A Phase I Study of Ipilimumab and Nivolumab in Advanced HIV Associated Solid Tumors With Expansion Cohort in HIV Associated Solid Tumors and a Cohort of HIV-Associated Classical Hodgkin Lymphoma
Phase: PHASE1
Conditions: Advanced Malignant Solid Neoplasm, Anal Carcinoma, HIV Infection, Kaposi Sarcoma, Lung Carcinoma, Metastatic Malignant Solid Neoplasm, Recurrent Classic Hodgkin Lymphoma, Refractory Classic Hodgkin Lymphoma, Unresectable Solid Neoplasm, HIV-associated Cancers
Sponsor: National Cancer Institute (NCI)



AMC #095 (Version 15.0) 24AUG2023 
 
2 
NCI Version Date 24AUG2023 
AMC PROTOCOL SIGNATURE PAGE 
 
I, _____________________, Principal Investigator at site ____, agree to conduct and follow this 
protocol: AMC Protocol #095 – A Phase I Study of Ipilimumab and Nivolumab in Advanced 
HIV-Associated Solid Tumors with Expansion Cohorts in HIV-Associated Solid Tumors 
and a Cohort of HIV-Associated Classical Hodgkin Lymphoma (Version 15.0, 
24AUG2023), as written according to AMC, NCI, and FDA guidelines. I understand that no 
deviations from the protocol eligibility criteria or waivers for protocol deviations will be 
permitted. 
 
 
_________________________________ 
 
_____________________ 
Signature 
 
 
 
 
 
Date (mm/dd/yyyy) 
 

AMC #095 (Version 15.0) 24AUG2023 
 
3 
NCI Version Date 24AUG2023 
TABLE OF CONTENTS 
 
SUMMARY OF CHANGES ......................................................................................................... i 
I. 
Changes Required by Request for Rapid Amendment for Nivolumab from Dr. 
Howard Streicher (streicherh@ctep.nci.nih.gov), dated 03AUG2023: ................... i 
II. 
Administrative and Editorial Changes: ................................................................... ii 
AMC PROTOCOL SIGNATURE PAGE ...................................................................................2 
TABLE OF CONTENTS ..............................................................................................................3 
LIST OF TABLES .........................................................................................................................7 
PROTOCOL ROSTER .................................................................................................................8 
ABBREVIATIONS LIST ............................................................................................................10 
PROTOCOL SYNOPSIS ............................................................................................................12 
PROTOCOL SCHEMA ..............................................................................................................16 
1.0 
OBJECTIVES ..................................................................................................................18 
1.1 
Primary Objective ..................................................................................................18 
1.2 
Secondary Objectives .............................................................................................18 
1.3 
Exploratory Objectives ..........................................................................................18 
2.0 
BACKGROUND ..............................................................................................................20 
2.1 
Study Disease .........................................................................................................20 
2.2 
Study Agents ..........................................................................................................24 
2.3 
Study Design and Rationale ...................................................................................29 
2.4 
Correlative Studies (Exploratory) ..........................................................................38 
3.0 
PARTICIPANT SELECTION .......................................................................................41 
3.1 
Eligibility Criteria ..................................................................................................41 
3.2 
Exclusion Criteria ..................................................................................................44 
3.3 
Criteria for Solid Tumor Expansion and Lymphoma Cohorts ...............................46 
3.4 
Number of Participants to be Enrolled ...................................................................47 
3.5 
Participant Enrollment Procedures ........................................................................47 
4.0 
TREATMENT PLAN ......................................................................................................48 
4.1 
Treatment Design ...................................................................................................48 
4.2 
Dose De-Escalation Cohorts: Stratum 1 and Stratum 2 .........................................48 
4.3 
Treatment Plan .......................................................................................................52 
4.4 
Definition of DLT ..................................................................................................54 

AMC #095 (Version 15.0) 24AUG2023 
 
4 
NCI Version Date 24AUG2023 
4.5 
Dose Adjustments, Dose Delays, and Missed Doses .............................................55 
4.6 
General Concomitant Medication and Supportive Care Guidelines ......................55 
4.7 
Duration of Therapy ...............................................................................................57 
4.8 
Duration of Follow-Up ..........................................................................................58 
4.9 
Criteria for Removal from Treatment ....................................................................58 
4.10 
Criteria to Resume Treatment ................................................................................59 
4.11 
Treatment of Nivolumab-Related and Ipilimumab Combination Infusion 
Reactions ................................................................................................................59 
5.0 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................61 
5.1 
Dose Modifications for Nivolumab and Nivolumab and Ipilimumab Combination
................................................................................................................................61 
5.2 
Other Guidance ......................................................................................................67 
6.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .......................74 
6.1 
Comprehensive AEs and Potential Risks Lists (CAEPRs) ....................................74 
6.2 
Classification of AEs by Severity and Relationship to Study Drug Administration
................................................................................................................................83 
6.3 
Expedited AE Reporting ........................................................................................83 
6.4 
Routine AE Reporting............................................................................................85 
6.5 
Secondary Malignancy ...........................................................................................86 
6.6 
Second Malignancy ................................................................................................86 
7.0 
PHARMACEUTICAL INFORMATION ......................................................................87 
7.1 
Nivolumab (NSC 748726) .....................................................................................87 
7.2 
Ipilimumab (NSC 732442) ....................................................................................88 
7.3 
Agent Ordering and Agent Accountability ............................................................90 
7.4 
Agent Inventory Records .......................................................................................90 
7.5 
Useful Links and Contacts .....................................................................................90 
8.0 
CLINICAL AND LABORATORY EVALUATIONS ..................................................92 
8.1 
Pre-Study Evaluations (Visit -1) ............................................................................92 
8.2 
Cycle 1, Day 1........................................................................................................94 
8.3 
Cycle 1, Day 8........................................................................................................95 
8.4 
Cycles 2-4, Day 1 ...................................................................................................96 
8.5 
Cycles 5-46, Day 1 .................................................................................................96 
8.6 
Combination Therapy Solid Tumor Expansion Cohort: Cycle 5-23 Day 1 ...........99 

