research specimen storage laboratory at the University of 
North Carolina at Chapel Hill (UNC-CH).  No protected health information (PHI) is 
included with the samples. All samples are identified by coded number only.  
 
The link between Participant Identifier Code on the samples and PHI is maintained 
in a secured file on a secured server in the control of the principal investigator at 
UNC-CH.  Future researchers would not have access to this link.  Only study 
personnel, people who work at the research specimen storage laboratory at UNC-
CH and IRB approved researchers will have access to the participants’ samples. 
Since all the stored specimens are de-identified, the people who work at the 
research specimen storage laboratory will not have any personally identifying 
information that would link to a participant.  The IRB approved researchers who 
receive the specimens may receive information pertaining to lab assay values, 
age, and sex of the specimen donor, but will not be given the name or any other 
information that identifies the donor/participant. These samples will be stored 
indefinitely. 
 
9. CLINICAL MANAGEMENT ISSUES 
 
Criteria for participant management, treatment interruption, and study discontinuation will be 
mandated only for toxicities possibly, probably, or definitely related to HXTC and/or VOR.  
 
NOTE: In the event that a participant develops toxicity related to his/her previously-stable 
ART, consultation with the protocol team will be required (preferably before appropriate 
therapy modification). Toxicities due to drugs in the antiretroviral regimen should be managed 
according to standard clinical practice, with the goal of maintaining continuous therapy, if 
possible. 
 
AEs assessed as related to non-study drugs (concomitant medications) should be handled 
according to the relevant package inserts and the best medical judgment of the site 
investigator or designee. 
 
Infusion site reactions will be graded according to the DAIDS toxicity grading table.  


 
 
 
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U.S. Department of Health and Human Services, National Institutes of Health, National 
Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS (DAIDS) Table 
for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1. [July 2017], which 
is available on the DAIDS RSC website. 
 
9.1. Toxicity 
 
Only toxicities considered related to HXTC and/or VOR will be managed directly by this 
protocol.   
 
Participants will be monitored closely for adverse effects. 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. 
 
For this study, the hemoglobin will be graded using version 2.1 [July 2017] of the DAIDS 
Table for Grading the Severity of Adult and Pediatric Adverse Events where a hemoglobin 
<11 mg/dl for men and <10.5 for women will be considered a Grade 1 toxicity. 
 
9.1.1. Grade 1 or 2 Toxicity  
 
Participants who develop a Grade 1 or 2 AE or toxicity that occurs following an 
HXTC infusion or VOR dosing that is thought to be possibly, probably, or definitely 
related to HXTC and/or VOR should be discussed with the study team.  
 
In the event of a grade 1 toxicity related to hemoglobin or anemia the study team 
should be contacted to guide the elimination of research labs as needed to avoid 
a grade 2 toxicity related to hemoglobin. 
 
9.1.2. Grade 3 Toxicity 
 
For participants who develop a Grade 3 AE that occurs following an HXTC infusion 
or VOR dosing not specifically discussed below that is judged by a site investigator 
to be at least possibly study treatment-related, the protocol team must be notified 
within 24 hours. Participants with a study treatment-related Grade 3 AE will not 
receive any additional doses of study treatment/product. Participants experiencing 
Grade 3 AEs should be followed closely and if the AE does not return to Grade ≤ 
2 within 2 weeks, the protocol team should again be notified within 24 hours. 
 
For participants who experience a Grade 3 AE that is judged not related to the 
study drug by the investigator or designee, continued study participation is at the 
discretion of the principal investigator in consultation with the protocol team. 
 
 
9.1.3. Grade 4 Toxicity 


 
 
 
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For participants who develop a Grade 4 AE that occurs following an HXTC infusion 
or VOR dosing not specifically discussed below that is judged by a site investigator 
or designee to be at least possibly study treatment-related, the protocol team must 
be notified within 24 hours. Participants with a study treatment-related Grade 4 AE 
will not receive any additional doses of study treatment/product. 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 should again be notified within 24 
hours. 
 
9.1.4. HXTC Infusion-related Toxicities 
 
Infusion reactions should be graded according to the criteria for acute systemic 
allergic reaction located in the Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events, Version 2.1. [July 2017], which 
can 
be 
found 
on 
the 
DAIDS 
RSC 
Web 
site: 
http://rsc.tech-
res.com/safetyandpharmacovigilance/. 
 
These reactions may manifest with signs and symptoms that may include, but are 
not limited to fever, chills, headache, rash, pruritus, arthralgia, hypo- or 
hypertension, bronchospasm, or other symptoms. 
 
9.1.4.1. 
Grade 1 or 2 Local or Systemic Reactions 
 
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. 
 
9.1.4.2. 
Grade 3 or 4 Local or Systemic Reactions  
 
For severe (Grade 3) or potentially life-threatening (Grade 4) local 
reactions, the protocol team must be notified within 24 hours. For Grade 4 
local reactions, definitive medical and/or surgical intervention should be 
undertaken as appropriate. Further infusions should not be administered 
prior to consultation with the core protocol team. 
 
9.1.5. Systemic Reactions  
 
The protocol team should be contacted within 24 hours for any non-local Grade 3 
or 4 AE thought definitely, possibly, or probably related to study treatment. 
Additional study product should not be administered prior to consultation with the 


 
 
 
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protocol team. For severe infusion (Grade 3 or 4) reactions, appropriate medical 
therapy including epinephrine, corticosteroids, intravenous antihistamines, and 
oxygen should be available for use in the treatment of such reactions. Participants 
should be carefully observed until the complete resolution of all signs and 
symptoms. In each case of an infusion reaction, the site investigator should 
institute treatment measures according to the best available medical practice. 
 
9.1.5.1. 
Grade 1 or 2 Local or Systemic Reactions 
 
Local reactions of mild (Grade 1) or moderate (Grade 2) severity will usually 
resolve spontaneously.  If needed, they may be managed with a 
combination of medical treatment measures as appropriate. 
 
