Safety and Immunotherapeutic Activity of an Anti-PD-1 Antibody (Cemiplimab) in Participants With HIV-1 on Suppressive cART: A Phase I/II, Double-blind, Placebo-controlled, Ascending Multiple Dose Study
Phase: PHASE1
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
A5370 
 
 
Safety and Immunotherapeutic Activity of an Anti-PD-1 Antibody (Cemiplimab) in 
HIV-1-infected Participants on Suppressive cART: A Phase I/II, Double-blind, 
Placebo-controlled, Ascending Multiple Dose Study 
 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
 
 
Sponsored by: 
 
National Institute of Allergy 
and Infectious Diseases 
 
Industry Support Provided by: 
 
Regeneron Pharmaceuticals, Inc. 
 
 
IND #137978 
 
 
 
The ACTG HIV Reservoirs and Viral Eradication 
Transformative Science Group: 
 
 
Rajesh Gandhi, MD, Chair 
 
Protocol Co-Chairs:  
 
 
Cynthia Gay, MD 
 
 
 
W. David Hardy, MD 
 
Protocol Vice Chair:  
 
 
Joseph J. Eron, Jr., MD 
 
DAIDS Clinical Representative: 
 
 
Randall Tressler, MD 
 
Clinical Trials Specialist: 
 
 
Chanelle Houston, BS 
 
 
 
 
FINAL Version 1.0 
November 16, 2018

A5370 
 
 
FINAL Version 1.0 
 
 
11/16/18 
A5370 
 
Safety and Immunotherapeutic Activity of an Anti-PD-1 Antibody (Cemiplimab) in HIV-1-infected 
Participants on Suppressive cART: A Phase I/II, Double-blind, Placebo-controlled, Ascending 
Multiple Dose Study 
 
SIGNATURE PAGE 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable U.S. Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
 
 
 
 
 
Principal Investigator: _______________________________________________ 
                                   Print/Type 
 
 
 
 
 
Signed: ___________________________________ Date: _____________ 
             Name/Title 
 

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TABLE OF CONTENTS 
Page 
 
SIGNATURE PAGE ............................................................................................................... 2 
SITES PARTICIPATING IN THE STUDY ................................................................................ 5 
PROTOCOL TEAM ROSTER ................................................................................................. 6 
STUDY MANAGEMENT......................................................................................................... 9 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ................................................................. 11 
SCHEMA ............................................................................................................................. 14 
1.0 
HYPOTHESES AND STUDY OBJECTIVES .............................................................. 15 
1.1 
Hypotheses ................................................................................................... 15 
1.2 
Primary Objective .......................................................................................... 15 
1.3 
Secondary Objectives .................................................................................... 15 
1.4 
Exploratory Objectives ................................................................................... 16 
2.0 
INTRODUCTION ...................................................................................................... 16 
2.1 
Background ................................................................................................... 16 
2.2 
Rationale ....................................................................................................... 17 
3.0 
STUDY DESIGN ....................................................................................................... 30 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ............................................. 31 
4.1 
Inclusion Criteria ............................................................................................ 31 
4.2 
Exclusion Criteria ........................................................................................... 35 
4.3 
Study Enrollment Procedures ......................................................................... 37 
4.4 
Co-enrollment Guidelines ............................................................................... 38 
5.0 
STUDY INTERVENTION........................................................................................... 39 
5.1 
Intervention, Administration, and Duration ....................................................... 39 
5.2 
Study Product Formulation and Preparation .................................................... 40 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability ............................. 48 
5.4 
Concomitant Medications ............................................................................... 49 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................ 51 
6.1 
Schedule of Evaluations (SOE) ...................................................................... 51 
6.2 
Timing of Evaluations ..................................................................................... 56 
6.3 
Instructions for Evaluations ............................................................................ 59 
7.0 
ADVERSE EVENTS AND STUDY MONITORING ...................................................... 70 
7.1 
Definition of Adverse Events (AEs) ................................................................. 70 
7.2 
AE Collection Requirements for This Protocol ................................................. 70 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS ...................................... 71 
7.4 
Study Monitoring ............................................................................................ 73 
8.0 
CLINICAL MANAGEMENT ISSUES .......................................................................... 74 
8.1 
Toxicity.......................................................................................................... 77 
8.2 
Infusion-related Toxicities and Management ................................................... 78 
8.3 
Other Potential AEs/Toxicity ........................................................................... 80 
8.4 
Suspected Ocular Toxicity .............................................................................100 
8.5 
Suspected Dermatologic Toxicity ...................................................................101 
8.6 
Suspected Hematologic Toxicity ....................................................................103 

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Page 
 
8.7 
Virologic Failure ............................................................................................105 
8.8 
Pregnancy ....................................................................................................105 
9.0 
CRITERIA FOR DISCONTINUATION .......................................................................106 
9.1 
Permanent and Premature Treatment Discontinuation....................................106 
9.2 
Premature Study Discontinuation ..................................................................107 
10.0 
STATISTICAL CONSIDERATIONS ..........................................................................107 
10.1 
General Design Issues ..................................................................................107 
10.2 
Outcome Measures ......................................................................................107 
10.3 
Randomization and Stratification ...................................................................109 
10.4 
Sample Size and Accrual ..............................................................................109 
10.5  
Data and Safety Monitoring ...........................................................................112 
10.6 
Analyses ......................................................................................................112 
10.7 
Unblinding ....................................................................................................114 
11.0 
PHARMACOLOGY PLAN ........................................................................................115 
11.1 
Pharmacology Objectives ..............................................................................116 
11.2 
Pharmacology Study Design .........................................................................117 
11.3 
Primary and Secondary Data, Modeling, and Data Analysis ............................118 
11.4 
Anticipated Outcomes ...................................................................................118 
12.0 
DATA COLLECTION AND MONITORING ................................................................119 
12.1 
Records to Be Kept .......................................................................................119 
12.2 
Role of Data Management ............................................................................119 
12.3 
Clinical Site Monitoring and Record Availability ..............................................119 
13.0 
PARTICIPANTS.......................................................................................................119 
13.1 
Institutional Review Board (IRB) Review and Informed Consent .....................119 
13.2 
Participant Confidentiality ..............................................................................120 
13.3 
Study Discontinuation ...................................................................................120 
14.0 
PUBLICATION OF RESEARCH FINDINGS ..............................................................120 
15.0 
BIOHAZARD CONTAINMENT..................................................................................120 
16.0 
REFERENCES ........................................................................................................121 
APPENDIX I: SAMPLE INFORMED CONSENT ...................................................................126 
APPENDIX II: PARTICIPANT ASSESSMENT OF UNDERSTANDING ..................................143 
 

 
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SITES PARTICIPATING IN THE STUDY 
 
A5370 is a multicenter study open to all US clinical research sites (CRSs).  
 
 

 
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PROTOCOL TEAM ROSTER 
 
Co-Chairs 
Cynthia Gay, MD 
Chapel Hill CRS 
Bioinformatics Building 
130 Mason Farm Road, Suite 2112 
Chapel Hill, NC 27599-7030 
Phone: 919-843-2726 
Fax: 919-966-8928 
Email: cynthia_gay@med.unc.edu 
 
W. David Hardy, MD 
Division of Infectious Diseases  
Johns Hopkins University School of 
Medicine 
4627 47th Street, NW 
Washington, DC 20016 
Phone: 310-709-3505 
Email: wdavidhardymd@gmail.com 
 
Vice Chair 
Joseph J. Eron, Jr., MD 
University of North Carolina Global HIV 
Prevention and Treatment CTU 
Bioinformatics Building 
130 Mason Farm Road, Suite 210 
Chapel Hill, NC 27599-7215 
Phone: 919-843-2722 
Fax: 919-966-6714 
Email: jeron@med.unc.edu  
 
DAIDS Medical Officer  
Randall Tressler, MD 
HIV Research Branch 
DAIDS, NIAID, NIH 
5601 Fishers Lane  
Room 9E49 
Rockville, MD  20852 
Phone: 240-627-3072 
Fax: 301-435-9282 
Email: Randall.tressler@nih.gov
Clinical Trials Specialist 
Chanelle Houston, BS 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: 301-628-3367 
Fax: 301-628-3302 
Email: CHouston@s-3.com 
 
Statisticians 
Ronald Bosch, PhD 
Statistical and Data Analysis Center 
Harvard TH Chan School of Public Health 
FXB Building, Room 603 
651 Huntington Avenue 
Boston, MA 02115-6017 
Phone: 617-432-3024 
Fax: 617-432-2843 
Email: ronbosch@sdac.harvard.edu 
 
Ashley McKhann, MS 
Statistical and Data Analysis Center 
Harvard TH Chan School of Public Health 
FXB Building, Room 604b 
651 Huntington Avenue 
Boston, MA 02115-6017 
Phone: 617-432-7986 
Fax: 617-432-2843 
Email: amckhann@sdac.harvard.edu 
 
Data Manager 
Bernadette M. Jarocki, BS  
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: 716-834-0900 (Ext. 7263)  
Fax: 716-834-8432 
Email: jarocki@fstrf.org

 
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DAIDS Pharmacist 
Lynette Purdue, PharmD 
Pharmaceutical Affairs Branch 
DAIDS, NIAID, NIH 
5601 Fishers Lane 
Room 9E28 
Rockville, MD 20852 
Phone: 240-627-3061 
Fax: 240-627-3112 
Email: lpurdue@niaid.nih.gov  
 
Immunologist 
Bernard J.C. Macatangay, MD 
University of Pittsburgh CRS 
S827 Scaife Hall 
3550 Terrace Street 
Pittsburgh, PA 15261 
Phone: 412-383-1272 
Fax: 412-648-8455 
Email: macatangaybj@upmc.edu 
 
Virologist 
Daniel R. Kuritzkes, MD 
Brigham and Women's Hospital 
Therapeutics (BWHT) CRS 
Section of Retroviral Therapeutics 
Harvard Medical School 
65 Landsdowne Street, Room 447 
Cambridge, MA 02139 
Phone: 617-768-8398 
Fax: 617-768-8738 
Email: dkuritzkes@partners.org 
 
Pharmacologists 
Gene Morse, PharmD 
University of Rochester Adult HIV 
Therapeutic Strategies Network CRS 
Translational Pharmacology Research Core 
NYS Center of Excellence in Bioinformatics 
and Life Sciences 
701 Ellicott Street 
Buffalo, NY 14203 
Phone: 716-881-7464 
Email: emorse@buffalo.edu 
 
 
 
Pharmacologists, cont’d 
Raymond Cha, PharmD 
University at Buffalo 
SUNY Buffalo 
212 Kapoor Hall 
Buffalo, NY 14214 
Phone: 716-645-4790 
Email: rcha@buffalo.edu 
 
Endocrinologist 
Kendall Moseley, MD 
Division of Endocrinology, Diabetes & 
Metabolism 
Johns Hopkins University School of 
Medicine 
5501 Hopkins Bayview Circle, 2A62 Asthma 
and Allergy Center 
Baltimore, Maryland 21224 
Phone: 410-550-8720 
Fax: 410-367-2042 
Email: kmosele4@jhmi.edu 
 
Oncologist 
Thomas Uldrick, MD, MS 
Deputy Head, Global Oncology 
Associate Member, Vaccine and Infectious 
Disease Division 
Associate Member, Clinical Research 
Division 
Fred Hutchinson Cancer Research Center 
1100 Fairview Avenue North 
Seattle, WA 98109-1024 
Phone: 206-667-7585 
Fax: 206-667-1965 
Email: tuldrick@fredhutch.org 
 
Field Representatives 
Susan Pedersen, RN, BSN 
University of North Carolina Global HIV 
Prevention and Treatment CTU 
Bioinformatics Building, Suite 2100 
130 Mason Farm Road 
Chapel Hill, NC 27599-7215  
Phone: 919-966-6713 
Fax: 919-966-6712 
Email: spederse@med.unc.edu 
 

 
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Field Representatives, cont’d 
Amanda Tipton, LPN 
Chapel Hill CRS 
130 Mason Farm Road, 2nd Floor 
Chapel Hill, NC 27599-7030 
Phone: 919-843-2239 
Fax: 919-966-6714 
Email: tiptoe13@med.unc.edu 
 
Laboratory Technologists 
Cheryl Jennings, BS 
Northwestern University CRS 
Clinical Retrovirology Research Laboratory 
1181 Jelke Building 
1750 West Harrison Street 
Chicago, IL 60612 
Phone: 312-942-5954 
Fax: 312-942-6787 
Email: cheryl_jennings@rush.edu 
 
Pamela Lankford-Turner, BS 
The Ponce de Leon Center CRS 
500 Irvin Court  
Suite 100 
Decatur, GA 30030 
Phone: 404-727-3747 
Fax: 404-499-9726 
Email: pturn01@emory.edu 
 
Community Scientific Subcommittee (CSS) 
Representative 
Danielle Campbell, MPH 
University of California, Los Angeles CARE 
Center CRS 
8810 South Mary Avenue 
Los Angeles, CA 90002 
Phone: 310-910-8341 
Email: danielle.m.campbell1@gmail.com 
 
Industry Representative 
Elizabeth Miller, MD 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road, 62-002 
Tarrytown, NY 10591 
Phone: 914-847-1290 
Email: elizabeth.miller@regeneron.com 
 
Laboratory Data Manager 
Kyle Whitson, MA 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14221 
Phone: 716-340-0900 (Ext. 7273) 
Email: whitson@fstrf.org 
 
Laboratory Specialists 
Emmanuell Choueiry, MSc 
IMPAACT Network Laboratory Center 
University of California Los Angeles 
11075 Santa Monica Blvd. Suite #200 
Los Angeles, CA 90025 
Phone: 310-794-9894  
Email: echoueiry@impaactlabcenter.org 
 
Sara Zabih 
IMPAACT Network Laboratory Center 
University of California Los Angeles 
11075 Santa Monica Blvd. Suite #200 
Los Angeles, CA 90025 
Phone: 310-794-9052 
Email: szabih@impaactlabcenter.org 

 
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STUDY MANAGEMENT 
 
All general questions concerning this protocol should be sent to actg.teamA5370@fstrf.org via 
e-mail. The appropriate team member will respond with a "cc" to actg.teamA5370@fstrf.org. A 
response should generally be received within 24 hours (Monday through Friday). 
 
Protocol E-mail Group 
Sites should contact the User Support Group at the Data Management Center (DMC) as soon 
as possible to have the relevant personnel at the site added to the actg.protA5370 e-mail group. 
Include the protocol number in the e-mail subject line. 
• Send an e-mail message to actg.user.support@fstrf.org. 
 
Clinical Management 
For questions concerning entry criteria, toxicity management, concomitant medications, and co-
enrollment, contact the core protocol team. 
• 
Send an e-mail message to actg.coreA5370@fstrf.org. Include the protocol number, patient 
identification number (PID), and a brief relevant history. 
 
Laboratory 
For questions specifically related to immunologic, virologic, or pharmacologic laboratory tests, 
contact the protocol immunologist, virologist, or pharmacologist. 
• Send an e-mail message to actg.teamA5370@fstrf.org (ATTENTION: [Beej Macatangay, 
immunologist; Dan Kuritzkes, virologist; Gene Morse, and Raymond Cha, pharmacologists]). 
 
Data Management 
• 
For nonclinical questions about transfers, inclusion/exclusion criteria, electronic case report 
forms (eCRFs), randomization/registration, and other data management issues, contact the 
data manager. Completion guidelines for eCRFs and participant-completed CRFs can be 
downloaded from the FSTRF website at www.frontierscience.org. 
• 
For transfers, reference the Study Participant Transfer SOP 119, and contact Bernie Jarocki, 
jarocki@fstrf.org, directly. 
• 
For other questions, send an e-mail message to actg.teamA5370@fstrf.org (ATTENTION: 
Bernie Jarocki). 
• 
Include the protocol number, PID, and a detailed question. 
 
Randomization/Participant Registration 
For randomization/participant registration questions or problems and study identification number 
SID lists: 
• 
Send an e-mail message to rando.support@fstrf.org or call the DMC Randomization Desk at 
716-834-0900, extension 7301. 
 
DMC Portal and Medidata Rave Problems 
Contact DMC User Support: 
• 
Send an e-mail message to actg.user.support@fstrf.org or call 716-834-0900 x7302. 
 
 

 
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Protocol Document Questions 
For questions concerning the protocol document, contact the clinical trials specialist. 
• 
Send an e-mail message to actg.teamA5370@fstrf.org (ATTENTION: Chanelle Houston). 
 
Copies of the Protocol 
To request a hard copy of the protocol, send an e-mail message to ACTGNCC@s-3.com. 
Electronic copies can be downloaded from the ACTG website at https://www.actgnetwork.org. 
 
Product Package Inserts and/or Investigator Brochures 
To request copies of product package inserts or investigator brochures (IBs), contact the DAIDS 
Regulatory Support Center (RSC) at RIC@tech-res.com or call 301-897-1708. 
 
Protocol Registration 
For protocol registration questions, send an e-mail message to Protocol@tech-res.com or call 
301-897-1707. 
 
Protocol Activation 
For questions related to protocol activation at US sites, contact the clinical trials specialist  
• 
Send an e-mail message to actg.teamA5370@fstrf.org (ATTENTION: [Chanelle Houston]). 
  
Study Product 
For questions or problems regarding study product, dose, supplies, records, and returns, call 
Lynette Purdue, protocol pharmacist, at 240-627-3061.  
 
Study Drug Orders 
Call the Clinical Research Products Management Center (CRPMC) at 301-294-0741. 
 
IND (Investigational New Drug) Number or Questions 
The IND number will be available on the protocol-specific web page (PSWP) within 30 days of 
the submission to the Food and Drug Administration (FDA). For any questions related to the 
IND submission, contact the DAIDS RSC at Regulatory@tech-res.com or call 301-897-1706. 
 
Expedited Adverse Event (EAE) Reporting/Questions 
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or 301-897-1709; or fax 1-800-275-7619 or 301-897-1710. 
 
Telephone Calls 
Sites are responsible for documenting telephone calls made to A5370 team members. 
• 
Send an e-mail message to actg.teamA5370@fstrf.org. 
 
Protocol-Specific Web Page 
Additional information about management of the protocol can be found on the protocol-specific 
web page (PSWP). 

 
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GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
ACTH 
adrenocorticotropic hormone 
ADA 
anti-drug antibodies 
ADLs 
activities of daily living  
AE 
adverse event 
AESI 
adverse event of special interest 
ALC 
absolute lymphocyte count 
ALT 
alanine transaminase 
ANA 
antinuclear antibody 
ANC 
absolute neutrophil count 
ANCA 
antineutrophil cytoplasmic antibody  
AST 
aspartate transaminase 
AUCt 
area under the concentration-time profile 
AUC6wk,ss 
area under the concentration-time profile over 6 weeks at steady-state 
AUCt 
 AUC until the last detectable concentration 
BLQ 
below the limit of quantification 
BSA 
body surface area 
BUN 
blood urea nitrogen 
Ceoi 
concentration at end of infusion 
Cmax 
maximum serum concentration of drug 
Ctrough 
concentration at trough (pre-dose) 
cART 
combination antiretroviral therapy 
CFSE 
carboxyfluorescein diacetate succinimidyl ester 
CL 
clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
COPD 
chronic obstructive pulmonary disease 
CR 
complete responses  
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for AEs  
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
DAERS 
DAIDS Adverse Experience Reporting System  
DILI 
drug-induced liver injury  
ECG 
electrocardiogram  
eCRF 
electronic case report form 
ESR 
erythrocyte sedimentation rate  
FIH 
first-in-human 
FL 
follicular lymphoma 
FSH 
follicle stimulating hormone-release factor 

 
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GAD65/GAD glutamic acid decarboxylase 65 
HBV 
hepatitis B virus 
HBsAg 
hepatitis B virus surface antigen 
HCC 
hepatocellular carcinoma  
HCV 
hepatitis C virus 
HgbA1c 
hemoglobin A1c 
ICI 
immune checkpoint inhibitors 
IgG 
immunoglobulin  
IFN-γ 
interferon gamma 
IGRA 
interferon-gamma release assay 
INR 
International Normalized Ratio 
irAE 
immune-related adverse event 
IRIS 
immune reconstitution syndrome 
IU 
international unit 
IUD 
 
intrauterine device  
IV 
intravenous 
LDMS 
laboratory data management system 
LTR 
long terminals repeats 
LPC 
Laboratory Processing Chart 
mAb 
monoclonal antibody 
MedDRA 
Medical Dictionary of Regulatory Activities System Organ Class 
MOPS 
Manual of Procedures 
NHP 
non-human primate  
NSCLC 
non-small cell lung carcinoma  
PBMC 
peripheral blood mononuclear cell 
PD 
pharmacodynamics 
PD-1 
programmed cell death 1 
PK 
pharmacokinetics 
PPD 
purified protein derivative 
PR  
partial responses  
PSWP 
Protocol-Specific Web Page 
PVC 
polyvinyl chloride 
qHBsAg 
quantitative HBV surface antigen  
RO 
receptor occupancy 
SAE 
Serious Adverse Event 
SCA 
single copy assay 

 
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SD  
standard deviation  
SMC 
study monitoring committee 
SOE 
schedule of evaluations 
t1/2 
elimination half-life 
T4 
free thyroxine  
TEN 
toxic epidermal necrolysis 
TB 
tuberculosis 
TK 
toxicokinetic 
TPO 
thyroid peroxidase  
TNFα 
tumor necrosis factor alpha 
TSH 
thyroid stimulating hormone 
TVR 
total virus recovery 
ULN 
upper limit of normal 
VL 
viral load  
WBC 
white blood cell  

 
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SCHEMA 
 
A5370 
 
Safety and Immunotherapeutic Activity of an Anti-PD-1 Antibody (Cemiplimab) in HIV-1-infected 
Participants on Suppressive cART: A Phase I/II, Double-blind, Placebo-controlled, Ascending 
Multiple Dose Study 
 
DESIGN 
This trial is a phase I/II, double-blinded (within each cohort), dose-
escalating, placebo-controlled study of the safety and immunotherapeutic 
activity of two infusions of anti-PD-1 (REGN2810/cemiplimab) monoclonal 
antibody in HIV-1-infected participants on combination antiretroviral 
therapy (cART) who have HIV-1 RNA below the limit of quantification and 
CD4+ T cell counts ≥350/mm3. 
 
Cemiplimab (0.3 mg/kg [Cohort 1], 1 mg/kg [Cohort 2], and 3 mg/kg 
[Cohort 3]) or placebo will be given to 15 participants in each Cohort (12 
active and 3 placebo). Participants will receive infusions of antibody or 
placebo at entry/day 0 and week 6, for a total of 2 infusions, with the 
primary safety endpoint through week 48 and the primary immunologic 
endpoint through week 12. The study will enroll sequential dose-rising 
cohorts with the second and third cohorts receiving the first infusion after 
all participants in the previous cohort have reached week 12 and an 
evaluation of safety outcomes is completed, which determines whether to 
dose escalate or not. 
 
DURATION 
Participants will be followed for 48 weeks 
 
SAMPLE SIZE 
45 participants (15 participants each in Cohorts 1-3).  
 
POPULATION 
HIV-1-infected men and women ages ≥18 and <65 years, on cART who 
have a CD4+ T cell count of ≥350 cells/mm3 and a screening plasma HIV-
1 RNA below the level of quantification by a FDA-approved HIV RNA 
assay. 
 
INTERVENTION  
Within each sequentially enrolled dose cohort, participants will be 
randomized 4:1 to receive REGN2810/cemiplimab or placebo infusion: 
 
Cohort 1: Two doses of REGN2810/cemiplimab 0.3 mg/kg or placebo (12 
active: 3 placebo); one dose at entry/day 0 and one dose at week 6 
 
Cohort 2: Two doses of REGN2810/cemiplimab 1 mg/kg or placebo (12 
active: 3 placebo; one dose at entry/day 0 and one dose at week 6 
 
Cohort 3: Two doses of REGN2810/cemiplimab 3 mg/kg or placebo (12 
active: 3 placebo); one dose at entry/day 0 and one dose week 6 

 
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HYPOTHESES AND STUDY OBJECTIVES 
 
1.1 
Hypotheses 
 
1.1.1 Two doses of the anti-PD-1 (programmed cell death) monoclonal antibody 
(mAb), cemiplimab, will be safe in HIV-1-infected participants on cART with 
plasma HIV-1 RNA suppressed below the level of quantification on standard 
assays. 
 
1.1.2 Blocking PD-1 interaction with its ligands (PD-L1 and PD-L2) with anti-PD-1 
antibody will enhance HIV-1-specific immune responses that promote the 
clearance (CL) of HIV-1-expressing cells. 
 
1.2 
Primary Objective 
 
1.2.1 To assess the safety of multiple dose levels (0.3, 1, and 3 mg/kg) of cemiplimab 
versus placebo in HIV-1-infected, cART-suppressed participants. 
 
1.3 
Secondary Objectives 
 
1.3.1 To evaluate the change in magnitude of HIV-1 gag-specific CD8+ T cells by 
intracellular staining for both CD107a and interferon gamma (IFN-γ) from a pre-
treatment baseline level (average of 2 measurements) to time points after one or 
two doses of cemiplimab (average of responses from weeks 2, 4, 6, 8, 10, and 
12). 
 
1.3.2 To evaluate the change in magnitude of HIV-1 gag-specific CD8+ T cell 
responses using both CD107a and IFN-γ expression from baseline to time points 
after the first dose of cemiplimab or placebo (average of responses from weeks 
2, 4, and 6), and to time points after the second dose or placebo (average of 
responses from weeks 8, 10, and 12). 
 
1.3.3 To evaluate the change in magnitude of HIV-1 gag-specific CD8+ T cells by 
intracellular staining for IFN-γ or CD107a alone, from baseline (pre-treatment 
average) to time points after one or two sequential doses of cemiplimab or 
placebo (average of responses from weeks 2, 4, 6, 8, 10, and 12) and explore 
difference following each dose. 
 
1.3.4 To evaluate changes in polyfunctional response of HIV-1-gag-specific CD8+ T 
cells by intracellular staining for IFN-γ, CD107a, IL-2, and TNFα from baseline 
(pre-treatment average) to time points after one or two sequential doses of 
cemiplimab or placebo and explore difference following each dose. 
 
1.3.5 To assess the durability of response to cemiplimab by evaluating the magnitude 
of HIV-1 gag-specific CD8+ T cell responses by intracellular staining of CD107a 
and IFN-γ and polyfunctional response through week 48. 

 
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1.3.6 To assess immunogenicity to cemiplimab after multi-dose administration to 
cART-treated HIV-1-infected participants. 
 
1.4 
Exploratory Objectives 
 
1.4.1 To evaluate changes in total HIV-1 DNA, intact proviral HIV-1 genomes, plasma 
HIV RNA by single copy assay (SCA), cell-associated HIV-1 RNA, and HIV-1 
RNA/DNA ratios in total CD4+ cells prior to and following cemiplimab 
administration. 
 
1.4.2 To explore the human genetic and gene expression correlates of response to 
cemiplimab administration.   
 
1.4.3 
To explore relationships between serum cemiplimab exposure and changes in 
biomarkers of virologic and immune response. 
 
1.4.4 
To explore the proportion of total and HIV-1 gag-specific CD8+ and CD4+ T cells 
that express PD-1, PD-L1, and other exhaustion markers by multi-parameter flow 
cytometry. The expression profile of PD-L2 on dendritic cells and monocyte 
derived-macrophages will also be determined. 
 
1.4.5 
To explore changes in poly-functionality of HIV-1-specific CD4+ T cells by 
intracellular staining for two or more immune mediators using flow cytometry. 
 
1.4.6 
To explore changes in immune activation and cell cycling of CD8+ and CD4+ T 
cells by quantifying CD38+ HLA-DR+ and Ki 67 expression prior to and following 
anti-PD-1 administration by flow cytometry. 
 
1.4.7 
To evaluate the relationship between pre-therapy ex vivo HIV-specific T cell 
proliferation to HIV antigens following cemiplimab exposure and the in vivo HIV 
specific immune responses post cemiplimab administration. 
 
1.4.8 
 To describe the pharmacokinetics (PK) and receptor occupancy (RO) of 
cemiplimab after administration to cART-treated HIV-1-infected participants. 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
In patients who are effectively treated with cART, HIV-1 persists in latently infected 
resting CD4+ T cells and possibly other tissues or cellular reservoirs. Elimination of 
latently infected cells with replication competent virus is necessary to cure HIV-1 
infection. Although recent evidence suggests that the histone deacetylase inhibitors, 
such as vorinostat and romidepsin, can increase expression of HIV-1 RNA in resting 
CD4+ T cells and in plasma [1-3], additional steps may be necessary to kill HIV-1-
expressing cells and reduce the resting CD4+ T cell reservoir [4]. Consequently, 
reduction or elimination of HIV-1 reservoirs that persist on suppressive cART may 

 
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require the combination of multiple therapeutic modalities including interventions that 
enhance the HIV-1-specific immune response. Hence, the testing of interventions that 
have the potential to impact persistent HIV-1, enhance HIV-specific immunity, and be 
combined with other interventions that may be additive or synergistic is a necessary step 
in a comprehensive strategy for cure research. 
 
cART clearly has been effective at suppressing plasma HIV-1 RNA to well below the 
limits of detection by conventional tests in most treated HIV-infected patients [5]. 
However, despite effective cART, low-level HIV-1 viremia persists in most patients [6]. 
Why this persistent viremia and the resulting antigenemia fail to stimulate effective HIV-
1-specific T cell responses and why virus-producing cells are ineffectively cleared is not 
completely understood. Chronic antigen stimulation results in marked down regulation of 
the antigen-specific cellular immune responses to HIV-1 and other chronic viral 
infections [7]. The resulting T cell “exhaustion” is characterized by reduced T cell 
proliferation, cytokine production, cytotoxic T lymphocyte (CTL) function, and cell 
survival [8]. The molecular mechanisms behind this “immune exhaustion” in the context 
of chronic infection are only recently coming to light [8, 9]. In individuals receiving 
suppressive ART, CD4+ T cells expressing PD-1 and other immune checkpoint 
molecules are enriched in HIV infection. In addition to reversing immune exhaustion, 
anti-PD-1 administration may target the latent cell pool [10, 11]. 
 
2.2 
Rationale 
 
T-cell Exhaustion in Chronic Viral Infections 
During chronic viral infections, persistent antigenic stimulation leads to the T cell 
expression of inhibitory co-receptors (e.g., PD-1 and cytotoxic T-lymphocyte-associated 
protein 4 [CTLA-4]) which are associated with a downregulation of immune responses. 
[12, 13] This loss of T cell function occurs in several stages starting with loss in 
proliferative potential, cytotoxic responses (i.e., T cell ability to lyse target cells), and 
polyfunctionality, followed by defects in cytokine production such as IFN-γ [8, 14]. 
Indeed, an important factor underlying ineffective HIV-1-specific immune responses is 
previous evidence that chronic HIV-1 infection leads to up-regulation of these inhibitory 
co-receptors on T cells. The expression of PD-1 and CTLA-4, on CD4+ and/or CD8+ T 
cells is associated with disease progression in untreated HIV-1 infection [15-18]. PD-1 
expression on HIV-1 specific CD8+ and CD4+ T cells is reduced by ART [15, 19], but in 
some studies expression remained elevated compared to that in uninfected persons [15, 
20], especially in patients with less robust CD4+ T cell responses [21]. In a study 
evaluating PD-1 expression in HIV-infected individuals starting ART early (within 6-12 
months of estimated infection) or later, PD-1 expression on total CD4+ and CD8+ T cells 
after several years of cART (median of 2.8 years and 2.3 years, respectively) was 
comparable to levels seen in the HIV-uninfected controls [22]. However, in this study 
median PD-1 mean fluorescent intensity remained elevated on the CD4+ effector 
memory T cells compared to uninfected controls, even in the early ART group (234 vs. 
206, P=0.007). Expression of PD-L1, a ligand for PD-1, in addition to being inducible on 
antigen-presenting cells [23], is also up-regulated on both CD4+ and CD8+ HIV-1-
specific T cells in response to HIV-1 infection. Levels of PD-L1 on T-cells in this context 
remain elevated despite suppression of HIV-1 by ART [20, 24]. Further, recently 

 
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published data with a single, low dose of anti-PD-L1 antibody (BMS-936559) in ACTG 
A5326 suggests that blockade of the PD-1/PD-L1 axis may improve HIV-specific 
immune responses, even in patients with durable viral suppression on ART [25]. In this 
study, two of six participants who received the anti-PD-L1 antibody demonstrated 
improvements in HIV-1-specific CD8+ responses, including improvement in the 
percentage of poly-functional HIV-1 gag-specific cells. In addition, CD8+ T cells obtained 
prior to study entry from these two apparent responders demonstrated proliferative 
responses to gag peptides after anti-PD-L1 exposure ex vivo compared to isotype 
antibody exposure. This proliferation corresponded to their in vivo response as assessed 
by IFN-γ, CD107a (a marker of T cell degranulation), and TNF and was not observed in 
non-responders. An additional rationale for evaluating anti-PD-1 in HIV-infected patients 
derives from the demonstration that CD8+ T cells from patients suppressed on ART 
were unable to kill infected resting CD4+ T cells after viral reactivation, suggesting 
diminished CTL function and residual dysfunction [26]. Whether blockade of the PD-
1/PD-L1 axis can restore function, specifically cytotoxic function and cytokine production, 
in exhausted T cells in chronic HIV-1 is an important unanswered question. 
 
Further, data suggest that CD4+ T cells expressing PD-1 are enriched for latent HIV 
infection, and thus, an antibody to PD-1 may provide a relevant strategy to target latently 
infected T cells [11]. 
 
We propose a study evaluating the safety of the anti-PD-1 antibody, cemiplimab 
(REGN2810), in HIV-infected participants on suppressive ART. Cemiplimab, is a high 
affinity hinge-stabilized IgG4P human antibody to the PD-1 receptor (PDCD1, CD279) 
that blocks PD-1/PD L1-mediated T cell inhibition. To characterize the pharmacological 
action of cemiplimab, in vitro cell-based assays were used to evaluate the binding of 
cemiplimab to PD-1, the blocking activity of cemiplimab on PD-1/PD-L1 interaction and 
its effect on T cell signaling. Also, the anti-tumor activity of cemiplimab was assessed in 
vivo using a MC38.Ova tumor model in mice genetically engineered to express human 
PD-1. To compare the activity of cemiplimab to the most clinically advanced anti-PD-1 
antibodies, the above assays were also performed on two in-house generated PD-1 
antibodies, REGN1672 (primary sequence identical to nivolumab) and REGN2626 
(primary sequence identical to pembrolizumab), produced based on publicly available 
sequences. Results from these studies demonstrate that cemiplimab binds human and 
cynomolgus PD-1 with high affinity and blocks PD-1/PD-L1-driven inhibitory T cell 
signaling. Cemiplimab also displayed a robust, dose-dependent suppression of 
MC38.Ova tumors in the syngeneic mouse tumor model. Furthermore, the nonclinical 
activity of cemiplimab is similar to the two in-house generated anti-PD-1 comparator 
antibodies (Investigator Brochure [IB], Edition 6). As an IgG4 subtype antibody, 
cemiplimab is not capable of inducing antibody-dependent cytotoxicity or complement-
dependent cytotoxicity cells. In addition, incubation of cemiplimab in blood samples from 
healthy human donors ex vivo did not result in any significant cytokine secretion and is 
thus not expected to independently promote T cell activation. 
 
As of 27 March 2018, 757 oncology patients with several different cancer types have 
been treated with cemiplimab either as monotherapy or in combination with radiotherapy 
and/or other cancer therapy in seven studies. The safety and efficacy information to date 

 
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for cemiplimab indicates that it is a clinically active inhibitor of the PD-1 pathway (IB, 
Edition 6). These preliminary clinical data suggest that the anti-tumor activity and safety 
profile of cemiplimab is similar with other anti-PD-1 agents, though no direct clinical 
comparisons exist between anti-PD-1 agents at this time. LIBTAYO (cemiplimab-rwlc) is 
approved in the United States for advanced cutaneous squamous cell carcinoma 
(CSCC). 
 
PD-1 and PD-L1 Blockade in Animal Models of Chronic Infection 
In a study of chronic hepatitis C (HCV) in chimpanzees, one of three animals treated 
with an anti-PD-1 antibody demonstrated a decline in viremia and improved HCV-
specific CD4+ and CD8+ T cell responses [27]. 
 
Blocking the PD-1 pathway using multiple doses of an antibody to PD-1 in a macaque 
model of SIV infection resulted in rapid expansion of virus-specific CD8+ T cells with 
improved functional quality of antiviral CD8+ T cells in the blood and gut as 
demonstrated by the generation of polyfunctional cells capable of co-producing 
cytokines IFN-γ, TNF-α, and IL-2 [28]. These immune responses were associated with 
significant reductions in plasma SIV RNA and prolonged survival in the absence of ART 
[28], as well as reduction in markers of immune activation and microbial translocation 
[29]. In animal models of vaccination, blocking PD-1/PD-L1 axis led to improved anti-
vaccine antibodies [30, 31]. However, the question of whether multiple doses of anti-PD-
1 will result in increased immunologic effects cannot fully be answered in the non-human 
primate (NHP) model given the rapid CL of human antibodies due to development of 
anti-drug antibodies (ADA) in the primate model. 
 
Clinical Data for PD-1 and PD-L1 Blockade in Humans: Malignancy, Hepatitis B and C, 
and HIV 
 
Malignancy 
The use of antibodies to the inhibitory receptors PD-1 and CTLA-4 have revolutionized 
immunotherapy for cancer [32] and become standard of care for several tumor types. 
Similar to HIV infection, PD-1 expression is increased on activated effector T cells in 
tumor tissues and results in an exhausted T cell phenotype with ineffective immune 
response to tumor antigens. Most recently, both anti-PD-1 and anti-PD-L1 antibodies 
given to patients with different types of cancer demonstrated substantial anti-tumor 
activity in a minority of patients [33, 34].   
 
Efficacy data for cemiplimab from a phase I, first-in-human (FIH) dose escalation study 
in CSCC and non-small cell lung cancer (NSCLC), and from a phase II study in CSCC 
are available. In the phase I study, among 60 patients who received cemiplimab in dose-
escalation cohorts (1 mg/kg, 3 mg/kg, or 10 mg/kg every 2 weeks), the investigator 
determined that the objective response rate was 18.3% (9 partial responses [PR], 2 
complete responses [CR]). Among 21 patients with NSCLC (1 patient in dose escalation, 
20 patients in expansion cohort 1 that studied cemiplimab 200 mg monotherapy every 2 
weeks), the response rate according to independent central review was 29% (6 PR). 
Among 26 patients in the CSCC expansion cohorts of the phase I study (including 
patients with locally advanced disease and those with metastatic disease), the response 

 
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rate according to independent central review was 50% (13 PR). The phase II CSCC 
study enrolled 59 patients with metastatic CSCC, and the response rate per independent 
central review was 48% (4 CR, 24 PR) (IB Edition 6). 
 