AMC #095 (Version 15.0) 24AUG2023 
 
5 
NCI Version Date 24AUG2023 
8.7 
Treatment Discontinuation Evaluations ...............................................................100 
9.0 
MEASUREMENT OF EFFECT ..................................................................................103 
9.1 
Antitumor Effect – Solid Tumors ........................................................................103 
9.2 
Evaluation of Response for Participants with Kaposi Sarcoma ...........................109 
9.3 
Evaluation of Response for Participants with HIV-Associated Hodgkin 
Lymphoma ...........................................................................................................111 
10.0 
STATISTICAL CONSIDERATIONS .........................................................................115 
10.1 
Study Design/Endpoints.......................................................................................115 
10.2 
Sample Size/Accrual Rate ....................................................................................116 
10.3 
Stratification Factors ............................................................................................117 
10.4 
Analysis of Secondary Endpoints ........................................................................117 
10.5 
Exploratory Objectives ........................................................................................117 
11.0 
ROLE OF DATA MANAGEMENT ............................................................................119 
11.1 
CRF Instructions ..................................................................................................119 
11.2 
Data Quality .........................................................................................................119 
11.3 
Data Monitoring ...................................................................................................119 
12.0 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................120 
12.1 
IRB Approval and Informed Consent ..................................................................120 
12.2 
Changes to the Protocol ......................................... Error! Bookmark not defined. 
12.3 
Women and Minorities ........................................................................................120 
13.0 
REFERENCES ...............................................................................................................122 
APPENDIX I: SCHEDULES OF EVALUATIONS ...............................................................132 
Schedule of Evaluations ...................................................................................................132 
Biological Sample Submissions for Correlative Studies .................................................136 
Schedule of Evaluations for participants on combination therapy solid tumor expansion 
cohort ...................................................................................................................138 
Biological Sample Submissions for Correlative Studies for participants on combination 
therapy solid tumor expansion cohort ..................................................................142 
APPENDIX II: COLLABORATIVE RESEARCH AGREEMENT ...........................................144 
APPENDIX III: PERFORMANCE STATUS SCALES .............................................................146 
APPENDIX IV: AIDS AND CANCER SPECIMEN RESOURCE (ACSR) SPECIMEN 
PREPARATION AND SHIPPING INSTRUCTIONS ...................................................147 
APPENDIX V: ACSR INFORMED CONSENT ........................................................................150 
APPENDIX VI: AMC DATA AND SAFETY MONITORING PLAN .....................................155 

AMC #095 (Version 15.0) 24AUG2023 
 
6 
NCI Version Date 24AUG2023 
APPENDIX VII: LIST OF PROHIBITED MEDICATIONS .....................................................160 
APPENDIX VIII: PROPHYLAXIS AGAINST OPPORTUNISTIC INFECTIONS IN 
PATIENTS WITH AIDS .................................................................................................161 
APPENDIX IX: IMAGING METHODOLOGIES .....................................................................162 
APPENDIX X: NIVOLUMAB: MANAGEMENT ALGORITHMS FOR 
ENDOCRINOPATHY, GASTROINTESTINAL, HEPATIC, NEUROLOGICAL, 
PULMONARY, RENAL, AND SKIN ADVERSE EVENTS ........................................163 
APPENDIX XI: DEFINITION OF AIDS INDICATOR CONDITIONS ...................................171 
APPENDIX XII: PHOTOGRAPHIC RECORD OF KS LESIONS ...........................................172 
APPENDIX XIII: KS STAGING CRITERIA .............................................................................173 
APPENDIX XIV: AMC BIOREPOSITORY SPECIMEN PREPARATION AND SHIPPING 
INSTRUCTIONS .............................................................................................................174 
APPENDIX XV: COLLECTION AND SHIPPING INSTRUCTIONS FOR PERIPHERAL 
BLOOD FOR IMMUNE RESPONSE (Cytokines and Soluble Receptors) ...................179 
APPENDIX XVI: HIV LATENT RESERVOIR AND VIRAL OUTGROWTH ASSAY 
SPECIMEN PREPARATION AND SHIPPING INSTRUCTIONS ...............................183 
APPENDIX XVII: PROCEDURE FOR INTRA-ANAL HPV DNA PCR SAMPLE 
COLLECTION, PACKAGING, AND SHIPPING .........................................................186 
 

AMC #095 (Version 15.0) 24AUG2023 
 
7 
NCI Version Date 24AUG2023 
LIST OF TABLES 
Table 1:  
Dose De-Escalation Schedule Stratum 1 and 2 ......................................................... 49 
Table 2:  
Dose Modification Tables for Nivolumab and Nivolumab and Ipilimumab 
Combination .............................................................................................................. 61 
Table 3:  
Ipilimumab Composition ........................................................................................... 89 
Table 4:  
Response Evaluation for Participants with Measurable Disease (i.e., Target Disease)
 ................................................................................................................................. 108 
Table 5:  
Response Evaluation for Participants with Non-Measurable Disease (i.e., Non-
Target Disease) ........................................................................................................ 109 
Table 6.  
Response Categories Based on Assessment of Target Lesions ............................... 114 
Table 7:  
Accrual Targets ....................................................................................................... 121 
 
 

AMC #095 (Version 15.0) 24AUG2023 
 
8 
NCI Version Date 24AUG2023 
PROTOCOL ROSTER 
AMC Protocol #095 
A Phase I Study of Ipilimumab and Nivolumab in Advanced HIV-Associated Solid Tumors 
with Expansion Cohorts in HIV-Associated Solid Tumors and a Cohort of HIV-Associated 
Classical Hodgkin Lymphoma 
 
 
Protocol Chair:  
Protocol Co-Chair (Hematologic Malignancies): 
Lakshmi Rajdev, MD, MS 
Northwell Health 
130 East 77th Street, 
New York, NY 10021 
Tel: 212-434-4736 
Fax: 212-434-2246 
Email: lrajdev2@gmail.com 
Paul Rubinstein, MD 
Stroger Hospital of Cook County 
Department of Medicine 
Section of Hematology/Oncology 
Administration Building 
1900 W. Polk Street, Suite 755 
Chicago, IL 60612 
Tel: 312-864-7277 
Fax: 312-864-9002 
Email: prubinstein@cookcountyhhs.org 
 
Protocol Co-Chairs: 
Protocol Statisticians: 
Mark H. Einstein, MD, MS 
Department of Obstetrics, Gynecology and 
Women’s Health 
Clinical Research Unit 
Medical Science Building, Room E506 
Rutgers, The State University of New Jersey 
185 South Orange Avenue 
Newark, NJ 07103 
Tel: 973-972-5266 
Fax: 973-972-4574 
Email: Mark.Einstein@Rutgers.edu 
 
 
Dirk P. Dittmer, PhD 
Lineberger Comprehensive Cancer Center 
University of North Carolina at Chapel Hill 
450 West Dr. Rm. #12-038, CB #7295 
Chapel Hill, NC 27599-7290 
Tel: 919-966-7960 
Fax: 919-962-8103 
Email: ddittmer@med.unc.edu 
 