9.2. Toxicity Management  
 
9.2.1. Adverse Events  
 
Reports of AEs will be elicited by verbally questioning the participant at all visits. 
The study coordinator will also telephone the participant approximately 2 to 3 days 
after the HXTC study product administration to inquire about any potential 
treatment emergent adverse events (TEAE). The participant will be instructed to 
contact the study coordinator or investigator if such events occur at any point 
during the study. 
 
Any events spontaneously reported by the participant or observed by the study 
team will be recorded. 
 
If an AE occurs, the study coordinator, in collaboration with the PI or designee, will 
evaluate the severity and seriousness of the AE and the relationship to the study 
product, and will document the findings. Appropriate countermeasures, including 
medical intervention or procedures, must be instituted if indicated clinically. 
 
AEs occurring at the HXTC administration site should be reported and analyzed in 
accordance with standard practices for clinical testing of novel therapeutic 
candidates. 
 
All reactions will be graded according to the Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 [July 
2017], 
which 
is 
available 
on 
the 
DAIDS 
RSC 
website: 
http://rsc.techres.com/safetyandpharmacovigilance/. 
 
 
 
9.2.2. Definition of an Adverse Event (AE) 


 
 
 
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An AE is any untoward medical occurrence in a participant administered a 
pharmaceutical product that does not necessarily have a causal relationship with 
the treatment. 
 
An AE can therefore be any unfavorable or unintended sign (including an abnormal 
lab finding, for example), symptom, or disease temporally associated with the use 
of a study drug, whether or not considered related to the study drug. 
 
An AE does include a/an: 
• 
Exacerbation of a pre-existing illness 
• 
Increase in frequency or intensity of a pre-existing episodic event or 
condition 
• 
Condition detected or diagnosed after study product administration even 
though it may have been present prior to the start of the study  
• 
Continuous persistent diseases or symptoms present at Baseline that 
worsen following the start of the study  
 
An AE does not include a/an: 
• 
Medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, 
transfusion); however, the condition that led to the procedure is an AE 
• 
Pre-existing diseases or conditions present or detected at the start of the 
study that do not worsen 
• 
Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalizations for cosmetic elective surgery, social, or convenience 
admissions) 
• 
The disease or disorder being studied or sign or symptom associated with 
the disease or disorder unless more severe than expected for the 
participant’s condition 
• 
Overdose of either the study medication or concurrent medications without 
any signs or symptoms 
 
In general, abnormal laboratory findings (e.g., clinical chemistries, hematology, 
urinalysis) or abnormal assessments (e.g., vital signs) are not recorded as AEs 
unless they are considered clinically significant by the investigator.  If an abnormal 
lab finding is considered clinically significant, it must be recorded in the AE log as 
follows: 
• 
If it contributes to a clinical diagnosis, the diagnosis must be recorded as 
the AE (e.g., a clinically significant elevation in blood glucose must be 
recorded as “diabetes” if a clinical diagnosis is made)  
• 
Or if an abnormal finding does not indicate a clinical diagnosis, the 
abnormality itself must be recorded 
 
9.2.3. Adverse Event Reporting Period 


 
 
 
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The AE reporting period for each participant begins when the participant signs the 
consent and lasts through the 30 days following the EOS visit in Step 6, Visit 24.  
During Step 1 and Step 3 (prior to study product administration), 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 (e.g., leukapheresis 
or large blood collection for HXTC manufacturing).   
 
AEs leading to discontinuation, AEs of ≥ Grade 3 severity, related adverse events, 
and lab abnormalities as well as safety concerns will be recorded in the database 
as well as communicated in a timely manner to the UNC IRB, Children’s National 
Health System IRB, NHLBI, FDA, and Merck per the reporting requirements of 
each regulatory entity. 
 
The Sponsor of this study is UNC-CH. The principal investigator (Dr. David 
Margolis) at UNC-CH will be responsible for reporting to all the regulatory bodies 
and funding sources listed above. 
 
9.2.4. Documentation of Adverse Events 
 
Throughout the trial, the study coordinator will monitor closely for the development 
of AEs and the investigator or designee will determine clinical significance of AEs, 
and initiation of medical interventions if required.  
 
Record the following in the participants’ study chart: 
• 
Concise diagnosis 
• 
Onset date 
• 
Criteria for regarding as an AE 
• 
Setting 
• 
Resolution date 
• 
Severity (per DAIDS toxicity grading table) 
• 
Relation to the study product (unrelated, unlikely, possibly, probably, 
definitely); an AE may be considered related if it follows a reasonable 
temporal sequence from administration of the study product, confirmed by 
improvement when the product is stopped and re-appears on repeated 
exposure  
• 
Study product change (interrupted or discontinued)  
• 
Seriousness (not serious, fatal, life-threatening, leads to or prolongs 
hospitalization, results in persistent or significant disability or incapacity, 
congenital anomaly or birth defect, important medical event) 
 
9.2.5. Definition of a Serious Adverse Event 
 


 
 
 
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As provided in Title 21 CFR part 312, an SAE is an AE occurring at any dose that 
results in any of the following outcomes: 
• Death 
• A life-threatening AE 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability or incapacity  
• A congenital anomaly or birth defect  
• Important medical event that may not result in death, be life-threating, or 
require hospitalization may be considered serious when, based upon 
appropriate medical judgment, it may jeopardize the participant and may 
require medical and surgical intervention to prevent one of the outcomes  
 
Any death (regardless of cause) that occurs from the time of the study product 
administration until 32 weeks after the final study product administration, and any 
death occurring after this time that is judged at least possibly related to prior 
treatment with the study product, will be promptly reported. 
 
9.2.6. Definition of a Serious Unexpected Adverse Event 
 
A serious adverse drug reaction is defined as an SAE that is not identified in the 
IB(s). 
 
9.2.7. Reporting of Serious Adverse Events 
 
All SAEs occurring during the study will be reported to the UNC IRB per the UNC 
IRB reporting requirements, NHLBI, the FDA, CNH IRB, and Merck, if required 
within 24 hours of knowledge of the occurrence. A written report (UNC IRB 
Unanticipated Problem Report Form and, if required Med Watch Form FDA 3500) 
will be faxed or sent within 24 hours of knowledge of the occurrence. Additional 
information will be supplied as requested.  The funding source of this study is the 
NHLBI. The principal investigator (David Margolis, MD) at UNC-CH will be 
responsible for reporting to all of the regulatory and funding agencies.  
 