Clinical Data for PD-1 Blockade in HCV Infection 
Cemiplimab has not been studied in hepatitis C, however nivolumab, a similar anti-PD-1 
mAb has been studied in patients with HCV mono-infection using a wide range of single 
doses (0.03 to 10 mg/kg). An antiviral effect was demonstrated in a minority of 
participants. Five out of 45 treated patients had a confirmed 0.5 log10 decline in HCV 
RNA, which was similar to the proportion in placebo (1/9). However, at the 10 mg/kg 
dose, 3 of 20 participants had a greater than 4.0 log10 decline in HCV RNA; 2 had levels 
fall below the limit of quantification. No response of this magnitude was observed in any 
placebo recipient. One patient treated with 10 mg/kg had an undetectable HCV RNA 1 
year following a single infusion of the anti-PD-1 antibody [35]. 
 
Clinical Data for PD-1 Blockade in Hepatitis B Virus (HBV) Infection  
A study evaluating PD-L1 blockade ex vivo in chronically infected patients with hepatitis 
B infection demonstrated increased HBV-specific CD8+ T cell responses, and notably, 
CD8+ responses in this study did not correlate with the percentage of PD-1+ cells or PD-
1 median fluorescence intensity [36]. Nivolumab was studied in 51 HBV-infected patients 
with hepatocellular carcinoma (HCC) in the Checkmate 040 study. In this study, 3 of 51 
patients with chronic HBV demonstrated a 1 log decline in hepatitis B virus surface 
antigen (HBsAg) during anti-PD-1 inhibition [37]. Nivolumab was also studied with and 
without a therapeutic HBV vaccine (GS-4774) in hepatitis B e antigen-negative virally 
suppressed HBV-infected participants in a single-dose study of 0.1 mg/kg and 0.3 mg/kg 
[38]. Participants who received 0.3 mg/kg nivolumab had a mean and median decline of 
quantitative HBsAg (qHBsAg) at 12 weeks from baseline of -0.3 and -0.13 IU/ml, 
respectively. HBsAg declined persisted through week 24 with mean and median declines 
of -0.47 and -0.14 IU/ml, respectively [38]. Nine (2/22) and 14% (3/22) of participants 
had a greater than 0.5 log reduction in HBsAg. Notably, there was no added benefit to 
qHBsAg decline with the addition of the HBV therapeutic vaccine GS-4774. One 
participant experienced HBsAb seroconversion and has been maintained off of HBV 
antiviral therapy. Of note, in this study, RO of nivolumab given at 0.3 mg/kg persisted at 
high levels for at least 6 weeks. 
 
Clinical Data for PD-L1 Blockade in HIV Infection  
There are data to suggest that improved immune function seen in cancer trials may 
translate to HIV infection. A recent case study demonstrated a decline in plasma HIV-1 
viremia as measured by a single-copy HIV RNA assay following CTLA-4 blockade with 
ipilimumab for metastatic melanoma in an HIV-infected individual suppressed on ART 
[39]. In addition and as noted above, in a study of HIV-infected participants suppressed 
on cART, a single, low dose (0.3 mg/kg) infusion of an anti-PD-L1 mAb (BMS-936559) 
appeared to enhance HIV-1-specific immunity in two of six participants, with 
improvements in HIV-1-specific CD8+ responses and the percentage of poly-functional 
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suppression for 5.2 years. This response correlated with pre-treatment ex vivo 
proliferative responses of HIV-1-specific CD8+ T cells to gag and was not observed in 
non-responders. 
 
Ipilimumab administered to 24 viremic HIV-infected participants as 2 or 4 doses of 0.1, 1, 
3, or 5 mg/kg every 28 days was well tolerated overall; 83% had ≥1 AEs but all were 
Grade 1 or 2 except for grade 3 neutropenia in a participant with mild neutropenia at 
baseline. Eight (33%) of these untreated HIV-infected participants had a potential 
immune-related adverse events (irAE) (seven with Grade 1 diarrhea not requiring 
corticosteroids; one with diarrhea and transient detectable antinuclear antibody (ANA); 
one with Grade 2 facial palsy requiring corticosteroids) [40]. In addition, an ongoing 
study of multiple doses of pembrolizumab administered to HIV-infected participants with 
relapsed/refractory malignancy will evaluate the safety and tolerability of every-3-weeks 
infusions in this study population (ClinicalTrials.gov Identifier NCT02595866). Notably, 
immunologic responses among healthy HIV-infected participants compared with 
participants in oncology studies may differ given that participants in oncology studies 
likely have impaired immune responses related to their underlying malignancy. 
Accordingly, evaluation of cemiplimab in healthy HIV-infected participants may be more 
likely to demonstrate an effect on immune responses. 
 
PK and Toxicology in Non-Human Primates (NHPs) 
Cemiplimab has similar binding affinities to monkey and human PD-1, therefore the 
cynomolgus monkey (Macaca fascicularis) was used for the preclinical assessment of 
PK and toxicology. The use of the cynomolgus monkey allows for a robust evaluation of 
cardiovascular and respiratory safety pharmacology endpoints, and provides clinically 
relevant PK and toxicokinetic (TK) evaluations of cemiplimab. The PK and TK of 
cemiplimab in cynomolgus monkeys were characterized by non-linear kinetics and 
predominance of target-mediated CL at low concentrations and linear kinetics at high 
concentrations, when the target was likely saturated. The prevalence of immunogenicity 
(anti-drug antibodies; ADA) was high; however, continuous drug exposure was 
maintained for 80% and 50% of animals throughout the 4-week and 26-week toxicology 
studies, respectively. As cemiplimab is a human antibody, the presence of ADA following 
cemiplimab administration to cynomolgus monkeys was not unexpected. However, the 
observed immunogenicity in monkeys is not necessarily predictive of immunogenicity in 
humans. The presence of ADA did not affect the ability to characterize the PK or safety 
profiles of cemiplimab in these studies (IB Edition 6). 
 
In the monkey model, cemiplimab was well-tolerated. There were no unscheduled 
deaths and no drug-related effects on morbidity and mortality, body weights, food 
consumption, ophthalmology, cardiovascular hemodynamics, including blood pressure 
and heart rate, body temperature, respiration rate and pulse oximetry, neurological 
examination, or any clinical pathology parameters evaluated. Cemiplimab administered 
once weekly for 4 weeks by intravenous (IV) infusion to male and female cynomolgus 
monkeys, at dose levels of 2, 10, and 50 mg/kg, resulted in a number of findings that 
were considered directly attributable to cemiplimab, and additional findings that were 
interpreted to be due to ADA production and subsequent ADA/drug complex (circulating 
immune complex) formation. Findings directly attributable to cemiplimab were limited to 

 
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dose-independent reversible increases in the frequency and absolute counts of 
proliferating T-lymphocytes, and increased T-cell-dependent antibody secondary 
responses. Given the tolerability of cemiplimab in the monkeys and that most findings 
were associated with immune complexes and/or ADA responses due to administration of 
a human IgG protein to monkeys, the no-observable-adverse-effect-level (NOAEL) is 
considered to be 50 mg/kg, the highest dose evaluated (IB Edition 6). 
 
PK of Cemiplimab in Humans 
In a FIH study of cemiplimab as monotherapy, or combined with radiation and/or 
cyclophosphamide, after the first dose cemiplimab was shown to have fairly dose 
proportional increases in Cmax (maximum concentration) and AUC (area under the 
concentration time curve) over the dosing interval, when administered at 1 mg/kg, 3 
mg/kg, or 10 mg/kg every 2 weeks. Target mediated drug disposition (non-linear PK) 
likely occurs at lower concentrations, i.e. at lower doses and/or at later time points than 
those observed in the FIH study. Based on a population PK analysis, the mean 
elimination half-life of cemiplimab at steady-state in patients with solid tumors is 19.2 
days. To date, there is no available data on RO with cemiplimab. Steady-state exposure 
appears to be reached by ~120 days (after eight doses, administered every 2 weeks). 
 
Human Safety Data with anti-PD-1 Antibodies  
There are considerable safety data on the use of immune checkpoint inhibitors (ICI) in 
oncology patients, given approval for their use in melanoma, non-small cell lung cancer, 
renal cell carcinoma, bladder cancer and squamous cell carcinoma of the head and 
neck, with expanding approvals for additional tumor types expected. Cemiplimab, along 
with other checkpoint blockers (e.g., anti-PD-1, anti-CTLA-4), are associated with a 
unique set of toxicities termed irAE. Immune-related adverse events are thought to be 
caused by unrestrained cellular immune responses directed at normal host tissues. An 
irAE can occur shortly after the first dose or several months after the last dose of 
treatment. Increasing use and experience has resulted in clinical algorithms addressing 
the management of more common irAEs and the recognition that a high suspicion and 
prompt management of new symptoms which could be due to irAEs is critical [41, 42]. 
 
A meta-analysis with 21 randomized controlled trials with ICIs included data with 
ipilimumab, nivolumab, pembrolizumab, and atezolizumab found a higher risk of specific 
irAEs in those receiving an ICI versus chemotherapy including colitis, AST elevation, 
rash, hypothyroidism, and pneumonitis [43]. In another meta-analysis of clinical trials 
with ICIs, the most common irAEs associated with PD-1 inhibitors included skin rash, 
diarrhea and/or colitis, pneumonitis, arthralgia, endocrine disorders (thyroid dysfunction 
most common), hepatic dysfunction, and neurologic dysfunction [41]. 
 
Safety of nivolumab (similar PD-1 inhibitor): Most recently, an open-label phase III study 
randomly assigned 423 patients with untreated stage IV or recurrent NSCLC to a similar 
anti-PD-1 antibody, nivolumab, versus chemotherapy in a 1:1 ratio [44]. Patients in the 
nivolumab arm received 3 mg/kg every 2 weeks with a 3.7-month median duration of 
treatment in the nivolumab group. Nivolumab had similar, but not longer, progression-
free survival among patients with PD-L1 expression of 5% or more. Treatment-related 
AEs Grade ≥3 were more common in the chemotherapy arm (51%) versus the 

 
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nivolumab arm (18%) and rates of treatment-related serious adverse events (SAEs) 
were similar in the two treatment groups. The most common AEs with a possible 
immunologic cause in the nivolumab group were skin-related AEs (24%). 
Hypothyroidism occurred in 17 (6.4%) patients in the nivolumab arm compared with 1 
(0.4%) in the chemotherapy arm. There were seven (2.6%) reported pneumonitis AEs of 
any grade, with four (1.5%) Grade ≥3. There were two deaths in the nivolumab group 
attributed to study treatment, one due to multi-organ failure and one due to pneumonitis. 
 
Safety Data with Cemiplimab in Oncology Patients 
Overall, toxicities observed to date with cemiplimab in oncology patients/study 
participants are similar to those noted for FDA-approved anti-PD-1 mAbs (nivolumab 
and pembrolizumab), and include fatigue, pyrexia, chills, infusion reactions, skin rash, 
diarrhea/colitis, endocrine toxicities, hepatic toxicities (mainly asymptomatic elevations in 
aspartate transaminase [AST] and alanine transaminase [ALT] levels), pneumonitis, 
uveitis, interstitial nephritis, pancreatitis, and neurologic syndromes. 
 
Cemiplimab is being evaluated in more than 20 phase I through phase III clinical studies. 
The safety profile of cemiplimab appears to be consistent across tumor types and dose 
of cemiplimab. Safety was obtained and assessed primarily from a pooled analysis of 
patients treated in non-randomized studies with cemiplimab monotherapy or cemiplimab 
in combination with standard chemotherapies and/or radiation therapy.  
 
As of 27 March 2018, 757 oncology patients have been treated with cemiplimab either 
as monotherapy or in combination with radiotherapy and/or other cancer therapy in 7 of 
the ongoing studies. A total of 512 patients (67.6%) experienced at least 1 treatment-
related adverse event (AE) of which 96 patients (12.7%) experienced Grade 3 or higher 
treatment-related AEs. Sixty-four patients (8.5%) experienced investigator-attributed 
treatment-related SAEs. Seven patients (0.9%) experienced fatal treatment-related AEs: 
two patients with hepatic failure (one patient with HCC and one patient with diffuse large 
B-cell lymphoma), paraneoplastic encephalomyelitis (one patient with soft tissue 
sarcoma), toxic epidermal necrolysis (TEN) (one patient with follicular lymphoma [FL]), 
nosocomial pneumonia secondary to Grade 4 mucositis (one patient with FL), and 
pneumonitis (two patients: one with NSCLC and one with cervical cancer) (IB Edition 6). 
The one patient who died due to TEN had previously received PI3K inhibitor treatment 
prior to enrollment on this study of cemiplimab. 
 
In the pooled analysis, cemiplimab-related AEs occur at similar frequency in patients on 
cemiplimab monotherapy compared to cemiplimab combination therapy, with a few 
exceptions such as nausea and pruritus. The most common (>5%) treatment-related 
treatment emergent AEs were fatigue (17.2% patients), nausea (9.2%), diarrhea (8.2%), 
arthralgia (6.3%), pruritus (6.2%), rash maculo-papular (5.9%), rash (5.8%), and 
hypothyroidism (5.2%). Amongst the most common treatment-related AEs, nausea 
occurred twice as frequently in combination therapy patients, whereas pruritus occurred 
twice as commonly in monotherapy patients. 
 
The most common Grade 3/4/5 treatment-related AEs for the total pooled population 
were pneumonitis (1.2% of patients), AST increased and autoimmune hepatitis (0.8% 

 
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each), and ALT increased and anemia (0.5% each). 
 
Immune-related Adverse Events (IrAEs) Attributed to Study Treatment 
Treatment-related AEs were characterized as potential irAEs based on a three-level 
approach that included a Regeneron-provided Medical Dictionary of Regulatory Activities 
System Organ Class (MedDRA) terms list (using known irAEs from previous studies in 
this class), AEs assessed as immune related by investigators (including those not on the 
MedDRA list), and review of these additional AEs by an independent four physician 
panel. A subset of potential irAEs categorized as identified irAEs were defined as 
potential irAEs requiring treatment with corticosteroid or events that were immune-
related endocrinopathies.  
 
A total of 339 patients (44.8%) experienced potential irAEs including 123 patients 
(16.2%) with identified irAEs. The majority of potential irAEs were mild to moderate. 
Sixty-three patients (8.3%) experienced potential irAEs of Grade 3 or higher including 53 
(7.0%) with identified irAEs. Forty-nine patients (6.5%) experienced serious potential 
irAEs including 41 patients (5.4%) with serious identified irAEs. Thirty-three (4.4%) 
patients discontinued study treatment due to potential irAEs. Six patients (0.8%) 
experienced fatal irAEs including hepatic failure, TEN, pneumonitis, and paraneoplastic 
encephalomyelitis.  
 
Potential irAEs 
The most common potential irAE preferred terms and composite terms were: 
• 
Immune-related skin adverse reactions in 123 (16.2%) patients including 13 (1.7%) 
patients with Grade 3-5 events; 
• 
Immune-related colitis (including diarrhea) in 67 (8.9%) patients including 5 (0.7%) 
patients with Grade 3-5 events; 
• 
Pruritus in 49 (6.5%) patients including 1 (0.1%) patient with a grade 3 event 
• 
Arthralgia in 48 (6.3%) patients (no Grade 3-5 events); 
• 
Immune-related hepatitis in 44 (5.8%) patients including 17 (2.2%) patients    
with Grade 3-5 events; and 
• 
Hypothyroidism in 39 (5.2%) patients including 1 (0.1%) patient with a   
Grade 3 event. 
 
The most common Grade 3-5 potential irAEs were: 
• 
 Immune-related hepatitis (17 [2.2%] patients); 
• 
 Immune-related skin adverse reactions (13 [1.7%] patients); and 
• 
 Immune-related pneumonitis (9 [1.2%] patients). 
 
Identified irAEs 
As of 27 March 2018, for the total pooled population, 123/757 (16.2%) of patients 
experienced an identified irAE including 53 (7.0%) that were Grades 3-5. The most 
common identified irAE composite terms were hypothyroidism (39 [5.2%] patients), 
immune-related pneumonitis (20 [1.2%] patients), immune-related hepatitis and immune-
related skin adverse reactions (14 [1.8%] patients each), and hyperthyroidism (12 [1.6%] 
patients). The most common Grade 3-5 identified irAEs were immune-related hepatitis 

 
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(13 [1.7%] patients), immune-related pneumonitis (9 [1.2%] patients), and immune-
related skin adverse reactions (8 [1.1%] patients). See Table 2.2-1 below for more 
details regarding identified irAEs attributed to cemiplimab in oncology patients (IB Edition 
6).   
 
Five (0.7%) patients presented with Type I diabetes, three with diabetic ketoacidosis, 
and all with ≥Grade 3 events requiring treatment.   
 
Table 2.2-1: Summary of Most Common Treatment-Emergent irAEs 
 
 

 
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Table 2.2-1 (continued): Summary of Most Common Treatment-Emergent irAEs 
 
Safety Data of Anti-PD-1 Antibodies in HIV-infected Patients with Cancer 
There is limited available safety data of anti-PD-1 treatment in HIV-infected patients 
receiving treatment for cancer. In the previously described study of an anti-PD-L1 mAb 
in six healthy, HIV-infected participants, viral rebound was not observed following a 
single dose. There was one potential irAE of hypophysitis without MRI changes, which 
occurred 36 weeks following a single dose, and for which relatedness to study treatment 
could not be ruled out [25]. 
 
In a small study (N=12) HIV-infected participants received multiple doses as second line 
treatment with nivolumab for NSCLC (n=11) and melanoma (n=1) [45]. Partial tumor 
responses or stability was observed in 6/12 (50%) participants. HIV viral rebound was 
not observed when measured with an HIV-1 RNA ultra-sensitive quantification, with only 
one viral blip to 101 copies/mL in one participant, and there were no significant changes 
in CD4+ or CD8+ T cells counts. HIV-specific IFNγ+CD8+ cells increased from 0.1% at 
baseline to 0.4% (gag) at day 30 in one participant and from 0.31 to 1.31% (RT+nef) of 
CD8+ T cells at day 120 in another participant. 
 
Finally, among six cART-treated HIV-infected patients who have received cemiplimab for 
cancer, treatment has been well-tolerated to date. We are not aware of any increase in 
HIV viremia during treatment, although this was not followed as an outcome measure in 
this study. 
 

 
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The Role of PD-1 and PD-L1 in Fetomaternal Tolerance 
In pregnancy, maternal tolerance of the developing fetus has been shown to depend on 
negative signals from the PD-1/PD-L1 co-stimulatory pathway. Early work demonstrated 
the expression of PD-L1 in human placenta by villous syncytiotrophoblasts and 
cytotrophoblasts, the fetal cells which lie adjacent to maternal blood and tissue [46]. As 
these are the only fetal cells exposed to maternal blood and tissues, the location of PD-
L1 in these cells suggests it may play a critical role in protecting the fetus against 
activated maternal leukocytes. Other studies have demonstrated that blockade of PD-1 
[47] and PD-L1 [48] during murine pregnancy increases abortion rates, possibly related 
to the finding that blockade or deficiency in PD-L1 increases expansion of alloreactive T 
cells and diminished Treg function at the fetal-maternal interface [49]. Additional studies 
have implicated PD-1 in the induction of apoptosis of paternal-antigen specific T-cells at 
the fetal-maternal interface during pregnancy [50], and shown that PD-L1 blockade 
inhibits antigen-specific alloreactive T-cell apoptosis and induces apoptosis of Tregs and 
a shift toward higher frequency of Th17 cells, breaking fetomaternal tolerance [51]. 
Based on these data, strict criteria for pregnancy prevention are warranted in the study 
given the lack of a proven benefit of anti-PD-1 mAb in HIV+ individuals and a potential 
risk to the fetus. 
 
Dose Rationale 
The doses selected for this study were guided primarily by the primary objective of 
evaluating the safety of cemiplimab in this first study with an anti-PD-1 in otherwise 
healthy, HIV-infected patients. In the oncology studies with cemiplimab described above 
with multiple IV administrations, doses have ranged from 1.0 mg/kg to 10 mg/kg. In 
clinical oncology studies with both anti-PD-1 and anti-PD-L1 mAbs, efficacy of multiple 
doses has been shown across several dose cohorts, and in particular, in the cohorts that 
received 1 mg/kg and 3 mg/kg. 
 
Multiple data sets support the dose panels selected for examination in this study. First, 
cemiplimab is an IgG4 subtype antibody and therefore is not capable of inducing 
antibody-dependent cytotoxicity or complement-dependent cytotoxicity cells. In addition, 
incubation of cemiplimab in blood samples from healthy human donors ex vivo did not 
result in any significant cytokine secretion and is thus not expected to independently 
promote T-cell activation. Given the need to establish safety in a different patient 
population from those patients previously tested (advanced malignancies), an initial dose 
of 0.3 mg/kg was selected with dose escalation to a top dose of 3 mg/kg based on 
interim review of safety during the protocol.  
 
The initial dose selected to assess safety in this population is 0.3 mg/kg dose of 
cemiplimab, which is lower than that commonly administered in oncology studies. A 
dose lower than that with confirmed efficacy related to tumor stabilization or response in 
the oncology studies with cemiplimab was felt to be warranted, given this is the first 
study of an anti-PD-1 mAb in otherwise healthy, HIV-infected participants. Further, the 
0.3 mg/kg cohort is important to help clearly define PK and RO in HIV-infected 
individuals, in addition to safety.  
 

 
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The dose of 1 mg/kg was selected based on prior use in the oncology studies described 
above with multiple doses of cemiplimab. As immunologic and virologic responses might 
be anticipated at the 1 mg/kg dose, data in this cohort will provide critical information for 
the lower dose response curve and the safety profile in the study population. The 1 
mg/kg dose also provides a conservative margin of safety with a dose escalation of 3.3-
fold (0.3 to 1 mg/kg).  
 
The highest dose of 3 mg/kg was selected given the primary objective of confirming 
safety in the proposed study population, and as the vast majority of patients in the 
oncology studies with multiple doses of cemiplimab have received the 3 mg/kg dose. 
Very few oncology patients have received the 10 mg/kg dose of cemiplimab, there is no 
clear evidence of a dose response at higher doses (>1 mg/kg) with cemiplimab and 
efficacy has been confirmed in oncology patients at the 3 mg/kg dose. Further, in other 
clinical oncology studies with both anti-PD-1 and anti-PD-L1 mAbs, efficacy of multiple 
doses has been shown primarily with 3mg/kg or the 350 mg every three weeks, fixed 
doses. Although there is no data on RO with cemiplimab in humans, mean peak RO of 
85% at 4-24 hours and average plateau occupancy of 72% (range 59% to 81%) at 57 
days and beyond was observed following one infusion of 0.3, 1.0, 3.0 or 10.0 mg/kg of 
nivolumab [52], suggesting sufficient binding is likely with the proposed 3 mg/kg 
cemiplimab dose. Given no dose-limiting toxicities were observed in pre-clinical studies 
in cynomolgus monkeys, dose escalation is not designed to determine a maximum 
tolerated dose in this study population, as unlikely to improve efficacy and to minimize 
risk. 
 
Rationale for Multi-dose Study 
This is a multiple dose escalation study with two doses administered 6 weeks apart. The 
interval of 6 weeks is designed to provide for prolonged safety assessment prior to 
subsequent dosing (versus every 2 week dosing in oncology patients/participants), as 
well as the opportunity to evaluate the kinetics of immune and viral parameters post-
dosing and is supported by the observation of prolonged RO in the recent study of 
nivolumab in participants with HBV [36]. Importantly, the second dose will permit 
evaluation of a potential additive benefit on these immune and viral parameters. As 
above, studies of SIV in the NHP that demonstrated immune enhancement and anti-viral 
activity have utilized multiple dosing strategies [28].  
 
In oncology studies there are no data on immune responses following multiple doses of 
cemiplimab, as oncology studies with ICIs primarily follow radiographic anti-tumor 
responses at approximately 6-8-week intervals following several doses, and antigen 
specific tumor responses are not readily identifiable in these patients. Accordingly, there 
are very limited data on immunologic effects following single doses or multiple doses of 
anti-PD-1 in oncology studies, and, to date, no data on the immunologic effect of single 
doses of cemiplimab. However, data suggest a potential benefit of multiple doses of anti-
PD-1. In a dose escalation study of nivolumab, patients with advanced malignancies 
received 0.3, 1, 3, or 10 mg/kg, and patients with tumor responses at 3 months could 
receive additional doses. In this study, 12 patients with stable or tumor regression at the 
first assessment at week 8 received multiple doses, and several had improvement in 
tumor response following additional multiple doses [52]. Accordingly, we propose 2 

 
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doses of cemiplimab to allow evaluation of an additive benefit, but separated by 6 
weeks, a longer duration than the every-2-weeks dosing schedule used in the oncology 
studies described above. 
 
Rationale for Placebo 
The proposed study is the first to evaluate cemiplimab in cART-suppressed individuals 
living with HIV. As a primary objective of the study is to evaluate the safety of 
cemiplimab in this study population, a placebo arm for each dose cohort is felt to be 
warranted and critical in the assessment of AEs, and particularly common events such 
as low grade diarrhea or respiratory illnesses. 
 
Rationale for PK Sampling 
For this study, a strategy will be implemented that aims to characterize cemiplimab 
concentrations with corresponding peripheral RO at similar time points, including 
maximal concentrations and throughout the elimination phase of cemiplimab, possibly 
including the target-mediated component of the elimination. No RO data are available for 
cemiplimab, and elimination data for two widely spaced doses are not available.  
 
In the current study, cemiplimab and RO sampling time points will occur over the course 
of the 48-week study to define the PK and RO profile in HIV-infected participants. RO 
data may be useful if prolonged responses or delayed AEs are observed.  
 
Risks versus Benefits of the Proposed Research 
Given that most HIV-1-infected patients on effective ART have persistent low level 
viremia and despite this viremia have blunted HIV-1-specific immune responses, 
interventions with the potential to improve HIV-specific immunity and limit viremia should 
be tested. Therapies which improve HIV-1-specific immune responses will likely be a 
necessary component of any HIV remission or eradication strategy. Based on the data 
outlined above there is sufficient expectation that the proposed study will show an 
improvement in HIV-specific immune responses and the potential for latency reversal 
such that this result would advance the field. Although participants in this early phase 
study will receive no direct benefit for their participation in this study, there remains a 
strong desire among HIV-infected individuals, and the HIV community at-large, to pursue 
an HIV cure and remission strategies. The potential adverse effects, stigmatization and 
financial costs encountered by HIV-infected persons receiving life-long antiretroviral 
therapy along with the potential harm of persistent immune activation/inflammation are 
strong reasons to pursue HIV cure and remission research. In short, an HIV cure or 
sustained remission off therapy remain desirable goals that would have substantial 
benefits for many individuals if achieved.  
 
In recognizing the risk of irAEs with the use of ICIs in the proposed study population and 
no immediate clinical benefit as previously seen in the setting of cancer treatment, we 
have attempted to mitigate risk to potential participants to the greatest degree possible. 
The proposed study will enroll HIV-infected participants with well-controlled HIV-1 
viremia on ART and high CD4+ T cell counts without acute illness or malignancy, 
following a thoughtfully designed and supported dose escalation protocol with close 
clinical and laboratory monitoring. Risk mitigation related to study drug includes: dose 

 
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escalation starting with a dose lower than normally used in the oncology dose escalation 
studies; and limiting treatment to only two doses of cemiplimab versus placebo 
separated by 6 weeks to allow for extended safety monitoring prior to the second dose, 
compared with ongoing every-2-weeks dosing in cancer studies. Eligibility criteria 
exclude individuals with an increased risk for an irAE including but not limited to: history 
of an autoimmune disorder, pneumonitis, asthma, diabetes or pre-existing conditions 
that could make detection or attribution of a potential irAE difficult (e.g., chronic 
obstructive pulmonary disease [COPD]), the presence of select pre-existing auto-
antibodies, or current or history of endocrine disorders. Building upon substantial 
experience in the cancer studies, we have adapted guidelines for toxicity management 
of irAEs to ensure prompt detection, appropriate management, and discontinuation of 
study drug in the event of an irAE. 
 
Summary 
The primary goal of this study is: 1) to test the safety of two doses of cemiplimab versus 
placebo in a dose rising fashion in participants on suppressive cART, and 2) to 
determine whether cemiplimab can improve HIV-1-specific cellular immune responses. 
In addition, we will evaluate the PK of cemiplimab in serum, and examine the time 
course of RO in whole blood. We plan to simultaneously measure and assess the impact 
of cemiplimab on: 1) HIV-1-specific T cell magnitude and function, 2) persistent viremia 
by SCA, and 3) additional measures of HIV-1 persistence in total CD4+ T cells from 
peripheral blood. Given that only a subset of cancer patients have responded to 
blockade of the PD-1/PD-L1 pathway in previous clinical trials, we will also explore 
whether ex vivo response to gag peptides in the presence of cemiplimab pre-treatment 
is associated with an in vivo response, to identify biomarker(s) predictive of a response 
to cemiplimab that could inform patient stratification in future studies [33]. 
 
If the goals of the study are achieved, the potential next steps would be a larger phase II 
multiple-dose study of cemiplimab, to further assess safety, HIV specific immune 
responses, and the impact on HIV reservoirs in blood and tissue, or studies in 
combination with latency reversing agents or HIV vaccines. 
 
3.0 
STUDY DESIGN 
 
This trial is a phase I/II, double-blinded (within each cohort), dose-escalating, placebo-
controlled study of the safety and immunotherapeutic activity of two infusions of anti-PD-
1 (cemiplimab) or placebo in HIV-1-infected participants on cART who have HIV-1 RNA 
below the limit of quantification and CD4+ T-cell counts ≥350/mm3. Cemiplimab (0.3 
mg/kg [Cohort 1], 1 mg/kg [Cohort 2], and 3 mg/kg [Cohort 3]) or placebo will be given to 
15 participants in each Cohort (12 active and 3 placebo). Participants will receive 
infusions of antibody or placebo at entry/day 0 and week 6, for a total of two infusions, 
with the primary safety endpoint through week 48 and the primary immunologic endpoint 
through week 12. The study will enroll sequential dose-escalating cohorts with the 
second and third cohorts receiving the first infusion after all participants in the previous 
cohort have reached week 12 and an evaluation of safety outcomes by the study team 
and the study monitoring committee (SMC) is completed, which determines whether to 

 
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dose escalate or not. Participants will be followed for 48 weeks with frequent safety 
evaluations. 
 
Cemiplimab/placebo infusion will occur over 30 minutes via IV infusion. Safety data from 
Cohort 1 (first dose level) will be reviewed by the core team (blinded to treatment 
assignment) and an SMC, before higher doses are administered. Guidance criteria for 
the SMC with respect to dose escalation are described in section 10.4.1. If the first dose 
level is well tolerated and the core team and SMC note no safety concerns, Cohort 2 will 
be enrolled after Cohort 1 reaches week 12. If the second dose level is well tolerated 
and the core team and SMC note no safety concerns, Cohort 3 will be enrolled after 
Cohort 2 reaches week 12. Immunologic and virologic response data from lower dose 
cohort(s) may not be available prior to the enrollment of the subsequent dose cohort(s). 
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria 
 
4.1.1 HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry 
and confirmed by a licensed Western blot or a second antibody test by a method 
other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 
RNA viral assay. 
 
NOTE: The term “licensed” refers to a US FDA-approved kit, which is required for 
all IND studies. 
 
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 (VL). 
 
4.1.2 On ART for at least 24 months prior to screening. 
 
4.1.3 Receiving a stable cART regimen (defined as no changes of the components of 
ART agents within 90 days prior to study entry) containing: 
 
1) at least three ART agents (not counting ritonavir if not more than 200 mg total 
daily dose or cobicistat as one of the agents). 
 
NOTE: One of the agents must include an integrase inhibitor, NNRTI (Non-
Nucleoside Reverse Transcriptase Inhibitors), or a boosted-PI (protease 
inhibitor).  
 
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2)  two ART agents in which one of the agents is either a boosted protease 
inhibitor or an integrase inhibitor and the 2-drug regimen is listed as an 
acceptable alternative regimen in the Department of Health and Human 
Services guidelines 
(https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf.) 
 
NOTE: Changes within treatment class, in drug formulation or dose are allowed 
>30 days prior to study entry (e.g., dolutegravir or elvitegravir to bictegravir, TDF 
to TAF, ritonavir to cobicistat, or separate ART agent dosing to fixed-dose 
combination). 
 
4.1.4 CD4+ T cell count ≥350 cells/mm3 obtained within 90 days prior to study entry at 
any US laboratory that has a Clinical Laboratory Improvement Amendments 
(CLIA) certification or its equivalent. 
 
4.1.5 At least two documented plasma HIV-1 RNA below quantifiable limit on cART 
obtained by FDA-approved assays by any US laboratory that has a CLIA 
certification or its equivalent within 18 months prior to screening HIV RNA 
(section 4.1.6). 
 
NOTE: A single unconfirmed plasma HIV-1 RNA ≥limit of quantification but 
<1000 copies/mL is allowed if followed by HIV-1 RNA below quantifiable limits. 
 
4.1.6 Plasma HIV-1 RNA level that is less than the quantification limit of an FDA-
approved HIV RNA assay within 90 days prior to study entry by any US 
laboratory that has a CLIA certification or its equivalent. 
 
4.1.7 The following laboratory values obtained within 90 days prior to entry by any US 
laboratory that has a CLIA certification or its equivalent. 
• 
Absolute neutrophil count (ANC) ≥1500 cells/mm3 
• 
Hemoglobin ≥14.0 g/dL for men and ≥12.0 g/dL for women 
• 
Platelet count ≥150,000/mm3 
• 
Creatinine clearance ≥60 mL/min estimated by the Cockcroft-Gault equation  
 
NOTE: A program for calculating creatinine clearance by the Cockcroft-Gault 
method is available on www.frontierscience.org. 
 
• 
Alanine aminotransferase (ALT) (SGPT) ≤upper limit of normal (ULN) 
• 
Aspartate aminotransferase (AST) (SGOT) ≤ULN 
• 
AM cortisol >10 mcg/dL and <ULN  
 

 
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NOTE A: Female participants on estrogen-containing oral contraception or other 
exogenous estrogen treatment may repeat the AM cortisol as part of 
screening to determine eligibility. AM cortisol should be drawn as early 
as possible before 9:00AM, and should not be drawn later than 10:00 
AM. 
 
NOTE B: Participants with a low cortisol level that was drawn after 10:00 AM 
may repeat the AM cortisol as part of screening to determine eligibility. 
 
• 
Thyroid stimulating hormone (TSH) within normal limits 
• 
Free thyroxine (T4) level within normal limits  
• 
Hemoglobin A1c (HgbA1c) <5.7%  
• 
Fasting blood glucose <110 mg/dL 
• 
Total bilirubin ≤1.6 x ULN 
 
NOTE: If the 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. 
 
4.1.8 
Interferon-gamma release assay (IGRA) for tuberculosis (TB) with negative 
results within 90 days prior to study entry, OR 
 
Prior positive TB IGRA or positive purified protein derivative (PPD) skin test with 
documented evidence of completed prophylaxis treatment (NOTE: IGRA does 
not need to be repeated at screening). These potential participants cannot have 
had TB exposure or have traveled to a TB-endemic area since completing 
prophylaxis treatment. A list of countries with high TB burden is accessible via 
the following link: 
http://www.who.int/tb/publications/global_report/high_tb_burdencountrylists2016-
2020.pdf. 
 
4.1.9 
HCV antibody negative result within 60 days prior to study entry or, if the 
participant is HCV antibody positive, undetectable HCV RNA result within 60 
days prior to study entry.  
 
4.1.10 Negative HBsAg result obtained within 60 days prior to study entry. 
 
4.1.11 Negative results for all of the following antibody tests at screening: thyroid 
peroxidase (TPO), glutamic acid decarboxylase 65 (GAD65/GAD), and islet cell 
antigen. 
 
4.1.12 Antinuclear antibody (ANA) <1:80 at screening. 
 
4.1.13 Men and women age ≥18 years and <65 years. 
 

 
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4.1.14 Documentation of the availability of the stored pre-entry plasma specimens for 
virology assays and stored pre-entry peripheral blood mononuclear cell (PBMC) 
specimens for CD8+ T-cell assays. Sites must receive confirmation from the 
processing lab via phone, e-mail, or fax, that specimens have been entered into 
the ACTG’s Laboratory Data Management System (LDMS). 
 
4.1.15 Ability and willingness of participant to provide informed consent. 
 
4.1.16 Ability and willingness of participant to continue cART throughout the study. 
 
4.1.17 In the opinion of the site investigator, the ability to construct a fully active 
alternative cART regimen in the event of virologic failure on the current ART 
regimen. 
 
4.1.18 Female participants of reproductive potential (defined as women who have not 
been post-menopausal for at least 24 consecutive months, i.e., who have had 
menses within the preceding 24 months, or women who have not undergone 
surgical sterilization, specifically hysterectomy and/or bilateral oophorectomy or 
bilateral salpingectomy) must have a negative serum pregnancy test with a 
sensitivity of at least 25 mIU/mL performed at screening, and a serum or urine 
pregnancy test within 48 hours prior to study entry. 
 
4.1.19 All participants must agree not to participate in a conception process (e.g., active 
attempt to become pregnant or to impregnate, sperm donation, in vitro 
fertilization, egg donation) during the study. 
 
4.1.20 When participating in sexual activity that could lead to pregnancy, all participants 
must agree to use at least two reliable forms of contraception simultaneously 
during the study (i.e., entry through week 48). Such methods include: 
• 
Condoms (male or female) with or without a spermicidal agent 
• 
Diaphragm or cervical cap with spermicide 
• 
Intrauterine device (IUD) 
• 
Tubal ligation 
• 
Hormone-based contraceptive 
 
4.1.21 Participants who are not of reproductive potential (women who have been post-
menopausal for at least 24 consecutive months or have undergone hysterectomy 
and/or bilateral oophorectomy or salpingectomy or men who have documented 
azoospermia or undergone vasectomy) are eligible without requiring the use of 
contraceptives. Acceptable documentation of sterilization and menopause is 
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Written or oral documentation communicated by clinician or clinician’s staff of one 
of the following: 
• 
Physician report/letter 
• 
Operative report or other source documentation in the patient record (a 
laboratory report of azoospermia is required to document successful 
vasectomy) 
• 
Discharge summary 
• 
Follicle stimulating hormone-release factor (FSH) measurement elevated into 
the menopausal range as established by the reporting laboratory 
 
4.1.22 Weight ≥50 kg 
 
4.2 
Exclusion Criteria 
 
4.2.1 History of malignancy within the last 5 years. 
 
NOTE: A history of non-melanoma skin cancer (e.g., basal cell carcinoma or 
squamous cell skin cancer) is not exclusionary with documentation of complete 
resection at least 3 months prior to enrollment). 
 