Himanshu Joshi, PhD, MSc, MPH, MBBS 
Icahn School of Medicine at Mount Sinai 
1425 Madison Avenue,  
New York, NY 10029 
Tel: 212-659-9635 
Fax: 212-423-2998 
Email: himanshu.joshi@mountsinai.org 
 
Mayuri Jain, MPH 
Icahn School of Medicine at Mount Sinai 
1425 Madison Avenue 
New York, NY 10029 
Email: mayuri.jain@mountsinai.org 
 
Data Management/Operations: 
AMC Operations and Data Management Center 
The Emmes Corporation 
401 N. Washington Street, Suite 700 
Rockville, MD 20850 
Tel: 301-251-1161 
Fax: 240-238-2842 
Email: amc-095@emmes.com  

AMC #095 (Version 15.0) 24AUG2023 
 
9 
NCI Version Date 24AUG2023 
Protocol Research Nurse: 
AMC Biorepository Director: 
Yoko Eng, NP 
Montefiore Medical Center 
#100 Hofheimer Building 
Bronx, NY 10461 
Tel: 718-920-2090 
Fax: 718-405-7412 
Email: yeng@montefiore.org 
Jeffrey M. Bethony, PhD 
Chair, AMC Laboratory Resource Committee 
Department of Microbiology, Immunology & 
Tropical Medicine 
The George Washington University 
2300 I Street NW, Room 523 
Washington, DC 20052 
Tel: 202-994-2663 
Cell: 202-590-8342 
Email: jbethony@gwu.edu 
 
AMC NADC Working Group Chair: 
AMC Lymphoma Working Group Chair 
Elizabeth Chiao, MD MPH 
Baylor College of Medicine 
Internal Medicine/Infectious Diseases 
One Baylor Plaza 
Houston, TX 77030 
Tel: 713-440-4485 
Fax: 713-748-7359 
Email: echiao@bcm.edu 
Ariela Noy, MD 
Memorial Sloan Kettering Cancer Center 
Lymphoma Service 
1275 York Avenue 
New York, NY 10065 
Tel: 212-639-7423 
Fax: 646-422-2284 
Email: noya@mskcc.org 
 

AMC #095 (Version 15.0) 24AUG2023 
 
10 
NCI Version Date 24AUG2023 
ABBREVIATIONS LIST 
 
ACSR 
AIDS and Cancer Specimen Resource 
AE 
Adverse event 
AERS 
Adverse Event Reporting System 
AIN 
Anal intraepithelial neoplasia 
AMC 
AIDS Malignancy Consortium 
AML 
Acute myelocytic leukemia  
ANA 
Anti-nuclear antibody 
ANC 
Absolute neutrophil count 
ART 
antiretroviral therapy 
BMS 
Bristol-Myers-Squibb 
CAEPR 
Comprehensive Adverse Events and Potential Risks List 
cART 
Combined antiretroviral therapy 
CHF 
Congestive heart failure 
cHL 
Classical Hodgkin lymphoma 
CLIA 
Clinical laboratory improvement amendments 
CMV 
Cytomegalovirus infection 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DARF 
Drug Accountability Record Form 
DCTD 
Division of Cancer Treatment and Diagnosis 
DHHS 
Department of Health and Human Services 
DL 
Dose level 
DLBCL 
Diffuse large B cell lymphoma 
DLT 
Dose-limiting toxicity 
EBV 
Epstein-Barr virus 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
FDA 
Food and Drug Administration 
FDF 
Financial Disclosure Form 
HAART 
Highly active antiretroviral therapy 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HIV-cHL HIV-associated classical Hodgkin lymphoma 
HPV 
Human papillomavirus 
hRS 
Hodgkin and Reid Sternberg cell 
IAM 
Identity and Access Management 
IBD 
Inflammatory bowel disease 
IDF 
Investigator Data Form 
IRB 
Institutional review board 

AMC #095 (Version 15.0) 24AUG2023 
 
11 
NCI Version Date 24AUG2023 
IRC 
Immune response criteria 
irAE 
Immune-related adverse event 
IV 
Intravenous 
KS 
Kaposi’s sarcoma 
KSHV 
Kaposi’s sarcoma-associated herpesvirus 
LFT 
Liver function tests 
MDS 
Myelodysplastic syndrome 
MRI 
Magnetic resonance imaging 
MSS 
Microsatellite stable [colorectal cancer] 
MTD 
Maximum tolerated dose 
mWHO 
Modified World Health Organization conventions 
NADC 
Non-AIDS-defining cancer 
NCI 
National Cancer Institute 
NHL 
Non-Hodgkin lymphoma 
OAOP 
Online Agent Order Processing 
ODMC 
Operations and data management center 
PMB 
Pharmaceutical Management Branch 
PCR 
Polymerase chain reaction 
PVC 
Polyvinyl chloride 
RECIL 
International Working Group consensus response evaluation criteria in lymphoma 
RR 
Response rate 
SAE 
Serious adverse event 
SPD 
Sum of Product of Diameters 
SPEER 
Specific Protocol Exceptions to Expedited Reporting 
TEN 
Toxic epidermal necrolysis 
ULN 
Institutional upper limit of normal 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
 
 

AMC #095 (Version 15.0) 24AUG2023 
 
12 
NCI Version Date 24AUG2023 
PROTOCOL SYNOPSIS 
 
Title: 
A Phase I Study of Ipilimumab and Nivolumab in Advanced HIV-
Associated Tumors with Expansion Cohorts in HIV-Associated Solid 
Tumors and a Cohort of HIV-Associated Classical Hodgkin 
Lymphoma 
Phase of Study: 
Phase I 
Participating 
Institutions: 
This protocol will be open to all AMC domestic member sites. 
Accrual Target: 
Minimum of four participants with a maximum of 96 participants. 
Population: 
 