9.2.8. Follow-Up of AEs and SAEs 
 
All AEs and SAEs must be followed until resolution, become chronic, or stable.  The 
resolution status of such an event must be documented. In addition, the principal 
investigator should report all follow-up for reportable SAEs to the UNC and CNH 
IRBs, NHLBI, FDA, and Merck. 
 
9.2.9. Post-Study AEs and SAEs 
 


 
 
 
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Investigators are not obligated to actively seek AEs and SAEs in former study 
participants. However, if the PI learns of an SAE during the 30 days following the 
final study visit, the PI must promptly notify the NHLBI. 
 
9.3. Discontinuation of HXTC and/or VOR  
 
Participants who prematurely discontinue the HXTC infusions or VOR should continue to 
undergo the protocol evaluations as per the Schedule of Events. 
 
The End of Study Intervention visit (Study Visit 23) will be also conducted any time a 
participant discontinues early from the study after receiving combination therapy with 
VOR and HXTCs in Steps 4 and 5 or upon the successful completion of the study 
interventions. If HXTC or VOR has been administered, the investigator must make every 
effort to perform the evaluations four weeks after the participant’s last dose but not more 
than 8 weeks in cases where the participant does not agree to conduct the remaining 
scheduled visits. Participants terminating early from the study after receiving combination 
therapy will be asked to complete the follow-up visit (Study Visit 24) after Visit 23 in Step 
6.   
 
9.4. Pregnancy  
 
If the pregnancy test is positive at screening, the potential participant will not be allowed 
to enroll on the study.  No further evaluations are necessary.  
 
If the participant becomes pregnant during the study, then study treatment must be 
discontinued immediately. The participant may continue in the study in an off treatment/on 
study status for safety labs only. The participant will be followed until the pregnancy 
outcome and up to 8 weeks after the delivery.   
 
All participants 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 to the UNC and CNH IRBs if required per their reporting requirements, 
the NHLBI, the FDA (US Food and Drug Administration), and Merck Research 
Laboratories.  
 
If a partner to a male study participant becomes pregnant, while male participant is 
actively on study, the pregnancy must be reported. The study investigator will make every 
effort to obtain permission to follow the outcome of the pregnancy and report the condition 
of the fetus or newborn to the UNC and CNH IRBs if required per their reporting 
requirements, NHLBI, FDA, and Merck 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).   
 


 
 
 
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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 12 weeks of 
completing the study.  
 
We will obtain a medical release or separate consent granting permission to follow the 
health of both the pregnant participant and her unborn child. We will conduct a post-
delivery interview and complete a case report form (CRF) to collect the data related to 
the pregnancy outcome.   
 
The Sponsor of this study is the University of North Carolina at Chapel Hill. The principal 
investigator (Dr. David Margolis) at UNC-CH will be responsible for reporting to all 
regulatory agencies and funding sources listed above. 
 
10. STATISTICAL CONSIDERATIONS 
 
10.1. 
General Design  
 
This is a phase I, single-site study to evaluate the effects of VOR and HXTC therapy on 
persistent HIV-1 Infection in HIV-infected individuals suppressed on ART. Twelve 
participants with durable viral suppression will be enrolled and will complete the study. 
All participants will receive the same treatment and if eligible, will be dosed with VOR 
and receive HXTC infusions. Participants will continue their baseline ART regimen 
throughout the study. 
 
If the baseline IUPM ≥ 0.3, participants will have a blood sample sent to CNH for 
production of HXTCs. Upon release of HXTC, participants will be clinically assessed to 
complete the two treatment series with oral VOR 400 mg doses combined with HXTC 
infusions over a 3 month period. VOR will be administered every 72 hours and each 
treatment series will consist of 10 doses of VOR 400 mg.  
 
In Step 4 (Series 1), participants will receive two HXTC infusions along with 10 doses of 
VOR 400 mg. The HXTC infusions will be administered 6 hours after the 1st and 6th 
VOR doses.    
 
In Step 5 (Series 2), participants will receive three infusions along with 10 doses of VOR 
400 mg. The first two infusions will be administered 6 hours after the 11th and 16th doses 
of VOR. The 5th and final HXTC infusion will occur 1 – 3 days after the 20th VOR dose.  
 
The 2nd and final leukapheresis will occur at least 4 weeks after the last HXTC infusion.  
 
Resting cell infection frequency will be determined pre VOR-HXTC dosing with the 
baseline leukapheresis and post VOR-HXTC dosing with 2nd leukapheresis.  
 


 
 
 
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Longitudinal follow-up to measure the effectiveness of the intervention will continue for 
9 weeks after the last HXTC infusion. Serial blood draws will be obtained pre and post- 
VOR-HXTC dosing throughout the study to monitor immune response. 
 
10.1.1. Study Hypothesis 
 
We hypothesize that HXTCs can be safely combined with VOR, and allow depletion 
of persistent HIV infection. 
 
10.2. 
Outcome Measures  
 
10.2.1. Primary Endpoints 
10.2.1.1. Safety  
Occurrence of at least one ≥ Grade 3 adverse event including 
signs/symptoms, lab toxicities, and/or clinical events that is possibly or 
definitely related to VOR or HXTC any time from the first day of study 
treatment through Step 6, Visit 23. 
 
Safety data will include local and systemic signs and symptoms, 
laboratory measures of safety/toxicity, and all adverse and serious 
adverse events. Safety data will be routinely collected throughout the 
duration of the study.   
 
NOTE: The occurrence of a Grade 3 infusion reaction that is sustained for 
less than 48 hours will not be included as a primary safety endpoint. 
 