4.2.2 History of HIV-related opportunistic infections within the last 5 years prior to study 
entry. 
 
NOTE: The CDC classifications are available on the A5370 PSWP. 
 
4.2.3 Prior history of immune reconstitution syndrome (IRIS), including a clinical 
diagnosis of IRIS and/or IRIS requiring intervention (e.g., steroids). 
 
4.2.4 Current chronic, acute, or recurrent bacterial, fungal or viral (other than HIV) 
infections that are serious, in the opinion of the site investigator, and required 
systemic therapy within 30 days prior to entry. 
 
4.2.5 History of COPD.  
 
4.2.6 History of prior radiation therapy. 
 
4.2.7 Active or previously treated active TB. 
 
4.2.8 Active asthma requiring any treatment in the prior 2 years, including “as needed” 
inhaler use prior to study entry. 
 
4.2.9 Type I or type II diabetes mellitus. 
 
4.2.10 History of or active autoimmune disorders including but not limited to 
inflammatory bowel diseases, scleroderma, severe psoriasis, myocarditis, uveitis, 
pneumonitis, systemic lupus erythematosus, rheumatoid arthritis, optic neuritis, 

 
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myasthenia gravis, adrenal insufficiency, hypothyroidism and/or hyperthyroidism, 
autoimmune thyroiditis, hypophysitis, or sarcoidosis. 
 
NOTE: For questions related to the definition of autoimmune disorders, 
sites should contact the team per the Study Management section. 
 
4.2.11 Immune deficiency other than that caused by HIV infection. 
 
4.2.12 Currently breastfeeding or pregnant. 
 
4.2.13 Known allergy/sensitivity or any hypersensitivity to mAb-based biologics, 
cemiplimab (anti-PD-1) or its formulation. 
 
4.2.14 Active drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with adherence to study requirements. 
 
4.2.15 Received investigational drug or device within 6 months prior to study entry. 
 
4.2.16 Use of immunomodulators (e.g., interleukins, interferons, cyclosporine, systemic 
corticosteroids exceeding physiologic doses), HIV vaccine, or systemic cytotoxic 
chemotherapy within 60 days prior to study entry. 
 
NOTE: Participants receiving stable physiologic glucocorticoid doses, defined as 
prednisone ≤10 mg/day or the equivalent, will not be excluded. Stable 
physiologic glucocorticoid doses should not be discontinued for the duration of 
the study. In addition, participants receiving topical corticosteroids will not be 
excluded. 
 
4.2.17 Intent to use immunomodulators (e.g., IL-2, IL-12, interferons, systemic 
corticosteroids exceeding physiologic doses, or TNF modifiers) during the course 
of the study. 
 
4.2.18 Any vaccination within 30 days prior to pre-entry or entry.  
 
NOTE: Individuals who require vaccination will delay screening for the study until 
30 days after receiving the last injection. 
 
4.2.19 HCV treatment within 6 months prior to study entry. 
 
4.2.20 Any acute or chronic psychiatric problems that, in the opinion of the investigator, 
make the participant ineligible for participation. 
 
4.2.21 History of solid organ transplant. 
 
NOTE: Participants with prior corneal transplant(s) may be allowed to enroll after 
discussion with and approval from the study medical officer. 
 

 
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4.2.22 History of previous treatment with a phosphoinositide 3-kinase inhibitor, including 
idelalisib. 
 
4.2.23 History of prior checkpoint inhibitor treatment including anti-PD-1, anti-PD-L1 or 
anti-CTLA-4 antibodies (including ipilimumab). 
 
4.2.24 History of prior immunoglobulin (IgG) therapy. 
 
4.2.25 Current use or intent to use biotin ≥5 mg/day, including within dietary 
supplements during the study. 
 
NOTE: Please see section 5.4 for a list of other names used for biotin that should 
be looked for on the labels of dietary supplements. 
 
4.3 
Study Enrollment Procedures 
 
4.3.1 Prior to implementation of this protocol, and any subsequent full version 
amendments, each site must have the protocol and the protocol consent form(s) 
approved, as appropriate, by their local institutional review board (IRB)/ethics 
committee (EC) and any other applicable regulatory entity (RE). Upon receiving 
final approval, sites will submit all required protocol registration documents to the 
DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory Support 
Center (RSC). The DAIDS PRO will review the submitted protocol registration 
packet to ensure that all of the required documents have been received. 
 
Site-specific informed consent forms (ICFs) WILL be reviewed and approved by 
the DAIDS PRO, and sites will receive an Initial Registration Notification from the 
DAIDS PRO that indicates successful completion of the protocol registration 
process. A copy of the Initial Registration Notification should be retained in the 
site's regulatory files. 
 
Upon receiving final IRB and any other applicable RE approvals for an 
amendment, sites should implement the amendment immediately. Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the 
RSC. The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all required documents have been received. Site-specific ICF(s) 
WILL NOT be reviewed and approved by the DAIDS PRO, and sites will receive 
an Amendment Registration Notification when the DAIDS PRO receives a 
complete registration packet. A copy of the Amendment Registration Notification 
should be retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific 
documents required for initial and amendment registrations, refer to the current 
version of the DAIDS Protocol Registration Manual. 
 
Once a candidate for study entry has been identified, details will be carefully 
discussed with the participant. The participant (or, when necessary, the legal 

 
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representative if the participant is under guardianship) will be asked to read and 
sign the approved protocol consent form. 
 
For participants from whom a signed informed consent has been obtained, an 
ACTG Screening Checklist must be entered through the DMC Subject Enrollment 
System. 
 
4.3.2 Protocol Activation 
 
Prior to enrollment, sites must complete the Protocol Activation Checklist found 
on the ACTG Member website. This checklist must be approved prior to any 
screening of participants for enrollment. 
 
4.3.3 Randomization 
 
For participants from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the initial protocol step, an ACTG 
Screening Failure Results form must be completed and keyed into the database. 
 
Participants who meet the enrollment criteria will be randomized to the study 
according to standard ACTG DMC procedures. 
 
4.4 
Co-enrollment Guidelines 
 
Sites are encouraged to co-enroll participants in A5128, “Plan for Obtaining Informed 
Consent to Use Stored Human Biological Materials (HBM) for Currently Unspecified 
Analyses.” Co-enrollment in A5128 does not require permission from the A5370 protocol 
chairs. 
 
Co-enrollment with A5332 (REPRIEVE) and substudies of REPRIEVE- A5333s and 
A5361s- will be permitted as long as A5332 participants have reached the 1 year visit for 
that study.  
 
For specific questions and approval for co-enrollment in other studies, sites should first 
check the A5370 PSWP or contact the protocol team via e-mail as described in the 
Study Management section. 
 

 
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5.0 
STUDY INTERVENTION 
 
Study treatment is defined as two infusions of REGN2810 (cemiplimab) or placebo. 
cART will not be provided by the study. 
 
5.1 
Intervention, Administration, and Duration 
 
5.1.1 Regimens 
 
Forty-five HIV-1-infected participants will be sequentially assigned to one of three 
cohorts, beginning with the lowest dose cohort: 
 
Cohort 1: Participants will receive 0.3 mg/kg of REGN2810 (cemiplimab) or 
placebo, administered at entry/day 0 and week 6 for a total of two 
infusions. 
 
Cohort 2: Participants will receive 1 mg/kg of REGN2810 (cemiplimab) or 
placebo, administered at entry/day 0 and week 6 for a total of two 
infusions. 
Cohort 3: Participants will receive 3 mg/kg of REGN2810 (cemiplimab) or 
placebo, administered at entry/day 0 and week 6 for a total of two 
infusions. 
 
5.1.2 Administration 
 
REGN2810 (cemiplimab)/placebo infusion will occur over 30 minutes via 
intravenous (IV) infusion. 
 
REGN2810 (cemiplimab) or diluent for REGN2810 (placebo) will be administered 
as an intravenous infusion mini-bag piggybacked onto a primary line of 0.9% 
sodium chloride for injection, USP. After infusing the REGN2810 (cemiplimab) or 
placebo for REGN2810 (cemiplimab) (diluent for REGN2810), flush the IV tubing 
with 0.9% sodium chloride for injection, USP.   
 
Administration of intravenous REGN2810 (cemiplimab) or diluent for REGN2810 
(cemiplimab) must include the use of a sterile, non-pyrogenic, low-protein binding 
0.2 micron to 5 micron in-line or add-on filter is required for dosing. The total 
volume of the infusion will vary with the dose and participant weight. The infusion 
rate will vary based on the total volume needed to administer the full dose. 
Infusion access should be maintained and the participant observed for a 
minimum of 2 hours following completion of the first infusion and for a minimum 
of 30 minutes following the second infusion (see section 8.0 for further detail). 
 
5.1.3 Duration 
 
Participants will be followed for a total of 48 weeks after the first infusion of study 
drug. 

 
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5.2 
Study Product Formulation and Preparation 
 
REGN2810 (cemiplimab) (50 mg/mL) is formulated in an aqueous buffered solution at 
pH 6.0 containing 10 mM histidine, 5% (w/v) sucrose, 1.5% (w/v) L proline, and 0.2% 
(w/v) polysorbate 80. REGN2810 drug product is supplied as a sterile liquid solution of 
5.5 mL in a 20 mL glass vial for IV administration. A volume of 5.0 mL can be withdrawn 
from each vial. Vials are for single use only. 
 
Diluent for REGN2810 (cemiplimab) is an aqueous buffered solution at pH 6.0 
containing 10 mM histidine, 5% (w/v) sucrose, 1.5% (w/v) L proline, and 0.2% (w/v) 
polysorbate 80. Diluent for REGN2810 (cemiplimab) will be used for 0.3 mg/kg cohort to 
prevent REGN2810 (cemiplimab) from binding to the bags and tubing when the 
REGN2810 (cemiplimab) is at low concentrations. Diluent for REGN2810 (cemiplimab) 
will also be used for the placebo for REGN2810 (cemiplimab) in all dose cohorts. 
 
Store REGN2810 (cemiplimab) vials and diluent for REGN2810 (cemiplimab) vials at 
2°C to 8°C. 
 
Any unused portion of a REGN2810 (cemiplimab) vial will not be used for another 
participant. 
The nurse responsible for administration and another clinician will each check the bag 
label and confirm that the identifier is correct and that the correct total milligrams to be 
administered is shown based on participant weight and the assigned mg/kg dose before 
beginning the IV administration. 
 
5.2.1 REGN2810 (cemiplimab) 0.3 mg/kg Dose Cohort: Preparation for Intravenous 
Administration 
 
The REGN2810 (cemiplimab) 0.3 mg/kg dose cohort requires the use of the 
diluent for REGN2810 (cemiplimab). REGN2810 (cemiplimab) must NOT be 
diluted lower than 1.0 mg/mL without adding diluent. 
 
Preparation of REGN2810 (cemiplimab) for IV administration will require either 
sterile empty IV bags made of polyvinyl chloride (PVC) or polyolefin 
(polyethylene and polypropylene) or 25 mL bags of 0.9% sodium chloride for 
injection, USP (normal saline), REGN2810 (cemiplimab) and diluent for 
REGN2810 (cemiplimab).  
 
For each IV infusion order, the participant’s weight and assigned treatment dose 
will be included in the pharmacy order. 
1. Remove the vial(s) of REGN2810 (cemiplimab) and diluent from the 
refrigerator.  
2. Observe vial(s) for damages, discoloration or particles. 
3. Using aseptic technique in compliance with USP <797> 

 
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a. Add 25 mL of 0.9% sodium chloride for injection, USP to the empty sterile 
IV bag (or start with a pre-made, commercially available 25 mL bag of 
0.9% sodium chloride for injection, USP). 
b. Add 1 mL of diluent for REGN2810 (cemiplimab) to the bag. Invert the 
bag 10 times to mix thoroughly.  
c. Using a 1 mL polypropylene syringe for volumes less than 0.8 mL or a 3 
mL polypropylene syringe for larger volumes, withdraw the correct volume 
of REGN2810 (cemiplimab) from the REGN2810 (cemiplimab) vial for the 
participant’s weight based on Table 5.2.2-1 below. 
d. Add the appropriate volume of REGN2810 (cemiplimab) to the IV bag 
then invert the IV bag 10 times to ensure that the investigational product 
and 0.9% sodium chloride are well mixed.  
4. Label the IV bag with patient identifier, protocol number, REGN2810 
(cemiplimab) x (mg) or placebo for REGN2810 (cemiplimab) in 0.9% sodium 
chloride Injection, USP, the final volume of the bag, final concentration, 
directions to infuse intravenously over 30 minutes the entire contents of the 
infusion bag plus sufficient volume of 0.9%. sodium chloride Injection, USP to 
flush the tubing, preparation date and time, expiration time of 8 hours after 
dilution if stored at controlled room temperature (15°C to 25°C) or 24 hours if 
refrigerated at 2°C to 8°C, Investigational Use Statement (“Limited by Federal 
Law to Investigational Use”), and manufacturer information. 
 
If using a commercially available 25 mL mini-bag of 0.9% sodium chloride, USP 
then the final concentration must be calculated based on the best estimate of the 
total volume. 
 
Expiration time includes the duration of infusion. 
 
5.2.2 Placebo for REGN2810 (cemiplimab) 0.3 mg/kg Dose Cohort: Preparation for 
Intravenous Administration 
 
Placebo for REGN2810 (cemiplimab) 0.3 mg/kg requires the use of two volumes 
of the diluent for REGN2810 (cemiplimab), the first as the diluent (1 mL per bag) 
and the second as placebo for REGN2810 (cemiplimab) calculated volume 
based on the participant’s weight (0.006 mL/kg).  
 
Preparation of placebo REGN2810 (cemiplimab) for IV administration will require 
either sterile empty IV bags made of PVC or polyolefin (polyethylene and 
polypropylene) or 25 mL bags of 0.9% sodium chloride for injection, USP (normal 
saline), and diluent for REGN2810 (cemiplimab).  
 
For each IV infusion order, the participant’s weight and assigned treatment dose 
will be included in the pharmacy order. 
1. Remove the vial of diluent for REGN2810 (cemiplimab) from the refrigerator. 
2. Observe vial for damages, discoloration or particles. 
3. Using aseptic technique in compliance with USP <797> 

 
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a. Add 25 mL of 0.9% sodium chloride for injection, USP to the empty sterile 
IV bag (or start with a pre-made, commercially available 25 mL bag of 
0.9% sodium chloride for injection, USP) 
b. Add to the bag the: 
i. 
1 mL of diluent for REGN2810 (cemiplimab) plus 
ii. Correct volume of diluent for REGN2810 (cemiplimab) for the 
participant’s weight based on Table 5.2.2-1 below.  
4. Invert the bag 10 times to mix thoroughly to ensure the investigational 
product and 0.9% sodium chloride are well mixed.  
5. Label the IV bag with patient identifier, protocol number, REGN2810 
(cemiplimab) x (mg) or placebo for REGN2810 (cemiplimab) in 0.9% sodium 
chloride Injection, USP, the final volume of the bag, final concentration, 
directions to infuse intravenously over 30 minutes the entire contents of the 
infusion bag plus sufficient volume of 0.9% sodium chloride Injection, USP to 
flush the tubing, preparation date and time, expiration time of 6 hours after 
dilution if stored at controlled room temperature (15°C to 25°C) or 24 hours if 
refrigerated at 2°C to 8°C, Investigational Use Statement (“Limited by Federal 
Law to Investigational Use”), and manufacturer information. 
 
If using a commercially available 25 mL mini-bag of 0.9% sodium chloride, 
USP then the final concentration must be calculated based on the best 
estimate of the total volume. 
 
Expiration time includes the duration of infusion.  
 
 
Table 5.2.2-1: 0.3 mg/kg REGN2810 (Cemiplimab) Dose Calculation Table with Volumes to Add 
to Sterile Empty IV Bag 
 
Weight Band in kg 
Based on Entry 
Weight 
Volume of 
0.9% Sodium 
Chloride for 
Injection 
Volume 
of 
Diluent 
to Add 
Dose 
in mg 
Drug 
Volume of 
REGN2810/ 
Cemiplimab 
or Diluent to 
Add to Bag 
Total 
Volume in 
Bag  
Concentration 
50 kg to <60 kg 
25 mL 
1 mL 
16 mg 
0.32 mL 
26.32 mL 
0.61 mg/ mL 
60 kg to <70 kg 
25 mL 
1 mL 
19 mg 
0.38 mL 
26.38 mL 
0.72 mg/ mL 
70 kg to <80 kg  
25 mL 
1 mL 
22 mg 
0.44 mL 
26.44 mL 
0.83 mg/ mL 
80 kg to <90 kg 
25 mL 
1 mL 
25 mg 
0.5 mL 
26.5 mL 
0.94 mg/ mL 
90 kg to <100 kg 
25 mL 
1 mL 
28 mg 
0.56 mL 
26.56 mL 
1.05 mg/ mL 
100 kg to <110 kg 
25 mL 
1 mL 
31 mg 
0.62 mL 
26.62 mL 
1.16 mg/mL 
110 kg to <120 kg  
25 mL 
1 mL 
34 mg 
0.68 mL 
26.68 mL 
1.27 mg/ mL 
120 kg to <130 kg 
25 mL 
1 mL 
37 mg 
0.74 mL 
26.72 mL 
1.38 mg/ mL 
130 kg to <140 kg 
25 mL 
1 mL 
40 mg 
0.8 mL 
26.8 mL 
1.49 mg/ mL 
140 kg to <150 kg  
25 mL 
1 mL 
43 mg 
0.86 mL 
26.86 mL 
1.6 mg/ mL 
150 kg to <160 kg 
25 mL 
1 mL 
46 mg 
0.92 mL 
29.91 mL 
1.71 mg/ mL 

 
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160 kg to <170 kg 
25 mL 
1 mL 
49 mg 
0.98 mL 
29.98 mL 
1.82 mg/ mL 
170 kg to <180 kg 
25 mL 
1 mL 
52 mg 
1.04 mL 
27.04 mL 
1.92 mg/ mL 
180 kg to <190 kg 
25 mL 
1 mL 
55 mg 
1.1 mL 
27.1 mL 
2.03 mg/ mL 
190 kg to <200 kg 
25 mL 
1 mL 
58 mg 
1.16 mL 
27.16mL 
2.14 mg/ mL 
 
5.2.3  REGN2810 (cemiplimab) 1 mg/kg Dose Cohort: Preparation for Intravenous 
Administration  
 
Preparation of REGN2810 (cemiplimab) for IV administration will require either 
sterile empty IV bags made of PVC or polyolefin (polyethylene and 
polypropylene) or 25 mL bags of 0.9% sodium chloride for injection, USP (normal 
saline), and REGN2810 (cemiplimab).  
 
For each IV infusion order, the participant’s weight and assigned treatment dose 
will be included in the pharmacy order. 
1. Remove the vial of REGN2810 (cemiplimab) from the refrigerator.  
2. Observe vial for damages, discoloration or particles. 
3. Using aseptic technique in compliance with USP <797> 
a. Add 25 mL of 0.9% sodium chloride for injection, USP to the empty sterile 
IV bag (or start with a pre-made, commercially available 25 mL bag of 
0.9% sodium chloride for injection, USP). 
b. Using a 3 mL or 5 mL polypropylene syringe withdraw the correct volume 
of REGN2810 (cemiplimab) from the REGN2810 (cemiplimab) vial for the 
participant’s weight based on Table 5.2.4-1 below. 
c. Add the appropriate volume of REGN2810 (cemiplimab) to the IV bag 
then invert the IV bag 10 times to ensure that the investigational product 
and 0.9% sodium chloride are well mixed.  
4. Label the IV bag with patient identifier, protocol number, REGN2810 
(cemiplimab) x(mg) or placebo for REGN2810 (cemiplimab) in 0.9% sodium 
chloride Injection, USP, the final volume of the bag, final concentration, 
directions to infuse intravenously over 30 minutes the entire contents of the 
infusion bag plus sufficient volume of 0.9% sodium chloride Injection, USP to 
flush the tubing, preparation date and time, expiration time of 6 hours after 
dilution if stored at controlled room temperature (15°C to 25°C) or 24 hours if 
refrigerated at 2°C to 8°C, Investigational Use Statement (“Limited by Federal 
Law to Investigational Use”), and manufacturer information. 
 
If using a commercially available 25 mL mini-bag of 0.9% sodium chloride, 
USP than the final concentration must be calculated based on the best 
estimate of the total volume. 
 
Expiration time includes the duration of infusion.  
 

 
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5.2.4  Placebo for REGN2810 (cemiplimab) 1 mg/kg Dose Cohort: Preparation for 
Intravenous Administration  
 
Preparation of placebo for REGN2810 (cemiplimab) for IV administration will 
require either sterile empty IV bags made of PVC or polyolefin (polyethylene and 
polypropylene) or 25 mL bags of 0.9% sodium chloride for injection, USP (normal 
saline) and diluent for REGN2810 (cemiplimab). 
 
For each IV infusion order, the participant’s weight and assigned treatment dose 
will be included in the pharmacy order. 
1. Remove the vial of diluent for REGN2810 (cemiplimab) from the refrigerator. 
2. Observe vial for damages, discoloration or particles 
3. Using aseptic technique in compliance with USP <797> 
a. Add 25 mL of 0.9% sodium chloride for injection, USP to the empty sterile 
IV bag (or start with a pre-made, commercially available 25 mL bag of 
0.9% sodium chloride for injection, USP). 
b. Using a 3 mL or 5 mL polypropylene syringe withdraw the correct volume 
of diluent for REGN2810 (cemiplimab) from the diluent for REGN2810 vial 
for the participant’s weight based on Table 5.2.4-1 below. 
c. Add the appropriate volume of diluent for REGN2810 (cemiplimab) to the 
IV bag then invert the IV bag 10 times to ensure that the investigational 
product and 0.9% sodium chloride are well mixed.  
4. Label the IV bag with patient identifier, protocol number, REGN2810 
(cemiplimab) x (mg) or placebo for REGN2810 (cemiplimab) in 0.9% sodium 
chloride Injection, USP, the final volume of the bag, final concentration, 
directions to infuse intravenously over 30 minutes the entire contents of the 
infusion bag plus sufficient volume of 0.9% sodium chloride Injection, USP to 
flush the tubing, preparation date and time, expiration time of 6 hours after 
dilution if stored at controlled room temperature (15°C to 25°C) or 24 hours if 
refrigerated at 2°C to 8°C, Investigational Use Statement (“Limited by Federal 
Law to Investigational Use”), and manufacturer information. 
 
If using a commercially available 25 mL mini-bag of 0.9% sodium chloride, 
USP then the final concentration must be calculated based on the best 
estimate of the total volume. 
 
Expiration time includes the duration of infusion.  
 

 
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Table 5.2.4-1: 1 mg/kg REGN2810 (Cemiplimab) Dose Calculation Table with Volumes to Add 
to Sterile Empty IV Bag 
Weight Band in KG 
Based on Entry 
Weight 
Volume of 
0.9% 
Sodium 
Chloride for 
Injection 
Dose in 
mg 
Drug Volume 
of 
REGN2810/ 
Cemiplimab 
or Diluent to 
Add to Bag 
Total 
Volume in 
Bag  
Concentration 
50 kg to <55 kg 
25 mL 
50 mg 
1 mL 
26 mL 
1.92 mg/mL 
55 kg to <60 kg  
25 mL 
55 mg 
1.1 mL 
26.1 mL 
2.11 mg/mL 
60 kg to <65 kg 
25 mL 
60 mg 
1.2 mL 
26.2 mL 
2.29 mg/mL 
65 kg to <70 kg 
25 mL 
65 mg 
1.3 mL 
26.3mL 
2.47 mg/mL 
70 kg to <75 kg  
25 mL 
70 mg 
1.4 mL 
26.4 mL 
2.65 mg/mL 
75 kg to <80 kg 
25 mL 
75 mg  
1.5 mL 
26.5 mL 
2.83 mg/mL 
80 kg to <85 kg 
25 mL 
80 mg 
1.6 mL 
26.6 mL 
3.01 mg/mL 
85  kg to <90 kg  
25 mL 
85 mg 
1.7 mL 
26.7 mL 
3.18 mg/mL 
90 kg to <95 kg 
25 mL 
90 mg 
1.8 mL 
26.8 mL 
3.36 mg/mL 
95 kg to <100 kg 
25 mL 
95 mg  
1.9 mL 
26.9 mL 
3.53 mg/mL 
100 kg to <105 kg 
25 mL 
100 mg 
2 mL 
27 mL 
3.7 mg/mL 
105 kg to <110 kg 
25 mL 
105 mg 
2.1 mL 
27.1 mL 
3.87 mg/mL 
110 kg to <115 kg 
25 mL 
110 mg 
2.2 mL 
27.2 mL 
4.04 mg/mL 
115 kg to <120 kg 
25 mL 
115 mg 
2.3 mL 
27.3 mL 
4.21 mg/mL 
120 kg to <125 kg 
25 mL 
120 mg 
2.4 mL 
27.4 mL 
4.38 mg/mL 
125 kg to <130 kg 
25 mL 
125 mg 
2.5 mL 
27.5 mL 
4.55 mg/mL 
130 kg to <135 kg 
25 mL 
130 mg 
2.6 mL 
27.6 mL 
4.71 mg/mL 
135 kg to <140 kg 
25 mL 
135 mg 
2.7 mL 
27.7 mL 
4.87 mg/mL 
140 kg to <145 kg 
25 mL 
140 mg 
2.8 mL 
27.8 mL 
5.04 mg/mL 
145 kg to <150 kg 
25 mL 
145 mg 
2.9 mL 
27.9 mL 
5.20 mg/mL 
150 kg to <155 kg 
25 mL 
150 mg 
3 mL 
28 mL 
5.36 mg/mL 
155 kg to <160 kg 
25 mL 
155 mg 
3.1 mL 
28.1 mL 
5.52 mg/mL 
160 kg to <165 kg 
25 mL 
160 mg 
3.2 mL 
28.2 mL 
5.67 mg/mL 
165 kg to <170 kg 
25 mL 
165 mg 
3.3 mL 
28.3 mL 
5.83 mg/mL 
170 kg to <175 kg 
25 mL 
170 mg 
3.4 mL 
28.4 mL 
5.99 mg/mL 
175 kg to <180 kg 
25 mL 
175 mg 
3.5 mL 
28.5 mL 
6.14 mg/mL 
180 kg to <185 kg 
25 mL 
180 mg 
3.6 mL 
28.6 mL 
6.29 mg/mL 
185 kg to <190 kg 
25 mL 
185 mg 
3.7 mL 
28.7 mL 
6.45 mg/mL 
190 kg to <195 kg 
25 mL 
190 mg 
3.8 mL 
28.8 mL 
6.6 mg/mL 
195 kg to <200 kg 
25 mL 
195 mg 
3.9 mL 
28.9 mL 
6.75 mg/mL 
 

 
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5.2.5  REGN2810 (cemiplimab) 3 mg/kg Dose Cohort: Preparation for Intravenous 
Administration  
 
Preparation of REGN2810 (cemiplimab) for IV administration will require either 
sterile empty IV bags made of PVC or polyolefin (polyethylene and 
polypropylene) or 25 mL bags of 0.9% sodium chloride for injection, USP (normal 
saline) and REGN2810 (cemiplimab). 
 
For each IV infusion order, the participant’s weight and assigned treatment dose 
will be included in the pharmacy order. 
1. Remove the vial(s) of REGN2810 (cemiplimab) from the refrigerator. 
2. Observe vial(s) for damages, discoloration or particles. 
3. Using aseptic technique in compliance with USP <797> 
a. Add 25 mL of 0.9% sodium chloride for injection, USP to the empty sterile 
IV bag (or start with a pre-made, commercially available 25 mL bag of 
0.9% sodium chloride for injection, USP). 
b. Using a 3 mL, 5 mL, or 10 mL polypropylene syringe withdraw the correct 
volume of REGN2810 from the REGN2810 (cemiplimab) vial for the 
participant’s weight based on Table 5.2.6-1 below. 
c. Add the appropriate volume of REGN2810 (cemiplimab) to the IV bag 
then invert the IV bag 10 times to ensure that the investigational product 
and 0.9% sodium chloride are well mixed.  
4. Label the IV bag with patient identifier, protocol number, REGN2810 
(cemiplimab) x (mg), or placebo for REGN2810 (cemiplimab) in 0.9% sodium 
chloride Injection, USP, the final volume of the bag, final concentration, 
directions to infuse intravenously over 30 minutes the entire contents of the 
infusion bag plus sufficient volume of 0.9% sodium chloride Injection, USP to 
flush the tubing, preparation date and time, expiration time of 6 hours after 
dilution if stored at controlled room temperature (15°C to 25°C) or 24 hours if 
refrigerated at 2°C to 8°C, Investigational Use Statement (“Limited by Federal 
Law to Investigational Use”), and manufacturer information. 
If using a commercially available 25 mL mini-bag of 0.9% sodium chloride, 
USP then the final concentration must be calculated based on the best 
estimate of the total volume. 
 
Expiration time includes the duration of infusion.  
 
5.2.6  Placebo for REGN2810 (cemiplimab) 3 mg/kg Dose Cohort: Preparation for 
Intravenous Administration  
 
Preparation of placebo for IV administration will require either sterile empty IV 
bags made of PVC or polyolefin (polyethylene and polypropylene) or 25 mL bags 
of 0.9% sodium chloride for injection, USP (normal saline) and diluent for 
REGN2810 (cemiplimab). 
 
For each IV infusion order, the participant’s weight and assigned treatment dose 
will be included in the pharmacy order. 

 
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1. Remove the vial(s) of diluent for REGN2810 (cemiplimab) from the 
refrigerator.  
2. Observe vial(s) for damages, discoloration or particles. 
3. Using aseptic technique in compliance with USP <797> 
a. Add 25 mL of 0.9% sodium chloride for injection, USP, to the empty 
sterile IV bag (or start with a pre-made, commercially available 25 mL bag 
of 0.9% sodium chloride for injection, USP). 
b. Using a 3 mL, 5 mL, or 10 mL polypropylene syringe withdraw the correct 
volume of diluent for REGN2810 (cemiplimab) from the diluent for 
REGN2810 (cemiplimab) vial for the participant’s weight based on Table 
5.2.6-1 below. 
c. Add the appropriate volume of diluent for REGN2810 (cemiplimab) to the 
IV bag then invert the IV bag 10 times to ensure that the investigational 
product and 0.9% sodium chloride are well mixed.  
4. Label the IV bag with patient identifier, protocol number, REGN2810 
(cemiplimab) x(mg) or placebo for REGN2810 (cemiplimab) in 0.9% sodium 
chloride Injection, USP, the final volume of the bag, final concentration, 
directions to infuse intravenously over 30 minutes the entire contents of the 
infusion bag plus sufficient volume of 0.9% sodium chloride Injection, USP to 
flush the tubing, preparation date and time, expiration time of 6 hours after 
dilution if stored at controlled room temperature (15°C to 25°C) or 24 hours if 
refrigerated at 2°C to 8°C, Investigational Use Statement (“Limited by Federal 
Law to Investigational Use”), and manufacturer information. 
 
If using a commercially available 25 mL mini-bag of 0.9% sodium chloride, 
USP, then the final concentration must be calculated based on the best 
estimate of the total volume. 
 
Expiration time includes the duration of infusion.  
 
Table 5.2.6-1: 3 mg/kg REGN2810 (Cemiplimab) Dose Calculation Table with Volumes to Add 
to Sterile Empty IV Bag 
Weight Band in KG 
Based on Entry 
Weight 
Volume of 
0.9% Sodium 
Chloride for 
Injection 
Dose in 
mg 
Drug volume 
of 
REGN2810/ 
Cemiplimab 
or Diluent to 
Add to Bag  
Total 
Volume in 
Bag  
Concentration 
50 kg to <55 kg 
25 mL 
150 mg 
3 mL 
28 mL 
5.36 mg/mL 
55 kg to <60 kg  
25 mL 
165 mg 
3.3 mL 
28.3 mL 
5.83 mg/mL 
60 kg to <65 kg 
25 mL 
180 mg 
3.6 mL 
28.6 mL 
6.29 mg/mL 
65 kg to <70 kg 
25 mL 
195 mg 
3.9 mL 
28.9 mL 
6.75 mg/mL 
70 kg to <75 kg  
25 mL 
210 mg 
4.2 mL 
29.2 mL 
7.19 mg/mL 
75 kg to <80 kg 
25 mL 
225 mg  
4.5 mL 
29.5 mL 
7.63 mg/mL 
80 kg to <85 kg 
25 mL 
240 mg 
4.8 mL 
29.8 mL 
8.05 mg/mL 
85  kg to <90 kg  
25 mL 
255 mg 
5.1 mL 
30.1 mL 
8.47 mg/mL 

 
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Weight Band in KG 
Based on Entry 
Weight 
Volume of 
0.9% Sodium 
Chloride for 
Injection 
Dose in 
mg 
Drug volume 
of 
REGN2810/ 
Cemiplimab 
or Diluent to 
Add to Bag  
Total 
Volume in 
Bag  
Concentration 
90 kg to <95 kg 
25 mL 
270 mg 
5.4 mL 
30.4 mL 
8.88 mg/mL 
95 kg to <100 kg 
25 mL 
285 mg  
5.7 mL 
30.7 mL 
9.28 mg/mL 
100 kg to <105 kg 
25 mL 
300 mg 
6 mL 
31 mL 
9.68 mg/mL 
105 kg to <110 kg 
25 mL 
315 mg 
6.3 mL 
31.3 mL 
10.06 mg/mL 
110 kg to <115 kg 
25 mL 
330 mg 
6.6 mL 
31.6 mL 
10.44 mg/mL 
115 kg to <120 kg 
25 mL 
345 mg 
6.9 mL 
31.9 mL 
10.82 mg/mL 
120 kg to <125 kg 
25 mL 
360 mg 
7.2 mL 
32.2 mL 
11.18 mg/mL 
125 kg to <130 kg 
25 mL 
375 mg 
7.5 mL 
32.5 mL 
11.54 mg/mL 
130 kg to <135 kg 
25 mL 
390 mg 
7.8 mL 
32.8 mL 
11.89 mg/mL 
135 kg to <140 kg 
25 mL 
405 mg 
8.1 mL 
33.1 mL 
12.24 mg/mL 
140 kg to <145 kg 
25 mL 
420 mg 
8.4 mL 
33.4 mL 
12.57 mg/mL 
145 kg to <150 kg 
25 mL 
435 mg 
8.7 mL 
33.7 mL 
12.91 mg/mL 
150 kg to <155 kg 
25 mL 
450 mg 
9 mL 
34 mL 
13.24 mg/mL 
155 kg to <160 kg 
25 mL 
465 mg 
9.3 mL 
34.3 mL 
13.56 mg/mL 
160 kg to <165 kg 
25 mL 
480 mg 
9.6 mL 
34.6 mL 
13.87 mg/mL 
165 kg to <170 kg 
25 mL 
495 mg 
9.9 mL 
34.9 mL 
14.18 mg/mL 
170 kg to <175 kg 
25 mL 
510 mg 
10.2 mL 
35.2 mL 
14.49 mg/mL 
175 kg to <180 kg 
25 mL 
525 mg 
10.5 mL 
35.5 mL 
14.79 mg/mL 
180 kg to <185 kg 
25 mL 
540 mg 
10.8 mL 
35.8 mL 
15.08 mg/mL 
185 kg to <190 kg 
25 mL 
555 mg 
11.1 mL 
36.1 mL 
15.37 mg/mL 
190 kg to <195 kg 
25 mL 
570 mg 
11.4 mL 
36.4 mL 
15.66 mg/mL 
195 kg to <200 kg 
25 mL 
585 mg 
11.7 mL 
36.7 mL 
15.94 mg/mL 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 Study Product Acquisition/Distribution 
 
REGN2810 (cemiplimab) and diluent for REGN2810 (cemiplimab) provided by 
Regeneron Pharmaceuticals, Inc., will be available through the NIAID Clinical 
Research Products Management Center (CRPMC). The site pharmacist should 
obtain the study product for this protocol by following the instructions in the 
manual Pharmacy Guidelines and Instructions for DAIDS Clinical Trials 
Networks.  
 
Any study product not provided by the study must comply with the NIAID 
(DAIDS) policy that outlines the process for authorizing the use of study products 
not marketed in the United States in NIAID (DAIDS)-supported and/or -
sponsored clinical trials. This policy is available on the NIAID (DAIDS) website at 
https://www.niaid.nih.gov/sites/default/files/NonFDAapprovedProducts.pdf. 
 

 
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5.3.2 Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all study products 
received from the NIAID CRPMC and subsequently dispensed. All unused study 
products in US CRSs must be returned to the NIAID CRPMC (or as otherwise 
directed by the sponsor) after the study is completed or terminated. The 
procedures to be followed are in the manual Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks. 
 
5.4 
Concomitant Medications 
 
Whenever a concomitant medication or study agent is initiated or a dose changed, 
investigators must review the concomitant medication’s and study agent’s most recent 
package insert, Investigator’s Brochure, or updated information from DAIDS to obtain the 
most current information on drug interactions, contraindications, and precautions. 
 
Additional drug information may be found on the ACTG Precautionary and Prohibited 
Medications Database located at https://www.ppmdb.org/PPMD 
 
5.4.1 Required Medications 
 
Participants must be on ART (not provided by the study) as specified in the 
inclusion criteria (section 4.1.3). 
 
5.4.2 Prohibited Medications 
 
Vaccinations are not allowed 30 days prior to any study visit. 
• 
Cytotoxic chemotherapy  
• 
Systemic immunosuppression (e.g. cyclosporin), except: 
o If indicated for treatment of toxicity or a life-threatening emergency. 
• 
Systemic corticosteroids, except: 
o Topical corticosteroids 
o Physiologic prednisone doses ≤10 mg/day (or prednisone equivalent)  
o If indicated for treatment of toxicity or a life-threatening emergency 
o Brief course for prophylaxis (e.g., contrast dye allergy)  
o Brief treatment of non-autoimmune conditions (e.g., delayed-type 
hypersensitivity reaction caused by contact allergen) 
• 
Inhaled steroids for reactive airway disease (e.g., asthma) (see section 
4.2.8), except: 
o If indicated for treatment of toxicity or a life-threatening emergency. 
• 
Immunomodulators (e.g., IL-2 or IL-12)  
• 
HIV vaccine  
• 
Investigational drug 
• 
IgG antibody therapy 
• 
Checkpoint inhibitors including anti-PD-1, anti-PD-L1, or anti-CTLA-4 
antibodies (including ipilimumab). 

 
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• 
Phosphoinositide 3-kinase inhibitors, including idelalisib 
• 
Biotin ≥5 mg/day 
 
NOTE: Biotin may also be listed as an ingredient in products (by itself or in 
supplements with multiple ingredients) by one of the following names: Factor 
S, vitamin B7, vitamin B complex, vitamin H, Biotina, Biotine, Biotine-D, 
Coenzyme R, D-Biotin, W Factor. 
 