Participants with histologically confirmed solid malignancy and HIV 
infection. Solid malignancy must be metastatic or unresectable and 
standard curative or palliative measures are nonexistent or no longer 
effective. Uncontrolled Kaposi sarcoma is permitted. Participants with 
relapsed refractory HIV-associated classical Hodgkin lymphoma 
(HIV-cHL) as a separate cohort.  
Regimen: 
In the dose de-escalation cohort, participants will be enrolled in 
separate strata: Stratum 1 will enroll participants with lymphocyte T 
CD4+ count above 200/mm3. Stratum 2 will enroll participants with 
lymphocyte T CD4+ count between 100-200/mm3. Enrollment will 
occur sequentially, initially in Stratum 1 and then in Stratum 2 after 
Stratum 1 has completed. 
Stratum 1 dosing will start with a full dose of nivolumab 3 mg/kg (dose 
level 1), and one dose de-escalation is allowed; after evaluating dosing 
for single agent nivolumab then participants will be treated with 
240mg of nivolumab and 1mg/kg of ipilimumab will be added to 
evaluate combination therapy (dose level 2) with one dose de-
escalation allowed. No intra-participant dose escalations will be 
allowed. The safety evaluation period is 6 weeks at a given dose level. 
Stratum 2 dosing will begin at the single agent therapy maximum 
tolerated dose (MTD) for Stratum 1 (dose level 1 or -1). Stratum 2 will 
not be allowed to escalate beyond the MTD for Stratum 1. Only 1 dose 
de-escalation will be allowed. 
The study treatment consists of up to 46 intravenous (IV) infusions of 
nivolumab on Day 1 of each 2-week cycle for the dose level -1 and 1 
cohorts. For dose level 2, IV infusions of nivolumab are given on Day 
1 of each 2-week cycle and ipilimumab on Day 1 every 6 weeks, i.e., 
every third cycle (cycles 1, 4, 7, etc.). For dose level -2, IV infusions 
of nivolumab are given on day 1 of each 2-week cycle, and ipilimumab 

AMC #095 (Version 15.0) 24AUG2023 
 
13 
NCI Version Date 24AUG2023 
is given on day 1 every 12 weeks, i.e., every sixth cycle (cycles 1, 7, 
13, etc.). Participants with an overall response of stable disease (SD), 
partial response (PR), complete response (CR), or unconfirmed 
progressive disease (PD) at Week 8 will continue treatment (Refer to 
Section 9.1 for Response Evaluation Criteria in Solid Tumors 
(RECIST) Criteria for up to 84 weeks, (42 IV infusions of nivolumab 
every 2 weeks, see the table below for the ipilimumab schedule if on 
dose level 2 or -2). 
Dose Level 
Nivolumab* 
q2 wk (46 doses) 
Ipilimumab** 
-1 
1mg/kg 
- 
1 
3mg/kg 
- 
2 
240mg 
1mg/kg q 6 wk(16 doses)(day 1 of 
nivolumab cycles 1, 4, 7, 10, 13, 16, 
19, 22, 25, 28, 31, 34, 37, 40, 43, and 
46) 
-2 
1mg/kg 
1mg/kg q 12 wk (8 doses)(day 1 of 
nivolumab cycles 1, 7, 13, 19, 25, 31, 
37, and 43) 
* Treatment will continue until documented disease progression, discontinuation due 
to toxicity, withdrawal of consent or end of study, up to 46 doses of nivolumab. 
** After evaluating single agent nivolumab dosing, the next dose level will be 2 if 
dose level 1 is the MTD for single agent nivolumab and dose level -2 if dose level -
1 is the single agent MTD. It is also possible to de-escalate from dose level 2 to -2. 
The combination therapy MTD will then be studied in a dose 
expansion cohort (12 participants) limited to only participants with 
Kaposi sarcoma, lung cancer, and anal cancer; CD4+ count eligibility 
criteria in the expansion cohort will be determined after reviewing 
results from Strata 1 and 2. If the MTDs differ between the two strata, 
expansion cohorts of six participants each will be enrolled. The study 
treatment consists of 12 IV infusions of nivolumab, 240 mg, on Day 1 
of each 2-week cycle and ipilimumab on Day 1 every 6 weeks with 
four total ipilimumab doses, i.e., every third cycle (cycles 1, 4, 7, 10). 
After completion of the 12th cycle of nivolumab, the nivolumab dose 
will change to a flat dose of 480mg, on Day 1 of each 4-week cycle 
without ipilimumab. Participants with an overall response of SD, PR, 
CR, or unconfirmed PD at Week 8 will continue treatment (Refer to 
Section 9.1 for RECIST Criteria) for up to 84 weeks. 
A single agent expansion cohort of 24 participants with solid tumors, 
excluding those histologies not known to respond to single agent 
nivolumab (i.e., pancreas, prostate, and microsatellite stable [MSS] 
colorectal cancer) and with CD4 count above 200 will receive single 
agent nivolumab at 240mg administered every 2 weeks for up to 46 

AMC #095 (Version 15.0) 24AUG2023 
 
14 
NCI Version Date 24AUG2023 
doses, or until disease progression, toxicity, study termination, or study 
withdrawal. 
Another single agent cohort of 12 participants with relapsed refractory 
HIV-associated cHL and with CD4 counts > 100/mm3, will also be 
treated with single agent nivolumab at a flat dose of 240mg 
administered every 2 weeks for 46 doses or until disease progression, 
toxicity, study termination, or study withdrawal (See Section 9.3 for 
the 2017 response evaluation criteria in lymphoma (RECIL) Criteria 
for evaluation of measurable disease in HIV-cHL and Section 4.7 and 
4.9 for study duration and criteria for removal from study). Participants 
with an overall response of SD, PR, CR, or unconfirmed PD at Week 
8 will continue treatment. Of note, this dose showed no dose-limiting 
toxicity (DLT) in this trial and is the current FDA approved dosing 
regimen for non-HIV classical Hodgkin lymphoma.  
Duration: 
Maximum of 92 weeks of treatment 
Primary Objective: 
Dose De-Escalation and Expansion Cohorts: 
To demonstrate safety and feasibility of ipilimumab and nivolumab at 
the standard doses of drug in solid tumor and relapsed refractory HIV-
cHL participants with HIV infection given the possibility of increased 
toxicity based on immune activation, co-morbidity, or interference 
with Highly active antiretroviral therapy (HAART) . The purpose for 
this would be to provide appropriate experience and guidelines, if 
necessary, to allow participants with HIV infections to participate in 
ongoing trials. 
Secondary Objectives: 
 
Dose De-Escalation Cohort: To evaluate the effects of single agent 
nivolumab, and the combination of ipilimumab and nivolumab, on 
immune function (HIV viral load in plasma using conventional HIV 
assay, CD4+/CD8+ cells). 
Solid Tumor Dose Expansion and cHL Cohorts: To preliminarily 
assess objective response rates associated with treatment for 
commonly represented solid tumors and relapsed refractory HIV-cHL. 
Solid Tumor Dose Expansion and cHL Cohorts: To evaluate the effects 
of single agent nivolumab, and the combination of ipilimumab and 
nivolumab, on immune function (HIV viral load in plasma using 
conventional HIV assay, CD4+/CD8+ cells). Only single agent 
nivolumab will be administered in the cHL cohort. 
Exploratory Objectives: 
Dose De-Escalation and Solid Tumor Expansion and cHL Cohorts: 