10.2.1.2. Change in the frequency of HIV infection per million resting CD4+T cells 
(RCI) from baseline to post-VOR/HXTC 
 
10.2.2. Secondary Endpoints 
 
10.2.2.1. The ability of combination VOR and HXTC therapy to increase HIV-1 
specific immune responses in participants maintained on suppressive 
ART 
 
 
 
 
 
 
10.3. 
Sample Size Considerations 
 


 
 
 
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For n=12 participants, if there are no primary adverse events (AEs), then the exact 95% 
confidence interval (CI) for the true AE rate will be [0.00, 0.26]. Thus, if no AEs are 
observed, one can confidently rule out event rates greater than 26%. If there is one AE 
among the 12 participants, then the exact 95% CI will be [0.00, 0.38]. 
 
10.4. 
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 of this study is grade 3 or 4 toxicity 
in no more than 1 of 12 participants. If 0 of 12 participants experience toxicity, we will 
have 95% confidence that the true toxicity rate is 22% or less and 80% confidence that 
it is 13% or less, based on 1-sided exact binomial confidence limits. If 1 participant has 
toxicity, the corresponding 95% and 80% 1-sided upper confidence limits are 34% and 
23%, respectively. 
 
Any participant who is not administered the full study treatment through Step 6 will be 
replaced until the target enrollment of participants is met. 
 
Because a focus of the study is on safety and potential adverse events, accrual will be 
staggered such that enrollment and treatment administration will include a maximum of 
2 participants per week, and never more than 1 
on any day. 
 
10.5. 
Monitoring  
 
Formal review will be performed at yearly 
intervals during the conduct of this study, and will 
be reviewed by an independent Safety Monitoring 
Committee (SMC). This review will be based on 
assessment of participant safety, and will serve 
as a basis for allowing enrollment to continue.  
 
The SMC will receive monthly study progress and safety monitoring reports. Study 
feasibility and the achievement of study milestones will be assessed in these reports. 
Additionally, 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 sent to and discussed with 
the protocol team on a regular monthly basis. The study protocol team will review the 
individual safety data monthly to assess relation of all reported toxicities and AEs to the 
study treatment. The monthly data will be shared with the SMC for review.   
 
It will be the responsibility of the study protocol team to interpret the toxicity data, make 
decisions needed to protect participants from undue risk, and determine whether or not 
participant replacements are needed. 
Observed proportion 
with >6 fold change 
from baseline 
Exact 95% 
confidence 
interval 
6/12=0.50 
[0.21, 0.79] 
7/12=0.58 
[0.28, 0.85] 
8/12=0.67 
[0.35, 0.90] 
9/12=0.75 
[0.43, 0.95] 
10/12=0.83 
[0.52, 0.98] 
11/12=0.92 
[0.62, 1.00] 
12/12=1.00 
[0.74, 1.00] 
Table 5: Confidence Intervals for Depletion of 
the Latent Reservoir 


 
 
 
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If at any time during the study, two or more participants experience a toxicity that is Grade 
3 or higher and definitely, probably, or possibly related to study treatment (as judged by 
the protocol team), then enrollment into the study will be temporarily suspended and the 
independent SMC will be asked to review all safety data; review the relation to study 
treatment of the event(s); and recommend how the study should proceed with respect to 
resuming enrollment and continuing study treatment. 
 
Site monitors, independently contracted by the UNC HIV Cure Center, per contract with 
NIH/NHLBI will visit the clinical research site to review participants’ records, including 
consent forms, CRFs, medical records (e.g., physicians’ progress notes, nurses’ notes, 
individuals’ hospital charts), and laboratory records to ensure protection of study 
participants, compliance with the EC/IRB approved protocol/amendments, and accuracy 
and completeness of records. The monitors will inspect sites’ regulatory files to ensure 
that local regulatory requirements, in addition to U.S. Federal regulations, are being 
followed. They will also inspect sites’ pharmacies to review product storage and 
management. 
 
10.6. 
Efficacy  
 
Due to the small size of this pilot, proof-of-concept trial, interim analyses for efficacy 
would not be appropriate. 
 
We will recruit and screen up to 48 participants to obtain 12 participants with evaluable 
data to study and compare pre-VOR/HXTC and post-VOR/HXTC frequency of HIV 
infection per million resting CD4+T cells, and will analyze using a non-parametric 2-sided 
sign test to determine whether or not a significant decrease of IUPM is observed, as 
below in section 10.7. 
 
10.7. 
Analysis  
 
10.7.1. Primary Analysis 
 
For the safety endpoint, we will record and describe all study treatment-related 
adverse events through the end of study. 
 
Ultimately, we aim to detect a significant depletion of the latent reservoir, by 
measuring the frequency of resting cell infection using the QVOA. We will analyze 
pre-VOR/HXTC and post-VOR/HXTC frequency of HIV infection per million resting 
CD4+T cells using a non-parametric 2-sided sign test (and the Wilcoxon signed rank 
test if no assay censoring) to determine whether or not a significant decrease of 
IUPM is observed. With 12 participants there is 80% power to reject H0 (change 
expected with ART alone) in favor of HA (greater change than expected with ART) if 


 
 
 
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the true probability of observing a decrease in IUPM in a participant after VOR/HXTC 
is 0.93.   
  
In addition to summarizing the number and proportion of participants who show 
decrease in IUPM after VOR/HXTC, we will describe the magnitude of the changes 
in decrease in IUPM after VOR/HXTC 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 [64]. We will therefore consider a >6 fold change from baseline to post VOR-
HXTC treatment as significant on an individual participant basis. For n=12 
participants, precision calculations are analogous to those for safety endpoints. In 
particular, if all 12 participants have a >6 fold change from baseline, then the exact 
95% confidence interval (CI) for the probability of significant depletion of the latent 
reservoir would be [0.74, 1.00], i.e., one could confidently rule out depletion 
probabilities less than 74%. If 11 of 12 participants achieve significant depletion, the 
95% CI would be [0.62, 1.00]. Other possible observed proportions and 95% CIs are 
given in Table 5. 
 