5.4.3 Precautionary Medications 
 
• 
Biotin >1 mg/day and <5 mg/day 
 
NOTE A: Biotin may also be listed as an ingredient in products (by itself or in 
supplements with multiple ingredients) by one of the following names: 
Factor S, vitamin B7, vitamin B complex, vitamin H, Biotina, Biotine, 
Biotine-D, Coenzyme R, D-Biotin, W Factor. 
 
NOTE B: If a participant is taking a biotin dose within this range, the site-specific 
laboratory where the participant will have laboratory tests performed 
will need to be contacted by the core team. Any immunoassays that 
may be subject to biotin interference will need to have their package 
insert reviewed to supply the team with the manufacturer’s 
recommendation for use of the assay with participants receiving biotin 
supplementation. 
 

 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Evaluations (SOE) 
 
Table 6.1-1: SOE: Screening through Week 48 
Evaluation 
Screening 
Pre-Entry 
Entry/Day 0 
Post-entry Evaluations  
(Weeks) 
Premature Study 
Discontinuation (D/C) Visit 
Confirm Virologic Failure (if 
needed) 
1 
2 
4 
6 
7 
8 
10 
12 
16 
20 
24 
28 
36 
48 
Window 
Between 60-90 
days prior to 
entry 
Between 30 
and 50 days 
prior to entry 
≤24 hours 
post-
randomization 
±2 
days 
-2/+7 
days 
±2 days 
-2/+7 days 
Documentation of 
HIV-1 Infection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical 
Assessments (see 
section 6.3.4) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Cemiplimab/Placeb
o Administration 
(see section 6.3.5) 
 
 
X 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment Prior 
to Week 6 
Cemiplimab/Placeb
o Administration 
(see section 6.3.5) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Evaluation 
Screening 
Pre-Entry 
Entry/Day 0 
Post-entry Evaluations  
(Weeks) 
Premature Study 
Discontinuation (D/C) Visit 
Confirm Virologic Failure (if 
needed) 
1 
2 
4 
6 
7 
8 
10 
12 
16 
20 
24 
28 
36 
48 
Window 
Between 60-90 
days prior to 
entry 
Between 30 
and 50 days 
prior to entry 
≤24 hours 
post-
randomization 
±2 
days 
-2/+7 
days 
±2 days 
-2/+7 days 
Telephone Contact 
 
 
2-3 days 
post 
infusion 
 
 
 
2-3 
days 
post 
infu-
sion 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
(ECG) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Liver Function 
Tests 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood Chemistries 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Autoimmune 
Studies (TPO, 
GAD65, islet cells 
[ANA only at 
screening]) 
X (see 
section 
6.3.7) 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
Stored 
Autoimmune 
Studies (see 
section 6.3.7) 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Hepatitis Screen 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TB Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Evaluation 
Screening 
Pre-Entry 
Entry/Day 0 
Post-entry Evaluations  
(Weeks) 
Premature Study 
Discontinuation (D/C) Visit 
Confirm Virologic Failure (if 
needed) 
1 
2 
4 
6 
7 
8 
10 
12 
16 
20 
24 
28 
36 
48 
Window 
Between 60-90 
days prior to 
entry 
Between 30 
and 50 days 
prior to entry 
≤24 hours 
post-
randomization 
±2 
days 
-2/+7 
days 
±2 days 
-2/+7 days 
FSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Free Testosterone 
(male participants 
only) 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
Urinalysis 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Pregnancy Testing 
X 
 
X 
If suspected 
X 
If suspected 
X 
If 
suspected 
X 
If 
suspecte
d 
X 
X 
If 
suspe
cted 
Metabolic Studies 
(see section 6.3.8) 
X 
X 
 
 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adherence 
Assessment 
 
 
X (see 
section 
6.3.9) 
X 
 
 
X (see 
section 
6.3.9) 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
CD4+/CD8+ 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Stored 
Plasma/PBMCs for 
Immunologic 
Studies 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Advanced Flow 
Analysis 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
Standard Plasma 
HIV-1 RNA 
X 
 
X 
X 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 

 
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Evaluation 
Screening 
Pre-Entry 
Entry/Day 0 
Post-entry Evaluations  
(Weeks) 
Premature Study 
Discontinuation (D/C) Visit 
Confirm Virologic Failure (if 
needed) 
1 
2 
4 
6 
7 
8 
10 
12 
16 
20 
24 
28 
36 
48 
Window 
Between 60-90 
days prior to 
entry 
Between 30 
and 50 days 
prior to entry 
≤24 hours 
post-
randomization 
±2 
days 
-2/+7 
days 
±2 days 
-2/+7 days 
Stored Plasma for 
HIV-1 RNA Single-
Copy Assay 
 
X 
X 
X 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
CD4+ T cell-
associated HIV-1 
RNA, DNA, 
RNA:DNA ratio, 
and Quantification 
of Intact Proviral 
Genomes 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
HIV-1 Drug 
Resistance 
Genotype 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

 
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Table 6.1-2: SOE for PK Evaluations - Pre-Entry through Week 48 
1For participants who do not complete cemiplimab infusion, the necessity for these studies will be determined on a case-by-case basis  
  in discussion with the core team. The actual date, and start and stop times of the infusion, and rate of infusion should be recorded. 
2The need to assay each of these timepoints will be based on changes observed from baseline.  
3For RO: A determination of the need to assay certain/all stored samples will be based on the serum cemiplimab concentration seen. 
4The date and time of the previous 3 doses of each antiretroviral medication(s) - must be documented in the eCRF with each sample. 
Evaluation 
Pre-Entry 
Entry/Day 0 
Week 1 
Week 2 
Week 4 
Week 6 
Week 7 
Week 8 
Week 10 
Week 12 
Week 16 
Week 20 
Week 24   
Week 28 
Week 36 
Week 48 
Premature Study 
Discontinuation 
Confirm Virologic 
Failure (if needed) 
±2 days 
Prior to 
infusion 
Following 
infusion 
Prior to 
infusion 
Following 
infusion 
Window 
Between 
30 and 50 
days prior 
to entry 
Within 
15 min 
prior to 
infusion 
Within 15 
min 
following 
infusion 
±2 days 
-2/+7 days 
Within 
15 min 
prior to 
infusion 
Within 15 
min 
following 
infusion 
±2 days 
-2/+7 days 
Cemiplimab 
Serum 
Concentrations1 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Stored Blood for 
Gene Expression 
Assays2 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
 
 
X 
 
Stored PBMCs for 
RO Studies1,3 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Stored Plasma for 
ARV PK Assays4 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
Anti-drug 
Antibody 
Detection Assays  
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
 

 
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6.2 
Timing of Evaluations 
 
6.2.1 Informed Consent 
 
The study physician investigator will directly participate in the informed consent 
process. The informed consent process will include completion of the A5370-
specific Assessment of Understanding tool to evaluate participants’ 
comprehension of the risks and lack of direct benefits of study participation. See 
assessment in Appendix II. 
 
6.2.2 Screening and Pre-Entry Evaluations 
 
Screening and pre-entry evaluations must occur prior to the participant starting 
any study medications, treatments, or interventions. 
 
Screening 
In order to optimally manage blood volume limits, screening evaluations to 
determine eligibility must be completed between 60-90 days prior to study entry 
as outlined in the SOE, unless otherwise specified.  
 
In addition to data being collected on participants who enroll into the study, 
demographic, clinical, and laboratory data on screening failures will be captured 
in an electronic case report form (eCRF) and entered into the ACTG database. 
 
Pre-Entry 
Pre-entry evaluations must be completed 30-50 days prior to entry evaluations 
unless otherwise specified. 
 
6.2.3 Entry Evaluations 
 
Entry/Day 0 evaluations and administration of treatment/placebo must occur 
within 24 hours after randomization unless otherwise specified. The entry 
laboratory values and plasma for HIV-1 RNA SCA must be obtained prior to 
initiating cemiplimab/placebo infusion. 
 
6.2.4 Post-Entry Evaluations 
 
Post-Treatment/Placebo Evaluations 
All evaluations and study visits occur in reference to the date and time for which 
the participant was administered cemiplimab/placebo. Study visits at weeks 1, 6, 
and 7 must be done ±2 days. Study visits at weeks 2, 4, 8, 10, 12, 16, 20, 24, 28, 
and 36 must be done -2/+7 days. 
 

 
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The cemiplimab/placebo infusion should be completed in 30 minutes. The date 
and time of start and end of infusion sample times will be recorded. All other 
cemiplimab/placebo and RO samples are collected as planned, the date and 
time of actual sample collection must be documented in the eCRF (see section 
6.3.12 for further details of pharmacokinetic sample collection). 
 
In the event that the infusion requires additional time, all subsequent time-points 
are calculated from the completion of the infusion (see section 6.3.5). 
 
All other evaluations should be completed per SOE: 
 
NOTE: The core team must be notified by email at actg.corea5370@fstrf.org for 
visits outside the window period for any visit through week 12. 
 
For stored samples, all sites must have established procedures for regular 
reconciliation and verification of specimens, which must be followed throughout 
the study per the Laboratory Processing Chart (LPC). Collection of sample 
aliquots is of particular importance for all time points from the screening visit 
through week 12. In the event of a missed visit or that the required volume or 
number of sample aliquots is not obtained at any time point, designated site clinic 
and/or laboratory staff must immediately inform the study core team, who will 
provide guidance on how to respond to the problem. 
 
In addition to following this guidance from the study team, designated site clinic 
and laboratory staff will work together to document the problem, take appropriate 
corrective and preventive action, and document all action taken. Reconciliation 
must be performed for all specimen types that are received by the laboratory and 
stored in the LDMS. 
 
For other evaluations, if an evaluation is not completed at a scheduled visit, effort 
should be made to obtain the evaluation as soon as possible. If unsuccessful, 
complete the evaluation at the next study visit if not already included as part of 
the regularly scheduled visit. 
 
Study Completion Evaluations 
Week 48 evaluations will serve as the study completion evaluations for 
participants and must occur -2/+7 days. 
 
Event-Driven Evaluations 
Participants who experience a Grade ≥3 AE or clinical event on study that is not 
resolved by week 48 will be followed until resolution or clinical stabilization as 
defined by the site investigator (see section 8.1). 
 
Participants who experience any grade of irAE on study that is not resolved by 
week 48 will be followed until resolution or stabilization as defined by the study 
team and DAIDS medical officer. 
 

 
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Confirmation of Virologic Failure 
Virologic failure is defined as two consecutive plasma HIV-1 RNA levels ≥200 
copies/mL. 
 
Participants with plasma HIV-1 RNA ≥200 copies/mL should have a confirmatory 
VL and a plasma sample for real-time genotyping obtained as soon as possible 
unless there is clear evidence of non-adherence to ART and have evaluations 
performed per the SOE. If ART non-adherence is confirmed, then HIV-1 RNA 
should be retested at least 2 weeks after ART is resumed. If HIV-1 RNA is 
confirmed ≥200 copies/mL then see section 8.7 for additional information 
regarding virologic failure management. 
 
6.2.5 Discontinuation Evaluations 
 
Evaluations for Randomized Participants Who Do Not Start Study Treatment 
Participants who withdraw from the study prior to starting study 
treatment/placebo should have entry/day 0 and off-study forms completed and 
keyed. No further evaluations or follow-up are required for these participants. 
Participants will be replaced. All eCRFs must be completed for the period up to 
and including entry/day 0. 
 
Premature Treatment/Placebo Discontinuation Evaluations 
Participants who begin but do not complete of both infusions of 
cemiplimab/placebo, but receive some of the investigational product, and are 
willing to stay on the study, will be followed for safety by completing all study 
visits and evaluations as outlined in the SOE. If one or both cemiplimab/placebo 
infusions have been administered, samples for serum cemiplimab, RO, and ADA 
will be collected per the SOE (duration of sampling in participants that do not 
receive or complete the second infusion will be decided on a case-by-case basis 
with the core team). Whether virologic, immunologic, and stored ARV plasma 
samples will be stored or performed following premature discontinuation of 
cemiplimab/placebo infusions will be determined on a case-by-case basis in 
discussion with the core team. The duration of the infusion (including actual start 
and stop times) and the volume of each cemiplimab/placebo infusion should be 
recorded. Participants who do not complete ≥90% of both infusions of 
cemiplimab/placebo will be replaced unless the participant has reached a 
protocol-defined safety endpoint. Participants who withdraw should be explicitly 
asked about the contribution of possible AEs to their decision to withdraw 
consent, and any AE information elicited should be documented. 
 
Discontinuation of Antiretroviral Therapy 
Participants who discontinue cART for any reason will be followed for safety by 
completing all study visits and evaluations as outlined in the SOE. If ART is 
discontinued prior to completion of cemiplimab/placebo infusions, then no further 
infusions should be given. Whether cemiplimab serum concentrations or RO 
assays will be collected following discontinuation of ART will be determined on a 
case-by-case basis in discussion with the core team. Stored plasma/PBMC for 

 
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immunologic studies, stored plasma for SCA and samples for CD4+ T cell 
associated HIV-1 RNA, DNA, and 2-long terminals repeats (2-LTRs) do not need 
to be obtained for time points after the participant has discontinued ART. 
 
Premature Study Discontinuation Evaluations 
Participants who prematurely discontinue study participation after completing one 
or more of the cemiplimab/placebo infusions will have the premature study 
discontinuation (D/C visit) evaluations performed per the SOE. Participants who 
discontinue the study prior to week 12 without having met the primary safety 
outcome measure will be replaced. 
 
6.3 
Instructions for Evaluations 
 
All clinical and laboratory information required by this protocol is to be present in the 
source documents. Sites must refer to the Source Document Guidelines on the DAIDS 
website for information about what must be included in the source document: 
https://www.niaid.nih.gov/sites/default/files/daids-sourcedocpolicy.pdf. 
 
All stated evaluations are to be recorded on the eCRF unless otherwise specified. Refer 
to section 7.0 for information on the DAIDS AE Grading Table and AE reporting of 
adverse events requirements. 
 
6.3.1 Documentation of HIV-1 
 
Section 4.1.1 specifies assay requirements for HIV-1 documentation. HIV-1 
documentation is not recorded on the eCRF. 
 
6.3.2 Medical History 
 
The medical history must include all signs and symptoms regardless of grade 
and all diagnoses identified by the ACTG criteria for clinical events and other 
diagnoses regardless of grade within the past 30 days. In addition, the following 
diagnoses should be recorded regardless of when the diagnosis was made: 
• 
AIDS-defining conditions 
• 
Bone fractures (verbal history accepted) 
• 
Coronary heart disease 
• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Diabetes 
• 
Asthma 
• 
Tuberculosis 
• 
Chronic hepatitis C 
• 
Chronic hepatitis B 
 
Any allergies to any medications and their formulations must also be 
documented. 
 

 
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Document the pre-ART HIV-1 RNA level and nadir CD4 count if available. If pre-
ART nadir CD4 count documentation or pre-ART HIV RNA level is not available, 
then collect and record participant recall. Document date of first undetectable 
HIV-1 RNA level prior to sustained VL suppression (may be estimated if exact 
date not available) and the date(s) of any previous virologic failure on ART. 
 
The medical history evaluation will be assessed at the screening and entry visit 
and recorded on the eCRFs at the study entry visit. 
 
6.3.3 Medication History 
 
A medication history must be obtained at screening and updated at entry, 
including start and stop dates. Table 6.3.3-1 below lists the medications that 
must be included in the history. 
 
Table 6.3.3-1: Medication History 
Medication Category 
Complete History or 
Timeframe 
Antiretroviral therapy 
Start date of the current 
ART regimen, ART 
history over the prior 5 
years and date of 1st use 
of ART 
Immune-based therapy 
Complete history 
Blinded study treatment 
Complete history 
HIV-1-related vaccines 
Complete history 
All prescription drugs  
Current use 
All over-the-counter drugs  
Current use 
Dietary and herbal supplements 
Current use 
Sex-hormone medications or 
sex-hormone analogues or 
antagonists* 
Last 12 months except as 
noted below 
Prescription drugs for treatment 
of opportunistic infections 
Current use 
Prescription drugs for 
prophylaxis of opportunistic 
infections 
Current use 
Alternative therapies 
Current use 
*Includes: hormone-releasing IUDs (e.g., Mirena inserted in the last 5 years); 
oral, injectable, implanted, or patch contraceptives; vaginal ring, creams, or 
inserts; estrogen, progesterone, or testosterone therapy; leuprolide or other 
synthetic gonadotropin-releasing hormone; tamoxifen, raloxifene, aromatase 
inhibitors or any other androgen, estrogen, or progesterone analogue or 
antagonist therapy; emergency contraception (current use only); anabolic 
steroids; gonadotropins. 

 
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6.3.4 Clinical Assessments 
 
Complete Physical Examination 
A complete physical examination is to be done at screening and should include 
at a minimum an examination of the skin, head, mouth, and neck (including 
thyroid exam); auscultation of the chest; cardiac examination; abdominal 
examination; gonadal exam in males, and examination of the lower extremities 
for edema. The complete physical examination will also include signs and 
symptoms, diagnoses, and vital signs (height, weight, temperature, pulse, 
respiration rate, and blood pressure). 
 
The complete physical examination at screening should also include a nondilated 
funduscopic eye exam by a physician or appropriately trained clinician and must 
be documented in source documents. 
 
Targeted Physical Examination 
A targeted physical examination is to be done at entry, and weeks 1, 2, 4, 6, 7, 8, 
10, 12, 16, 20, 24, 28, 36, and 48, and should include vital signs (temperature, 
pulse, respiration rate, and blood pressure), and is to be driven by any previously 
identified or new AE/targeted event (as described in below bullets), that the 
participant has experienced since the last visit. 
 
Height 
Height (cm) will be recorded on the eCRF at screening or pre-entry. 
 
Weight 
Weight in kilograms (kg) should be assessed at screening, entry, weeks 6, 12, 
and 48. Weight should be documented prior to dosing, and the first infusion dose 
will be based on weight from entry. Week 6 dosing should also be based on 
weight from the entry visit unless there is a >10% change in body weight, in 
which case the dose should be adjusted accordingly. 
 
Post entry, see section 8.8 for collection requirements for pregnancy. 
 
Post entry, record the following targeted event(s) regardless of grade: 
• 
Uterine pregnancy 
• 
Autoimmune diseases 
• 
Immune deficiency syndromes 
• 
All potential irAEs including but not limited to pneumonitis, colitis, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, diabetes, 
hypophysitis, allergic skin reaction. 
• 
Cancers 
• 
Tuberculosis 
• 
AIDS-defining conditions 
  
Refer to section 7.2 for AE collection requirements.   

 
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Concomitant Medications Including Antiretroviral Drugs 
At entry and all subsequent visits, the following new and discontinued 
concomitant medications must be recorded on the eCRFs since the last visit: 
• 
Prescription medications 
• 
Sex-hormone medications or sex-hormone analogues or antagonists (see 
section 6.3.3 for examples). 
• 
Antiretroviral drugs 
• 
Dietary and herbal supplements 
• 
Over-the-counter medications 
• 
Endocrine therapies 
• 
Immunomodulatory agents (e.g., steroid injections/infusions/oral, inhalations, 
physiologic replacement) 
• 
Alternative therapies 
 
NOTE: Ongoing medications, other than antiretrovirals, do not have to be 
recorded at each visit. Once they have been captured, only changes in dosing, or 
discontinuation are to be recorded. 
 
6.3.5 Study Treatment Administration and Evaluation 
 
Study Treatment Administration  
Record the cemiplimab infusion/placebo, including dose administered, the total 
volume contained in the infusion bag, the concentration of the cemiplimab 
infusion preparation (e.g., mg/mL), the rate of infusion (e.g., mL/min), whether 
the rate of the infusion changed, and what the rate changed to. Record whether 
administration was temporarily halted for any reason (record the time it was 
halted and the time if restarted). Record the start and stop infusion times, the 
time a change in infusion rate occurs, and whether the full dose was 
administered. If the full dose was not administered, the amount of 
cemiplimab/placebo (the volume and concentration) that was administered 
should be recorded and the core team should be notified. 
 
NOTE A: The maximum time of infusion should not exceed 3 hours (180 
minutes) (see sections 8.2.2 and 8.2.1). 
 
NOTE B: If the second infusion is delayed for any reason, participants should 
complete all evaluations for the week 6 study visit per the SOE without 
the second infusion of cemiplimab/placebo. These participants should 
be followed for safety and at unscheduled visits from week 10 onward 
(from date of the first infusion) per the SOE, until the second infusion 
can be rescheduled. 
 

 
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NOTE C: If the second infusion is rescheduled for a later date, then a 
subsequent protocol visit should be timed in relationship to the second 
infusion (e.g., week 7 would occur 1 week following the second 
infusion and so forth). 
 
NOTE D: If the second infusion is delayed, the week 4 visit should be repeated if 
it has been >4 weeks since collection of the week 4 laboratory 
evaluations before the date of the rescheduled second infusion. Do 
not, however, re-draw stored blood for gene expression assays or 
stored PBMCs for RO studies.   
 
Assessment Prior to Week 6 Cemiplimab/Placebo Administration  
Prior to administering the second infusion at week 6 in all dose cohorts, the 
safety-related items in sections 4.1 and 4.2 should be re-assessed by a site 
investigator or designee based on the week 4 evaluations (or the visit prior to the 
week 6 infusion, as appropriate). If the following are not confirmed, then the 
second infusion should not be given:  
• 
Negative results for TPO antibody, GAD65/GAD antibody, and islet cell 
antibody. 
• 
Negative or within normal range results for metabolic studies (fasting glucose, 
AM cortisol, TSH, and free T4). 
 
These must be done at a laboratory that possesses a CLIA certification or 
equivalent. 
 
Also, if any irAEs were identified following the first infusion or suspected irAEs 
are under investigation for relatedness, the second infusion must not be given. 
 
NOTE A: If enrollment safety pause criteria are met (see section 10.4.1), 
participants already enrolled on study should not receive the second 
infusion pending SMC review, but should be followed for safety per 
NOTE B above. The study leadership will notify sites if and when a 
safety pause is needed and will also notify sites when the pause is 
lifted. 
 
NOTE B: If enrollment is re-opened following SMC review, the above safety labs 
designated for week 4 should be repeated if collected >4 weeks prior 
to the rescheduled second infusion. 
 
This information should be captured on the appropriate eCRF. 
 
Telephone Contact 
Participants will be contacted by telephone (2 to 3 days post-infusion) to assess 
for changes in health status and to answer questions about infusion-related signs 
and/or symptoms. This information should be captured on the appropriate eCRF. 
See pre-specified telephone script in the A5370 Manual of Procedures (MOPS). 
 

 
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NOTE: If participants prefer not to be contacted by telephone, then they may 
return to the clinic and the same procedures should be followed as noted above. 
 
6.3.6 Electrocardiogram 
 
ECG will be performed prior to cemiplimab/placebo infusion at pre-entry, per the 
SOE and should be read per institutional protocol within 72 hours to establish 
baseline for further evaluation as clinically indicated.  
 
6.3.7 Laboratory Evaluations 
 
At screening, pre-entry, and entry all laboratory values must be recorded on the 
eCRF. The entry laboratory values must be obtained prior to initiating 
cemiplimab/placebo infusion. 
 
For post-entry assessments, record on the eCRF all laboratory values for 
creatinine, AST, ALT, total bilirubin, hemoglobin, white blood cell count, ANC, 
platelets, absolute lymphocyte count (ALC), TSH, free T4, HgbA1c, fasting blood 
glucose, cortisol, FSH, free testosterone, anti-TPO antibody, anti-GAD65 
antibody, anti-islet cell antibody, and other autoimmune studies (if indicated) 
regardless of grade; record abnormal laboratory findings as per section 7.2. 
 
At entry and week 6, all lab tests should be drawn pre-infusion unless otherwise 
specified.  
 
Hematology 
Hemoglobin, hematocrit, red blood cells, mean corpuscular volume, white blood 
cell count (WBC), differential WBC, ANC, platelets, ALC. 
 
Liver Function Tests 
Total bilirubin, AST [SGOT], ALT [SGPT], alkaline phosphatase. 
 
NOTE: For participants on ritonavir-boosted atazanavir, direct bilirubin should be 
measured. 
 
Blood Chemistries 
Glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphate, 
creatinine, creatinine clearance, blood urea nitrogen (BUN), uric acid, albumin. 
 
NOTE: A program for calculating creatinine clearance by the Cockcroft-Gault 
method is available on www.frontierscience.org. 
 
Autoimmune Studies 
TPO antibody, GAD65 antibody, and islet cell antibody, per the SOE. ANA titer 
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Potential participants who are found to be ineligible based on positive 
autoimmune results at screening will be provided with these results and referred 
for further clinical evaluation as appropriate. 
 
If a participant receives a positive antibody result for any of those listed above at 
week 4, he/she will not receive a second infusion of cemiplimab/placebo. 
 
Autoantibody test results should be shared with study participants and 
appropriate clinical follow-up should be arranged, as needed. 
 
Stored Samples for Autoimmune Studies 
Serum will be stored for autoimmune studies per the SOE.  
 
Hepatitis Screen 
HCV antibody, HCV RNA (if HCV antibody positive), and HBsAg testing per the 
SOE. 
 
These values should be captured on an eCRF. 
 
TB Screen 
Interferon-gamma Release Assay (IGRA) per the SOE. 
 
NOTE A: TB test results do not need to be entered on the eCRF. 
 
NOTE B: Participants with a prior positive TB IGRA or positive PPD and 
documented evidence of completed prophylaxis treatment may enroll 
in the study and do not need to undergo IGRA at screening. 
 
FSH 
For female participants, FSH should be measured at screening if they are 
believed to be not of reproductive potential but lack medical record.  
 
NOTE: Female participants who have not had a menses for at least 24 
consecutive months and have an FSH greater than 40 international units (IU) 
documented by medical record or have documentation of a hysterectomy, 
bilateral oophorectomy and/or bilateral salpingectomy, do not require an FSH at 
screening. 
 
Free Testosterone 
For male participants, free testosterone should be measured per the SOE. 
Samples should be drawn prior to 12 noon or per local lab requirements. 
 
Urinalysis 
A dipstick urinalysis with microscopic examination will be performed per the SOE 
to assess for nephritis. 
 

 
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Pregnancy Test 
For females of reproductive potential or if they are believed to be not of 
reproductive potential but lack medical record, a serum pregnancy test with a 
sensitivity of at least 25mIU/mL must be performed at screening. A serum or 
urine pregnancy test must be completed within 48 hours of entry, and again prior 
to infusion of cemiplimab/placebo at week 6, and at weeks 12, 24, and 48 or if 
suspected, at weeks 1, 2, 4, 7, 8, 10, 16, 20, 28, and 36. Record pregnancy and 
pregnancy outcome per section 8.8.   
 
6.3.8 Metabolic Studies 
 
HgbA1c values should be obtained at screening only.  
 
Fasting glucose and AM cortisol (drawn prior to 10:00 AM) values should be 
obtained at screening (cortisol only), pre-entry, and weeks 4, 6, 12, 16, 20, 24, 
28, 36, and 48.  
 
TSH and Free T4 should be obtained at screening (TSH only) and weeks 4, 6, 
12, 16, 20, 24, 28, 36, and 48. 
 
NOTE: Fasting refers to nothing to eat or drink except oral medications and plain 
water for at least 8 hours. Participants must be fasting for the screening visit. For 
subsequent visits if participants are in a non-fasting state, the visit should 
proceed and the fact that the participant is not fasting should be documented. 
 
6.3.9 Adherence Assessment 
 
A standardized assessment to monitor ART adherence will be administered per 
the SOE and will include assessment for ART interruption of more than 7 
consecutive days. An interruption of more than 7 days will be considered 
treatment discontinuation. For ART discontinuation, see section 6.2.5. 
 
At Entry/Day 0 and week 6, the adherence assessment should be performed 
prior to infusion. 
 
The adherence eCRF is posted on the DMC Portal in the Forms Management 
Utility. 
 
6.3.10 Immunologic Studies 
 
Documentation of the availability of the stored pre-entry plasma specimens for 
virology assays and stored pre-entry peripheral blood mononuclear cell (PBMC) 
specimens for CD8+ T-cell assays is required. Sites must receive confirmation 
from the processing lab via phone, e-mail, or fax, that specimens have been 
entered into the ACTG’s LDMS. 
 

 
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CD4+/CD8+ T cells 
Obtain absolute CD4+/CD8+ T cell counts and percentages within 90 days prior 
to entry from a laboratory that possesses a CLIA certification or equivalent. 
 
For entry and post-entry evaluations, all laboratories must possess a CLIA 
certification or equivalent and must be certified for protocol testing by the DAIDS 
Immunology Quality Assurance (IQA) Program. 
 
Stored Plasma/PBMC for Immunologic Studies 
Cryopreserved PBMC will be stored for HIV-1-specific immune response assays 
as well as T-cell immune analysis by flow cytometry per the SOE. Specific testing 
will include the following: 
• 
Determination of HIV-specific T cell responses measured by intracellular 
cytokine staining (a validated assay) pre- and post-administration of 
cemiplimab. 
• 
Determination of cytolytic potential of HIV-1-specific CD8+ T cells. 
• 
Poly-functionality of HIV-1-specific CD8+ and CD4+ T cells. 
• 
Activation and cycling of CD4+ and CD8+ T cells. 
• 
The proportion of total and HIV-1-specific CD4+ and CD8+ T cells that 
express exhaustion markers by multi-parameter flow cytometry. The 
expression profile on dendritic cells and monocyte-derived macrophages will 
also be determined. 
• 
Ex vivo proliferation of HIV-specific T cell responses in the presence of anti-
PD-1. 
 
NOTE: Stored PBMCs for T Cell Proliferation and Gene Expression Assays, and 
Stored Plasma/PBMC for Immunology Studies are not necessary for participants 
who discontinue ART for any reason. After the start of infusion, for participants 
who do not complete cemiplimab/placebo infusion, the necessity for these 
studies will be determined on a case-by-case basis in discussion with the core 
team. The duration of the infusion and the volume of cemiplimab/placebo infused 
should be recorded (see section 6.3.5 for details of Study Treatment 
Administration Documentation). 
 
Advanced Flow 
Stored PBMCs for advanced flow analysis requires a CD4+/CD8+ T cell ratio and 
WBC with differential from a sample obtained at the same time. 
 
6.3.11 Virologic Studies 
 
Plasma HIV-1 RNA Assay 
Screening HIV-1 RNA must be performed within 90 days prior to study entry 
using an FDA-approved assay by a laboratory that possesses a CLIA certification 
or equivalent, and should be performed between 60 and 90 days prior to entry to 
optimally manage blood volume. Eligibility will be determined based on the 
screening value. 

 
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Entry and post-entry plasma HIV-1 RNA should be performed per the SOE. 
Samples should be processed and shipped to the designated central ACTG 
testing laboratory (refer to LPC for shipping information). 
 
All occurrences of confirmed HIV viral loads above 200 copies/mL must be 
recorded on the eCRF. 
 
Stored Plasma for HIV-1 RNA SCA 
Plasma for HIV-1 RNA SCA will be obtained as required per the SOE and stored 
for batched analyses. The sample at entry for SCA must be collected prior to 
initiating cemiplimab/placebo infusion. 
 
See the LPC located on the A5370 PSWP, for details on processing plasma 
samples for SCA. 
 
The baseline SCA value will be the mean of the pre-entry and entry 
determinations, which must have been obtained at least 7 days apart. 
 
CD4+ T cell-associated HIV-1 RNA 
Cell-associated HIV-1 RNA will be measured in total CD4+ T cells isolated from 
cryopreserved PBMC obtained at pre-entry, prior to cemiplimab/placebo infusion 
at entry/day 0 and week 6, and thereafter per the SOE.  
 
CD4+ T cell-associated HIV-1 DNA 
Total HIV-1 DNA in total CD4+ T cells isolated from cryopreserved PBMC will be 
measured to normalize cell-associated HIV-1 RNA data, at pre-entry, prior to 
cemiplimab/placebo infusion at entry/day 0 and week 6, and thereafter per the 
SOE. 
 
Stored PBMCs for Quantification of Intact Proviral Genomes  
PBMCs will be stored for quantification of intact proviral genomes per the SOE. 
See the LPC for details on processing PBMC samples. 
 
T cell-associated HIV-1 RNA: DNA Ratios 
Cell-associated HIV-1 RNA: DNA ratios in total CD4+T cells isolated from 
cryopreserved PBMC will be calculated from the cell-associated HIV-1 DNA and 
RNA data described above. 
 
HIV-1 Drug Resistance Genotype 
An HIV-1 drug resistance genotype (virus population sequencing) will be 
performed at local CLIA-certified commercial laboratories in those individuals 
with confirmed virologic failure. 
 
NOTE: Standard Plasma HIV-1 RNA Assay, CD4+ T cell-associated HIV-1 RNA, 
and CD4+ T cell-associated HIV-1 DNA are not necessary for participants who 
discontinue ART for any reason. After the start of infusion, for participants who 

 
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do not complete cemiplimab/placebo infusion, the necessity for these studies will 
be determined on a case-by-case basis in discussion with the core team. The 
duration of the infusion and the volume of cemiplimab/placebo infused should be 
recorded. 
 
6.3.12 Pharmacokinetic Studies (refer to section 11.0) 
 
Cemiplimab Serum Concentrations  
Blood will be collected for determination of cemiplimab in serum using a validated 
ligand binding assay. A pre-entry sample will be drawn. At entry/day 0 and week 
6, samples are drawn within 15 minutes following infusion (and must be obtained 
from the contralateral arm), and within 15 minutes prior to the infusion on week 6. 
At weeks 1, 2, 7, 8, 10, 12, 16, 20, 24, 28, 36, and 48, samples can be drawn at 
any time during the visit. Record the date and actual time of dosing and of 
sample drawn in the eCRF. 
 
Stored Blood for Gene Expression Assays 
Samples will be collected for the gene expression analysis as per the SOE. 
Samples collected on infusion days (day 0 and week 6), should be collected pre-
infusion. All samples that are collected may not be tested. Please refer to the 
LPC for specimen collection and processing instructions. 
 
RO Studies 
Cryopreserved PBMC samples will be used to assay PD-1 RO by cemiplimab by 
flow cytometry. At pre-entry and within 15 minutes prior to infusion at week 6, 
samples are drawn. At weeks 1, 2, 7, 8, 10, 12, 16, 20, 24, 28, 36, and 48, 
samples can be drawn at any time during the visit. Record the actual date and 
time of dosing and of sample drawn in the eCRF. 
 
Stored Plasma for ARV PK Studies  
At entry/day 0 (prior to infusion). At weeks 2, 4, 6 (prior to infusion), 8, and 10. 
Samples obtained on non-infusion days can be drawn during the participant’s 
visit (a specific time of day is not required), documentation of the date and time 
samples are drawn is required in the eCRF. Documentation of the date and time 
of the 3 previous doses of all antiretroviral medication(s) are to also be recorded 
in the eCRF. Samples will undergo testing as indicated if the participant is 
viremic. 
 
6.3.13 Anti-drug Antibody (ADA) Assessments 
 
Serum samples for the assessment of anti-cemiplimab antibody may be collected 
at Entry/Day 0 (prior to infusion), weeks 12, 24, 48, and at premature study 
discontinuation. Additional ADA samples may be collected at or near any 
suspected immune mediated adverse events of special interest (AESI) in 
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On a case-by-case basis, in discussion with the core team, remaining serum 
from cemiplimab samples may be assessed for ADA, if deemed necessary based 
on the PK profile seen. 
 
7.0 
ADVERSE EVENTS AND STUDY MONITORING 
 
7.1 
Definition of Adverse Events (AEs) 
 
An AE is any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or diagnosis that occurs in a study participant during the conduct of 
the study REGARDLESS of the attribution (i.e., relationship of event to medical 
treatment/study product/device or procedure/intervention). This includes any occurrence 
that is new in onset or aggravated in severity or frequency from the baseline condition. 
 
7.2 
AE Collection Requirements for This Protocol 
 
Post-entry, all AEs must be recorded on the eCRFs if any of the following criteria have 
been met.   
• 
All Grade ≥1 AEs 
• 
All suspected or confirmed irAEs  
• 
All infusion reactions  
• 
All AEs that led to a change in study intervention  
• 
All AEs meeting SAE definition or Expedited Adverse Event (EAE) reporting 
requirement 
• 
All targeted events listed in section 6.3.4 
 
NOTE: SAEs or events meeting EAE reporting requirements should also be entered into 
the DAIDS Adverse Experience Reporting System (DAERS), an Internet-based reporting 
system. All SAEs, irAEs, and AESIs will be recorded in DAERS, regardless of causality. 
 
All AEs that are reported must have their severity graded. To grade AEs, sites must refer 
to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017, which can be 
found on the DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-
sites/daids-adverse-event-grading-tables. 
 
Infusion reactions, adrenal insufficiency, and pneumonitis should be graded per the 
National Cancer Institute’s (NCI) Common Terminology Criteria for AEs (CTCAE) 
guidelines as outlined in section 8.0, and can also be found in the National Cancer 
Institute’s Table for CTCAE, version 5.0, found on the National Cancer Institute Web 
site: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Q
uick_Reference_5x7.pdf 
 

 
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Serious Adverse Events (SAEs) 
A SAE is defined as any untoward medical occurrence that: 
• 
Results in death. 
• 
Is life-threatening. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/incapacity. 
• 
Is a congenital anomaly/birth defect. 
• 
Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the participant or may require 
intervention to prevent one of the other outcomes listed in the definition above. 
 
Adverse Events of Special Interest (AESI) 
An AESI (serious or non-serious) is one of scientific and medical concern specific to the 
sponsor’s product or program, for which ongoing monitoring and rapid communication by 
the investigator to the sponsor can be appropriate. Such an event might warrant further 
investigation in order to characterize and understand it. Depending on the nature of the 
event, rapid communication by the trial sponsor to other parties (e.g., regulators) might 
also be warranted. 
 
AESIs include all cases of irAEs, felt to be related to study treatment, including:  
• 
Grade 2 or greater infusion-related reactions 
• 
Grade 2 or greater allergic/hypersensitivity reactions 
• 
All irAEs regardless of grade, including but not limited to: dermatitis, pneumonitis, 
myocarditis, colitis, adrenal insufficiency/crisis, hypo- or hyperthyroidism, thyroiditis, 
diabetes, hypophysitis, hepatitis, systemic lupus erythematosus, nephritis, 
myasthenia gravis, and/or drug-induced liver injury (DILI) 
 
For all AESIs, the core team should be contacted immediately via email at 
actg.coreA5370@fstrf.org (See section 7.3.2). 
 
NOTE: Participants with an ongoing AESI at week 48, should be followed until the AE 
has resolved or stabilized in the opinion of the core team (see section 6.2.4). 
 
Infusion Reactions 
Infusion reactions are defined as any AE that occurs during the infusion or within 24 
hours after the infusion is completed. All infusion reactions must be reported as AEs and 
graded using the grading scales as instructed in section 8.2. 
 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS 
 
7.3.1 Expedited Reporting of Adverse Events to DAIDS 
Requirements, definitions, and methods for expedited reporting of AEs are 
outlined in Version 2.0 of the DAIDS EAE Manual, which is available on the RSC 
website at https://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-
reporting-adverse-events-daids. 
 