AMC #095 (Version 15.0) 24AUG2023 
 
15 
NCI Version Date 24AUG2023 
1. Understand the immune response to agent in the context of 
antiretroviral therapy (ART), of altered immune function, and 
repertoire due to prior HIV infection. 
• To evaluate the effects of single agent nivolumab, and the 
combination of ipilimumab and nivolumab, on intratumor 
immune cells by IHC for PD1, PDL-1, and others. 
• To evaluate the effects of single agent nivolumab, and the 
combination of ipilimumab and nivolumab on circulating 
cytokine markers by multiplex assay. 
2. To understand the response of human tumor viruses (Human 
papillomavirus (HPV), Epstein-Barr virus (EBV), and Kaposi’s 
sarcoma-associated herpesvirus (KSHV)) to agent. 
• To evaluate the effects of single agent nivolumab, and the 
combination of ipilimumab and nivolumab on herpesvirus 
loads (EBV, KSHV, Cytomegalovirus infection (CMV) in 
plasma. 
• To evaluate the effects of single agent nivolumab, and the 
combination of ipilimumab and nivolumab on latent 
herpesvirus (EBV, KSHV, CMV) in peripheral blood 
mononuclear cells (PBMC). 
• To evaluate the effects of single agent nivolumab, and the 
combination of ipilimumab and nivolumab on herpesvirus 
specific CD8 and CD4 T cells in PBMC. 
• In cases of Kaposi sarcoma, to evaluate the effects of single 
agent nivolumab, and the combination of ipilimumab and 
nivolumab on viral transcription in tumor biopsies, when 
feasible. 
• In cases of anal cancer, to evaluate the effects of single agent 
nivolumab, and the combination of ipilimumab and nivolumab 
on HPV types in anal swabs, when feasible. 
3. Understand the response of HIV to agent. 
• To evaluate the effects of single agent nivolumab, and the 
combination of ipilimumab and nivolumab on latent HIV loads 
in PBMC using outgrowth assay. 
• To evaluate the effects of single agent nivolumab, and the 
combination of ipilimumab and nivolumab on HIV reactive T 
cells. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
18 
NCI Version Date 24AUG2023 
1.0 
OBJECTIVES 
1.1 
Primary Objective 
Dose De-Escalation and Dose Expansion Cohorts: To demonstrate safety and feasibility of 
ipilimumab and nivolumab at the standard doses of drug in solid tumor and relapsed 
refractory HIV-cHL participants with human immunodeficiency virus (HIV) infection 
given the possibility of increased toxicity based on immune activation, co-morbidity, or 
interference with highly active antiretroviral therapy (HAART). The purpose for this would 
be to provide appropriate experience and guidelines, if necessary, to allow participants with 
HIV infections to participate in ongoing trials. 
1.2 
Secondary Objectives 
1.2.1 Dose De-Escalation Cohort: To evaluate the effects of single agent nivolumab, and 
the combination of ipilimumab and nivolumab, on immune function (HIV viral load 
in plasma using conventional assay, CD4+, and CD8+ cells). 
1.2.2 Solid Tumor Dose Expansion and cHL Cohorts: To preliminarily assess objective 
response rates associated with treatment for commonly represented solid tumors 
(Kaposi Sarcoma, anal cancer, and lung cancer) and relapsed refractory HIV-cHL. 
1.2.3 Solid Tumor Dose Expansion and cHL Cohorts: To evaluate the effects of single 
agent nivolumab, and the combination of ipilimumab and nivolumab, on immune 
function (HIV viral load in plasma using conventional HIV assay, CD4+, and CD8+ 
cells). Only single agent nivolumab will be utilized in the cHL cohort. 
1.3 
Exploratory Objectives 
The exploratory objectives are part of both the dose de-escalation phase and the expansion 
phase. Some of the correlative biomarkers are only present in a subset of tumor types, e.g. 
HPV in anal cancer. All exploratory objectives will be addressed in batch at the completion 
of enrollment/study as applicable. 
1.3.1 Understand the immune response to agent in the context of antiretroviral therapy 
(ART), of altered immune function, and repertoire due to prior HIV infection 
1.3.1.1 To evaluate the effects of single agent nivolumab, and the combination of 
ipilimumab and nivolumab, on intratumor immune cells by IHC such as 
PD1, PDL-1, and others. 
1.3.1.2 To evaluate the effects of single agent nivolumab, and the combination of 
ipilimumab and nivolumab on circulating cytokine markers by multiplex 
assay, such as: IL-2, IL-4, IL-6, IL-10, IL-8, IP10, CXCL13, IFN-γ, TNF-
α, sIL2R-α, sCD27, sTNFR1, and sTNFR2. 
1.3.2 To understand the response of human tumor viruses (Human papillomavirus 
(HPV), Epstein-Barr virus (EBV), and Kaposi’s sarcoma-associated herpesvirus 
(KSHV)) to agent 
1.3.2.1 To evaluate the effects of single agent nivolumab, and the combination of 
ipilimumab and nivolumab on herpesvirus loads (EBV, KSHV, 
Cytomegalovirus infection (CMV)) in plasma. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
19 
NCI Version Date 24AUG2023 
1.3.2.2 To evaluate the effects of single agent nivolumab, and the combination of 
ipilimumab and nivolumab on latent herpesvirus (EBV, KSHV, CMV) in 
peripheral blood mononuclear cells (PBMC). 
1.3.2.3 To evaluate the effects of single agent nivolumab, and the combination of 
ipilimumab and nivolumab on herpesvirus specific CD8 and CD4 T cells in 
PBMC. 
1.3.2.4 In cases of Kaposi sarcoma, to evaluate the effects of single agent 
nivolumab, and the combination of ipilimumab and nivolumab on viral 
transcription in tumor biopsies. 
1.3.2.5 In cases of anal cancer, to evaluate the effects of single agent nivolumab, 
and the combination of ipilimumab and nivolumab on HPV types in anal 
swabs, when feasible. 
1.3.3 Understand the response of HIV to agent 
1.3.3.1 To evaluate the effects of single agent nivolumab, and the combination of 
ipilimumab and nivolumab on latent HIV loads in PBMC using outgrowth 
assay. 
1.3.3.2 To evaluate the effects of single agent nivolumab, and the combination of 
ipilimumab and nivolumab on HIV reactive T cells. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
20 
NCI Version Date 24AUG2023 
2.0 
BACKGROUND 
2.1 
Study Disease 
HIV infected individuals have an increased propensity to develop malignancy [1, 2]. Early 
in the AIDS epidemic, a dramatic increase in Kaposi sarcoma (KS), non-Hodgkin 
lymphoma (NHL), and cervical cancer was noted, and these tumors ultimately were 
classified as AIDS-defining cancers. With the widespread use of potent combination 
antiretroviral therapy (cART), there was a decrease in the incidence of KS and NHL and a 
significant increase in the incidence of several other malignancies (non-AIDS-defining 
cancers). The risk of dying from non-AIDS-defining cancers (NADC) has been increasing 
[3]. At present NHL, KS, and NADC each account for approximately 1/3 of cancers in 
HIV patients on cART. 
Malignancies in patients infected with HIV are often characterized by earlier age at onset, 
atypical pathology (higher tumor grade), more aggressive clinical behavior, and/or more 
advanced stage at presentation [4, 5]. 
Multiple factors may contribute to the increased incidence of malignancy in patients 
infected with HIV. These include immunosuppression, perhaps direct effects of the HIV 
virus itself, coinfection with other oncogenic viruses, environmental factors, and possibly 
the use of antiretroviral drugs. 
The immunosuppression seen in the HIV infected patients may accelerate the development 
of neoplasia. The cancers are similar to that observed in solid organ transplant recipients 
who receive chronic immunosuppressive agents, as well as in patients with profound 
inherited immune deficiencies. Even after years of successful ART and complete 
“virologic” response, the T cell repertoire in HIV+ patients remain compromised. It is 
unclear if and to what degree T cell function remains compromised as well. 
2.1.1 HIV-associated neoplasia: the HIV virus and other oncogenic viruses 
Role of the HIV virus. A direct molecular role for HIV in cancer remains a matter 
of discussion. HIV infection may have a direct effect on a variety of cellular 
processes that contribute to the development of cancer [5]. Postulated mechanisms 
include the activation of proto-oncogene’s, alterations in cell cycle regulation, 
inhibition of tumor suppressor genes, and possibly other genetic alterations that 
lead to oncogenesis though the most likely contribution of HIV to tumorigenesis is 
through immune suppression/ systemic immune activation and modulation of the 
tumor microenvironment. 
Coinfection with oncogenic viruses. Patients infected with HIV are at increased 
risk of coinfection with other viruses that are known to cause cancer [5]. 
Furthermore, the natural history of these viral infections may be accelerated in 
patients with HIV. 
HHV-8 infection. KS is caused by a human herpes virus 8 (HHV-8) or KSHV. 
KSHV has also been associated with the multicentric form of Castleman’s disease 
and primary effusion lymphoma. In the U.S., both of these entities are found 
primarily in patients with HIV infection. 
HPV infection. In addition to its relationship to cervical neoplasia, HPV infection 