For the first 6 participants who had HIV RNA expression per million resting CD4+T 
cells measured after VOR exposure (ex vivo exposure to VOR in the screening step; 
in vivo exposure to first VOR dose), as a gateway to advance through the study 
protocol, we will assess within-participant RNA changes. We will analyze using the 
non-parametric 2-sided Wilcoxon rank sum test to determine whether or not a 
significant increase of RNA expression is observed in these participants comparing 
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.  
 
For the first 6 participants, the pre-VOR 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 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. 
 
10.7.2. Secondary Analysis  
 
The virologic analysis will include comparison of the SCA levels pre-treatment 
(screening and entry) compared to post-treatment in Steps 5 and 6. We assume that 
the probability would be 0.10 (10%) for a baseline (pre-entry, entry) detectable SCA 
≥ 1 copy and the probability would be at least 0.29 (29%) for a post-treatment 
measure for analyses. The assumption that 10% of participants with a quantifiable 
SCA at screening will have SCA below the limit of detection at a pre-treatment 


 
 
 
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measure is an estimate based on data from A5244 in which 6 of 50 (12%) enrolled 
participants had undetectable SCA at pre-entry and 5 of 51 (10%) at entry after 
having a screening SCA ≥ 1 copy [65].   
 
For additional secondary endpoints, most endpoints are defined as change in a 
quantitative measure from baseline to post-infusion (e.g., change from baseline to 
week 13 in HIV-1 RNA by SCA). Assuming two-sided 0.05 significance, 5000 
empirical simulations from a normal distribution with mean change equal to 1 
standard deviation with n=12 evaluable participants achieved 85% power to detect 
a statistically significant change from baseline to post-infusion using an exact 
Wilcoxon signed-rank test (paired data). Thus, with n=12 there is reasonable power 
to detect a mean change of 1 standard deviation (SD) or larger. Observed virologic  
measurements may not be normally distributed or may be partially censored due to 
assay limits of quantification, and thus, an exact Wilcoxon signed-rank test will be 
used. Potential immune correlates of antiviral impact will be assessed via exact, non-
parametric Spearman rank correlation based methods. 
 
Descriptive statistics and graphical data displays will be used to summarize in vivo 
measurements of HIV-specific T-cells over the pre- to post-infusion period to assess 
the pattern and magnitudes of T-cell expansion and persistence for each virus. 
Measurements of immunity will be evaluated by descriptive statistics at each time 
point and analyzed by exact, nonparametric methods for paired data to compare 
changes from pre- to post-infusion. HIV-1 specific immune responses using standard 
immunoassays and measures of HIV-1 persistence will be analyzed similarly. 
 
11. ETHICS/PROTECTION OF HUMAN SUBJECTS 
 
11.1. 
Ethical Standard 
 
The principal investigator will ensure that this study is conducted in full conformity with 
the principles set forth in The Belmont Report: Ethical Principles and Guidelines for the 
Protection of Human Subjects of Research, as drafted by the US National Commission 
for the Protection of Human Subjects of Biomedical and Behavioral Research (April 18, 
1979) and codified in 45 CFR Part 46 and/or the ICH E6. 
 
11.2. 
Institutional Review Board 
 
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 in the study. 
 
11.3. 
Informed Consent Process 
 


 
 
 
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Informed consent is a process that is initiated prior to the individual agreeing to participate 
in the study and continues throughout study participation. Extensive discussion of risks 
and possible benefits of study participation will be provided to participants and their 
families, if applicable. A consent form describing in detail the study procedures and risks 
will be given to the participant. Consent forms will be IRB-approved, and the participant 
is required to read and review the document or have the document read to him or her. 
The principal investigator or designee will explain the research study to the participant 
and answer any questions that may arise. The participant will sign the informed consent 
document prior to any study-related assessments or procedures. Participants will be 
given the opportunity to discuss the study with their surrogates and/or family/friends and 
think about it prior to agreeing to participate. They may withdraw consent at any time 
throughout the course of the study.  A copy of the signed informed consent document will 
be given to participants for their records. The rights and welfare of the participants will be 
protected by emphasizing to them that the quality of their clinical care will not be adversely 
affected if they decline to participate in this study. 
 
The consent process will be documented in the clinical and research record. 
 
11.4. 
Amendments 
 
Upon receiving final IRB/EC and any other applicable regulatory approval(s) for any 
amendment after Version 1.0, UNC should implement the amendment immediately. UNC 
is required to submit amendments to NHLBI. A copy of the final amendment approvals 
and documents issued by the NHLBI should be retained in the site's regulatory files. 
 
11.5. 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked.  All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by IRB(s), the FDA, the NHLBI, or the 
industry supporters or designee. 
 
11.6. 
Study Discontinuation 
 
The study may be discontinued at any time by the UNC-CH IRB, the NHLBI, the industry 
supporters, the FDA, or other government agencies as part of their duties to ensure that 
research participants are protected. 
 
 
 
12. DATA COLLECTION, MONITORING, AND ADVERSE EVENT REPORTING 
  


 
 
 
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12.1. 
Records to be kept 
 
Source documents will be provided for each participant. Participants will be identified by 
name in the source documents but will not be identified by name in the database or on 
any report associated with the study. Participants will be identified by the participant 
identification number (PID) and study identification number (SID) provided by the study 
database upon screening. 
 
12.2. 
Role of the Data Manager 
 
It is the responsibility of the study site to assure the quality of data for this study. This 
role extends from protocol development to generation of the final study databases. 
 
12.3. 
Clinical Site Monitoring and Record Availability 
 
12.3.1. Clinical Site Monitors 
 
Site monitors will visit the site to review the individual participant records, including 
consent forms, source documents, supporting data, laboratory specimen records, 
and medical records (physicians’ progress notes, nurses’ notes, individuals’ hospital 
charts), to ensure protection of study participants, compliance with the protocol, and 
accuracy and completeness of records. The monitors also will inspect sites’ 
regulatory files to ensure that regulatory requirements are being followed and sites’ 
pharmacies to review product storage and management. 
 
12.3.2. Site Investigators 
 
The site principal investigator will make study documents (e.g., consent forms, drug 
distribution forms, and source documents) and pertinent hospital or clinic records 
readily available for inspection by the local IRB, the site monitors, the FDA, the 
NHLBI, and the industry supporters or designee for confirmation of the study data. 
 