 
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DAERS must be used for EAE reporting to DAIDS. In the event of system 
outages or technical difficulties, EAEs may be submitted using the DAIDS EAE 
Form. This form is available on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting. 
 
For questions about DAERS, please contact NIAID CRMS Support at 
CRMSSupport@niaid.nih.gov. Please note that site queries may also be sent 
from within the DAERS application itself. 
 
For questions about expedited reporting, please contact the DAIDS RSC Safety 
Office at (DAIDSRSCSafetyOffice@tech-res.com). 
 
7.3.2 Reporting Requirements for this Study 
 
• 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE 
Manual, will be used for this study. 
• 
The study agents for which expedited reporting are required are: cemiplimab 
(anti-PD-1 mAb) and placebo for cemiplimab.  
• 
In addition to the EAE Reporting Category identified above, other AEs that 
must be reported in an expedited manner are: All AESIs as noted in section 
7.2 felt related to study treatment.  
 
If a particular sign/symptom is not specifically listed in the Division of AIDS Table 
for Grading the Severity of Adult and Pediatric Adverse Events, corrected 
Version 2.1, July 2017, refer to the Estimating Severity Grade section for the 
'Clinical Adverse Events Not Otherwise Identified in the DAIDS AE Grading 
Table' grading scale. 
 
NOTE: Possible DILI (or Hy’s Law) is defined as any elevated ALT and/or AST of 
Grade 2 or greater (≥3 x ULN), alkaline phosphatase <2 x ULN, and an increase 
in bilirubin ≥2 x ULN with no other immediately apparent possible causes of AST 
or ALT elevation and hyperbilirubinemia (such as concomitant use of atazanavir), 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver 
disease, or the administration of other drug(s) known to be hepatotoxic. 
 
AESI: All AESIs, serious and non-serious, must be reported using the same 
reporting process as for SAE reporting.  
 
Other AEs that must be reported in an expedited manner (i.e., within 3 business 
days to the sponsor or designee) are as follows. 
 
Pregnancy: Although pregnancy is not considered an AE, it is the responsibility of 
the investigator to report to the sponsor (or designee), within 3 business days of 
identification, any pregnancy occurring in a female or female partner of a male 
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Any complication of pregnancy affecting a female study participant or female 
partner of a male study participant, and/or fetus, and/or newborn that meets the 
SAE criteria must be reported as an SAE. Outcome for all pregnancies should be 
reported to the sponsor. 
 
7.3.3 Grading Severity of Events 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017, 
must be used and is available on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-
tables. 
 
The grading system for suspected or confirmed infusion-related reactions, 
adrenal insufficiency, and pneumonitis is listed in sections 8.2, 8.3.4, and 8.3.5, 
and can also be found in the National Cancer Institute’s Table for CTCAE, 
version 5.0, found on the National Cancer Institute Web site: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCA
E_v5_Quick_Reference_5x7.pdf 
 
7.3.4 Expedited AE Reporting Period 
 
• 
The expedited AE reporting period for this study is the entire study duration 
for an individual participant (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 DAIDS if the study staff 
become aware of the events on a passive basis (from publicly available 
information). See Reference Safety Information table as found in the IB for 
determination of SUSARs. 
 
7.4 
Study Monitoring 
 
The Protocol Core Team will monitor the conduct and safety of the study via regular 
summaries by cohort pooled over treatment arms of accrual, baseline characteristics, 
study conduct (including premature study discontinuations and premature study 
treatment discontinuations), any missed doses of study treatment/placebo, any reported 
interruptions of ART, HIV-1 RNA levels ≥200 copies/mL (see section 6.2.4/Confirmation 
of Virologic Failure), data completeness, specimen collection, and AEs. The core 
protocol team will review the individual participant-level safety data frequently to assess 
the relation of all reported AEs to study treatment/placebo. 
 
The DAIDS clinical representative will review and assess EAE reports for potential 
impact on the study participant safety and protocol conduct as per DAIDS policies, 
guidance documents, and SOPs, as applicable.  
 

 
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The study will undergo interim review at least annually by an independent ACTG-
appointed SMC. The first review is anticipated to be review of the first cohort, regarding 
dose escalation to the second cohort. The SMC will review information by cohort on 
accrual, baseline characteristics, conduct of the study (including premature study 
discontinuations and premature study treatment discontinuations), AEs by treatment arm 
(including core protocol team assessment of relationship to study treatment), CD4+ T 
cell counts, virologic failures, and HIV-1 RNA levels/suppression over time by treatment 
arm, and completeness of follow-up and sample availability. In particular, irAEs will be 
monitored.  
 
After the last enrolled participant in each cohort receives study treatment and completes 
follow-up through the week 12 visit and the blinded data become available for review by 
the core team, safety data including the core team decision on relation of AEs to study 
treatment will be reviewed by the SMC, unblinded to treatment arm, to determine 
whether to dose escalate or modify the study. Complementing the SMC reviews, a 
designated study chair or co-chair may notify the SMC of Grade 4 AEs or deaths, as 
wells as notable Grade 3 AEs among the events that the sites email to the core team per 
section 8.0. An interim review may also be convened if a concern is identified by the 
DAIDS clinical representative, the study chairs, or study statisticians in consultation with 
the team. See also section 10.4 for statistical considerations related to interim 
monitoring. 
 
Detailed plans for study monitoring will be outlined in a Study Monitoring Plan developed 
by the Statistical and Data Management Center prior to enrollment of the first participant. 
 
8.0 
CLINICAL MANAGEMENT ISSUES 
 
The recommendations and toxicity management guidelines within this section should be 
seen as guidelines, and the treating physician should exercise clinical judgment 
regarding best clinical management, based on the symptoms and condition of the 
individual participant. 
 
Criteria for participant management, dose interruption (i.e., withholding doses), and 
treatment discontinuation will be mandated only for toxicities related to cemiplimab 
/placebo. 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. Participants must remain at the clinic for observation for 2 hours following the 
first infusion of cemiplimab/placebo and 30 minutes following the second infusion (see 
section 5.1.2 for cemiplimab/placebo administration instructions). All participants who 
receive at least one infusion, including those participants who have an AE, either related 
or unrelated, are strongly encouraged to stay on study for the duration of the protocol to 
collect potential AE data and may continue study procedures unless clinically 
contraindicated. 
 

 
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The grading system for drug toxicities is located in the Division of AIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events, corrected Version 2.1, July 
2017, which can be found on the DAIDS RSC Web site: https://rsc.niaid.nih.gov/clinical-
research-sites/daids-adverse-event-grading-tables. 
 
The grading system for suspected or confirmed infusion-related reactions, adrenal 
insufficiency, and pneumonitis is listed in sections 8.2, 8.3.4, and 8.3.5, and can also be 
found in the National Cancer Institute’s Table for CTCAE, version 5.0, found on the 
National Cancer Institute Web site: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Q
uick_Reference_5x7.pdf 
 
NOTE A: The core A5370 study team must be notified within 24 hours by email at 
actg.coreA5370@fstrf.org regarding any toxicities considered to be associated 
with cemiplimab/placebo that result in the discontinuation of the infusion.  
 
NOTE B: The core team must be notified within 48 hours by email at 
actg.coreA5370@fstrf.org regarding any Grade 3 or 4 adverse reactions that 
are related to study treatment.  
 
NOTE C: The core team must be notified within 24 hours by email at 
actg.coreA5370@fstrf.org regarding any suspected or confirmed irAE of any 
grade that are considered to be related to study treatment. In such cases, 
cemiplimab/placebo should be withheld. 
 
NOTE D: Should there be any question about whether an AE is considered an irAE, 
sites should withhold cemiplimab/placebo and immediately contact one of the 
protocol chairs (see contact information in Protocol Team Roster on page 6).  
 
NOTE E: For toxicities that cause DISCONTINUATION of cemiplimab/placebo, future 
doses of cemiplimab/placebo should not be given to the participant. Whereas, 
for toxicities that cause WITHHOLDING of cemiplimab/placebo, there is 
potential for continued/future doses to be given once the toxicity(ies) in 
question have been further investigated by site investigator and the study core 
team.  
 
Guidelines for Management of Adverse Events of Special Interest (AESI) 
All participants who receive treatment/placebo on this study should be closely monitored 
for any symptoms or signs related to irAEs including: gastrointestinal (colitis), 
endocrinopathies (hypo- and hyperthyroidism, adrenal insufficiency, hypophysitis, 
diabetes), symptoms or signs suggestive of pneumonitis, myocarditis, hepatitis, uveitis, 
dermatitis, or other irAEs. Such participants must be carefully followed, and managed at 
the first onset of these clinical symptoms. Sites should discuss any potential immune-
related symptom with the A5370 core study team. For example, a high index of  

 
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suspicion for immune-related colitis should be maintained in participants who present 
with diarrhea or other abdominal symptoms, and a high index of suspicion for immune-
related pneumonitis should be maintained in participants who present with respiratory 
symptoms.  
 
Documentation of the immunopathologic nature of a suspected irAE by biopsy 
confirmation should be considered if there is no other clear cause, and/or when 
symptoms are severe or persistent. Discussion with the A5370 core study team prior to 
biopsy or institution of steroid therapy is strongly recommended if feasible. Prompt 
initiation of appropriate therapy should be instituted as outlined in the specific toxicity 
sections of the protocol (sections 8.1-8.6). Additional information is in the IB and a copy 
of the most current version of the IB should be readily available to study and other 
medical personnel following study participants. 
 
Infusions of cemiplimab/placebo should be held in any participant who develops a 
suspected irAE regardless of grade. If the suspected irAE is confirmed as an irAE of any 
grade OR if the suspected irAE cannot be excluded, infusions should be discontinued. If, 
however, the AE is attributed to another cause, then infusions can be continued.   
 
Case Definitions for irAEs 
Based on the emerging safety profile of cemiplimab and other antibodies targeting the 
PD-1/PDL1 axis [53, 54] the following working case definitions are provided to help 
investigators distinguish irAEs from non-immune AEs. These case definitions pertain to 
the more commonly reported irAEs associated with PD-1 inhibition [53, 54] and is not 
exhaustive of all possible irAEs. Clinical presentations of less common irAEs, including 
neurologic, musculoskeletal, cardiac, renal, and ocular events [55, 56] should be 
reviewed in participants with concerning presentations. 
 
The case definitions below have not been validated and are intended only as guidance 
for investigators to help distinguish irAEs from non-immune AEs. Investigators’ clinical 
judgment may include other factors when determining immune-relatedness. The case 
definitions for irAEs may evolve as clinical experience increases with cemiplimab and 
other antibodies targeting the PD-1/PD-L1 axis. 
a. Immune-related rash: Skin examination demonstrates a rash that is usually 
maculopapular, but other presentations may occur, including papulopustular, 
follicular, or urticarial dermatitis. Consider dermatologic consultation and biopsy for 
atypical presentations. Exclude other cause such as virally-induced rash or contact 
dermatitis. 
b. Immune-related diarrhea/colitis: These events are on a continuum, with diarrhea 
defined as increased stool frequency, and colitis involving abdominal pain and/or 
radiologic evidence of colonic inflammation [54]. Onset at 4 to 6 weeks is 
common [53]. A computed tomography (CT) scan usually demonstrates diffuse 
colitis [57]. Exclude clostridium difficile or other infectious etiologies and exclude 
laxative misuse. 
c. Immune-related hepatitis: Laboratory findings are notable for elevated ALT and/or 
AST that is usually asymptomatic. Viral or other drug-induced hepatitis is excluded. 
Exclude alcohol-related liver toxicity. If clinically appropriate, consider radiologic 

 
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imaging to exclude malignant causes.  
d. Immune-related hypothyroidism: Laboratory findings are notable for elevated TSH 
associated with low serum free T4. If elevated TSH is detected, it is recommended 
that free T4 level also be tested. Elevated TSH with low free T4 establishes the 
diagnosis of hypothyroidism. Hypothyroidism may be asymptomatic or associated 
with symptoms such as fatigue, constipation, cold intolerance, dry skin, weight gain, 
and/or bradycardia.  
e. Immune-related hyperthyroidism: Hyperthyroidism should be managed with standard 
antithyroid pharmacotherapy, and consultation with an endocrinologist is 
recommended. 
f. Immune-related pneumonitis: Pneumonitis, defined as inflammation of the lung 
parenchyma, may present as shortness of breath, cough, fever, and/or chest pain. 
Median time from start of anti-PD-1 therapy to onset of pneumonitis is 2.6 months 
[57], but delayed onset of pneumonitis has been reported. The most common 
radiologic pattern on chest CT scan has been described as cryptogenic organizing 
pneumonia, but other radiographic patterns may occur [58]. If performed, biopsy may 
demonstrate lymphocyte-predominant interstitial pneumonitis with areas of 
organizing pneumonia [58]. Exclude infectious causes of pneumonitis. 
  
NOTE: For any severe (Grades 3-4) irAE, if symptoms worsen or do not improve on 
adequate corticosteroids within 48 to 72 hours, consider adding additional 
immunosuppressive agents (to be selected from agents such as: infliximab, 
cyclophosphamide, cyclosporine, mycophenolate mofetil). Referral of the participant to a 
specialized unit for assessment and treatment should be considered. 
 
8.1 
Toxicity 
 
All AESIs must be reported and the study team notified within 24 hours of identification 
(see sections 7.2, 7.3, and 8.0), and include the following:   
• 
Grade 2 or greater infusion-related reactions 
• 
Grade 2 or greater allergic/hypersensitivity reactions 
• 
All immune-related, treatment-related toxicities (irAEs) regardless of grade 
 
8.1.1 Grade 1 or 2 Toxicity 
 
Participants who develop a Grade 1 or 2 AE or toxicity that occurs 
following infusion of cemiplimab/placebo, not specifically discussed below 
nor a possible irAE, and that is associated with symptoms and thought to 
be related to cemiplimab/placebo should be discussed with the study 
team. The site should notify the A5370 core team as soon as possible by 
email at actg.coreA5370@fstrf.org.  
 
Participants who experience a Grade 1 or 2 AE that is judged not to be 
related to the study drug by the investigator, may continue study 
treatment at the discretion of the site investigator.   
 

 
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8.1.2 Grade 3 Toxicity 
 
Participants who develop a Grade 3 AE that occurs following an infusion of 
cemiplimab/placebo not specifically discussed below nor a possible irAE, and 
that is thought to be related to cemiplimab/placebo should be discussed with the 
study team. The A5370 core study team must be notified within 48 hours by 
email at actg.coreA5370@fstrf.org. The participant should be followed closely 
and if the AE does not return to Grade ≤2 within 2 weeks, the study team should 
again be notified within 48 hours by email at actg.coreA5370@fstrf.org. 
 
Participants who experience a Grade 3 AE that is judged not to be related to the 
study drug by the investigator, may continue study participation at the discretion 
of the site investigator in consultation with the study team. 
 
8.1.3 Grade 4 Toxicity 
 
Participants who develop a Grade 4 AE that occurs following an infusion of 
cemiplimab/placebo not specifically discussed below nor a possible irAE, and 
that is judged by the site investigator to be study drug-related, should be 
discussed with the study team. The core team must be notified within 48 hours 
by email at actg.coreA5370@fstrf.org.  
 
All participants experiencing Grade 4 AEs should be followed closely with 
additional clinical assessments and laboratory testing as clinically indicated in 
consultation with the study team. If the AE does not return to Grade ≤2 within 2 
weeks, the study team should again be notified within 48 hours by email at 
actg.coreA5370@fstrf.org. 
 
8.2 
Infusion-related Toxicities and Management  
 
Infusion reactions should be graded according to the criteria for infusion-related reaction 
located in the National Cancer Institute’s Table for CTCAE, version 5.0, found on the 
National Cancer Institute Web site: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Q
uick_Reference_5x7.pdf 
 
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. Severe infusion (Grade 3 or 4) reactions require the 
immediate interruption of study drug. The infusion should not be restarted and no further 
study medication (cemiplimab/placebo) should be given. Appropriate medical therapy 
including epinephrine, corticosteroids, IV antihistamines, bronchodilators, and 
supplemental oxygen should be available for use in the treatment of such reactions. 
Participants should be carefully observed until complete resolution of all signs and 
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institute treatment measures according to the best available medical practice. The core 
study team must be notified within 24 hours by email at actg.coreA5370@fstrf.org 
regarding toxicities associated with cemiplimab/placebo that result in the discontinuation 
of the infusion.  
 
8.2.1 Grade 1: Mild transient reaction; infusion interruption not indicated; intervention 
not indicated.  
 
For participants who develop a Grade 1 AE or toxicity during infusion, it is 
recommended that the study drug infusion rate be decreased by 50% and the 
participant should be monitored closely for any worsening of the initial signs of 
symptoms. If the infusion reaction recurs and/or persists at the decreased rate of 
infusion, the rate of the infusion may be further reduced. The maximum time of 
infusion should not exceed 3 hours (180 minutes). If symptoms persist but do not 
worsen, completion of the cemiplimab/placebo infusion will be at the discretion of 
the site investigator with careful monitoring.  
 
NOTE: Blood draws for PK analysis should be timed to occur within 15 minutes 
after the end of the infusion.  
 
If a participant chooses to discontinue a cemiplimab/placebo infusion, the site 
should notify the A5370 core study team by email at actg.coreA5370@fstrf.org 
and encourage the participant to complete subsequent study visits until the end 
of the study. Refer to section 6.2.5 for discontinuation evaluation instructions. 
 
8.2.2 Grade 2: Moderate reaction; infusion interruption indicated but participant 
responds promptly to symptomatic treatment (e.g., antihistamines, NSAIDS, 
narcotics, IV fluids); prophylactic medications indicated for ≤24 hours.   
 
For participants who develop a Grade 2 AE or toxicity during a 
cemiplimab/placebo infusion, the infusion should be stopped and the core study 
team must be notified within 24 hours by email at actg.coreA5370@fstrf.org. 
Administer epinephrine, corticosteroids, IV antihistamines, bronchodilators, 
and/or supplemental oxygen as medically indicated. At the discretion of the site 
investigator, the infusion may be continued at 50% of the previous infusion rate 
once the adverse reaction has resolved or has decreased to Grade 1 in severity. 
Participant must be monitored closely for any recurrence or worsening or signs or 
symptoms. If the infusion reaction recurs at this rate of infusion, the rate may be 
further reduced, again at the discretion of the site investigator. The maximum 
time of infusion should not exceed 3 hours (180 minutes). 
 
Participants who develop a Grade 2 AE or toxicity during a cemiplimab/placebo 
infusion may complete the infusion at the discretion of the site investigator, with 
careful monitoring. Grade 2 AEs that may be related to cemiplimab/placebo 
should be handled according to standard clinical practice and documented on the 
eCRF.  
 

 
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8.2.3 Grade 3: Prolonged reaction (participant not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion) or recurrence of symptoms 
following initial improvement or hospitalization indicated for clinical sequelae 
 
DISCONTINUE further doses of cemiplimab/placebo. 
 
Participants who develop a Grade 3 AE or toxicity during a cemiplimab/placebo 
infusion should have infusion discontinued immediately and be disconnected 
from the infusion tubing. Administer epinephrine, corticosteroids, IV 
antihistamines, bronchodilators, and/or supplemental oxygen as medically 
indicated. No further study drug treatment should be administered. The core 
study team must be notified within 24 hours by email at 
actg.coreA5370@fstrf.org. 
 
8.2.4 Grade 4: Life-threatening consequences; urgent intervention indicated 
 
DISCONTINUE further doses of cemiplimab/placebo. 
 
Participants who develop a Grade 4 AE or toxicity during a cemiplimab/placebo 
infusion should have infusion discontinued immediately and be disconnected 
from the infusion tubing. Administer epinephrine, corticosteroids, IV 
antihistamines, bronchodilators, and/or supplemental oxygen as medically 
indicated. No further study drug treatment should be administered. The core 
study team must be notified within 24 hours by email at 
actg.coreA5370@fstrf.org. 
 
8.3 
Other Potential AEs/Toxicity 
 
8.3.1 Diarrhea or Colitis  
 
Diarrhea, blood, or mucus in stool, and/or abdominal pain 
A high index of suspicion for immune-related colitis should be maintained in 
participants who present with diarrhea or other abdominal symptoms. The core 
study team must be notified immediately of all suspected cases of immune-
related colitis by email at actg.coreA5370@fstrf.org. 
 
For any suspected or defined immune-related colitis diagnosed following 
cemiplimab/placebo infusion, further doses of the study drug MUST BE 
WITHHELD until the etiology of the colitis is evaluated and determined. 
 
If there is evidence or history supporting a non-cemiplimab/placebo-related 
cause, documentation of this evidence and treatment of the non-
cemiplimab/placebo-related cause should proceed. Routine, comprehensive 
medical assessment of diarrheal illness should be considered including stool 
culture, C. difficile testing as well as appropriate testing for ova and parasites, if 
indicated. 
 

 
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If there is no evidence of a non-cemiplimab-related cause, then manage diarrhea 
or colitis as per grade of severity (DAIDS, corrected version 2.1) as follows: 
 
8.3.1.1 Grade 1: Transient or intermittent episodes of unformed stools OR 
increase of ≤three stools over baseline per 24-hour period 
 
Participants who develop Grade 1 diarrhea should be treated 
symptomatically with medically indicated anti-diarrheal agents but 
without systemic steroids. Participants will continue study procedures as 
per protocol. Routine, comprehensive medical assessment of diarrheal 
illness should be considered including stool culture, C. difficile testing as 
well as appropriate testing for parasitic infestation with ova and parasite 
(O&P) diagnostic studies, if indicated. If above diagnostic tests are 
negative and diarrhea persists for 3 days, then obtain flexible 
sigmoidoscopy and biopsy to evaluate for immune mediated colitis. If 
there is an alternative diagnosis and/or symptoms resolve and the 
participant has not been diagnosed with immune-related colitis, then 
cemiplimab/placebo administration can proceed. 
 
8.3.1.2 Grade 2: Persistent episodes of unformed to watery stools OR increase 
of four to six stools over baseline per 24-hour period 
 
WITHHOLD further doses of cemiplimab/placebo. 
 
Participants who develop Grade 2 diarrhea should be treated 
symptomatically with medically indicated anti-diarrheal agents but 
without systemic steroids and continue study procedures as per 
protocol. If symptoms worsen or do not improve to Grade ≤1 within 1 
week, the following should be completed immediately: 
• 
Stool WBC  
• 
Stool culture 
• 
Clostridium difficile toxin 
• 
Stool O&P (if indicated) 
 
The core study team must be notified within 24 hours by email at 
actg.coreA5370@fstrf.org. 
 
If stool studies reveal an infectious cause, specific treatment for the 
infection should be started. If stool studies are negative and/or 
inconclusive and Grade 2 symptoms persist, obtain endoscopic studies 
and/or abdominal CT scan. If colitis is observed per any diagnostic 
modality or clinically suspected, treatment with systemic corticosteroids 
should be started (recommended: prednisone 60 mg/day orally or 
methylprednisolone 0.5-1 mg/kg/day IV). Discussion with the A5370 
study team prior to performing gastrointestinal biopsy and/or institution 
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If symptoms do not improve or worsen within 3 days of initiating 
steroids, obtain appropriate gastrointestinal or immunologic clinical 
consultation and consider use of high-dose steroids (recommended 
methylprednisolone 1-2 mg/kg/day IV) and taper over 4-6 weeks. 
Discussion with the A5370 study team prior to starting higher doses of 
steroid therapy is strongly recommended. Participants may continue 
study procedures unless clinically contraindicated. 
 
8.3.1.3 Grade 3: Increase of ≥seven stools per 24-hour period OR IV fluid 
replacement indicated 
 
WITHHOLD further doses of cemiplimab/placebo. 
 
Participants who develop Grade 3 diarrhea should have the following 
diagnostic evaluations completed immediately: 
• 
Stool WBC  
• 
Stool culture 
• 
Clostridium difficile toxin 
• 
Endoscopy or abdominal CT scan 
 
The core team must be notified within 24 hours by email at: 
actg.coreA5370@fstrf.org. 
 
If stool studies reveal an infectious cause, treatment for the specific 
infection should be started. If colitis is observed per endoscopy or 
abdominal CT scan or highly clinically suspected and infectious disease 
work-up is negative, appropriate subspecialty clinical consultation 
should be obtained. Discussion with the A5370 study team prior to 
biopsy or institution of systemic steroid therapy is strongly 
recommended. Consider systemic corticosteroids (recommend: 
methylprednisolone 1-2 mg/kg/day IV for 3 days then reduced to 1 
mg/kg/day and taper over at least 1 month [59]). Participants may 
continue study procedures unless clinically contraindicated. 
 
8.3.1.4 Grade 4: Life-threatening consequences (e.g., hypotensive shock) 
 
DISCONTINUE further doses of cemiplimab/placebo. 
 
Participants who develop Grade 4 diarrhea should have the following 
diagnostic studies completed immediately: 
• 
Stool WBC  
• 
Stool culture 
• 
Clostridium difficile toxin 
• 
Endoscopy or abdominal CT scan 
 

 
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The core study team must be notified within 24 hours by email at: 
actg.coreA5370@fstrf.org. 
• 
If stool studies reveal an infectious cause, treatment for specific 
infection should be started. If colitis is observed per endoscopy or 
abdominal CT scan or highly clinically suspected and infectious 
disease work-up is negative, appropriate subspecialty clinical 
consultation should be obtained. Consider systemic corticosteroids 
(recommend: methylprednisolone 1-2 mg/kg/day IV for 3 days, then 
reduced to 1 mg/kg/day and tapered over at least 1 month. 
Discussion with the A5370 study team prior to biopsy or institution 
of systemic steroid therapy is strongly recommended. Participants 
may continue study procedures unless clinically contraindicated. 
 
8.3.2  Suspected Hepatotoxicity  
 
Abnormal AST, ALT, or total bilirubin (if total bilirubin is elevated, direct and 
indirect bilirubin should be obtained).   
 
NOTE: Regarding reporting of suspected hepatotoxicity, the following 
combination of hepatic laboratory results raise significant concern for potentially 
severe DILI and should prompt expedited reporting: an elevated AST and/or ALT 
of Grade 2 (2.5 to <5.0 x ULN) or greater, alkaline phosphatase <2 x ULN and 
bilirubin ≥2 x ULN with no other immediately apparent possible causes of AST or 
ALT elevation and hyperbilirubinemia (such as concomitant use of atazanavir), 
including but not limited to, viral hepatitis, pre-existing chronic or acute liver 
disease, or the administration of other drug(s) known to be hepatotoxic (Hy’s law, 
see Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation Https://www.fda.gov/downloads/Drugs/.../guidances/UCM174090.pdf).   
 
Management of suspected hepatotoxicity should be addressed as outlined 
below. 
 
8.3.2.1 Grade 1: AST or ALT (1.25 to <2.5 x ULN); total bilirubin (1.1 to <1.6 x 
ULN) 
 
Participants who develop Grade 1 elevation in ALT, AST, or total 
bilirubin should have routine monitoring of ALT, AST, and total bilirubin, 
per protocol. If associated symptoms are present, additional work-up 
may be indicated to rule out other etiologies for hepatitis. 
 
8.3.2.2 Grade 2: AST or ALT (2.5 to <5.0 x ULN); total bilirubin (1.6 to <2.6 x 
ULN) 
 
WITHHOLD further doses of cemiplimab/placebo until clinical and 
laboratory evaluation are completed and diagnosis and etiology of the 
symptoms or laboratory abnormalities are defined. 
 

 
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Participants who develop Grade 2 elevation in ALT, AST or total bilirubin 
should have additional labs to rule out non-cemiplimab/placebo-related 
causes of hepatitis.  
 
NOTE: For participants with a Grade 1 elevation in total bilirubin at 
baseline due to atazanavir, additional labs and imaging may not be 
indicated for an isolated Grade 2 total bilirubin elevation in the absence 
of symptoms or ≥two-fold increase in total bilirubin from baseline. 
 
If a non-cemiplimab/placebo-related cause is found, it is important to 
document the supporting scientific evidence for this cause and treat the 
underlying etiology per standard clinical practice.  
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 
• 
Radiographic imaging should be considered to rule out biliary 
obstruction. 
• 
Repeat AST, ALT, total bilirubin, and alkaline phosphatase within 48 
hours (via non-scheduled visit if necessary) 
• 
Follow AST/ALT/total bilirubin/direct bilirubin/albumin/International 
normalized ratio (INR) at least every 3 days until stable or resolving, 
then weekly thereafter until AST and ALT decline to Grade <2, then 
monitor per protocol. 
• 
If any or all AST, ALT, total bilirubin or alkaline phosphatase values 
continue to increase, obtain immediate appropriate subspecialty 
clinical consultation and consider liver biopsy.  
• 
Consider use of corticosteroids (recommended: prednisone 60 
mg/day orally or methylprednisolone 1 mg/kg/day IV). If 
corticosteroids are begun, complete a taper over at least 1 month. 
• 
Discussion with the core study team prior to biopsy or institution of 
corticosteroid therapy is strongly recommended.  
 
8.3.2.3 Grade 3: AST or ALT (5.0 to <10.0 x ULN); total bilirubin (2.6 to <5.0 x 
ULN) with other signs and symptoms of hepatotoxicity 
 
WITHHOLD further doses of cemiplimab/placebo until clinical and 
laboratory evaluation are completed and diagnosis and etiology of the 
symptoms or laboratory abnormalities are defined.  
 
Participants who develop Grade 3 elevations in ALT, AST, or total 
bilirubin should have the following diagnostic evaluations completed as 
soon as possible and within 48 hours after receiving the abnormal 
results: 
• 
Repeat ALT, AST, and total bilirubin 
• 
Additional labs to rule out non-cemiplimab-related causes of 
hepatitis including testing for acute hepatitis A, B, and C, as 
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• 
Repeat ALT/AST/total bilirubin/direct bilirubin/albumin/INR at least 
every 3 days until stable or resolving, then weekly thereafter until 
ALT and AST decline to Grade <2, then monitor per SOE. 
• 
Imaging to rule out biliary obstruction  
• 
Appropriate subspecialty clinical consultation (hepatologist, 
immunologist)  
• 
Consider liver biopsy in consultation with a hepatologist 
• 
Treat with high-dose IV corticosteroids for 24-48 hours 
• 
If transaminase levels do not decrease 48 hours after initiation of 
systemic corticosteroids, oral mycophenolate mofetil 500 mg every 
12 hours may be given. Infliximab is not recommended due to its 
potential for hepatotoxicity.  
• 
When AST/ALT improve to Grade 1 or less, begin a corticosteroid 
taper with prednisone 1-2 mg/kg/day orally or methylprednisolone 1 
mg/kg/day (IV) over no less than 4 weeks. 
 
The core study team must be notified within 24 hours by email at 
actg.coreA5370@fstrf.org. 
 
If a non-cemiplimab/placebo-related cause is found, it is important to 
document the scientific evidence for this conclusion and treat the 
underlying etiology per standard clinical practice.  
 
Discussion with the A5370 study team prior to biopsy or institution of 
corticosteroid therapy is strongly recommended. If corticosteroids are 
begun, complete a taper over at least 1 month. 
 
8.3.2.4 Grade 4: AST or ALT (≥10.0 x ULN); total bilirubin (≥5.0 x ULN) with life-
threatening consequences (e.g., signs and symptoms of liver failure) 
 
DISCONTINUE further doses of cemiplimab/placebo. 
 
Participants who develop Grade 4 elevations in ALT, AST, or total 
bilirubin should have the following diagnostic evaluations completed as 
soon as possible and within 48 hours after receiving the abnormal 
results: 
• 
Repeat AST, ALT, total bilirubin, and alkaline phosphatase  
• 
Appropriate subspecialty clinical consultation (hepatologist, 
immunologist) 
• 
Consider liver biopsy in consultation with a hepatologist 
• 
Additional labs to rule out non-cemiplimab-related causes of 
hepatitis including testing for acute hepatitis A, B and C, as 
appropriate 
• 
Imaging to rule out biliary obstruction  
• 
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• 
Treat with high-dose IV corticosteroids for 24-48 hours 
(recommended: prednisone 240 mg/day orally or 
methylprednisolone 4 mg/kg/day IV). 
• 
If transaminase levels do not decrease 48 hours after initiation of 
systemic corticosteroids, oral mycophenolate mofetil 500 mg every 
12 hours may be given. Infliximab is not recommended due to its 
potential for hepatotoxicity. 
• 
When AST/ALT improve to Grade 1 or less, begin a corticosteroid 
taper with prednisone 1-2 mg/kg/day orally or methylprednisolone 1 
mg/kg/day (IV) over no less than 4 weeks. 
• 
After 48 hours, repeat ALT/AST/total bilirubin/direct 
bilirubin/albumin/INR every 2 to 3 days until AST/ALT decreases to 
≤10x ULN and/or total bilirubin decreases to ≤5x ULN, then repeat 
at least weekly until decline to Grade <2, then resume routine 
monitoring per protocol. 
 
Participants may continue study procedures unless clinically 
contraindicated. 
 
The core study team must be notified within 24 hours by email at 
actg.coreA5370@fstrf.org. Discussion with the team prior to biopsy or 
institution of steroid therapy is strongly recommended.   
 
8.3.3 Suspected Hyperthyroidism or Hypothyroidism   
 
Suspected hyperthyroidism or hypothyroidism are most commonly based on 
clinical symptoms and/or laboratory abnormalities 
 
NOTE: Cases of thyroid dysfunction have typically been identified through routine 
monitoring of laboratories or as part of a work-up for symptoms such as fatigue. 
 
As Grade 1 hypothyroidism and hyperthyroidism are defined per the DAIDS AE 
grading table as asymptomatic, the protocol includes repeat testing for TSH and 
free T4 to allow detection of asymptomatic abnormalities and allow prompt 
detection and management. Criteria for Grade 1 hypothyroidism and 
hyperthyroidism based on laboratory results are as follows: 
 
Grade 1 hypothyroidism is defined as a TSH >4.0 mIU/L (the upper limit of 
normal) in conjunction with a free T4 below the lower limit of normal range of the 
laboratory where testing is performed and are confirmed on a subsequent visit.  
 
Grade 1 hyperthyroidism is defined as a TSH <0.5 mIU/L (lower limit of normal) 
in conjunction with a free T4 result that is above the upper limit of normal of the 
laboratory where testing is performed and are confirmed on a subsequent visit.  
 

 
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The core study team must be notified within 24 hours by email at 
actg.coreA5370@fstrf.org. 
 
8.3.3.1 For suspected hypothyroidism or hyperthyroidism proceed with the 
following: 
• 
WITHHOLD further doses of cemiplimab/placebo until clinical and 
laboratory evaluation are completed and diagnosis and etiology of 
the symptoms or laboratory abnormalities are defined  
• 
Prompt consultation with endocrinology immediately 
• 
If based on asymptomatic TSH or free T4 levels, repeat the TSH 
and free T4 assays, and obtain thyroglobulin and TPO antibodies 
and thyroid stimulating immunoglobulin 
• 
If the participant has symptoms consistent with hypo- or 
hyperthyroidism, obtain TSH and free T4 assays, and obtain 
thyroglobulin and TPO antibodies and thyroid stimulating 
immunoglobulin  
• 
Obtain serum cortisol and/or adrenocorticotropic hormone (ACTH) 
stimulation test if adrenal insufficiency suspected 
 
NOTE: If TSH, free T4 and thyroglobulin and TPO antibodies and 
thyroid stimulating immunoglobulin labs are normal, consider other 
etiologies for the participant’s symptoms. 
 
If any of the above endocrine labs are abnormal, proceed with the 
following: 
• 
Consult endocrinology immediately 
• 
Initiate appropriate hormone replacement to manage 
endocrinopathy in consultation with endocrinologist 
• 
Consider corticosteroids in consultation with endocrinology for 
Grade ≥3 hyperthyroidism 
• 
If evidence of non-cemiplimab/placebo-related cause, it is important 
to document the scientific evidence for and treat the underlying 
cause identified for the symptoms or laboratory abnormalities. 
• 
Continue hormone replacement as needed 
• 
Monitor TSH and free T4 as appropriate, at least every 2 weeks 
• 
Participants may continue study procedures unless clinically 
contraindicated. 
 
8.3.4 Suspected Adrenal Insufficiency/Adrenal Crisis  
 
Suspected adrenal insufficiency or adrenal crisis is most commonly based on 
clinical symptoms and/or laboratory abnormalities 
 
NOTE: Cases have typically been identified through routine monitoring of 
laboratories or as part of a work-up for symptoms such as fatigue, hypotension, 
and shock. 

 
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Adrenal insufficiency should be graded per the National Cancer Institute’s 
CTCAE guidelines as outlined below and available at the NCI Web site: 
  
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCA
E_v5_Quick_Reference_5x7.pdf 
 
NOTE A: It is important to draw labs outlined below at appropriate times; for 
example, serum cortisol and ACTH should be obtained at 8:00 AM if 
feasible and will not delay work-up. 
 
NOTE B: If endocrine labs are normal, consider other etiologies of symptoms. If 
adrenal insufficiency is suspected, WITHHOLD further doses of 
cemiplimab/placebo and proceed with management per Grade of 
severity (see sections 8.3.4.1 to 8.3.4.4).  
 
The core study team must be notified within 24 hours by email at 
actg.coreA5370@fstrf.org. 
 