 
AMC #095 (Version 15.0) 24AUG2023 
 
21 
NCI Version Date 24AUG2023 
is associated with cancers of the head and neck (especially the oropharynx and base 
of tongue) and anogenital (anus, penis, vagina, vulva) regions. Anal cancers have 
increased in incidence in HIV+ persons since the introduction of cART. 
EBV infection. Hodgkin lymphoma (HL) is not an AIDS-defining malignancy, 
EBV-associated NHL such as CNS lymphoma are AIDS-defining. EBV infection 
has an established etiologic role in some cases of lymphoma, and EBV is more 
frequently implicated in HL in HIV infected individuals than in non-HIV infected 
people. 
HBV and HCV infection. Infections with hepatitis B virus (HBV) or hepatitis C 
virus (HCV) are a major cause of hepatocellular carcinoma. Coinfection with HIV 
and either HBV or HCV can result in more rapid progression of liver disease, 
resulting in cirrhosis and hepatocellular carcinoma. 
Merkel cell polyomavirus. Merkel cell polyomavirus has a causative role in Merkel 
cell carcinoma, which is much more frequent in HIV infected people. 
2.1.2 The immune system and oncogenic viruses: pathogenesis of HIV-associated 
neoplasia 
Oncogenic viruses such as HPV and KSHV are capable of causing cancer not just 
in the HIV infected individuals but also in recipients of organ and bone marrow 
transplants who are immunosuppressed as well as in elderly and patients with no 
prior history of dramatic immune suppression. It is not exactly known what the 
trigger is that initiates neoplasia development. On the one hand, the immune system 
continuously controls chronic and persistent virus infection through the production 
of virus-antigen-specific B and T cells. For instance, approximately 10% of all 
circulating CD8 T cells are directed against human cytomegalovirus encoded 
epitopes, fewer against EBV, KSHV, HPV, and other persistent viruses. On the 
other hand, continuous antigenic stimulation that occurs during chronic virus 
infections causes severe immune dysfunction [6-8], and a concomitant induction of 
immuno-regulatory processes, which all result in the loss of tumor immune-
surveillance and may lead to cancer establishment and/or progression. 
In the HIV infected individual, there is a clear relationship between progressively 
lower CD4+ T cell levels and increased detection of HPV types in the anus. One of 
the most consistent risk factors for anogenital IN is a lower CD4+ level, suggesting 
that HIV-related immune suppression plays an important role in disease 
pathogenesis [9,10]. Loss of the appropriate immune response to HPV may play its 
most important role in permitting the development of high-grade IN, which has the 
potential to progress to cancer. However, progression from high-grade IN to cancer 
likely depends on additional factors as well. Increasing evidence suggests that one 
of these factors may be changes in host gene expression secondary to HPV-induced 
chromosomal instability and copy number abnormalities. 
It is speculated that if there is a low number of circulating HPV-specific memory 
cells, then HPV-specific immunity may be particularly vulnerable to the effects of 
HIV. Moreover, HPV-specific immunity may not recover fully after immune 
response is restored, which may explain the relatively limited beneficial effect of 