12.3.3. Adverse Events Reporting to NHLBI 
 
All human participant research supported by NHLBI must include procedures for 
identifying, monitoring, and reporting all AEs, including both serious (SAE) and non-
serious events, and UPs. All NHLBI human participant research will follow a uniform 
policy, which is based on the FDA/Office for Human Research Protections (OHRP) 
regulations and guidance including definitions and timelines. 
 
The study site will reference the IRB-approved Study Progress and Safety Monitoring 
Plan (SPSMP) and report all SAE, AE, and UP Events per reporting timelines 
outlined in this document.  
 


 
 
 
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12.4. 
Reporting Requirements for this Study 
 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE Manual, will 
be used in this study. This SAE Reporting Category is redefined in the DSMP.  
 
The study products, for which expedited reporting is required, are: HIV Expanded T-Cells 
(HXTC) and VOR. 
 
12.5. 
Expedited AE Reporting Period  
 
The expedited AE reporting period for this protocol is the entire study duration for an 
individual participant, once treatment is initiated (from study enrollment until study 
completion or discontinuation of the participant from study participation for any reason).  
 
After the protocol-defined AE reporting period, unless otherwise noted, only suspected, 
unexpected serious adverse reactions (SUSARs), as defined in Version 2.0 of the EAE 
Manual, will be reported to NHLBI, FDA, or UNC IRB per their reporting requirements if 
the study staff become aware of the events on a passive basis (from publicly available 
information). 
 
13. PUBLICATION/DATA SHARING POLICY 
 
Publication of the results of this trial will be governed by NHLBI (NIH) policies. Any 
presentation, abstract, or manuscript will be made available for review by the industry 
supporters prior to submission. 
 
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cells. Nat Med, 1999. 5(1): p. 34-41. 
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47. 
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can be expanded ex vivo to augment systemic and mucosal immunity in vivo. Blood, 
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48. 
Varela-Rohena, A., et al., Control of HIV-1 immune escape by CD8 T cells expressing 
enhanced T-cell receptor. Nat Med, 2008. 14(12): p. 1390-5. 
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Lam, S., et al., Broadly-specific cytotoxic T cells targeting multiple HIV antigens are 
expanded from HIV+ patients: Implications for immunotherapy. Mol Ther, 2014. 
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52. 
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induces differentiation of human breast cancer cells. Cancer Res, 2001. 61(23): p. 8492-
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Mitsiades, N., et al., Molecular sequelae of histone deacetylase inhibition in human 
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the treatment of cancer. Cell Cycle, 2004. 3(6): p. 779-88. 
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Glaser, K.B., et al., Gene expression profiling of multiple histone deacetylase (HDAC) 
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Bali, P., et al., Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone 
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Archin, N.M., et al., HIV-1 expression within resting CD4+ T cells after multiple doses of 
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Tan, R., et al., Rapid death of adoptively transferred T cells in acquired 
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Whiteside, T.L., et al., Generation and characterization of ex vivo propagated autologous 
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Torpey, D., 3rd, et al., Effects of adoptive immunotherapy with autologous CD8+ T 
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Appendix A: Schedule of Events (SOE) 
 
Step 1  
Pre-Treatment  
Ste
p 2  
Step 3  
HXTC Production  
Evaluations 
Screen 
Enrollment 
Leukapheresis 
(#1) 
Step 2 Eliminated 
Cell Collection 
for HXTC 
Pre-Treatment 
Screen 
Visit Window 
 
≤30 days 
≤45 days 
4-6 weeks 
after 
leukapheresis 
4- 10 weeks 
after Visit 5 
 
 
 
at or after 
enrollment 
 
≤21 days 
before visit 6 
Study Week  
 
 
 
 
 
Study Visit  
1 
2 
2.1 
3 
4 
5 
6 
Clinical Procedures  
 
Consent, Eligibility, Demographics & Medical History 
X 
 
 
Step 2 Eliminated 
 
 
Assignment of PID 
X 
 
 
 
 
Assignment of SID 
 
X 
 
X1 
 
Complete Physical Examination (vital signs & weight)  
X 
 
 
 
 
Height^ 
X 
 
 
 
 
Assess venous access 
X 
 
 
 
 
Advancement Criteria  
 
 
X 
 
 
Pre-Dose Clinical Assessment 
 
 
 
 
X 
Targeted Clinical Assessment2 
 
 
 
X 
X 
Review medical history (including new medical conditions) 
 
X 
 
X 
X 
Assess Adverse Event  
X 
 
X 
X 
X 
Review ART & ART Adherence  
X 
X 
X 
X 
X 
Review Concomitant Medication 
X 
X 
X 
X 
X 
Phone Assessment 
 
 
 
 
 
Vorinostat Administration (400 mg) (home) 
 
 
 
 
 
CTL Infusion 
 
 
 
 
 
CTL Pre-medication                                                   
 
 
 
 
 
Post infusion assessment 
 
 
 
 
 
Leukapheresis (& meal)  
 
 
X 
 
 
Clinical Laboratory Procedures  
 
Chemistries  
X◊ 
 
 
Step 2 Eliminated 
 
X3 
Coagulations (PT/INR/PTT)  
X 
 
 
 
 
CBC with differential  
X 
 
X∞ 
 
X 
Pregnancy Test or FSH Test 
X 
 
 
 
X 
CD4+ T Cell Differential Panel  
X 
 
 
 
X 
HIV-1 RNA PCR 
X 
 
 
 
X 
HBsAg & HCV Ab 
X 
 
 
 
X 
Donor ID Panel 4 
 
 
 
X 
 
RPR 
X 
 
 
 
X 
Urine Pregnancy – POCT5 
 
 
 
 
 
Urinalysis  
X 
 
 
 
 
Research Laboratory Procedures 4 
 
Single Copy Assay   
 
 
X 
Step 2 
Eliminated 
 
X 
PBMC for HDAC Responsive Gene Measurement 
 
X6 
 
X 
 
Single PK sample (VOR) 
 