8.3.4.1 Grade 1: Asymptomatic (clinical or diagnostic observations only; 
intervention not indicated) 
• 
Obtain cortisol level, renin, plasma ACTH, ACTH stimulation test, 
and chemistries 
• 
Obtain TSH and free T4 if fatigue is present or thyroid disorder 
suspected 
• 
If evidence of non-cemiplimab-related cause, treat underlying cause 
and document evidence of non-cemiplimab/placebo-related cause 
• 
If labs are abnormal, consider consulting an endocrinologist   
 
8.3.4.2 Grade 2: Moderate symptoms (medical intervention indicated) 
• 
WITHHOLD further doses of cemiplimab/placebo until clinical and 
laboratory evaluation are completed and diagnosis and etiology of 
the symptoms or laboratory abnormalities are defined 
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 
• 
Obtain serum cortisol level, renin, plasma ACTH, ACTH stimulation 
test, and chemistries  
• 
Obtain TSH, free T4, thyroglobulin, TPO antibodies, and thyroid 
stimulating immunoglobulin if fatigue is present or thyroid disorder 
suspected 
• 
Consult endocrinology immediately 
• 
If any of above labs are abnormal, consider short course of high-
dose steroids (recommend methylprednisolone 1 g/day IV) in 
consultation with an endocrinologist 

 
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8.3.4.3 Grade 3: Severe symptoms (hospitalization indicated) 
• 
WITHHOLD further doses of cemiplimab/placebo until clinical and 
laboratory evaluation are completed and diagnosis and etiology of 
the symptoms or laboratory abnormalities are defined 
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 
• 
Obtain stat labs including serum cortisol, plasma ACTH, ACTH 
stimulation test, TSH, free T4, and if abnormal obtain thyroglobulin 
TPO antibodies, thyroid stimulating immunoglobulin, and 
chemistries 
• 
Consult endocrinology immediately 
• 
Consider hospitalization 
• 
Initiate high dose steroids (recommend methylprednisolone 1 g/day 
IV) in consultation with an endocrinologist 
• 
Rule out sepsis 
• 
If evidence of non-cemiplimab-related cause, treat underlying cause 
and document evidence of non-cemiplimab-related cause 
• 
High dose steroids should be tapered, if used, in consultation with 
an endocrinologist 
• 
Monitor endocrine labs as appropriate 
 
8.3.4.4 Grade 4: Life-threatening consequences (urgent intervention indicated) 
• 
DISCONTINUE cemiplimab/placebo 
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 
• 
Obtain stat labs including serum cortisol, plasma ACTH, ACTH 
stimulation test, TSH, free T4, thyroglobulin, TPO antibodies, 
thyroid stimulating immunoglobulin, and chemistries 
• 
Immediately hospitalize participant 
• 
Consult endocrinology immediately 
• 
Initiate high dose steroids (recommend methylprednisolone 1 g/day 
IV) in consultation with an endocrinologist 
• 
Rule out sepsis 
• 
If evidence of non-cemiplimab/placebo-related cause, treat 
underlying cause and document evidence of non-cemiplimab-
related cause 
• 
High dose steroids should be tapered, if used, in consultation with 
an endocrinologist 
• 
Monitor endocrine labs as appropriate 
 
8.3.5 Suspected Pulmonary Toxicity  
 
New or worsening pulmonary symptoms 
A high index of suspicion for pulmonary toxicity or immune-related pneumonitis 
should be maintained in participants who present with respiratory symptoms. 

 
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Signs and symptoms include dyspnea, cough, hypoxia, and other respiratory 
complaints. The core study team must be notified immediately of all suspected 
cases by email at actg.coreA5370@fstrf.org. For participants who have new or 
worsening pulmonary-related signs or symptoms or radiographic changes, 
radiographic imaging should be obtained/repeated immediately (chest X-ray, 
chest CT, chest CT with pulmonary embolism protocol) if not yet obtained.  
 
For any suspected immune-related pneumonitis, WITHOLD further doses of 
cemiplimab/placebo until diagnostic evaluation has been completed and etiology 
of the signs and symptoms has been determined. 
 
If grading criteria for a particular pulmonary diagnosis or sign/symptom is not 
specifically listed in the Division of AIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events, corrected Version 2.1, July 2017, refer to the 
Estimating Severity Grade section for the “Clinical Adverse Events Not Otherwise 
Identified in the DAIDS AE Grading Table” grading scale. 
 
Of note, pneumonitis should be graded per the National Cancer Institute’s 
CTCAE guidelines as outlined below and available at the NCI Web site: 
  
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCA
E_v5_Quick_Reference_5x7.pdf 
 
The categories listed below are for management of suspected 
cemiplimab/placebo related pulmonary toxicity. 
 
If evaluation provides evidence for a non-cemiplimab/placebo-related cause, it is 
important to document the scientific evidence for and treat per standard clinical 
practice. Participants may continue study procedures unless clinically 
contraindicated. 
 
If there is no evidence of a non-cemiplimab/placebo-related cause, then manage 
respiratory symptoms per category below which best describes changes: 
 
8.3.5.1 Grade 1: Asymptomatic; (clinical or diagnostic observations only; 
intervention not indicated). (Examples: asymptomatic findings on 
physical exam or abnormality on chest X-ray obtained outside of the 
study) 
 
The following steps should be taken: 
• 
WITHHOLD further doses of cemiplimab/placebo until clinical and 
laboratory evaluation are completed and diagnosis and etiology of 
the symptoms or laboratory abnormalities are defined  
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 
• 
Monitor symptoms every 2-3 days 

 
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• 
Pulmonary and ID consultation as clinically indicated 
• 
Consider steroids (recommend: prednisone 60 mg/day orally or 
methylprednisolone 1 mg/kg/day IV) 
• 
Consider empiric antibiotics (if concurrent infection suspected) 
• 
Repeat radiologic assessment within 3 weeks 
 
Re-assess management at least every 3 weeks until resolution, clinical 
stabilization or documented as non-cemiplimab-related cause.   
 
8.3.5.2 Grade 2: Symptomatic; medical intervention indicated; limiting 
instrumental Activities of Daily Living (ADLs) 
 
The following steps should be taken: 
• 
WITHHOLD further doses of cemiplimab/placebo until clinical and 
laboratory evaluation are completed and diagnosis and etiology of 
the symptoms or laboratory abnormalities are defined 
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 
• 
Pulmonary and ID consultation as clinically indicated 
• 
Consider diagnostic BAL or VATS as indicated 
• 
Monitor symptoms daily 
• 
Consider hospitalization 
• 
Treat with moderate-dose steroids (recommend: prednisone 240 
mg/day orally or methylprednisolone 4 mg/kg/day IV) 
• 
Consider empiric antibiotics (if concurrent infection suspected) 
• 
Repeat radiologic assessment  
 
Re-assess management every 1-3 days. If participant stabilizes, 
continue daily monitoring and consideration of other medical 
management as above. If participant improves, begin steroid taper to be 
completed over several weeks.  
 
8.3.5.3 Grade 3: Severe symptoms; limiting self-care; oxygen indicated 
 
The following steps should be taken: 
• 
WITHHOLD further doses of cemiplimab/placebo until clinical and 
laboratory evaluation are completed and diagnosis and etiology of 
the symptoms or laboratory abnormalities are defined 
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 
• 
Hospitalization 
• 
Pulmonary and ID consultation  
• 
Treat with high-dose steroids (recommended methylprednisolone 1 
g/day IV) 
• 
Consider empiric broad spectrum antibiotics (if concurrent infection 
suspected) 

 
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• 
Consider bronchoscopy if clinically feasible 
• 
Consider lung biopsy (via VATS, open-lung, or bronchoscopic 
procedures) 
 
Re-assess management at least daily. If participant is improving, initiate 
steroid taper to be completed over several weeks. If participant is not 
improving after 48 hours or worsening, consider the following: 
• 
Additional immunosuppressive medication (e.g., infliximab, 
mycophenolate mofetil, cyclophosphamide, IVIG) in consultation 
with the core team.  
• 
Additional antibiotics.  
• 
When improving, slow taper of immunosuppression in consultation 
with pulmonologist and core team.  
 
8.3.5.4 Grade 4: Life-threatening respiratory compromise (urgent intervention 
indicated (e.g., tracheotomy or intubation) 
 
The following steps should be taken: 
• 
DISCONTINUE cemiplimab/placebo 
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 
• 
Hospitalization 
• 
Pulmonary and ID consultation 
• 
Treat with high-dose steroids (recommend methylprednisolone 1 
g/day IV) 
• 
Consider empiric broad spectrum antibiotics (if concurrent infection 
suspected) 
• 
Consider bronchoscopy if clinically feasible 
• 
Consider lung biopsy (via VATS, open-lung, or bronchoscopic 
procedures) 
 
Re-assess management at least daily. If participant is improving, initiate 
steroid taper to be completed over several weeks. If participant is not 
improving after 48 hours or worsening, consider the following: 
• 
Additional immunosuppressive medication (e.g., infliximab, 
mycophenolate mofetil, cyclophosphamide, IVIG) in consultation 
with the core team.  
• 
Additional antibiotics. 
• 
When improving, slow taper of immunosuppression in consultation 
with pulmonologist and core team.  
 

 
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8.3.6 Suspected Myocarditis 
 
For participants who have new or worsening signs or symptoms of myocarditis 
(see below), an ECG should be obtained immediately. Signs and symptoms of 
myocarditis include chest pain, rapid or abnormal heart rhythms, shortness of 
breath, and lower extremity edema. For any suspected immune-related cardiac 
toxicity, WITHHOLD further doses of cemiplimab/placebo until diagnostic 
evaluation has been completed and etiology of the signs and symptoms has 
been determined.  
 
Signs and symptoms related to the cardiovascular system other than myocarditis 
(as diagnosed by a cardiologist) should be managed in accordance with standard 
clinical care in conjunction with a cardiologist. 
 
If grading criteria for a particular cardiovascular diagnosis or sign/symptom is not 
specifically listed in the Division of AIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events, corrected Version 2.1, July 2017, refer to the 
Estimating Severity Grade section for the Clinical Adverse Events Not Otherwise 
Identified in the DAIDS AE Grading Table grading scale. 
 
Management of potentially associated ECG abnormalities: 
 
8.3.6.1 Grade 1 Arrhythmia: No symptoms AND no intervention indicated  
• 
WITHHOLD further doses of cemiplimab/placebo until clinical and 
laboratory evaluation are completed and diagnosis and etiology of 
the symptoms or laboratory abnormalities are defined 
• 
Repeat ECG within 24 hours of notification 
• 
Consult cardiologist 
• 
Consider systemic corticosteroids (starting with 1 mg/kg prednisone 
orally or equivalent once per day or dexamethasone 4 mg orally 
once daily for 4 days; when symptoms improve, steroid taper should 
be started and continued over no less than 4 weeks in consultation 
with a cardiologist) 
 
8.3.6.2 Grade 2 Arrhythmia: No symptoms AND non-urgent intervention 
indicated  
• 
WITHHOLD further doses of cemiplimab/placebo until clinical and 
laboratory evaluation are completed and diagnosis and etiology of 
the symptoms or laboratory abnormalities are defined 
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 

 
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• 
Consult cardiologist immediately 
• 
Consider systemic corticosteroids (starting with 1 mg/kg prednisone 
or equivalent once per day or dexamethasone 4 mg orally once daily 
for 4 days; when symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks in 
consultation with a cardiologist) 
 
8.3.6.3 Grade 3 Arrhythmia: Non-life-threatening symptoms AND non-urgent 
intervention indicated  
WITHHOLD further doses of cemiplimab/placebo until clinical and 
laboratory evaluation are completed and diagnosis and etiology of the 
symptoms or laboratory abnormalities are defined 
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 
• 
Consult cardiologist immediately 
• 
Treat with moderate-dose steroids (recommend prednisone 240 
mg/day orally or methylprednisolone 4 mg/kg/day IV); when 
symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks in consultation with 
a cardiologist 
• 
If no significant response to initial corticosteroid treatment, consider 
high-dose corticosteroids (recommended methylprednisolone 1 
g/day IV); if high-dose corticosteroids used, they should be tapered 
in consultation with a cardiologist 
 
8.3.6.4 Grade 4 Arrhythmia: Life-threatening arrhythmia OR Urgent intervention 
indicated  
• 
WITHHOLD further doses of cemiplimab/placebo 
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 
• 
Immediate hospitalization 
• 
Consult cardiologist immediately 
• 
Treat with high-dose steroids (recommended methylprednisolone 1 
g/day IV) in consultation with a cardiologist 
• 
High-dose corticosteroids should be tapered in consultation with a 
cardiologist 
 
8.3.6.5 Grade 1 Heart Failure: No symptoms AND laboratory or cardiac imaging 
abnormalities  
• 
Consult cardiologist immediately 
• 
Repeat ECG within 24 hours of notification 
• 
Obtain echocardiogram 

 
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• 
Consider systemic corticosteroids (starting with 1 mg/kg prednisone 
or equivalent once per day or dexamethasone 4 mg orally once daily 
for 4 days); when symptoms improve, steroid taper should be started 
and continued over no less than 4 weeks in consultation with a 
cardiologist. 
• 
Proceed with standard of care diagnostics and management for new 
onset heart failure 
 
8.3.6.6 Grade 2 Heart Failure: Symptoms with mild to moderate activity or 
exertion  
• 
WITHHOLD further doses of cemiplimab/placebo until clinical and 
laboratory evaluation are completed and diagnosis and etiology of 
the symptoms or laboratory abnormalities are defined 
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 
• 
Consult cardiologist immediately 
• 
Initiate systemic corticosteroids (starting with 1 mg/kg prednisone or 
equivalent once per day or dexamethasone 4 mg orally once daily 
for 4 days); when symptoms improve, steroid taper should be started 
and continued over no less than 4 weeks in consultation with a 
cardiologist. 
• 
If no response to initial corticosteroids, consider moderate dose 
steroids (recommend: prednisone 240 mg/day orally or 
methylprednisolone 4 mg/kg/day IV); when symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks in consultation with a cardiologist. 
• 
Repeat ECG within 24 hours notification 
• 
Obtain echocardiogram  
• 
Proceed with standard of care diagnostics and management for new 
onset heart failure 
 
8.3.6.7 Grade 3 Heart Failure: Symptoms at rest or with minimal activity or 
exertion (e.g., hypoxemia) OR intervention indicated (e.g., oxygen)  
• 
WITHHOLD further doses of cemiplimab/placebo until clinical and 
laboratory evaluation are completed and diagnosis and etiology of 
the symptoms or laboratory abnormalities are defined 
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 
• 
Consult cardiologist immediately 
• 
Initiate moderate dose steroids (recommend prednisone 240 mg/day 
orally or methylprednisolone 4 mg/kg/day IV); when symptoms 
improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks in consultation with a 
cardiologist. 

 
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• 
If no response to initial corticosteroids, consider high-dose steroids 
(recommended methylprednisolone 1 g/day IV) in consultation with a 
cardiologist 
• 
Repeat ECG within 24 hours notification 
• 
Obtain echocardiogram  
• 
Proceed with standard of care diagnostics and management for new 
onset heart failure 
 
8.3.6.8 Grade 4 Heart Failure: Life-threatening consequences OR urgent 
intervention indicated (e.g., vasoactive medications, ventricular assist 
device, heart transplant)  
• 
DISCONTINUE further doses of cemiplimab/placebo 
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 
• 
Consult cardiologist immediately 
• 
Initiate high-dose steroids (recommended methylprednisolone 1 
g/day IV) in consultation with a cardiologist 
• 
Repeat ECG within 24 hours notification 
• 
Obtain echocardiogram  
• 
Proceed with standard of care diagnostics and management for new 
onset heart failure 
 
8.3.7 Suspected Immune-related Renal Dysfunction 
 
For participants with worsening renal function, the following should be obtained: 
repeat BUN, serum creatinine, and serum electrolytes within 48 hours of the first 
abnormal value. For any suspected immune-related renal toxicity, WITHHOLD 
further doses of cemiplimab/placebo until diagnostic evaluation has been 
completed and etiology of the signs and symptoms has been determined. 
 
NOTE: The DAIDS AE Grading Table, corrected Version 2.1, July 2017, for 
grading creatinine should be used, and can be found on the DAIDS RSC website 
at https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-
tables. 
 
8.3.7.1 Grade 1 Creatinine Abnormality: Serum creatinine of 1.1 to 1.3 x ULN 
• 
WITHHOLD further doses of cemiplimab/placebo until clinical and 
laboratory evaluation are completed and diagnosis and etiology of 
the symptoms or laboratory abnormalities are defined 
• 
Ensure participant is well-hydrated and repeat serum creatinine 
• 
Obtain urinalysis, erythrocyte sedimentation rate (ESR), complement 
levels (C3, C4, CH50), anti-DNA levels, and antineutrophil 
cytoplasmic antibody (ANCA)  
• 
Monitor serum creatinine weekly until it returns to <1.1 x ULN 
 

 
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8.3.7.2 Grade 2 Creatinine Abnormality: Serum creatinine of >1.3 to 1.8 x ULN 
OR increase to 1.3 to <1.5 x participant’s baseline 
• 
WITHHOLD further doses of cemiplimab/placebo until clinical and 
laboratory evaluation are completed and diagnosis and etiology of 
the symptoms or laboratory abnormalities are defined 
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 
• 
Ensure participant is well-hydrated and repeat serum creatinine 
• 
Obtain urinalysis, erythrocyte sedimentation rate (ESR), complement 
levels (C3, C4, CH50), anti-DNA levels, and antineutrophil 
cytoplasmic antibody (ANCA)  
• 
Monitor serum creatinine every 72 hours  
• 
Consider renal ultrasound and 24 hour urine studies 
• 
Consider consulting nephrologist 
• 
Consider systemic corticosteroids (starting with 1 mg/kg prednisone 
or equivalent once per day or dexamethasone 4 mg orally once daily 
for four days); when creatinine improves to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks in 
consultation with a nephrologist. 
 
8.3.7.3 Grade 3 Creatinine Abnormality: >1.8 to <3.5 x ULN OR increase to 1.5 
to <2.0 x participant’s baseline 
• 
WITHHOLD further doses of cemiplimab/placebo until clinical and 
laboratory evaluation are completed and diagnosis and etiology of 
the symptoms or laboratory abnormalities are defined 
• 
Consult nephrologist immediately 
• 
Obtain urinalysis, erythrocyte sedimentation rate (ESR), complement 
levels (C3, C4, CH50), anti-DNA levels, and antineutrophil 
cytoplasmic antibody (ANCA)  
• 
Monitor creatinine every 72 hours  
• 
Obtain renal ultrasound and 24 hour urine studies 
• 
Initiate moderate-dose steroids (recommend prednisone 240 mg/day 
orally or methylprednisolone 4 mg/kg/day IV); when creatinine 
improves to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks in consultation with a 
nephrologist. 
• 
If no response to initial corticosteroids, consider high-dose steroids 
(recommended methylprednisolone 1 g/day IV) in consultation with a 
nephrologist; high-dose corticosteroids should be tapered, if used, in 
consultation with a nephrologist. 
 
8.3.7.4 Grade 4 Creatinine Abnormality: ≥3.5 x ULN OR increase of ≥2.0 x 
participant’s baseline 
• 
WITHHOLD further doses of cemiplimab/placebo until clinical and 
laboratory evaluation are completed and diagnosis and etiology of 
the symptoms or laboratory abnormalities are defined 

 
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• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 
• 
Consult nephrologist immediately 
• 
Obtain urinalysis, erythrocyte sedimentation rate (ESR), complement 
levels (C3, C4, CH50), anti-DNA levels, and antineutrophil 
cytoplasmic antibody (ANCA)  
• 
Monitor creatinine every 72 hours  
• 
Obtain renal ultrasound and 24 hour urine studies 
• 
Initiate high-dose steroids (recommended methylprednisolone 1 
g/day IV) in consultation with a nephrologist; high-dose 
corticosteroids should be tapered, if used, in consultation with a 
nephrologist. 
 
8.3.8 Suspected Immune-related Neurologic Dysfunction  
 
8.3.8.1 Grades 1-4 Altered mental status, neuromuscular weakness, or seizures 
• 
WITHHOLD further doses of cemiplimab/placebo until clinical and 
laboratory evaluation are completed and diagnosis and etiology of 
the symptoms or laboratory abnormalities are defined 
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 
• 
Perform appropriate diagnostics which may include but are not 
limited to imaging with MRI with contrast of affected region and CSF 
sampling 
• 
Hospitalization as per standard of care 
• 
Consult neurologist immediately 
• 
Initiate systemic corticosteroids in consultation with a neurologist 
• 
High-dose corticosteroids should be tapered, if used, in consultation 
with a neurologist. 
 
8.3.8.2 Grades 1 and 2 Headache or Neurosensory Alteration 
 
(See DAIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events, corrected Version 2.1, July 2017, which can be found 
on the DAIDS RSC Web site https://rsc.niaid.nih.gov/clinical-research-
sites/daids-adverse-event-grading-tables). 
• 
Monitor participant as outpatient daily for 72 hours for worsening or 
improvement of headache or neurosensory alteration. 
• 
Consider consultation with a neurologist 
 
8.3.8.3 Grades 3 and 4 Headache or Neurosensory Alteration 
• 
WITHHOLD further doses of cemiplimab/placebo until clinical and 
laboratory evaluation are completed and diagnosis and etiology of 
the symptoms or laboratory abnormalities are defined 
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 

 
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• 
Perform appropriate diagnostics which may include but are not 
limited to imaging with MRI with contrast of affected region and CSF 
sampling 
• 
Hospitalization as per standard of care 
• 
Consult neurologist immediately 
• 
Initiate systemic corticosteroids (e.g., hydrocortisone) in consultation 
with a neurologist 
• 
High dose corticosteroids should be tapered, if used, in consultation 
with a neurologist. 
 
8.3.9 Suspected Development of Diabetes 
 
8.3.9.1 Development of hyperglycemia meeting the diagnosis of diabetes (see 
below) of any grade is considered an immune mediated adverse event 
and results in the discontinuation of any further infusions. 
 
(See DAIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events, corrected Version 2.1, July 2017, which can be found 
on the DAIDS RSC Web site: https://rsc.niaid.nih.gov/clinical-research-
sites/daids-adverse-event-grading-tables) 
 
The diagnosis of diabetes for this study is made on the basis of one of 
the following criteria: 
 
1. HgbA1c ≥6.5%. This lab is drawn at screening only. The test should 
be performed using CLIA-certified laboratory standard methods.* 
OR 
2. Fasting plasma glucose ≥126 mg/dl (7.0 mmol/l) measured from any 
fasting lab draw during screening or post-screening. Fasting is 
defined as no caloric intake for at least 8 hours.* 
 
OR 
 
3. Two-hour plasma glucose ≥200 mg/dl (11.1 mmol/l) during an oral 
glucose tolerance test. The test should be performed as described 
by the WHO, using a glucose load containing the equivalent of 75 g 
anhydrous glucose dissolved in water.* 
 
OR 
 
4. In a participant with classic symptoms of hyperglycemia or 
hyperglycemic crisis (polyuria, polydipsia, blurred vision, confusion, 
nausea/vomiting, disesthesias), or in labs drawn in a non-fasting 
participant for other study reasons, a random plasma glucose ≥200 
mg/dl (11.1 mmol/l). 
 

 
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8.3.9.2 Grades 1-4 Diabetes 
• 
DISCONTINUE further doses of cemiplimab/placebo 
• 
*In the absence of unequivocal hyperglycemia, criteria 1-3 (above) 
should be confirmed by repeat testing with preference given to a 
repeat fasting blood glucose level 
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org when a diagnosis of diabetes is suspected 
or confirmed 
• 
New onset diabetes of any grade should be managed with the 
assistance of an endocrinologist who may order additional, 
confirmatory testing (i.e., oral glucose tolerance testing). 
 
8.4 
Suspected Ocular Toxicity  
 
New or worsening eye symptoms 
A high index of suspicion for ocular toxicity or immune-related uveitis should be 
maintained in participants who present with eye or visual symptoms. The core team 
must be notified immediately of all suspected cases of uveitis by e-mail at 
actg.coreA5370@fstrf.org.   
 
For participants who have new or worsening ocular signs or symptoms, ophthalmologic 
evaluation should be obtained immediately. Signs and symptoms include eye pain, 
redness, irritation, swelling of the eye and conjunctiva, and changes in vision.  
 
All grades, signs and symptoms related to the eye other than uveitis (as diagnosed by 
an ophthalmologist) should be managed in accordance with standard clinical care in 
conjunction with an ophthalmologist. 
 
If grading criteria for a particular ocular diagnosis or sign/symptom is not specifically 
listed in the Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events, corrected Version 2.1, July 2017, refer to the Estimating Severity Grade 
section for the “Clinical Adverse Events Not Otherwise Identified in the DAIDS AE 
Grading Table” grading scale. 
 
8.4.1 Grade 1 Uveitis: Asymptomatic but detectable on exam. 
• 
DISCONTINUE further doses of cemiplimab/placebo if uveitis confirmed by 
ophthalmologist 
• 
Immediately contact the core team via email at actg.coreA5370@fstrf.org 
• 
Consult ophthalmologist for examination of the conjunctiva, anterior and 
posterior chambers, and retina 
• 
Consider topical steroids such as 1% prednisolone acetate suspension and 
iridocyclitics in consultation with an ophthalmologist 
 
8.4.2 Grade 2 Uveitis: Symptomatic anterior uveitis or medical intervention indicated. 
• 
DISCONTINUE further doses of cemiplimab/placebo 
• 
Immediately contact the core team via email at actg.coreA5370@fstrf.org 

 
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• 
Consult ophthalmologist immediately 
• 
Treat with topical corticosteroids such as 1% prednisolone acetate 
suspension and iridocyclitics in consultation with an ophthalmologist 
• 
Consider systemic corticosteroids if symptoms do not improve within 3-5 days 
in consultation with an ophthalmologist, (starting with 1 mg/kg prednisone or 
equivalent once per day or dexamethasone 4 mg orally once daily for 4 days) 
 
8.4.3 Grade 3 Uveitis: Posterior or pan-uveitis OR operative intervention indicated. 
• 
DISCONTINUE further doses of cemiplimab/placebo 
• 
Immediately contact the core team via email at actg.coreA5370@fstrf.org 
• 
Consult ophthalmologist immediately 
• 
Consider systemic corticosteroids (starting with 1 mg/kg prednisone or 
equivalent once per day or dexamethasone 4 mg orally once daily for 4 
days); when symptoms improve, steroid taper should be started and 
continued over no less than 4 weeks in consultation with an ophthalmologist.  
• 
If no response to initial systemic corticosteroids, consider moderate-dose 
steroids (recommend prednisone 240 mg/day orally or methylprednisolone 4 
mg/kg/day IV). When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks in consultation 
with an ophthalmologist.  
• 
If evidence of non-cemiplimab/placebo-related cause, treat underlying cause 
and document evidence of non-cemiplimab/placebo-related cause 
 
8.4.4 Grade 4 Uveitis: Disabling visual loss in affected eye(s). 
• 
DISCONTINUE cemiplimab/placebo 
• 
Immediately contact the core team via email at actg.coreA5370@fstrf.org 
• 
Consult ophthalmologist immediately 
• 
Initiate high-dose corticosteroids (recommended methylprednisolone 1 g/day 
IV) in consultation with an ophthalmologist; high-dose corticosteroids should 
be tapered, if used, in consultation with an ophthalmologist 
• 
If evidence of non-cemiplimab/placebo-related cause, treat underlying cause 
and document evidence of non-cemiplimab/placebo-related cause 
 
8.5 
Suspected Dermatologic Toxicity 
 
New or worsening dermatologic signs or symptoms 
A high index of suspicion for dermatologic toxicity or immune-related dermatitis should 
be maintained in participants who present with skin-related signs and/or symptoms. The 
core team must be notified immediately of all suspected cases of suspected immune-
related dermatitis by e-mail at actg.coreA5370@fstrf.org.  
 
Dermatologic toxicity is the most common irAE associated with checkpoint inhibitors. 
Approximately 50% of patients treated with ipilimumab experience rash and/or pruritus, 
and approximately 30% to 40% of those treated with nivolumab or pembrolizumab will 
have dermatologic complications [28]. For most patients, dermatologic toxicity is the 
earliest irAE experienced, with onset an average of 3.6 weeks after treatment initiation 

 
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[59]. Typical physical examination findings consist of a reticular, maculopapular, faintly 
erythematous rash on the trunk or extremities. Vitiligo is also seen commonly [60]. Oral 
mucositis and/or complaints of dry mouth appear to be more frequent with PD-1 receptor 
checkpoint inhibitors than with CTLA-4 blockade. In the phase I study of nivolumab; this 
was observed in 6.5% of patients, including one case with Grade 3 toxicity [61].  
 
The types of suspected skin-related AEs include but are not limited to the following: 
exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, and TEN. 
 
For participants who have new or worsening dermatologic signs or symptoms, prompt 
dermatologic consultation should be obtained immediately [62, 63]. 
 
8.5.1 Grade 1 Dermatitis: Macules/papules covering <10% body surface area (BSA) 
with or without symptoms (e.g., pruritus, burning, tightness) 
• 
Consult dermatologist for examination of the affected skin  
• 
Symptomatic treatment should be given in consultation with the dermatologist 
such as topical corticosteroids (e.g., betamethasone 0.1% cream or 
hydrocortisone 1%) or urea-containing creams in combination with oral 
antipruritics (e.g., diphenhydramine HCl or hydroxyzine HCl). 
 
8.5.2 Grade 2 Dermatitis: Macules/papules covering 10%-30% BSA with or without 
symptoms (e.g., pruritus, burning, tightness); limiting instrumental ADLs 
• 
WITHHOLD further doses of cemiplimab/placebo until clinical and laboratory 
evaluation are completed and diagnosis and etiology of the symptoms or 
laboratory abnormalities are defined 
• 
Immediately contact the core team via email at actg.coreA5370@fstrf.org 
• 
Consult dermatologist immediately 
• 
Symptomatic treatment should be given such as topical corticosteroids (e.g., 
betamethasone 0.1% cream or hydrocortisone 1%) or urea-containing 
creams in combination with oral antipruritics (e.g., diphenhydramine HCl or 
hydroxyzine HCl) 
• 
Consider systemic corticosteroids if symptoms do not improve within 3-5 days 
(starting with 1 mg/kg prednisone or equivalent once per day or 
dexamethasone 4 mg orally once daily for 4 days). When symptoms improve, 
steroid taper should be started and continued over no less than 4 weeks in 
consultation with a dermatologist 
 
8.5.3 Grade 3 Dermatitis: Macules/papules covering >30% BSA with or without 
associated symptoms; limiting self-care ADLs 
• 
WITHHOLD further doses of cemiplimab/placebo until clinical and laboratory 
evaluation are completed and diagnosis and etiology of the symptoms or 
laboratory abnormalities are defined 
• 
Immediately contact the core team via email at actg.coreA5370@fstrf.org 
• 
Consult dermatologist immediately and biopsy skin lesions for confirmation of 
diagnosis. 
• 
Treatment with moderate-dose oral corticosteroids is recommended 

 
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(prednisone 240 mg/day orally or methylprednisolone 4 mg/kg/day IV). When 
symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks in consultation with a dermatologist. 
• 
If evidence of non-cemiplimab/placebo-related cause, treat underlying cause 
and document evidence of non-cemiplimab/placebo-related cause 
 
8.5.4 Grade 4 Dermatitis: Stevens-Johnson Syndrome, TEN defined as skin sloughing 
covering with associated signs (e.g., erythema, purpura epidermal detachment, 
and/or mucous membrane detachment) 
• 
DISCONTINUE further doses of cemiplimab/placebo 
• 
Immediately contact the core team via email at actg.coreA5370@fstrf.org 
• 
Consult dermatologist immediately and biopsy skin lesions for confirmation of 
diagnosis 
• 
Initiate high-dose corticosteroids (recommend methylprednisolone 1 g/day 
IV); when symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks in consultation with a 
dermatologist  
• 
If evidence of non-cemiplimab/placebo-related cause, treat underlying cause 
and document evidence of non-cemiplimab-related cause 
 
8.6 
Suspected Hematologic Toxicity 
 
8.6.1 Thrombocytopenia 
 
8.6.1.1 Grade 1 Platelet Count: 100,000 to <125,000/mm3 
• 
No change in cemiplimab/placebo dose 
 
8.6.1.2  Grade 2 Platelet Count: 50,000 to <100,000/mm3 
• 
WITHHOLD further doses of cemiplimab/placebo until clinical and 
laboratory evaluation are completed and diagnosis and etiology of 
the symptoms or laboratory abnormalities are defined 
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 
• 
Consider systemic corticosteroids (starting with 1 mg/kg prednisone 
or equivalent once per day or dexamethasone 4 mg orally once daily 
for 4 days); when symptoms improve, steroid taper should be started 
and continued over no less than 4 weeks in consultation with a 
hematologist 
 
8.6.1.3  Grade 3 Platelet Count: 25,000 to <50,000/mm3 
• 
WITHHOLD further doses of cemiplimab/placebo until clinical and 
laboratory evaluation are completed and diagnosis and etiology of 
the symptoms or laboratory abnormalities are defined 
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 
• 
Consult a hematologist 

 
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• 
Treatment with moderate-dose oral corticosteroids is recommended 
(prednisone 240 mg/day orally or methylprednisolone 4 mg/kg/day 
IV); when symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks in 
consultation with a hematologist  
 
8.6.1.4  Grade 4 Platelet Count: <25,000/mm3 
• 
DISCONTINUE cemiplimab/placebo 
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 
• 
Consult a hematologist 
• 
Initiate high-dose corticosteroids (recommend methylprednisolone 1 
g/day IV); when symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks in 
consultation with a hematologist  
 
8.6.2 Neutropenia 
 
8.6.2.1  Grade 1 Absolute Neutrophil Count (ANC): 800 to 1000/mm3 
• 
No change in cemiplimab/placebo dose  
 
8.6.2.2 Grade 2 ANC of 600 to 799/mm3 
• 
WITHHOLD further doses of cemiplimab/placebo until clinical and 
laboratory evaluation are completed and diagnosis and etiology of 
the symptoms or laboratory abnormalities are defined 
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 
• 
Consider systemic corticosteroids (starting with 1 mg/kg prednisone 
or equivalent once per day or dexamethasone 4 mg orally once daily 
for 4 days); when symptoms improve, steroid taper should be started 
and continued over no less than 4 weeks in consultation with a 
hematologist 
• 
Participants may continue study procedures and 
cemiplimab/placebo unless clinically contraindicated 
 
8.6.2.3 Grade 3 ANC of 400 to 599/mm3  
• 
DISCONTINUE further doses of cemiplimab/placebo 
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 
• 
Consult a hematologist 
• 
Treatment with moderate-dose oral corticosteroids is recommended 
(prednisone 240 mg/day orally or methylprednisolone 4 mg/kg/day 
IV); when symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks in 
consultation with a hematologist. 
 

 
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8.6.2.4 Grade 4 ANC of <400 cells/mm3 
• 
DISCONTINUE further doses of cemiplimab/placebo 
• 
Immediately contact the core team via email at 
actg.coreA5370@fstrf.org 
• 
Consult a hematologist 
• 
Initiate high-dose corticosteroids (recommend methylprednisolone 1 
g/day IV); when symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks in 
consultation with hematologist  
 
8.7 
Virologic Failure  
 
If two consecutive plasma HIV-1 RNA ≥200 copies/mL are resulted at any time on study, 
the participant will be considered to have virologic failure. Adherence to antiretroviral 
therapy should be carefully assessed.  
 
If the participant discontinues ART before the first infusion, the first infusion should not 
be given and the participant can end the study prematurely. 
 
If the participant discontinues ART after the first infusion but before the second infusion, 
the second infusion should not be given but the participant should continue on study for 
safety follow-up, assessment of PK and RO as noted in the SOE. Stored plasma/PBMC 
for immunologic studies, stored plasma for SCA and samples for CD4+ T cell-associated 
HIV-1 RNA, DNA, and 2-LTR do not need to be obtained.  
 
If the participant is adherent to ART, then ART should be managed by the site 
investigator and primary care provider in discussion with the A5370 core team 
(actg.coreA5370@fstrf.org), and all study evaluations should proceed as scheduled. 
 
8.8 
Pregnancy 
 
If pregnancy is suspected in a woman on study after receiving cemiplimab/placebo, then 
a pregnancy test should be obtained. Confirmed pregnancy will result in immediate 
discontinuation of the study medication and initiation of counseling regarding the lack of 
information on safety of cemiplimab in pregnancy. Participants who become pregnant 
while on study should contact the site to schedule an unplanned study visit and will be 
followed on study/off-treatment until study completion. Male participants whose partners 
become pregnant will continue treatment as outlined in the SOE. 
 
Pregnant women should be encouraged to continue on study (off study medication) for 
safety follow-up, and assessment of PK and RO as noted in the SOE. Stored 
plasma/PBMC for immunologic studies, stored plasma for SCA and samples for CD4+ T 
cell-associated HIV-1 RNA, DNA, and 2-LTR should not be obtained to minimize blood 
volume. 
 

 
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Pregnancy Outcomes and Reporting 
Pregnancy outcomes will be submitted on an outcome eCRF at the end of the 
pregnancy and again at 6 months following the end of pregnancy.   
 
If a woman has completed the study or chooses to discontinue from the study before the 
end of the pregnancy, then site staff should request permission to contact her regarding 
pregnancy outcomes at the end of pregnancy. If the information is obtained, pregnancy 
outcomes will be submitted on an eCRF at the end of the pregnancy. 
 
Sites must collect and record information on pregnancy complications and outcome for 
all pregnancies that occur during study follow-up.  
 
Pregnancies that occur on study should be reported prospectively to The Antiretroviral 
Pregnancy Registry. More information is available at www.apregistry.com. Telephone: 
800-258-4263; Fax: 800-800-1052. (For studies conducted at sites outside the United 
States, report to The Antiretroviral Pregnancy Registry—Telephone: 910-679-1598; Fax: 
44-1628-789-666 or 910-256-0637.) 
 
9.0 
CRITERIA FOR DISCONTINUATION 
 
9.1 
Permanent and Premature Treatment Discontinuation 
 
Study treatment is two single infusions of cemiplimab (anti-PD-1 antibody) or placebo. 
Study treatment should be discontinued for: 
• 
Drug-related toxicity (see section 8.1) 
• 
A Grade 3 or 4 infusion reaction occurs (see section 8.2) 
• 
Discontinuation of ART 
• 
Requirement for prohibited concomitant medications (see section 5.4) 
• 
Pregnancy or breastfeeding 
• 
Request by participant to terminate treatment 
• 
Clinical reasons believed life-threatening by the physician, even if not addressed in 
section 8.1 of the protocol 
• 
Positive results for antibodies to TPO, GAD65/GAD or islet cell antigen  
• 
An irAE of any grade occurs 
• 
Prolonged need (>7 days) for systemic steroids 
 
NOTE A: Participants who receive one infusion but for whom treatment was 
discontinued prematurely will be followed on study off treatment per the 
schedule of events. 
 
NOTE B: If the study participant experiences an irAE after the first infusion of 
cemiplimab/placebo at entry, study treatment should be discontinued (i.e., the 
participant would not receive the second infusion). 
 

 
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9.2 
Premature Study Discontinuation 
 
A primary goal of this study is to assess the safety of two single infusions of 
cemiplimab/placebo. Therefore, every effort should be made to retain participants on 
study to assess safety outcomes. Participants should discontinue study if: 
• 
Request by the participant to withdraw 
• 
At the discretion of the IRB/EC, FDA, NIAID, Office for Human Research Protections 
(OHRP), other government agencies as part of their duties, investigator, or industry 
supporter 
 
10.0 
STATISTICAL CONSIDERATIONS  
 
10.1 
General Design Issues 
 
A5370 is a phase I/II, double-blinded (within each cohort), dose-escalating, placebo-
controlled study of the safety and immunotherapeutic activity of two infusions of anti-PD-
1 (cemiplimab) in HIV-1-infected participants on cART who have HIV-1 RNA below the 
limit of quantification and CD4+ T-cell counts ≥350/mm3. Each participant will be 
followed for 48 weeks, with frequent visits in the first 12 weeks. The decision to enroll 
into each successively higher dose cohort will be based on review of the safety data 
seen in participants who received cemiplimab or placebo doses in the previous dose 
cohorts (see sections 7.4 and 10.4.1). Accrual for each dose cohort is anticipated to take 
3-4 months. Taking into account the time needed for data review regarding dose 
escalation between each cohort (data entry, core team review, SMC report generation, 
and SMC review) and assuming that all three cohorts complete enrollment, the total time 
to complete accrual is expected to be about 20 months. This may take longer if 
participant replacements are needed. Laboratory assays and study analyses may 
commence, and findings reported, after each cohort has completed accrual and follow-
up through the week 12 visit. 
 