 
AMC #095 (Version 15.0) 24AUG2023 
 
22 
NCI Version Date 24AUG2023 
HAART on HPV-associated lesions. HAART does not appear to either prevent the 
development of AIN, nor the progression of AIN towards SCCA [11]. 
HIV-associated attenuation of HPV-specific immune responses may allow for 
persistence of oncogenic HPV, of high-grade IN and for sufficient time for 
accumulation to accumulate genetic changes that are important in progression to 
cancer. 
KS skin lesions, analogous to melanoma, at times regress spontaneously. The 
clinical experience in transplant KS shows rapid regression upon tapering of 
immune suppression [12]. In the HIV infected individual, there is a relationship 
between progressively lower CD4+ T cell levels and increased KS lesion 
development, though Maurer et al. as well as a review of AMC studies showed that 
KS now occurs in patients with undetectable KSHV viral load and near-normal 
CD4 counts [Even though the exact mechanism has not been elucidated, both 
immune presenting (Langerhans, NK, macrophage) and CD8+ T lymphocytes have 
been implicated. KSHV viral epitopes are recognized by human T cells and CD8 T 
cells attenuation has been observed in progressive KS, including in the setting of 
HIV [13-15]. In sum, like anal cancer KS is caused by a virus and KS tumor cells 
express viral T cell epitopes; like melanoma there is evidence of tumor-specific 
antigens and evidence of tumor regression in response to immune modulation. 
The pathogenesis of HIV-associated cHL and NHL is multifactorial, and in part 
depends on the tumor microenvironment, the presence of oncogenic viruses, and 
the CD4+ T cell count. The microenvironment of classical HL has been closely 
linked to the microenvironment. Data by Skinnider et al. has shown that CD4+ T 
cells initiate trophic signals promoting the survival of the malignant cell associated 
with HIV-cHL, the Reid Sternberg cell (hRS) [16]. This could also explain the 
increase in incidence of HIV-cHL from the pre-HAART to the HAART era 
[1,16,17]. 
Oncogenic viruses associated with HIV/AIDS-related lymphomas are mainly 
KSHV and EBV. Approximately 100% in primary effusion lymphoma, 90% of 
classical HL, 100% of primary CNS lymphoma in the HIV-population, and 80-
100% of immunoblastic diffuse large B cell lymphoma (DLBCL) are associated 
with EBV. All primary effusion lymphoma cells are co-infected with both EBV and 
KSHV viruses. These viruses can alter mechanisms of apoptosis and cell cycle 
regulation, activate oncogenes, and inhibit tumor suppressor genes [1]. 
Chronic antigenic stimulation of B cells and macrophages induced by EBV, HIV, 
and HHV-8 have also been reported to elicit cytokine and growth factor release that 
promotes B cell proliferation and the outgrowth of a monoclonal B cell population 
[1]. 
PD-1 is an inhibitory receptor expressed by an activated CD4+ and CD8+ T cells. 
In chronic infection, the PD-1 pathway mediates pathogen-specific and cancer 
specific CD8+ T cell dysfunction as demonstrated in HIV [24-26], HCV [27,20], 
HBV [29] infections. In chronic HCV infection, increased PD-1 expression on 
HCV-specific CD8+ T cells is associated with impaired proliferation and cytokine 
production [27]. Apart from inhibition of T cell function, PD-1 expression can also 

 
AMC #095 (Version 15.0) 24AUG2023 
 
23 
NCI Version Date 24AUG2023 
led to spontaneous or FAS-mediated apoptosis of virus-specific T cells [30]. 
CTLA-4 is another inhibitory receptor expressed by activated CD4+ and CD8+ T 
cells. It has a higher affinity for the B7 ligands (CD80 and CD86) allowing it to 
out-compete CD28, hence it is a powerful negative regulator of CD28-dependent T 
cell responses. It is significantly up-regulated on CD4+ T cells during HIV-1 and 
HCV infections where it correlates positively with disease progression and 
negatively with antigen-specific IL-2 production [31]. CTLA-4 is abundantly 
expressed on Treg as it is required for optimum suppressive function. 
For these reasons, anti-PD1 and anti-CTLA-4 may have therapeutic potential in 
virally mediated neoplasia. 
2.1.3 Immune check point blockade 
Tumors are able to evade detection and destruction by the immune system, despite 
the fact that many tumors appear to elicit a strong immune response that is evident 
in lymphocyte infiltrates of the primary lesion. Tumor immune evasion can be 
divided into two main mechanisms: 1) the induction of immune tolerance and 2) 
resistance to killing by activated immune effector cells [32]. The concept of 
‘‘immunoediting’’ relates to the manner in which tumors manipulate their 
microenvironment through tumor-derived cytokines, chemokines, and other 
soluble factors [33]. By the time tumors have become clinically detectable, they 
have already evolved mechanisms to evade immune response mounted by the host 
that must be overcome to create effective and durable antitumor immunity. 
Antigen-induced activation and proliferation of T cells are regulated by the 
temporal expression and binding of both co-stimulatory and co-inhibitory 
receptors. The signaling through these receptors in adaptive cellular immunity 
modulates the initiation, escalation, and subsequent resolution of host immune 
responses. In the absence of co-inhibitory signaling, persistent T cell activation can 
lead to excessive tissue damage in the setting of infection as well as autoimmunity. 
In the context of cancer immunology, in which immune responses are directed 
against antigens specifically or selectively expressed by cancer cells, these immune 
checkpoints can represent major obstacles to overcoming tumor-specific tolerance 
and generating clinically meaningful tumor control. Therefore, efforts have been 
made in the clinical arena to investigate blockade of immune checkpoints as novel 
therapeutic approaches to cancer tumors may exploit several distinct pathways to 
actively evade immune destruction, including endogenous “immune checkpoints” 
that normally terminate immune responses after antigen activation. 
These observations have resulted in intensive efforts to develop immunotherapeutic 
approaches for cancer, including immune-checkpoint-pathway inhibitors such as 
anti-CTLA-4 antibody (ipilimumab) and anti-PD1 antibody (nivolumab). 
 
 