 
 
 
 
Cells for CTL production 
 
 
 
X 
 
HLA typing  
 
 
 
X 
 
Immune Response, Viral Inhibition & Epitope Mapping 
 
X10 
XL 
X 
X10 
Resting Cell Assay and CTL Latency 
 
 
 
 
 
 
 


 
 
 
Protocol v4.0_31-Jan-2022 
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Step 4: Second Series of VOR 400 mg x 10 doses at 72 hours and 2 HXTC infusions 
Evaluations 
VOR Dose #1 and 
HXTC infusion #1
Safety check and 
research labs 
VOR Dose #2 
VOR Dose #3 
VOR Dose #4 
VOR Dose #5 
VOR Dose #6 and 
HXTC Infusion #2 
Safety check and 
research labs 
VOR Dose #7 
VOR Dose #8 
VOR Dose #9 
VOR Dose #10 
Clinical Assessment 
– Pre-Step 5 
Visit Windows - reference table in section 7.3.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Week  
0 
 
 
1 
 
2 
 
 
3 
 
4 
 
6 
Study Visit  
7 
8 
 
9 
 
 
10 
11 
 
 
 
12 
13 
Clinical Procedures  
 
Consent, Eligibility, Demographics & Medical History 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assignment of PID 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assignment of SID 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination (vital signs & weight)  
 
 
 
 
 
 
 
 
 
 
 
 
X 
Height 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess venous access 
 
 
 
 
 
 
 
 
 
 
 
 
 
Advancement Criteria  
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-Dose Clinical Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Targeted Clinical Assessment2 
X 
X 
 
X 
 
 
X 
X 
 
 
 
X 
 
Review medical history (including new medical conditions) 
X 
X 
 
X 
 
 
X 
X 
 
 
 
X 
X 
Assess Adverse Event  
X 
X 
 
X 
 
 
X 
X 
 
 
 
X 
X 
Review ART & ART Adherence  
X 
X 
 
X 
 
 
X 
X 
 
 
 
X 
X 
Review Concomitant Medication 
X 
X 
 
X 
 
 
X 
X 
 
 
 
X 
X 
Phone Assessment 
(T) 
 
(T) 
(T) 
(T) 
(T) 
(T) 
 
(T) 
(T) 
(T) 
(T) 
 
Vorinostat Administration (400 mg) (home) 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
CTL Infusion 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
CTL Pre-medication                                                   
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Post infusion assessment 
X 
X 
 
 
 
 
X 
X 
 
 
 
 
 
Leukapheresis (& meal)  
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Laboratory Procedures  
 
Chemistries  
 
X3 
 
X3 
 
 
X3,7 8 
 
 
 
 
X3 
X3 
Coagulations (PT/INR/PTT)  
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differential  
 
X 
 
X 
 
 
X7,8 
 
 
 
 
X 
X 
Pregnancy Test or FSH Test 
 
 
 
 
 
 
 
 
 
 
 
 
X 
CD4+ T Cell Differential Panel  
 
 
 
 
 
 
 
 
 
 
 
 
X 
HIV-1 RNA PCR 
 
 
 
 
 
 
 
 
 
 
 
 
X 
HBsAg & HCV Ab 
 
 
 
 
 
 
 
 
 
 
 
 
 
Donor ID Panel 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
RPR 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine Pregnancy – POCT5 
X7,8 
 
 
 
 
 
X7,8 
 
 
 
 
 
 
Urinalysis  
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Laboratory Procedures 4 
 
Single Copy Assay   
X 
X 
 
 
 
 
 
 
 
 
 
 
 
PBMC for HDAC Responsive Gene Measurement 
X6 
X 
 
 
 
 
X6 
X 
 
 
 
X 
X 
Single PK sample (VOR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Cells for CTL production 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA typing  
 
 
 
 
 
 
 
 
 
 
 
 
 
Immune Response & Epitope Mapping 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Resting Cell Assay and CTL latency  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
Protocol v4.0_31-Jan-2022 
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Step 5: Second Series of VOR 400 mg x 10 doses at 72 hours and 3 HXTC infusions 
Evaluations 
VOR Dose #11 and 
HXTC infusion #1 
Safety check 
research labs 
VOR Dose #12 
VOR Dose #13 
VOR Dose #14 
VOR Dose #15 
VOR Dose #16 and 
HXTC Infusion #2 
Safety check and 
research labs 
VOR Dose #17 
VOR Dose #18 
VOR Dose #19 
VOR Dose #20 
HXTC Infusion #5 
Safety check and 
research labs 
Visit Window - reference table in section 7.3.4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Week  
8 
 
 
9 
 
 
10 
 
 
11 
 
 
12 
 
Study Visit  
14 
15 
 
 
 
 
16 
17 
 
 
 
18 
19 
20 
Clinical Procedures  
 
Consent, Eligibility, Demographics & Medical 
History 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assignment of PID 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assignment of SID 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination (vital signs & weight)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess venous access 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Advancement Criteria  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-Dose Clinical Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted Clinical Assessment2 
X 
X 
 
 
 
 
X 
X 
 
 
 
X 
X 
X 
Review medical history (including new medical 
conditions) 
X 
X 
 
 
 
 
X 
X 
 
 
 
X 
X 
X 
Assess Adverse Event  
X 
X 
 
 
 
 
X 
X 
 
 
 
X 
X 
X 
Review ART & ART Adherence  
X 
X 
 
 
 
 
X 
X 
 
 
 
X 
X 
X 
Review Concomitant Medication 
X 
X 
 
 
 
 
X 
X 
 
 
 
X 
X 
X 
Phone Assessment 
(T) 
 
(T) 
(T) 
(T) 
(T) 
(T) 
 
(T) 
(T) 
(T) 
(T) 
(T) 
 
Vorinostat Administration (400 mg) (home) 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
CTL Infusion 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
CTL Pre-medication                                                   
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Post infusion assessment 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
Leukapheresis (& meal)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Laboratory Procedures  
 
Chemistries  
 
X3 
 
 
 