10.2 
Outcome Measures 
 
Primary and secondary outcome measures listed below will be addressed in the study’s 
primary Statistical Analysis Plan, which will define the content of the Primary Analysis 
Report. This report will form the basis for the primary study manuscript and results 
reporting to ClinicalTrials.gov. Outcomes of interest for exploratory objectives or for 
secondary objectives intended for subsequent publications are listed under Exploratory 
Outcome Measures. 
 
10.2.1 Primary Outcome Measures  
 
10.2.1.1 Safety 
 
Occurrence of a Grade ≥3 AE, or Grade ≥1 irAE (such as, but not 
limited to, pneumonitis, colitis, adrenal insufficiency, or 
hypothyroidism), that is related to study treatment (as judged by the 

 
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core team, blinded to treatment arm) any time from study treatment 
administration through the week 48 visit. 
 
10.2.2 Secondary Outcome Measures 
 
10.2.2.1 Frequency of HIV-1 gag-specific CD8+ T cells by intracellular staining 
for CD107a and IFN-γ  at baseline and through week 12 
 
10.2.2.2 Frequency of HIV-1 gag-specific CD8+ T cells by intracellular staining 
for CD107a and IFN-γ  at baseline, after the first dose (average of 
weeks 2-6) and after the second dose (average of weeks 8-12) 
 
10.2.2.3 Frequency of HIV-1 gag-specific CD8+ T cells by intracellular staining 
for IFN-γ or CD107a alone at baseline and through week 12 
 
10.2.2.4 Polyfunctional response of HIV-1 gag-specific CD8+ T cells by 
intracellular staining for IFN-γ, CD107a, IL-2, and TNFα at baseline 
and through week 12 
 
10.2.3 Exploratory Outcome Measures 
 
10.2.3.1 Total HIV-1 DNA, cell-associated HIV-1 RNA and RNA/DNA ratios in 
CD4+ T cells, and plasma HIV RNA by SCA at baseline, prior to the 
second infusion at week 6, and also at week 12 
 
10.2.3.2 Gene array analysis 
 
10.2.3.3 Intact proviral HIV-1 genomes at baseline and following treatment 
 
10.2.3.4 Ex vivo HIV-specific T cell responses following cemiplimab exposure 
 
10.2.3.5 Expression of PD-1, PD-L1 and other exhaustion markers on CD4+ 
and CD8+ T cells and expression of PD-L2 on dendritic and monocyte-
derived macrophages, at baseline and following treatment 
 
10.2.3.6 Polyfunctional response of HIV-1-specific CD4+ T cells by intracellular 
staining at baseline and through week 12 
 
10.2.3.7 Immune activation and cell cycling (expression of CD38/HLA-DR and 
Ki67 on CD4+ and CD8+ T cells) at baseline and following treatment 
 
10.2.3.8 Levels of immunologic and virologic measures through week 48  
 
10.2.3.9 Pharmacokinetic parameters (including Cmax, t1/2) and RO of anti-PD-1 
antibody following treatment 
 

 
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10.3 
Randomization and Stratification 
 
The three dose cohorts will enroll sequentially. Within each cohort, 15 eligible 
participants will be randomized 4:1 to receive cemiplimab (n=12) or placebo (n=3). 
Randomization will use the permuted block method without institutional balancing or 
stratification. After enrollment of each dose cohort is complete, study enrollment will be 
suspended until a decision is made on opening the next (higher dose) cohort to 
enrollment, based on the dose escalation criterion and SMC review. 
 
10.4 
Sample Size and Accrual 
 
The total sample size of this study is 45 evaluable participants. Within each dose cohort, 
there will be 12 active-treated participants and 3 placebo participants. Ultimately, there 
will be a total of nine placebo recipients for comparison of immunologic and virologic 
outcomes. Participants who do not receive study treatment will be replaced. In addition, 
any participant who does not receive ≥90% of both study treatment infusions, or 
discontinues the study prior to week 12 without having met the primary safety endpoint 
(section 10.2.1.1), will be replaced.  
 
10.4.1 Safety 
 
The criteria to be used to guide the SMC when determining dose resumption or 
dose escalation for each cohort are defined as not having observed: 
 
A. Three or more active-treated participants have experienced a Grade ≥3 AE 
that is related to study treatment (as judged by the core team, blinded to 
treatment arm and by the SMC who will receive unblinded data); 
B. Two or more active-treated participants have experienced an irAE (not 
including an infusion reaction AE) that is related to study treatment (as judged 
by the core team, blinded to treatment arm, and by the SMC who will receive 
unblinded data) as defined by: 
i 
Grade ≥1 pneumonitis, adrenal insufficiency, myocarditis, diabetes, or 
uveitis;  
ii 
Grade ≥2 colitis, myositis, rash, hyperthyroidism or hypothyroidism, or 
elevated AST or ALT. 
C. One or more active-treated participants have experienced a Grade ≥4 clinical 
AE (excluding asymptomatic laboratory abnormalities) that is related to study 
treatment (as judged by the core team, blinded to treatment and by the SMC 
who will receive unblinded data). 
 
NOTE A: Asymptomatic Grade 4 laboratory abnormalities are addressed within 
A. 
 
NOTE B: The following probability calculations assume a deterministic dose-
escalation rule and do not reflect the essential element of SMC review 
and clinical consideration by the SMC of the data presented with 
respect to dose-escalation decisions. 

 
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Table 10.4.1-1 below shows the probabilities of dose escalation under various 
assumed true rates for the three types of AEs as described above, considering 
12 participants receiving active treatment. In the table, the column “True 
participant-specific probability of AE event type A” is the probability of a Grade ≥3 
AE conditional on not having an event of type C (Grade 4 or higher clinical AE). 
Similarly, the column “True participant-specific probability of AE event type B” is 
the probability of observing an irAE conditional on not having an event of type C. 
To calculate these probabilities of dose escalation, event types A and B were 
subdivided into three mutually exclusive groups: X=Grade ≤2 events in B, 
Y=Grade ≥3 events in B, and Z=Grade ≥3 events in A not part of B. Participant-
specific probabilities of X, Y, and Z were assumed (conditional on not having an 
event of type C) and the events X, Y, and Z were assumed independent 
(conditional on not having an event of type C).  Probabilities of A and B 
(conditional on not having an event of type C) as displayed in the table were 
each then calculated (i.e., Pr(A|C=0) = Pr(Y|C=0) + Pr(Z|C=0) - 
Pr(Y|C=0)*Pr(Z|C=0)). The probability of dose escalation was computed by 
numerical simulation with 100,000 replicates based on Pr(C), Pr(X|C=0), 
Pr(Y|C=0), and Pr(Z|C=0) for each listed scenario in the table. 
 
The proposed sample size provides a reasonably high probability of dose 
escalation when the true event rates are, in fact, acceptable. For example, if the 
probability of a participant in the active treatment arm of a given dose cohort 
experiencing an AE of type A as described above is 0.03 (3%), the probability of 
experiencing an AE listed in B above is 0.02 (2%) and the corresponding 
probability of experiencing a Grade 4 or higher AE as described in C above is 
0.01 (1%), then the probability that the study will dose escalate to the next higher 
dose is 0.86 (86%). Given that this is an acceptable safety profile, this means 
that the probability of incorrectly concluding the current dose is unsafe is 0.14 
(14%). On the other hand, the proposed sample size provides a low probability of 
dose escalation when the true event rates are unacceptable. For example, if the 
probability of a participant in the active treatment arm of a given dose cohort 
experiencing an AE of type A as described above is 0.2 (20%), the probability of 
experiencing an AE listed in B above is 0.2 (20%) and the corresponding 
probability of experiencing a Grade 4 or higher AE as described in C above is 0.1 
(10%), then the probability that the study will dose escalate to the next higher 
dose is 0.06 (6%); the corresponding probability of not dose escalating and 
correctly concluding the dose unsafe is 0.94 (1-0.06). 
 

 
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Table 10.4.1-1: Probabilities of Meeting the Dose Escalation Criterion under 
Various Assumed True Rates 
True Participant-
specific Probability of 
AE Type A (Grade ≥3 
AE related to study 
drug) 
True Participant-
specific Probability 
of AE Type B (irAE 
related to study 
drug) 
True Participant-
specific Probability of 
AE Type C (Grade 4 
or higher clinical AE 
related to study drug) 
Probability 
of Dose 
Escalation 
Criterion 
0.008 
0.009 
0.005 
0.94 
0.03 
0.02 
0.01 
0.86 
0.03 
0.02 
0.02 
0.76 
0.04 
0.04 
0.03 
0.64 
0.06 
0.06 
0.05 
0.44 
0.14 
0.10 
0.07 
0.22 
0.18 
0.18 
0.08 
0.11 
0.20 
0.20 
0.10 
0.06 
0.25 
0.25 
0.15 
0.015 
 
Considering 12 treated participants in a cohort, Table 10.4.1-2 displays the 
probability of observing at least one participant with an event, and the probability 
of observing at least two participants with an event, for various underlying event 
probabilities. For example, consider an irAE as the event. Then 12 treated 
participants provides >70% likelihood of observing such an event if the 
participant-specific probability is at least 0.10 (10%). 
 
Table 10.4.1-2: Probability of Observing at Least One Participant with an Event, 
and the Probability of Observing at Least Two Participants with an Event, for 
Various Underlying Event Probabilities 
Participant-specific 
Probability of Event 
Probability of Observing 
≥1 Participant with Event, 
N=12 Treated 
Probability of Observing 
≥2 Participants with an 
Event, N=12 Treated 
.1 
0.72 
0.34 
.2 
0.93 
0.73 
.3 
0.99 
0.91 
 
10.4.2 Efficacy 
 
For the secondary outcome measure of efficacy, statistical power is described for 
the paired t-test which will be used (two-sided, alpha=0.05), testing that CD8+ T 
cell responses (10.2.2.1) increase pre- to post-treatment among the active-
treated study participants. The key assumption is that CD8+ T cell responses 
would be stable (mean change of zero) without intervention (i.e., with continued 
cART). Because estimates of the anticipated standard deviation (SD) of the 
change are not available, power is described in terms of SD units. With 11 
evaluable treated participants in a dose group (allowing for one unevaluable, 
e.g., due to issues with the sample or assay), power is >80% to detect a 
treatment effect in a dose group if the mean change is at least 0.94 SD units; this 

 
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corresponds under assumed normality to a probability of 0.83 or larger that a 
participant would have an observed increase in CD8+ T cell responses after 
treatment (the null hypothesis is that the probability is 0.5, corresponding to zero 
mean change). Combining the three dose groups (n=33), power is >80% to 
detect a treatment effect of 0.504 SD units, corresponding to a probability of 0.69 
or larger that a participant would have an observed increase in CD8+ T cell 
responses after treatment.  
 
Adjustments for separate statistical testing in each of the dose cohorts have not 
been incorporated into power calculations for this study. 
 
10.5  Data and Safety Monitoring  
 
If at any time within a given dose cohort:  
a) Three or more participants experience a Grade ≥3 AE related to study treatment 
(section 10.2.1.1) (as judged by the core team, blinded to treatment arm); or  
b) Two or more participants experienced an irAE (not including an infusion reaction AE) 
(see section 10.4.1B) that is related to study treatment (as judged by the core team, 
blinded to treatment arm); or 
c) One or more participants experience a Grade 4 clinical AE or death and related to 
study treatment (as judged by the core team, blinded to treatment arm);  
 
then enrollment into the study and treatment infusions will be temporarily suspended 
and the SMC, unblinded to treatment assignment, will be asked to review all safety 
data; review the relation to study treatment of the event(s) thought by the blinded 
core team to be a primary safety outcome; and recommend how the study should 
proceed with respect to resuming enrollment, continuing study treatment and dose 
escalation. 
 
10.6 
Analyses 
 
10.6.1 Primary Analyses 
 
For the primary safety analysis, AEs attributed to study treatment (see section 
10.2.1.1) will be described separately for the treatment arm of each dose cohort, 
and for the combined placebo arms. All participants who have been exposed to 
the study treatment/placebo will be included in this analysis. As 
supplemental/secondary analyses, all other reported AEs will be summarized for 
the treatment arm of each dose cohort, and combined placebo arm. 
 
10.6.2 Secondary Analyses 
 
For the HIV-1-specific CD8+ T cell efficacy outcome (section 10.2.2.1), post-
treatment changes will be evaluated, comparing measurements at baseline 
(averaging the pre-treatment measures) to an average of post-treatment 
measurements through week 12, jointly analyzing the actively treated participants 
from all dose cohorts using the paired t-test. As supplemental analyses, the 

 
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same methods will separately analyze each dose cohort. The rationale to 
average over multiple post-treatment timepoints is that the timing and dynamics 
of treatment-induced immunologic (or virologic) effects is not known; the average 
of multiple time points aims to capture both early effects that may wane (for 
example, as seen in one of the immunologic responders to a single-dose of the 
anti-PD-L1 antibody [26]; or, for example, a response that only appears following 
the second infusion). Graphical approaches will display the means at each visit 
and mean changes from baseline to each follow-up visit (and separately to the 
average of weeks 2-6 and to weeks 8-12), by dose cohort and separately for the 
placebo participants. Longitudinal participant-specific plots will also be presented 
for each treatment dose and for the placebo participants. 
 
Because the aim of this phase I/II study is to investigate the biologic effects of the 
treatment (anti-PD-1 antibody cemiplimab), efficacy analyses will be “as-treated” 
and also, to maximize the ability to identify treatment effects, efficacy analyses 
will be based only on participants who completed ≥90% of both study treatment 
infusions. In addition, if any participant interrupts cART for more than 7 
consecutive days during the study, only measurements prior to cART interruption 
will be used in efficacy analyses. 
 
Analyses of other immunologic and virologic measures will parallel the efficacy 
analyses as outlined above. For example, cell-associated HIV-1 RNA levels will 
be compared pre-treatment to post-treatment using paired t-tests separately by 
dose group (and for the combined treated participants) and for the placebo 
participants. Virologic measures such as cell-associated HIV-1 RNA will be log-
transformed prior to analyses. Because low-level viremia as measured by SCA is 
anticipated to be below assay limit in a substantial fraction (~50%) of participants, 
binary (GEE) or censored-data [64] longitudinal analysis approaches are planned 
to assess treatment effects on SCA. 
 
Descriptive summaries, by dose group, will be presented for the estimated PK 
parameters (see section 11.0). Graphical approaches will display concentration 
curves over time, as well as RO over time.  
 
Designated staff at identified laboratories may be unblinded prior to database 
lock to facilitate bioanalytical analyses of pharmacokinetic samples and ex vivo 
immunogenicity studies.  
 
The timing of treatment effects on immunologic and virologic outcome measures 
will be investigated by identifying, for each measure, the post-treatment timepoint 
with the greatest magnitude change from baseline. It is also of interest to 
evaluate whether there is evidence that the second dose of treatment further 
“boosts” responses following the first dose. For this reason, samples are 
collected at a comparable schedule following the first and second doses. 
 

 
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The associations between ex vivo HIV-specific T-cell responses following 
cemiplimab exposure (based on pre-treatment samples) and in vivo HIV-specific 
immune responses to treatment will be evaluated using Spearman correlations. 
Bioinformatics approaches will be used to evaluate changes in gene expression 
profiles before versus after treatment. 
 
Regression models, graphical displays and correlation analyses will investigate 
dose-response relationships with respect to immunologic and virologic changes 
after treatment across the dose groups, and in relation to PK parameters 
estimated as outlined in section 11.0. 
 
10.7 
Unblinding 
 
For unblinding requests, including emergency unblinding, refer to ACTG Standard 
Operating Procedure (SOP)-123, Unblinding Participants, 
(https://member.actgnetwork.org/cms/folder/6184).  
 
In the event that emergency disclosure of treatment assignment is thought to be 
required, the site investigator must follow ACTG SOP- 123, Unblinding Participants. 
 
(1) Sudden (or unplanned) unblinding of one or more arms due to interim analysis 
results or results of another trial: The decision to unblind one or more arms of an 
ongoing study is made by the team in conjunction with the relevant Scientific Committee 
and the Executive Committee. This can occur based on a recommendation from the 
DSMB or an SMC or the results of another trial (also see the DAIDS SOP “Termination 
of a Trial or a Single Treatment Arm”).  
 
(2) Participant contact: If the decision is made to unblind, participants should be 
unblinded as soon as possible. Unblinding is conducted through the DMC, which sends 
treatment assignments to the sites soon after the unblinding decision. Every effort 
should be made by the sites to contact participants who have completed follow-up in 
order to explain the study results.  
 
(3) Implications of unblinding on study data: When a treatment comparison is unblinded 
based on an interim analysis, the results of that interim analysis must be reported in 
publications. Data from visits that occurred before the interim review but that were not in 
the database at the data cutoff date have little potential for bias and may be reported 
with a comment. Data from visits that occurred after unblinding are potentially biased 
and must not be used if the intent is to claim that all the data are from a blinded study. In 
unblinding due to both “interim analysis” and the “other trial results” situations, if 
analyses are reported on clinical data or samples taken after the unblinding date, the 
conditions under which these data were gathered must be made clear in any publication.  
 

 
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Unblinding will not occur to allow replacement of participants (see section 6.2.5). 
Premature treatment discontinuation, other than for a treatment-related AE, would result 
in an increase in the applicable limit for enrollment into the active or placebo arm (as 
appropriate) for the designated cohort by the ACTG randomization department.  
 
All site e-mails to the team should be carefully worded to prevent unblinding the team, if 
possible. 
Unblinding of all study participants will take place after the last participant has completed 
the study, all data have been entered into the database and cleaned for primary and 
secondary endpoints.  
 
11.0 
PHARMACOLOGY PLAN 
A5370 will examine the safety, PK, and immune responses in HIV-1 infected participants 
on suppressive cART receiving cemiplimab. The pharmacology plan will be integrated 
into the overall protocol objectives and provide valuable information that will guide 
subsequent studies of cemiplimab in HIV-1-infected individuals on suppressive cART. 
Animal and human studies of the clinical pharmacology of cemiplimab indicate bi-
exponential decline following an IV dose. The systemic CL of mAbs is primarily though 
intracellular catabolism and therefore direct interaction with antiretrovirals is likely to be 
minimal. However, the pharmacodynamics (PD) response to cemiplimab binding to the 
PD-1 receptor results in enhanced immune function mediated by T cell activation with 
subsequent cytokine production. This increase in cytokines may alter certain 
antiretroviral PK, therefore stored antiretroviral plasma samples will be collected within 
the pharmacology plan. 
Noteworthy pharmacologic characteristics of cemiplimab include nM activity with regard 
to PD-1 receptor competitive binding. Peak and trough serum cemiplimab concentrations 
achieved in cancer studies using every-2-weeks IV dosing are in the mcg/ml range 
following doses of 1-3 mg/kg. The serum elimination half-life is prolonged (~19 days), 
with an estimate of ~80% PD-1 RO expected for the current dosage regimens proposed 
in this protocol, based on data from a currently approved PD-1 receptor blocker, 
nivolumab [28, 34]. 
A population PK model for cemiplimab was built using data from 505 patients, combining 
rich data from Study 1423 in patients with solid tumors (26 patients with CSCC), together 
with data from 114 patients with advanced CSCC from study 1540 (IB, Edition 6). The 
majority of patients in the population PK model received cemiplimab at the 3 mg/kg dose 
twice a week. A two-compartment model with zero-order IV infusion and first-order 
elimination was selected as a structural model. Inclusion of a function describing a time-
varying change in CL significantly improved the model fit. In the overall oncology patient 
population after repeated dosing, the total CL of cemiplimab appears to decrease over 
time by about 34.6% over the first 2 months of treatment, i.e., from a baseline value of 
0.325 L/day down to 0.211 L/day. However, this decrease in CL was not considered 
clinically relevant. Based on the population PK analysis, the total volume of distribution 
at steady-state was 5.20 L. Following a single dose of cemiplimab, mean exposure 

 
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generally increased in a dose proportional manner over the dose range of cemiplimab 
studied (1 mg/kg to 10 mg/kg once every two weeks). These observations were 
consistent with the results in the base model development, in which a linear-elimination 
model was considered to adequately describe the PK of cemiplimab. Systemic 
accumulation was evident based on an accumulation index of approximately 2.0-fold in 
AUC6wk,ss. The following intrinsic factors were found to have no clinically important effect 
on the exposure of cemiplimab: age (27-96 years), sex, body weight (31-156 kg), race 
(white, black, Asian, and other), cancer type, tumor burden, albumin level (22-48 g/L), 
renal function (creatinine clearance 25-420 mL/min), and hepatic function (total bilirubin 
0.35-45 μmol/L). To be noted, cemiplimab has not been studied in patients with 
moderate or severe hepatic impairment.  
The incidence of treatment-emergent ADA in all patients with solid tumors and in the 
subset of patients who received cemiplimab 3 mg/kg once every two weeks was 1.26% 
(5/398) and 1.17% (4/341), respectively. Antibody titers were considered low to 
moderate (titer levels: low [<1,000], moderate [≥1000 to ≤10,000] and high [>10,000]). Of 
the patients who developed treatment-emergent antibodies to cemiplimab, none 
developed neutralizing antibodies. The incidence of persistent ADA was low (0.251%) in 
all patients receiving cemiplimab. There was no evidence of altered PK profile in the 
small number of patients with treatment emergent ADA responses. The presence of 
ADA was not associated with AEs or irAE. 
Pharmacokinetic sampling of cemiplimab reported in the IB, Edition 6, for participants 
with advanced solid tumors provided a more intensive sampling strategy for obtainment 
of data to understand the pharmacokinetic properties of this drug in humans. Target 
mediated drug disposition (non-linear PK) likely occurs at lower concentrations, i.e., at 
lower doses and/or at later time points than those observed in the FIH studies. To date, 
there is no available data on RO with cemiplimab. For our design, a strategy will be 
implemented that aims to capture cemiplimab maximum concentration and terminal 
elimination phase, possibly including the target-mediated component of elimination with 
corresponding peripheral RO at similar time points. The later time points planned in the 
current pharmacology section include the duration of evaluation since this is the first 
clinical trial of cemiplimab in a population of HIV- infected participants. Based on the 
possibility of prolonged RO with this drug, the data provided from later sampling time 
points can provide valuable information in the event of prolonged responses or delayed 
AEs. 
 
11.1 
Pharmacology Objectives 
 
11.1.1 To characterize the systemic exposure of cemiplimab and determine PK 
parameters. 
 
11.1.2 To investigate the relationship of cemiplimab exposure and PD-1 peripheral RO 
with baseline participant-specific factors and investigate the relationship to PD 
responses in HIV-infected individuals on suppressive cART. 
 
11.1.3 To collect and store antiretroviral plasma concentrations before and after 

 
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administration of cemiplimab, to be assayed for pharmacokinetic analysis based 
on determination by core team of participant response. 
 
11.2 
Pharmacology Study Design 
 
11.2.1 Pharmacokinetics 
 
Sampling will be obtained: 
 
For cemiplimab 
• 
Pre-entry sample 
• 
Entry/day 0: Within 15 minutes following the end of infusion. 
• 
Week 6 (within 15 minutes prior to infusion and within 15 minutes following 
the end of infusion); any time during the visit at weeks 1, 2, 7, 8, 10, 12, 16, 
20, 24, 28, 36, and 48. 
• 
Samples obtained on non-infusion days can be drawn during the participant’s 
visit (a specific time of day is not required), documentation of the date and 
time of dosing, and of all PK samples drawn is required in the eCRF.  
 
For Stored Antiretroviral Sampling 
• 
Entry/day 0: Prior to infusion. 
• 
Weeks 2, 4, 6 (prior to infusion), 8, and 10. 
• 
Samples obtained on non-infusion days can be drawn during the participant’s 
visit (a specific time of day is not required), documentation of the date and 
time the sample is drawn is required in the eCRF. Documentation of the date 
and time of the 3 previous doses of each antiretroviral medication are to be 
recorded in the eCRF prior to each sample taken.  
 
Peripheral RO 
• 
Pre-entry sample  
• 
Week 6 (within 15 minutes prior to infusion); any time during the visit at 
weeks 1, 2, 7, 8, 10, 12, 16, 20, 24, 28, 36, and 48. 
• 
Determination of the need to assay certain/all samples will be based on the 
serum cemiplimab concentration seen. Samples obtained on non-infusion 
days can be drawn during the participant’s visit (a specific time of day is not 
required); documentation of the date and time of dosing and of all RO 
samples drawn is required in the eCRF.  
See section 6.0 for details of sample collection. 
 
11.2.2  Pharmacodynamics: To characterize the relationship of cemiplimab serum 
concentration and peripheral PD-1 RO with biomarker changes for example, HIV-
1 RNA by SCA, total HIV-1 DNA, intact proviral HIV-1 genomes, cell-associated 
HIV-1 RNA, HIV-1 RNA/DNA ratios in total CD4+ T cells, and markers of immune 
response. Relationships will be evaluated through PK/PD modeling. These 
PK/PD analyses will include exposure-response analyses for safety and efficacy 
endpoints as appropriate. 

 
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11.3 
Primary and Secondary Data, Modeling, and Data Analysis 
 
11.3.1 Serum cemiplimab concentrations will be assayed at Regeneron 
Pharmaceuticals, Inc., using a validated ligand-binding assay. 
 
11.3.1.1 The cemiplimab assay validation report will be provided to the ACTG 
Clinical Pharmacology Quality Assurance Program for peer review 
prior to analysis of protocol samples. 
 
11.3.2 Plasma antiretroviral samples will be assayed at the University at Buffalo 
Pharmacology Specialty Laboratory by a DAIDS Clinical Pharmacology Quality 
Assurance Program validated assay. 
 
11.3.3 Cryopreserved PBMCs will be used to assay PD-1 RO by cemiplimab by flow 
cytometry. 
 
11.3.4 Pharmacokinetic analysis will include cemiplimab serum concentration data, and 
evaluate the influence of PD-1 receptor binding on cemiplimab PK. The formation 
of ADA will be evaluated and may be incorporated into the model building 
process as a covariate, if appropriate. Population and individual cemiplimab PK 
parameters, including Cmax, AUC, half-life, and Cmin, will be determined using 
population PK approaches. The population PK model will provide an assessment 
of the influence of specific covariates on the disposition and variability in 
exposure of cemiplimab in HIV-infected adults on suppressive antiretroviral 
therapy. 
 
In addition, cemiplimab serum concentration data will be related to peripheral RO 
data in a PK/PD analysis. 
 
11.4 
Anticipated Outcomes 
 
We anticipate that participants receiving cemiplimab will have similar disposition to 
previous studies by Regeneron in participants with malignancies. This will be evaluated 
by comparing the Cmax, Tmax, AUC, and dose-normalized exposure values in this study to 
those reported in the IB, Edition 6, for participants with malignancies. In addition, we 
anticipate that exposure to cemiplimab and blocking of the PD-1 receptor will enhance 
HIV-1-specific immune responses that promote the CL of HIV-1-expressing cells. The 
clinical pharmacology objectives will provide an important evaluation of cemiplimab 
serum concentrations, the impact of participant-specific characteristics, RO, the 
relationship between cemiplimab serum concentrations and peripheral RO, and their 
relationship with safety, virologic, and immunologic responses. 
 

 
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12.0 
DATA COLLECTION AND MONITORING 
 
12.1 
Records to Be Kept 
 
Electronic case report form (eCRF) screens will be made available to sites for data entry. 
Participants must not be identified by name on any data submitted to the DMC. 
Participants will be identified by the patient identification number (PID) and study 
identification number (SID) provided by the ACTG DMC upon randomization. 
 
12.2 
Role of Data Management 
 
12.2.1 Instructions concerning entering study data on eCRFs will be provided by the 
ACTG DMC. Each CRS is responsible for keying the data in a timely fashion. 
 
12.2.2 It is the responsibility of the ACTG DMC to assure the quality of computerized 
data for each ACTG 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 Site monitors under contract to the NIAID will visit participating clinical research 
sites to review the individual participant records, including consent forms, eCRFs, 
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 The site investigator will make study documents (e.g., consent forms, drug 
distribution forms, eCRFs) and pertinent hospital or clinic records readily 
available for inspection by the local IRB, the site monitors, the FDA, the NIAID, 
the OHRP, the industry supporter(s), other local, US, and international regulatory 
entities for confirmation of the study data. 
 
13.0 
PARTICIPANTS 
 
13.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document (Appendix I) and any subsequent 
modifications will be reviewed and approved by the IRB or EC responsible for oversight 
of the study.  
 
A signed consent form will be obtained from the participant (or legal guardian, or person 
with power of attorney for participants who cannot consent for themselves. Study 
physician investigators will directly participate in the informed consent process. The 
consent form will describe the purpose of the study, the procedures to be followed, and 

 
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the risks and benefits of participation. A copy of the consent form will be given to the 
participant, and this fact will be documented in the participant’s record. 
 
13.2 
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 the ACTG, IRB/EC, FDA, NIAID, 
OHRP, other local, US, and international regulatory entities as part of their duties, or the 
industry supporter(s). 
 
13.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, FDA, NIAID, OHRP, 
other government agencies as part of their duties to ensure that research participants 
are protected, or the industry supporters. 
 
14.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by ACTG policies. Any 
presentation, abstract, or manuscript will be made available for review by the industry 
supporter(s) prior to submission. 
 
15.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the CDC and the 
National Institutes of Health. 
 
All dangerous goods and materials, including diagnostic specimens and infectious 
substances, must be transported using packaging mandated by CFR 42 Part 72. Please 
refer to instructions detailed in the International Air Transport Association (IATA) 
Dangerous Goods Regulations. 

 
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16.0 
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Reported by NATAP http://www.natap.org/2017/EASL/EASL_55.htm. 
39. Wightman F, Solomon A, Kumar SS, et al. Effect of ipilimumab on the HIV reservoir in 
an HIV-infected individual with metastatic melanoma. AIDS 2015;29:504-6. 
40. Colston E, Grasela D, Gardiner D, et al. An open-label, multiple ascending dose study of 
the anti-CTLA-4 antibody ipilimumab in viremic HIV patients. PLoS One 
2018;13:e0198158. 
41.  Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with 
immune checkpoint blockade: a comprehensive review. Eur J Cancer 2016;54:139-48. 
Epub 2016 Jan 5. doi: 10.1016/j.ejca.2015.11.016. 
42. Villadolid J, Amin A. Immune checkpoint inhibitors in clinical practice: update on 
management of immune-related toxicities. Transl Lung Cancer Res 2015;4:560-75. doi: 
10.3978/j.issn.2218-6751.2015.06.06. 
43. De Velasco G, Je Y, Bosse D, et al. Comprehensive meta-analysis of key immune-
related adverse events from CTLA-4 and PD-1/PD-L1 Inhibitors in cancer patients. 
Cancer Immunol Res 2017;5:312-18. epub 2017 Feb 28. doi: 10.1158/2326-6066.CIR-
16-0237. 
44. Carbone DP, Reck M, Paz-Ares L, et al. First-line nivolumab in stage IV or recurrent 
non-small-cell lung cancer. N Engl J Med 2017;376:2415-26. 
45.  Samri A, Lavole A, Even S, et al. PD-1 blockade in 12 HIV-infected patients with lung 
cancer. IAS 2017, Paris France. 
46.  Petroff MG, Chen L, Phillips TA, et al. B7 family molecules are favorably positioned at 
the human maternal-fetal interface. Biol Reprod 2003;68:1496-504. 

 
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47. Wafula PO, Teles A, Schumacher A, et al. PD-1 but not CTLA-4 blockage abrogates the 
protective effect of regulatory T cells in a pregnancy murine model. Am J Reprod 
Immunol 2009;62:283-92. 
48. Guleria I, Khosroshahi A, Ansari MJ, et al. A critical role for the programmed death 
ligand 1 in fetomaternal tolerance. J Exp Med 2005;202:231-7. 
49. Habicht A, Dada S, Jurewicz M, et al. A link between PDL1 and T regulatory cells in 
fetomaternal tolerance. J Immunol 2007;179:5211-19. 
50. Taglauer ES, Yankee TM, Petroff MG. Maternal PD-1 regulates accumulation of fetal 
antigen-specific CD8+ T cells in pregnancy. J Reprod Immunol 2009;80:12-21. 
51. D'Addio F, Riella LV, Mfarrel BG, et al. The link between the PDL1 costimulatory 
pathway and Th17 in fetomaternal tolerance. J Immunol 2011;187:4530-41. 
52. Brahmer JR, Drake CG, Powderly JD, et al. Phase I study of single-agent anti-
programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, 
pharmacodynamics, and immunologic correlates. J Clin Oncol 2010;28:3167-75. 
53. Weber JS, Yang JC, Atkins MB, et al. Toxicities of Immunotherapy for the Practitioner. J 
Clin Oncol. 2015; 33:2092-2099. 
54. Naidoo J, Page DB, Li BT, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune 
checkpoint antibodies. Ann Oncol 2015;26:2375-91. 
55. Zimmer L, Goldinger SM, Hofmann L, et al. Neurological, respiratory, musculoskeletal, 
cardiac and ocular side-effects of anti-PD-1 therapy. Eur J Cancer 2016;60: 210-25. 
56. Hofmann L, Forschner A, Loquai C, et al. Cutaneous, gastrointestinal, hepatic, 
endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer 2016;60:190-209. 
57. Tirumani SH, Ramaiya NH, Keraliya A, et al. Radiographic profiling of immune-related 
adverse events in advanced melanoma patients treated with ipilimumab. Cancer 
Immunol Res 2015;3:1185-92. 
58. Nishino M, Ramaiya NH, Awad MM, et al. PD-1 inhibitor-related pneumonitis in 
advanced cancer patients: radiographic patterns and clinical course. Clin Cancer Res 
2016;22:6051-60. 
59. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and 
kinetics of response with ipilimumab. J Clin Oncol 2012;30:2691-7. 
60. Lacouture ME, Wolchok JD,Yosipovitch G, Kähler KC, Busam KJ, Hauschild A. 
Ipilimumab in patients with cancer and the management of dermatologic adverse events. 
J Am Acad Dermatol 2014;71:161-9. 
61. Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-
term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 
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62. Michot JM, Mazeron R, Dercle L, et al. Abscopal effect in a Hodgkin lymphoma patient 
treated by an anti-programmed death 1 antibody. Eur J Cancer 2016;66:91-4. 
63. Patel AB, Pacha O. Skin reactions to immune checkpoint inhibitors. Adv Exp Med Biol 
2017;995:175-84. doi: 10.1007/978-3-319-53156-4_9. 
64. Riddler SA, Aga E, Bosch RJ, et al. Continued slow decay of the residual plasma viremia 
level in HIV-1-infected adults receiving long-term antiretroviral therapy. J Infect Dis 
2016;213:556-60. 

 
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APPENDIX I: SAMPLE INFORMED CONSENT 
 
DIVISION OF AIDS  
AIDS CLINICAL TRIALS GROUP (ACTG) 
For Protocol: A5370 
 
FINAL VERSION 1.0, 11/16/18: Safety and Immunotherapeutic Activity of an Anti-PD-1 
Antibody (Cemiplimab) in HIV-1-infected Participants on Suppressive cART: A Phase I/II, 
Double-blind, Placebo-controlled, Ascending Multiple Dose Study 
 
SHORT TITLE FOR THE STUDY: Anti-PD-1 Antibody Cemiplimab in HIV-1-Infected 
Participants on Suppressive cART 
 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you are living with human 
immunodeficiency virus (HIV-1) and: 
1. You have been taking the same combination of antiretroviral drugs (cART) for at least the 
past 3 months. 
2. Your HIV-1 RNA level (viral load, the amount of HIV in your blood) has been below the limit 
of detection for the past 18 months.  
 
This study is sponsored by the National Institutes of Health (NIH). The doctor in charge of this 
study at this site is: (insert name of Principal Investigator). Before you decide if you want to be a 
part of this study, we want you to know about the study. This is a consent form. It gives you 
information about this study. The study staff will talk with you about this information. You are 
free to ask questions about this study at any time. If you agree to take part in this study, you will 
be asked to sign this consent form. You will get a copy to keep. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
HIV medications can reduce HIV virus to very low levels in the blood and partially repair the 
immune system (the way your body responds to diseases). However, these medications do not 
cure (remove) the HIV and a small amount of the virus continues to live in the body even when 
the viral load (amount of HIV virus in your body) is very low. In most participants taking HIV 
medications, very sensitive tests can find small amounts of HIV virus in the blood even when 
regular viral load test results do not find HIV. This helps explain why the HIV virus levels come 
back when these medications are stopped. The reason why HIV can still be found in the body is 
likely because there are cells that live for a long time after becoming infected with HIV. These 
cells are thought to carry the HIV virus in a latent or hidden form (“non-active state”). As long as 
the virus exists in this latent, non-active state, persons living with HIV cannot be cured. HIV 
virus may come from these non-active cells that may at times produce low levels of HIV, or it 
may come from other cells in the body. The immune system does not seem to be able to get rid 
of these cells that produce virus. HIV medications are only able to block multiplying (active 
virus) cells. 

 
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Cemiplimab (LIBTAYO) is a drug approved by the Food and Drug Administration (FDA) to treat 
advanced cutaneous squamous cell carcinoma. It has been tested to treat other types of 
cancer. It has been tested to treat various types of cancer. Cemiplimab is an antibody (a protein 
in the body that finds infection) that has been created to help wake up cells in the immune 
system that do not function well. These cells are called exhausted (tired) T cells. One reason 
that the immune system does not clear the cells that produce low levels of HIV is that the cells 
that fight HIV are exhausted and do not work well. If these cells are able to wake up, it is 
possible that they can function better and help clear the cells infected with HIV. This study is 
being done to see if cemiplimab is safe in persons living with HIV and whether it can improve 
the HIV-specific immune response. The overall goals of this study are: 
• 
To see if two doses of cemiplimab will be safe in persons living with HIV on treatment, 
• 
To see whether there is improvement in the body’s immune response to HIV, 
• 
To see whether cemiplimab can lower the amount of HIV that is present in the blood and 
reduce the amount of latent HIV.  
 
In this study, you will receive two infusions of either the active form of cemiplimab or placebo (a 
salt solution with no medication). You have four out of five chances to receive the active 
medication and one out of five chances to receive placebo. Cemiplimab and placebo will be 
provided to you at no cost. 
 