 
X3,7,8 
 
 
 
 
X3 
 
 
Coagulations (PT/INR/PTT)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differential  
 
X 
 
 
 
 
X7,8 
 
 
 
 
X 
 
 
Pregnancy Test or FSH Test 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4+ T Cell Differential Panel  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV-1 RNA PCR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBsAg & HCV Ab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Donor ID Panel 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RPR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy – POCT5 
X7,8 
 
 
 
 
 
X7,8 
 
 
 
 
 
X7,8 
 
Urinalysis  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Laboratory Procedures 4 
 
Single Copy Assay   
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PBMC - HDAC Responsive Gene Measurement 
X 
X 
 
 
 
 
X6 
X 
 
 
 
X 
X 
X 
Single PK sample (VOR) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Cells for CTL production 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA typing  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immune Response, Viral Inhibition & Epitope 
Mapping 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Resting Cell Assay and CTL latency  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
Protocol v4.0_31-Jan-2022 
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Step 6; Immune Monitoring  
Evaluations 
IM Visit #1 
IM Visit #2 
Eliminated 
IM Visit #3 & 
Leukapheresis #2 
IM Visit #4 
IM Visit #5 
Eliminated 
IM Visit #6 
Eliminated 
Time to Visit  
~ 7 days after 
Visit 19 
 
~ 4 weeks 
after Visit 19 
~ 9 weeks after 
Visit 19 
 
 
Visit Windows  
3 days (+/-) 
 
1 week (+/-) 
1 weeks (+/-) 
 
 
Study Week  
13 
 
16 
21 
 
 
Study Visit  
21 
22 
23 
24 
25 
26 
Clinical Procedures  
 
Consent, Eligibility, Demographics & Medical History 
 
Visit Eliminated 
 
 
Visit Eliminated 
Visit Eliminated 
Assignment of PID 
 
 
 
Assignment of SID 
 
 
 
Complete Physical Examination (vital signs & weight)  
 
X 
 
Height 
 
 
 
Assess venous access 
 
 
 
Advancement Criteria  
 
 
 
Pre-Dose Clinical Assessment 
 
 
 
Targeted Clinical Assessment2 
X 
 
X 
Review medical history (including new medical 
conditions) 
X 
X 
X 
Assess Adverse Event  
X 
X 
X 
Review ART & ART Adherence  
X 
X 
X 
Review Concomitant Medication 
X 
X 
X 
Phone Assessment 
 
 
 
Vorinostat Administration (400 mg) (clinic) 
 
 
 
CTL Infusion 
 
 
 
CTL Pre-medication                                                   
 
 
 
Post infusion assessment 
 
 
 
Leukapheresis (& meal)  
 
X 
 
Clinical Laboratory Procedures  
 
Chemistries  
X3 
Visit Eliminated 
X◊ 
 
Visit Eliminated 
Visit Eliminated 
Coagulations (PT/INR/PTT)  
 
 
 
CBC with differential  
X 
X∞ 
X 
Pregnancy Test or FSH Test 
 
 
 
CD4+ T Cell Differential Panel  
X 
X 
X 
HIV-1 RNA PCR 
X 
X 
X 
HBsAg & HCV Ab 
 
 
 
Donor ID Panel 4 
 
 
 
RPR 
 
 
 
Urine Pregnancy – POCT5 
 
 
 
Urinalysis  
 
X 
 
Research Laboratory Procedures 4 
 
Single Copy Assay   
X 
Visit 
Eliminated 
X 
 
Visit 
Eliminated 
Visit 
Eliminated 
PBMC for HDAC Responsive Gene Measurement 
 
 
 
Single PK sample (VOR) 
 
 
 
Cells for CTL production 
 
 
 
HLA typing  
 
 
 
Immune Response, Viral Inhibition & Epitope Mapping 
 
 
 
Resting Cell Assay and CTL Latency 
 
 
XL 
X 
 
 
 
 
 


 
 
 
Protocol v4.0_31-Jan-2022 
Page 99 of 99 
 
Legend 
 
1  CNH product ID will be assigned at this time. 
 
^ Height will be obtained at screening in the CTRC – without shoes.  
 
2  Targeted clinical assessments are driven by signs and/or symptoms experienced since the 
last visit or unresolved signs or symptoms experienced previously and included weight and vital 
signs (temperature, blood pressure, pulse and respirations). 
 
◊  Clinical labs for screening only include sodium (Na), potassium (K), chloride (Cl), bicarbonate 
(CO2), glucose, blood urea nitrogen (BUN), creatinine (Cr), calcium (Ca), magnesium (Mg), 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (Alk 
Phos), total bilirubin (total bili). A direct bilirubin will be obtained if participant is on atazanavir. 
Lipase, albumin, total protein, triglyceride and cholesterol are obtained at screening and Visit 23 
only.  
 
3  Clinical safety laboratory tests: Na, K, Cl, CO2, Cr, glucose, LT, AST, alk phos, total bili, Ca 
and Mg.  
 
4  Reference Study Specific Lab Manual for collection and processing requirements for research 
samples. 
 
∞ CBC is required for Apheresis procedures. Labs for UNC can be obtained up to 24 hours prior 
to visit or STAT on the day of the procedure. The CBC for the American Red Cross or other 
local blood collection agency will be drawn per facility requirement up to 30 days prior to the 
collection.  
 
5  POCT pregnancy testing will be done on all women prior to initiation of VOR and at all HXTC 
infusions.  
 
6  Draw 25.5 mL (3 – 8.5 mL ACD tubes) at these selected time points.  
 
L  Samples come from the leukapheresis product and are sent to Margolis Lab at UNC ambient 
for processing. 
 
(T) Participants will be contacted via agreed upon communication mechanism to assess for 
adverse events. 
 
7  Labs may be obtained up to 48 hours prior to visit. 
 
8  Draw labs STAT, if done on day of visit. Results must be obtained and reviewed prior to 
procedure or infusion.  
  
 
10  If enrollment occurs on the day of the baseline leukapheresis, draw these samples on Visits 5 
and 6, as indicated on the SOE.