There are 3 doses levels (amount of medication with each infusion) being used in this study to 
test safety and to look at whether the higher doses are better at improving the immune response 
to HIV. The doses for this study were chosen based on studies that were done in people with 
cancer who did not have HIV. The most important goal of this study is to test if cemiplimab is 
safe. The smallest and first dose of 0.3 mg/kg is much lower than the doses used in studies 
against cancer. The doses of 1 mg/kg and 3 mg/kg were chosen given their effectiveness in 
treating cancer in some cancer patients. In prior studies with cemiplimab, participants receiving 
the higher doses did not have more side effects than with lower doses. 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
Screening 
If you would like to be in this study, after you have read and signed this informed consent form, 
you will come to the clinic for a screening visit to make sure you meet the requirements for 
joining the study. You will need to fast before this visit (fasting means that you have had nothing 
to eat or drink except plain water and required prescription medications for at least 8 hours 
before this visit). If you are not able to fast before this visit, you will be asked to reschedule your 
visit. This visit will take about 1-2 hours. At this visit: 
• 
Whether you are living with HIV will be confirmed. If there is no record available, another 
HIV test will be done. You may have to sign a separate consent form before this is done. 
• 
You will be asked questions about your medical history and any medications you are taking 
or have taken in the past. 
• 
You will have a complete physical exam, including vital signs (temperature, pulse, 
respiration rate [the number of breaths you take in a minute], and blood pressure), an eye 
exam, and height and weight.  

 
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• 
You will have about 3.7 tablespoons (56 mL) of blood drawn to see if you have tuberculosis 
in your body; for metabolic tests (to test how your body uses the food that you eat); 
autoimmune (studies to see if your immune system is attacking healthy cells in your body); 
studies for routine lab tests for safety; for virologic studies (to help study the virus); to 
measure the amount of HIV in your blood; and to measure your CD4+ and CD8+ cell counts 
(cells that help fight infection). 
• 
If you are a woman and able to get pregnant, some of your blood or urine will be tested for 
pregnancy. 
• 
If you are a woman, follicle stimulating hormone-release factor (FSH) will be measured if you 
are not able to get pregnant and you do not have a medical record that says this.  
• 
You will agree to continue taking combination antiretroviral drugs as prescribed throughout 
the entire study. 
 
If You Do Not Enroll into the Study 
If you decide not to take part in this study or if you do not meet the eligibility requirements, we 
will still use some of your information. As part of this screening visit, some demographic (age, 
gender, race), clinical (disease condition, diagnosis), and laboratory (CD4 cell count, viral load) 
information is being collected from you so that the AIDS Clinical Trials Group (ACTG) 
researchers may help determine whether there are patterns or common reasons why people do 
not join a study. 
 
Pre-Entry 
• 
If you are eligible for the study, you will come in for a pre-entry visit. This visit will take about 
1 hour. You will need to fast before this visit (fasting means that you have had nothing to eat 
or drink except plain water and required prescription medications for at least 8 hours before 
this visit). At this visit: 
• 
Your height may be recorded. 
• 
You will have about 7.2 tablespoons (108 mL) of blood drawn for routine lab tests for safety; 
to see if you are living with the hepatitis B virus and/or you have been diagnosed with the 
hepatitis C virus (an infection of the liver); for metabolic tests (to test how your body uses the 
food that you eat); for virologic studies (to measure the amount of HIV in your blood); for 
immunologic studies (to test how your body fights infection); pharmacokinetic (PK) studies 
(to test how the study drug works in your body) studies; and for immunogenicity studies (to 
test your body’s immune response). You will be told the results of these tests when they 
become available. Some of the blood you provide will be stored for future protocol-required 
testing.  
• 
You will have an electrocardiogram (ECG). An ECG is a test that checks for problems with 
the electrical activity of your heart. 
• 
If you are a man, some of your blood will be tested to look at the amount of testosterone in 
your blood before receiving study treatment.  
 

 
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Entry 
After your pre-entry visit, you will come in for an entry visit. This visit will take about 4 hours. At 
this visit: 
• 
You will be asked questions about your medical history.  
• 
You will be asked about your health and any changes in your medicines since your last visit. 
• 
You will have a brief physical exam including vital signs and weight.  
• 
If you are a woman and able to get pregnant, some of your blood or urine will be tested for 
pregnancy. 
• 
You will provide a urine sample for a urinalysis to see if you have nephritis (inflammation of 
the kidneys). 
• 
You will have about 7.1 tablespoons (106.5 mL) of blood drawn for routine lab tests for 
safety; virologic, immunologic, PK, and autoimmune (studies to see if your immune system 
is attacking the healthy cells in your body) studies; to measure the amount of HIV in your 
blood; and to measure your CD4+ and CD8+ cell counts. Some of the blood you provide will 
be stored for future protocol-required testing, including gene expression assays. Most of our 
cells have exactly the same genetic information (blueprint) but some of the information is 
turned off and some is turned on depending on the type of cell. This study will test gene 
expression (which genes are “on” and which genes are “off”) in lymphocytes (immune cells) 
before and after receiving the study medication. 
• 
You will receive cemiplimab or placebo once during this visit through a small plastic flexible 
tube placed into a vein in your arm (intravenous [IV] infusion). This IV infusion will take 
about 30 minutes or in some cases the IV infusion may be slowed to help stop any side 
effects that you may have. At the entry visit, blood will be drawn to determine cemiplimab 
amounts in your body. This blood draw will happen right after the infusion. 
• 
You will be asked questions about how well you take your HIV medications. 
• 
You will be contacted by telephone 2 to 3 days after this visit in which you have received the 
study drug or placebo. Someone from the site will call you to see how you are doing and to 
ask you about any signs and/or symptoms you may have.  
 
Study Medication 
Depending on when you enter this study, you will be assigned to one of the three groups. In 
each group: 12 participants will receive cemiplimab and 3 participants will receive placebo salt 
diluent/solution that does not contain cemiplimab. You cannot choose whether you receive 
cemiplimab or placebo because you will be randomly assigned (like flipping a coin), and neither 
you nor the study staff will know whether you will receive cemiplimab or the placebo. 
• 
Group 1 will enroll first to receive cemiplimab 0.3 mg/kg or placebo. If this dose is found to 
be safe, then  
• 
Group 2 will enroll to receive cemiplimab 1 mg/kg or placebo. If this dose is found to be safe, 
then  
• 
Group 3 will enroll to receive cemiplimab 3 mg/kg or placebo. All participants will receive one 
dose of cemiplimab/placebo at entry and one dose of cemiplimab/placebo at week 6. 
However, the second dose at week 6 may not be given to you if any concerning side effects 
have occurred in you or in other participants enrolled in the study (see section “Risks of 
Cemiplimab” below). If this occurs, the study monitoring committee (SMC) will review this 
side effect and decide if it is safe for participants to continue with a second dose of 
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If the second dose is delayed for any reason, you will still come in for your week 6 visit and all 
week 6 evaluations will be done, except you will not receive the second dose of 
cemiplimab/placebo. If the SMC decides it is safe for participants to receive a second dose, then 
another visit will be scheduled for you to receive this second dose. In this case, you may need 
to have your week 4 evaluations done again before scheduling your second dose.  
 
You will not know whether you received cemiplimab or placebo until all participants have 
completed the study, unless this information is important to your care in an emergency. 
 
Study Visits 
After your entry visit, you will come to the clinic at weeks 1, 2, 4, 6, 7, 8, 10, 12, 16, 20, 24, 28, 
36, and 48. Most study visits will last about 1 hour with the exception of your week 6 visit, which 
will last about 2 hours.  
 
During Most Study Visits 
• 
You will be asked about your health and any changes in your medicines since your last visit. 
• 
You will have a brief physical exam including vital signs and weight (only done weeks 6, 12, 
and 48).   
• 
You will have about 5.3 tablespoons (up to 78.5 mL) of blood drawn to measure the amount 
of HIV in your blood, for future protocol-required testing, routine lab safety tests, and for 
immunologic and virologic studies. Some of this blood will be stored for future gene 
expression assays.  
• 
You will have about 1.0 tablespoon (15 mL) of blood drawn for metabolic studies on weeks 
4, 6, 12, 16, 20, 24, 28, 36, and 48. You will need to fast before these study visits (fasting 
means that you have had nothing to eat or drink except plain water and required prescription 
medications for at least 8 hours before these visits). 
• 
You will have a little more than 0.5 tablespoon (7 mL) of blood drawn for autoimmune 
studies on weeks 4, 12, and 48.   
• 
You will have a little more than 0.5 tablespoon (7 mL) of blood drawn and stored for 
autoimmune studies on weeks 6, 16, 20, 24, 28, and 36.   
• 
You will have about 1 teaspoon (4 mL) of blood drawn to measure your CD4+ and CD8+ T 
cell counts on weeks 6, 12, 24, and 48.  
• 
You will have about 1.2 tablespoon (up to 18 mL) of blood drawn for PK studies on weeks 1, 
2, 4, 6, 7, 8, 10, 12, 16, 20, 24, 28, 36, and 48.  
• 
During your week 6 study visit, some of your labs drawn at your week 4 visit will be checked 
to see whether it is ok for you to receive the second dose of study drug at week 6.  
• 
If you are a woman and able to get pregnant, some of your blood or urine will be tested for 
pregnancy at week 6 before you receive the second dose of study drug. 
• 
At the week 6 visit, you will receive cemiplimab or placebo once through a small plastic 
flexible tube placed into a vein in your arm (intravenous [IV] infusion). This IV infusion will 
take about 30 minutes; in some cases, the IV infusion may be slowed to help stop any side 
effects that you may have. Blood will be drawn to determine cemiplimab amounts in your 
body. These blood draws will happen right before and after the infusion. 
• 
On weeks 1, 6, 7, 12, 16, 20, 24, 28, 36, and 48, you will be asked questions about how well 
you take your HIV medications. 
• 
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• 
You will be given the results of some of the study tests as soon as they are available, 
including all standard viral loads, CD4+ counts, and safety blood tests. 
• 
If you are a man, you will have about 0.3 tablespoon (5 mL) of blood drawn to look at the 
amount of testosterone in your blood on weeks 4, 12, and 48.  
• 
If it has been decided that you will not receive the second dose at week 6, you will still have 
all week 6 evaluations done. See information above under “Study Medication.” 
• 
After you receive the second dose of cemiplimab or placebo at week 6, you will be 
contacted by telephone 2 to 3 days. Someone from the site will call you to see how you are 
doing and to ask you about any signs and/or symptoms you may have.  
• 
If you are a woman and able to get pregnant, some of your blood or urine will be tested for 
pregnancy at weeks 12, 24, and 48 (in addition to week 6), or at weeks 1, 2, 4, 7, 8, 10, 16, 
20, 28, or 36 if you might be pregnant.   
 
Confirmation of Virologic Failure 
If at any time during the study the result of your viral load test shows measurable virus above 
the limit of detection of the test, you will be asked to return to the clinic. At this visit: 
• 
You will have about 1.2 tablespoon (18 mL) of blood drawn to measure the amount of HIV in 
your blood, for an HIV resistance test (resistance means that the drugs are not likely to fight 
the HIV in your body), and PK studies (to look at the amount of study drug in your body).  
• 
If you are a woman and you think you might be pregnant, some of your blood or urine will be 
tested for pregnancy.   
• 
You will be asked questions about how well you take your HIV medications. 
• 
You will be asked to stay on the study and complete all of the study visits. 
 
If You Stop Taking Your HIV Drugs during the Study 
If you stop taking your HIV drugs during the study: 
• 
You will be asked to stay on the study and complete the study visits so that you can be 
monitored for safety. You will have all of the regularly scheduled evaluations listed above, 
except blood for some of the immunologic and virologic studies will not need to be taken. 
• 
If HIV drugs are stopped for more than 7 days before the first infusion of cemiplimab or 
placebo, the infusion will not be administered.  
• 
If HIV drugs are stopped after the first infusion for more than 7 days, but before the second 
infusion, the second infusion will not be administered.  
• 
You will be given the results of some of the study tests as soon as they are available, 
including all standard viral loads, CD4+ counts, and safety blood tests. 
 
If You Have to Stop the Infusion of Cemiplimab Early 
If the infusion of cemiplimab or placebo is stopped early for any reason and cannot be 
completed: 
• 
You will be asked to stay on the study and complete the study visits so that you can be 
monitored for safety. You will have all of the regularly scheduled evaluations listed above, 
except you may not have the blood draws to determine the levels of cemiplimab in your 
body. 
• 
If you are unable to complete the first infusion, the second infusion will not be administered.  

 
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• 
The study team will decide whether blood for the immunologic and virologic studies will need 
to be taken. 
 
If You Have to Stop the Study Early 
If you have to stop the study early, you will be asked to come to the clinic for an additional study 
visit. At this visit: 
• 
You will have a brief exam physical including vital signs. 
• 
You will have about 7.0 tablespoons (103.5 mL) of blood drawn for routine lab tests for 
safety; for virologic, immunologic, metabolic, PK, and autoimmune studies; to measure the 
amount of HIV in your blood; and to measure your CD4+ and CD8+ cell counts. Some of the 
blood you provide will be stored for future protocol-required testing, including gene 
expression assays. 
• 
You will provide a urine sample for a urinalysis. 
• 
If you are a man, some of your blood will be tested to look at the amount of testosterone in 
your blood. 
• 
If you are a woman and able to get pregnant, some of your blood or urine will be tested for 
pregnancy. 
 
Other 
Some of your blood samples will be stored (with usual protectors of identity) and used for testing 
that is required for this study. Usual protectors of identity are defined as: All laboratory 
specimens, evaluation forms, reports, and other records that leave the site will be identified only 
by coded number 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 your written permission, except as necessary for 
monitoring by the ACTG, Institutional Review Board (IRB), FDA, National Institute of Allergy and 
Infectious Diseases (NIAID), Office for Human Research Protections (OHRP), other government 
agencies as part of their duties, or the industry supporter or designee. 
 
While you are in this research study, there will be some remaining blood following the 
completion of required testing. Researchers will use these unused samples along with your 
associated health information for future research. This information includes your medical 
condition(s). It may also include personal facts about you, such as your race, ethnicity, gender 
identity, and sex at birth. You are free to ask questions at any time. You may discuss it with 
others.  
 
What samples will researchers collect and store? 
Researchers will not collect any extra samples for future research. They will only use already 
collected unused samples.  
  
Where will researchers store my information and samples? 
Researchers will store your information electronically in computer databases. This information 
will include your associated health information and any new information learned from research 
done with your samples. Researchers will store your samples at the clinical research sites. To 
maximize research opportunities, researchers may store your samples in other storage facilities 
or “bio-banks.” There is a possibility that researchers may send your samples to other 

 
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researchers in your country or outside of your country. (For Local Investigators and CRS 
personnel. Make sure that the shipment of samples outside the country complies with country 
and local regulations or policies.) 
 
How will researchers use my information and samples? 
Researchers may use your information and samples in different types of future research to fight 
HIV and other related diseases. Some of these research studies may include genetic testing. 
 
What other research could researchers do with my information? 
Researchers may produce a lot of new information or “data” through the research done with 
your samples. This new information may be placed in large databases for other researchers to 
use. These databases may be only for genetic information, while others may store non-genetic 
information or both. All these databases store the information electronically without your 
personal identifiers, such as your name. No one will know just from looking at the information in 
any of these databases that the information belongs to you. 
 
How long will researchers store my samples for future research? 
Researchers will store your samples indefinitely. However, you can change your mind and 
withdraw your permission at any time. (For Local Investigators and CRS personnel, make sure 
the length of time does not contradict country and local regulations or policies.)   
 
What are the risks of storing my samples and information for future research? 
There is a small risk that someone may use your stored samples or information incorrectly. For 
example, someone could find out which test results are yours and use this information against 
you. This incorrect use of information may cause discrimination, distress or other problems to 
you. For this incorrect use to happen, the person would have to get into a database that links 
results with your name. To reduce this risk, researchers have security measures in place such 
as limiting access to databases, not linking names to results, and not placing results in medical 
records. (For Local Investigators and CRS personnel. Make sure to consider and insert here 
any known risks to participants agreeing to have samples stored for future research, e.g., being 
denied life/disability/long-term care insurance for involvement in HIV research or genetic 
research.) 
 
What are the benefits of storing my samples and information for future research? 
There will be no direct benefit to you from future research using your stored samples and 
information. However, the information learned may help others. It may take the researchers 
many years to have any results. In most cases, you will not receive future research results from 
the researchers. 
 
What other choices do I have? 
It is your choice whether or not to give permission for the storage and use of unused samples, 
as described in this document. If you choose not to give permission, researchers will not store 
any of your unused samples. 
 
Can I change my mind about the storage and use of my samples and information? 
Yes, you can decide to withdraw your permission for the storage and use of your samples and 
information for future research, whenever you want. If you decide to withdraw your permission, 

 
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contact the research staff. There are two ways to withdraw your permission. You could allow 
researchers to remove all your personal identifiers from your samples, so that they are not 
linked to you anymore. These samples will then become anonymous. You could also ask 
researchers to destroy your samples, so that they cannot be used for future research.  
Researchers will make reasonable efforts to obtain and destroy information and/or samples if 
consent is withdrawn. However, in either case, researchers will not be able to destroy samples 
or information from research that is already underway. If you withdraw your permission, there 
will be no negative consequences for you. (For Local Investigators and CRS personnel, insert 
here local guidelines pertaining to disposal of samples, e.g., need for written request.) 
 
Your signature below confirms your voluntary decision to give permission for the collection, 
storage, and use of your blood samples and information in future research. 
 
You do not have to give permission for storage of these samples. This will not affect your 
participation in the study and you may withdraw your permission at any time.   
 
________ YES                     ________ NO 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 45 men and women 18 years of age to 64 years of age will take part in this study. Women 
who are capable of having a baby are eligible for this study.  
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for about 48 weeks. 
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
• 
The study is stopped or cancelled.  
• 
The IRB, FDA, NIAID, OHRP, or another government agency with the duty to ensure that 
research participants are protected, or the industry supporters, recommends that the study 
be stopped early. An SMC is an outside group of experts who monitor the study. An IRB is a 
committee that watches over the safety and rights of research participants. 
 
The study doctor may also need to take you off the study drug without your permission if: 
• 
Continuing the study drug infusion may be harmful to you. 
• 
You are pregnant or breastfeeding. 
• 
You stop taking your HIV medications.  
• 
You need a treatment that you may not take while on the study. 
• 
You are not able to receive the study drug infusion as required by the study. 

 
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• 
You have positive results for antibodies to TPO, GAD65/GAD, or islet cell antigen (from 
testing done at week 4 prior to week 6 infusion).  
 
If you must stop participating in this study before completing the study drug infusion or after 
receiving the study drug before the study is over, the study doctor may ask you to return for one 
or more study visits. 
  
WHAT ARE THE RISKS OF THE STUDY? 
 
We will now be talking about the known risks of the study medication, some of which are listed 
below. Before we go through the lists, we want to make you aware that there are serious risks 
associated with this medication. The study team has tried to minimize the risks to you as much 
as possible. However, there are still life-altering or life-threatening risks that are possible. The 
study team will carefully monitor you and act quickly to avoid more danger to you if these risks 
occur. However, some of these serious risks may not be reversed.  
 
The lists below include only the more serious or common side effects with a known or possible 
relationship to the study drug. There is minimal data on adverse events and the relationship to 
specific dose levels. If you have questions concerning additional study drug side effects please 
ask the medical staff at your site. Safety data from each lower dose level will be carefully 
reviewed before higher doses are administered.  
 
There is a risk of serious and/or life-threatening side effects when non-study medications are 
taken with the study drug. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study and also before starting any new 
medications while on the study. Also, you must tell the study doctor or nurse before enrolling in 
any other clinical trials while on this study. 
 
Risks of Social Harm 
Although the study site will make every effort to protect your privacy and confidentiality, it is 
possible that your involvement in the study as a participant could become known to others if it is 
not already and that social harms may result (because you could become labeled as living with 
HIV). For example, you could be treated unfairly or discriminated against by family members, 
friends, and/or the community. 
 
Risks of Cemiplimab 
As of March 2018, 757 patients with cancer have received at least one dose of cemiplimab (1 
mg/kg, 3 mg/kg, 10 mg/kg, or a 200 mg or 350 mg flat dose) alone or in combination with other 
treatment regimens in cemiplimab studies. Based on experience, the most common side effects 
related to cemiplimab treatment are as follows: 
 
Very common side effects (>10% or more of patients): fatigue (tiredness), nausea, diarrhea, 
constipation, and decreased appetite. 
 
Common (1 to ≤10% of cancer patients):  
• 
vomiting 
• 
dizziness 

 
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• 
weakness 
• 
underactive or overactive thyroid gland 
• 
increased blood test of liver function 
• 
increased blood test of renal function 
• 
anemia 
• 
dry mouth 
• 
flu-like illness 
• 
swelling or pain of an arm or leg 
• 
trouble sleeping 
• 
shortness of breath 
• 
itching 
• 
cough 
• 
joint pain 
• 
muscle pain 
• 
fever 
• 
headache 
• 
pneumonia (infection in the lungs) 
• 
pneumonitis (inflammation of the lung) 
• 
pulmonary embolism (blood clot in the lungs) 
• 
abdominal pain 
• 
low white blood counts 
• 
chills 
• 
rash 
• 
dry skin 
• 
stomatitis (inflammation of mouth and lips) 
• 
decreased weight, dehydration 
• 
infusion reactions 
• 
muscle spasms 
• 
back pain 
• 
low phosphate, potassium, or calcium in the blood 
• 
urinary tract infection 
• 
sepsis (infection in your bloodstream) 
• 
blurry vision 
 
Uncommon (≤1% of patients) but serious:  
• 
Encephalomyelitis (inflammation of the brain) which may result in severe memory loss and 
occasionally death 
• 
Myasthenia gravis, a disease that causes muscle weakness 
• 
Colitis, inflammation of the colon  
• 
Bronchospasm, a narrowing of air passages in the lungs causing shortness of breath 
• 
Diabetes and diabetic ketoacidosis, a severe complication of diabetes (high blood sugar) 
where the body makes too much acid in the blood 
• 
Myocarditis, inflammation of the heart wall 
 

 
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Because cemiplimab may stimulate the immune system, side effects can include symptoms of 
increased immune response (autoimmune reactions) targeting specific organs. The symptoms 
of these immune responses may include:  
• 
Inflammation of the intestines (colitis) which usually includes diarrhea 
• 
Skin rashes or hives 
• 
Low or high thyroid levels (hypothyroidism or hyperthyroidism) which may cause fatigue, 
feeling hot or cold, or decreased or increase energy and may require treatment 
• 
Low output from the adrenal gland which can cause low blood pressure or dizziness and 
required treatment 
• 
Inflammation of the liver (hepatitis) 
• 
Diabetes (elevated blood glucose levels), which may cause nausea, abdominal pain and 
require insulin treatment 
• 
Low levels of white blood cells, red blood cells (anemia), or platelets 
• 
Neuropathy (tingling or numbness in the feet or hands) 
• 
Severe pneumonitis (inflammation of the lungs), which may cause cough and shortness of 
breath 
• 
Myocarditis (inflammation of the heart wall) 
• 
Myasthenia gravis (muscle weakness and fatigue)  
• 
Uveitis (inflammation of the eye), which can cause eye pain, redness, irritation, and changes 
in vision 
• 
Encephalitis (inflammation in the brain), causing headache and confusion 
 
In cancer patients, most of these symptoms and syndromes related to immune responses have 
been reversible, but may require treatment with steroids to suppress the immune system for 
several weeks. It is important that these syndromes are managed early to avoid severe 
symptoms which can be life-threatening.  
 
Some of the immune responses (how your body responds to something by making hormones 
[chemical messengers in your body]) seen in cancer patients may be irreversible (permanent), 
and require ongoing and possibly lifelong treatment. The different parts of the body that could 
be involved are the thyroid (makes hormones that are in charge of digestion), adrenal glands 
(makes many different hormones in your body), and the pituitary (controls the release of all 
hormones in your body). The risk for irreversible conditions which would require daily, lifelong 
treatment appears to be highest for hypothyroidism (your thyroid is not as active as it should be; 
seen in 5-9% of cancer patients, hyperthyroidism (your thyroid is too active; 1-5% patients), and 
diabetes (<1% patients). It is important that you understand this is a potential risk in being a 
participant in this study. In a study of a similar anti-PD-L1 antibody given to participants with 
HIV, there was one potential treatment-related toxicity of inflammation of the pituitary gland 
following one dose that could have been related to study treatment. 
 
To minimize the possibility of these side effects, participants with diabetes, thyroid problems, 
abnormal cortisol levels (a hormone released in response to stress), or other known problems 
with their immune system other than HIV or abnormal results on screening for these disorders 
are excluded from participating in this study. During this study, you will undergo repeated testing 
for thyroid problems, diabetes, cortisol levels, and liver problems to detect them early if they 
occur and allow early treatment. Early treatment for these conditions has been shown to be 

 
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important in decreasing the severity of symptoms. As such, you should let the study team know 
if you develop any symptoms while on study, so we can determine if they are possibly related to 
the study treatment. 
 
Risks of Drawing Blood or IV Placement 
Having blood drawn may cause some discomfort, lightheadedness, bleeding, swelling, or 
bruising where the needle enters the body, and in rare cases fainting or infection. Placement of 
an IV catheter can cause bleeding, swelling, or bruising where the needle enters the body.  
 
Unknown Risks 
Other side effects that are not known at this time could happen during the study. There is a risk 
that waking up immune cells may cause immune problems (your immune cells may cause 
problems with the normal function of your body). We will monitor you carefully for this. All drugs 
have a possible risk of an allergic reaction, which if not treated right away, could become life-
threatening. There is the potential for a life-threatening risk including death due to an 
autoimmune or infusion reaction as described above, or an unknown side effect. During the 
study, you will be told about any new information that may affect your decision to stay in the 
study. If you decide to stay in the study, you will be asked to sign an updated consent form. If 
you decide to leave the study early, the study staff will talk with you about your treatment 
options. 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
Treatment in animals with drugs similar to cemiplimab has shown an increased frequency of 
miscarriage. Given this potential risk to unborn babies, all volunteers participating in sexual acts 
that could lead to pregnancy for themselves or their partners must agree to use two effective 
forms of birth control for the duration of the study. 
 
You should not participate in this study if you plan to become pregnant or cannot commit to 
consistent use of effective birth control for the duration of the study. It is not known if the drug in 
this study will harm unborn babies. Tests in pregnant animals do show risk and harm to unborn 
babies. In addition, potential symptoms related to immune responses discussed above could be 
harmful to unborn babies. The risks to unborn babies is listed in the section called “What Are the 
Risks of the Study?” If you are having sex that could lead to pregnancy, you must agree not to 
become pregnant or make a woman pregnant. 
 
Because of the risk involved, you and your partner must use two methods of effective birth 
control that you discuss with the study staff. You must continue to use both methods for the 
duration of the study. You may choose two of the birth control methods listed below: 
• 
Consistent use of birth control drugs that prevent pregnancy given by pills, shots, or placed 
under the skin. 
• 
Consistent use of male or female condoms with or without a cream or gel that kills sperm. 
• 
Consistent use of diaphragm or cervical cap with a cream or gel that kills sperm. 
• 
Intrauterine device (IUD). 
• 
Tubal ligation. 
 

 
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If you can become pregnant, you must have a pregnancy test before you enter this study. The 
test must show that you are not pregnant. If you think you may be pregnant at any time during 
the study, tell your study staff right away and you will be given a pregnancy test, as needed. If 
you are pregnant while in the study, you may choose to stay on the study but you will not 
receive study drug. Blood tests will be limited to safety blood tests and blood tests that measure 
the levels of cemiplimab/placebo in your body. You will be asked to have an extra visit 6 months 
after the end of your pregnancy in order for the research team to get information on the outcome 
of the pregnancy (even if it is after your participation in the study ends). If you are taking anti-
HIV drugs when you become pregnant, your pregnancy will be reported to an international 
database that collects information about pregnancies in women taking anti-HIV drugs. This 
report will not use your name or other information that could be used to identify you. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
This is the first use of cemiplimab in participants living with HIV. This is mainly a safety study. 
There is no expected direct benefit to your participating in this study. Information learned from 
this study may help others who have HIV. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study you have the choice of: 
• 
Treatment with prescription drugs available to you 
• 
Treatment with experimental drugs, if you qualify  
• 
No treatment 
 
Please talk to your doctor about these and other choices available to you. Your doctor will 
explain the risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
We will do everything we can to protect your privacy. In addition to the efforts of the study staff 
to help keep your personal information private, we have gotten a Certificate of Confidentiality 
from the U.S. Federal Government. This certificate means that researchers cannot be forced to 
tell people who are not connected with this study, such as the court system, about your 
participation. Also, any publication of this study will not use your name or identify you 
personally. Further, the Genetic Information Nondiscrimination Act of 2008 (GINA) is a federal 
law that protects individuals from genetic discrimination in health insurance and employment. 
Genetic discrimination is the misuse of genetic information. 
 
People who may review your records include the ACTG, OHRP, or other local, US, and 
international regulatory agencies as part of their duties, FDA, (insert name of site), IRB (a 
committee that protects the rights and safety of participants in research), NIH, study staff, study 
monitors, drug companies supporting this study, and their designees. If you are a woman and 
you become pregnant while on this study, your pregnancy will be reported to the Antiretroviral 

 
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Pregnancy Registry. Having a Certificate of Confidentiality does not prevent you from releasing 
information about yourself and your participation in the study. 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities. 
 
A description of this clinical trial will be available on http://clinicaltrials.gov, as required by U.S. 
law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time.  
 
 
WHAT ARE THE COSTS TO ME? 
 
There will be no cost to you for the study drug, cemiplimab, or placebo, study-related visits, 
physical examinations, required laboratory tests, or other procedures. This study will not provide 
you with antiretroviral drugs. You, your insurance company, or your health care system may 
need to assume the cost of drugs not provided by the study. In some cases, it is possible that 
your insurance company or health care system will not pay for these costs because you are 
taking part in a research study. 
 
 
WILL I RECEIVE ANY PAYMENT? 
 
[Insert site-specific information on compensation to study participants.] 
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of being in this study, you will be given immediate treatment for 
your injuries. The cost for this treatment will be charged to you or your insurance company. 
There is no program for compensation either through this institution or the National Institutes of 
Health. You will not be giving up any of your legal rights by signing this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. Your decision will not have any impact on your participation in 
other studies conducted by NIH and will not result in any penalty or loss of benefits to which you 
are otherwise entitled. 
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. If you want the results of the study, let the study staff 
know. 
 
 

 
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WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
 
• 
[Name of the investigator or other study staff] 
• 
[Telephone number of above]  
 
For questions about your rights as a research participant, contact: 
 
• 
[Name or title of person on the IRB or other organization appropriate for the site] 
• 
[Telephone number of above] 

 
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SIGNATURE PAGE 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered, and you agree to take part in this study, please sign your name below. 
 
 
____________________________ 
_________________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
____________________________              _________________________________________ 
Participant’s Legal Guardian (print) 
Legal Guardian’s Signature and Date 
(As appropriate) 
 
 
____________________________ 
_________________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
____________________________ 
_________________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 
 
 
____________________________ 
_________________________________________ 
Study Physician Investigator                         Study Physician Investigator’s Signature and Date 
Conducting Consent Discussion (print)     
 

 
1 4 3  
A 5 3 7 0  
FI N A L V er si o n 1. 0  
1 1/ 1 6/ 1 8  
 
 
A P P E N DI X  II: P A R TI CI P A N T A S S E S S M E N T O F U N D E R S T A N DI N G  
 
N ot e f or Sit e s: T h e b el o w p arti ci p a nt a s s e s s m e nt of u n d er st a n di n g s h o ul d b e a d mi ni st er e d aft er t h e 
p arti ci p a nt h a s r e a d t h e c o n s e nt f or m . If t h e parti ci p a nt d o e s n ot a n s w er  all q u e sti o n s c orr e ctl y , t h e 
p h y si ci a n s h o ul d h el p t h e p arti ci p a nt t o u n d er st a n d t h e i n c orr e ct q u e sti o n s. If aft er t hi s h a s o c c urr e d,  at 
t h e j u d g m e nt of p h y si ci a n , t h e p arti ci p a nt still d o e s n ot u n d er st a n d t h e st u d y, t h e p arti ci p a nt s h o ul d n ot 
e nr oll.  A n s w er k e y f o u n d aft er a s s e s s m e nt.  S e e A 5 3 7 0 M O P S f or a d diti o n al i nf or m ati o n.  
 
 
Tr u e  
F al s e  
1.  
P arti ci p ati o n i n t h e st u d y will l a st f or a b o ut 4 8 w e e k s.  
 
 
2.  
Y o u m a y l e a v e t h e st u d y at a n y ti m e, if y o u c h o o s e t o d o s o, wit h o ut p e n alti e s.  
 
 
3.  
Y o u will r e c ei v e st u d y -r el at e d m e di c ati o n d uri n g a 3 0-mi n ut e i ntr a v e n o u s (I V, dir e ctl y i nt o 
y o ur v ei n i n y o ur ar m) i nf u si o n.  
 
 
4.  
T h er e i s n o e x p e ct e d dir e ct b e n efit a s a r e s ult of y o ur p arti ci p ati o n i n t h e st u d y.  
 
 
5.  
S o m e p arti ci p a nt s i n t hi s st u d y will r e c ei v e a pl a c e b o ( s ali n e wit h n o st u d y dr u g) i n st e a d of 
t h e st u d y dr u g ( c e mi pli m a b - a n a nti -P D -1 a nti b o d y).  
 
 
6.  
O n e of t h e p ur p o s e s of t hi s st u d y i s t o s e e if t h e st u d y dr u g i s s af e i n y o ur b o d y.  
 
 
7.  
O n e of t h e p ur p o s e s of t hi s st u d y i s  t o s e e w h et h er t h e st u d y dr u g c a n l o w er t h e a m o u nt of 
HI V t h at i s pr e s e nt i n t h e bl o o d a n d r e d u c e t h e a m o u nt of HI V t h at m a y b e hi di n g i n t h e 
c ell s (l at e nt r e s er v oir).  
 
 
8.  
Y o u m a y e x p eri e n c e s eri o u s i m m u n e -r el at e d si d e eff e ct s s u c h a s: s ki n r a s h, di arr h e a/ c oliti s 
( c ol o n i nfl a m m ati o n), h e p atiti s (li v er i nfl a m m ati o n), or p n e u m o niti s (l u n g i nfl a m m ati o n) a s a 
r e s ult of y o ur st u d y p arti ci p ati o n. 
 
 
9.  
Y o u m a y e x p eri e n c e i m m u n e -r el at e d si d e eff e ct s s u c h a s h y p o-/ h y p ert h yr oi di s m 
(i n cr e a s e d/ d e cr e a s e d t h yr oi d h or m o n e) or di a b et e s t h at c o ul d r e q uir e y o u t o t a k e lif e-l o n g 
m e di c ati o n s.  
 
 
1 0.  
Y o u will r e c ei v e t w o i nf u si o n s of pl a c e b o or st u d y m e di c ati o n d uri n g t hi s st u d y.  
 
 
1 1.  
T h e p ur p o s e of t hi s st u d y i s t o fi n d a c ur e f or HI V.  
 
 
1 2.  
T h er e m a y b e si d e eff e ct s of t h e st u d y m e di c ati o n t h at w e d o n ot k n o w a b o ut y et.  
 
 
1 3.  
Aft er j oi ni n g t h e st u d y, y o u will n ot  n e e d t o pr a cti c e s af er s e x b y u si n g at l e a st 2 f or m s of 
birt h c o ntr ol.  
 
 
1 4.  
M al e p arti ci p a nt s w h o s e f e m al e p art n er s b e c o m e pr e g n a nt w hil e o n st u d y will c o nti n u e 
tr e at m e nt. 
 
 
1 5.  
F or f e m al e p arti ci p a nt s w h o ar e a bl e t o b e c o m e pr e g n a nt, aft er y o u j oi n t h e st u d y, it d o e s 
n ot m att er if y o u b e c o m e pr e g n a nt.  
 
 
1 6.  
T h er e i s p ot e nti al f or s eri o u s si d e eff e ct s/ c o n diti o n s fr o m t h e i nf u si o n of st u d y dr u g t h at 
c a n n ot b e r e v er s e d (fi x e d).  
 
 
1 7.  
S eri o u s a n d irr e v er si bl e si d e eff e ct s/ c o n diti o n s T H A T M A Y B E P E R M A N E N T C A N 
R E S U L T fr o m t h e i nf u si o n of st u d y dr u g A N D m a y r e q uir e tr e at m e nt. 
 
 
1 8.  
P arti ci p ati n g i n t hi s st u d y m a y n ot h a v e a dir e ct h e alt h b e n efit f or m e, b ut will h el p 
i n v e sti g at or s tr yi n g t o a n s w er a v er y i m p ort a nt s ci e ntifi c q u e sti o n. 
 
 
 
 

 
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ANSWER KEY- Remove from assessment prior to giving to participant. 
True 
False 
1. 
Participation in the study will last for about 48 weeks. 
 
 
2. 
You may leave the study at any time, if you choose to do so, without penalties. 
 
 
3. 
You will receive study-related medication during a 30-minute intravenous (IV, 
directly into your vein in your arm) infusion. 
 
 
4. 
You will most likely receive no direct benefit as a result of your participation in the 
study. 
 
 
5. 
Some participants in this study will receive a placebo (saline with no study drug) 
instead of the study drug (cemiplimab - an anti-PD-1 antibody). 
 
 
6. 
One of the purposes of this study is to see if the study drug is safe in your body. 
 
 
7. 
One of the purposes of this study is to see whether the study drug can lower the 
amount of HIV that is present in the blood and reduce the amount of HIV that may 
be hiding in the cells (latent reservoir). 
 
 
8. 
You may experience immune-related side effects such as: skin rash, 
diarrhea/colitis (colon inflammation), hepatitis (liver inflammation), or pneumonitis 
(lung inflammation) as a result of your study participation. 
 
 
9. 
You may experience immune-related side effects such as hypo-/hyperthyroidism 
(increased/decreased thyroid hormone) or diabetes that could require you to take 
life-long medications. 
 
 
10. 
You will receive two infusions of placebo or study medication during this study. 
 
 
11. 
The purpose of this study is to find a cure for HIV. 
 
 
12. 
There may be side effects of the study medication that we do not know about yet. 
 
 
13. 
After joining the study, you will not need to practice safer sex by using at least 2 
forms of birth control. 
 
 
14. 
Male participants whose female partners become pregnant while on study will 
continue treatment. 
 
 
15. 
For female participants who are able to become pregnant, after you join the   
study, it does not matter if you become pregnant. 
 
 
16. 
There is potential for serious side effects/conditions from the infusion of study drug 
that cannot be reversed (fixed). 
 
 
17. 
Serious and irreversible side effects/conditions THAT MAY BE PERMANENT CAN 
RESULT from the infusion of study drug AND may require treatment. 
 
 
18. 
Participating in this study may not have a direct health benefit for me, but will help 
investigators trying to answer a very important scientific question. 