 
AMC #095 (Version 15.0) 24AUG2023 
 
24 
NCI Version Date 24AUG2023 
2.2 
Study Agents 
2.2.1 Nivolumab 
Nivolumab (BMS-936558, MDX-1106, and ONO-4538) is a fully human 
monoclonal immunoglobulin G4 (IgG4) antibody (HuMAb) that is specific for 
human programmed death-1 (PD-1, cluster of differentiation 279 [CD279]) cell 
surface membrane receptor [34]. PD-1 is a negative regulatory molecule that is 
expressed transiently following T cell activation and on chronically stimulated T 
cells characterized by an “exhausted” phenotype. Nivolumab binds to cynomolgus 
monkey PD-1 but not mouse, rat, or rabbit molecules. Clinical activity of 
nivolumab has been observed in patients with melanoma, non-small cell lung 
cancer (NSCLC), and renal cell carcinoma (RCC). The combination of nivolumab 
and ipilimumab (anti-cytotoxic T lymphocyte associated antigen-4 [anti-CTLA-4]) 
in a phase 1/2 trial showed markedly enhanced clinical activity with an acceptable 
safety profile in melanoma patients [35]. 
The clinical use of monoclonal antibodies to T cell inhibitory receptors has 
provided transformative information on the nature of the immune system and 
cancer. An emerging picture suggests that endogenous immune responses can 
mediate effective tumor regression and/or improved survival even in patients with 
large volume tumors resistant to other forms of therapy. Some of the unique 
features of this type of therapy, based largely on experience in advanced melanoma, 
include improved overall survival (OS) with or without radiographic responses or 
improved progression-free survival (PFS); responses that may be delayed or occur 
after radiographic disease progression; combinations of immune modulators with 
enhanced or novel activities (in the example of ipilimumab and nivolumab); and 
toxicity that is almost exclusively immune or inflammatory in nature. It is not yet 
clear what factors determine responses and which components of the immune 
system are needed for this to occur. It seems likely that both memory helper and 
effector cells would be needed to sustain long-term responses. Increasing emphasis 
has been placed on understanding the relationships of the tumor, cellular infiltrate, 
and immunologic milieu surrounding each tumor. 
PD-1, a 55-kDa type 1 transmembrane protein, is a member of the CD28 family of 
T cell co-stimulatory receptors that include Ig super family member CD28, CTLA-
4, inducible co-stimulator (ICOS), and B and T lymphocyte attenuator (BTLA) 
[34]. PD-1 is transiently but highly expressed on activated T cells functioning to 
limit immune effectors at the site of activation. Chronic stimulation may prevent 
the re-methylation of the PD-1 gene leading to continuous expression and 
characterizes a state of “exhausted” T cells that lose function and proliferative 
capacity while enhancing a suppressive tumor microenvironment. PD-1 may act 
together with other T cell modulating molecules, including CTLA-4, TIM-3, 
lymphocyte activation gene 3 (LAG-3) as well as indoleamine-pyrrole 2,3-
dioxygenase 1 (IDO-1), cytokines, and transforming growth factor beta (TGF-
beta). 
Two ligands specific for PD-1 have been identified: PD-ligand 1 (PD-L1, also 
known as B7-H1 or CD274, expressed on tumor, antigen-presenting cells [APCs], 

 
AMC #095 (Version 15.0) 24AUG2023 
 
25 
NCI Version Date 24AUG2023 
and dendritic cells [DCs]) and PD-L2 (also known as B7-DC or CD273, expressed 
on endothelial cells). The interaction of PD-1 with PD-L1 and PD-L2 results in 
negative regulatory stimuli that down-modulate the activated T cell immune 
response through SHP-1 phosphastase. 
PD-1 knockout mice develop strain-specific lupus-like glomerulonephritis 
(C57BL/6) and cardiomyopathy (BALB/c). In transplantable tumor models that 
expressed PD-1 and LAG-3 on tumor-infiltrating CD4+ and CD8+ T cells dual anti-
LAG-3/anti-PD-1 antibody treatment cured most mice of established tumors that 
were largely resistant to single antibody treatment [36]. Despite minimal 
immunopathologic sequelae in PD-1 and LAG-3 single knockout mice, dual 
knockout mice abrogated self-tolerance with resultant autoimmune infiltrates in 
multiple organs, leading to eventual lethality. 
PD-L1 expression is found on a number of tumors and is associated with poor 
prognoses based on OS in many tumors, including melanoma [37], renal [38-40], 
esophageal [41], gastric [42], ovarian [43], pancreatic [44], lung [45], and other 
cancers [34]. 
PD-L1 is also found on hematological malignancies, in particular cHL. The 9p24.1 
locus is found in many copies in cHL, the location of the PD-L1 locus. Increased 
copy number upregulates PD-L1 expression on the hRS cell. Also located at the 
9p24 locus is the Janus kinase 2, and the Janus kinase 2/signal transducer can 
further induce PD-L1 ligand transcription [18]. Lastly, as stated above, HIV-
associated cHL has a 90% association with EBV coinfection of the hRS, another 
mechanism of PD-L1 overexpression, possibly a viral survival tactic to evade the 
immune system [1,18].
 The high expression of PD-L1 makes this disease, HL, 
particularly susceptible to anti-PD-1 therapy. (See efficacy in hematological 
malignancies below.)
 
The PD-1/PD-L1 axis plays a role in human infections, particularly in HCV and 
HIV. In these cases, high expression levels of PD-1 were found in viral-specific 
CD8+ T cells that also display a non-responsive or exhausted phenotype. Non-
responsive PD-1-high T cells were observed in simian immunodeficiency virus 
(SIV) infection in rhesus macaques. Treatment of SIV-infected macaques with an 
anti-PD-1 mAb (3 mg/kg x4) resulted in decreased viral loads and increased 
survival along with expanded T cells with increased T cell functionality. 
Non-clinical development of nivolumab 
In intravenous (IV) repeat-dose toxicology studies in cynomolgus monkeys, 
nivolumab alone was well tolerated [34]. Combination studies have highlighted the 
potential for toxicity when combined with ipilimumab, MDX-1408, and BMS-
986016. Nivolumab bound specifically to PD-1 (and not to related members of the 
CD28 family such as CD28, ICOS, CTLA-4, and BTLA) with a Kd = 3.06 nM. A 
surrogate rat anti-mouse PD-1 antibody (4H2) was derived and expressed as 
chimeric IgG1 murine antibody. Antitumor activity was seen for several tumor 
models, including colon carcinoma and fibrosarcoma. 
Clinical development of nivolumab 

 
AMC #095 (Version 15.0) 24AUG2023 
 
26 
NCI Version Date 24AUG2023 
Nivolumab is being evaluated as monotherapy and in combination with cytotoxic 
chemotherapy, other immunotherapy (such as ipilimumab), anti-angiogenesis 
therapy, and targeted therapies in completed and ongoing BMS-sponsored clinical 
trials in NSCLC, melanoma, RCC, hepatocellular carcinoma (HCC), 
gastrointestinal (GI) malignancies including microsatellite instability (MSI) in 
colorectal cancer, and triple-negative breast cancer (TNBC) with an expanding 
group of indications [34]. In addition, two investigator-sponsored trials (ISTs) of 
nivolumab in combination with a peptide vaccine in melanoma are being conducted 
in the adjuvant setting and advanced disease. 
Seven nivolumab studies were conducted in Japan, including six studies in 
advanced solid tumors and recurrent or unresectable stage III/IV melanoma 
sponsored by Ono Pharmaceuticals Co. Ltd., and one IST in recurrent or advanced 
platinum-refractory ovarian cancer. 
In addition, nivolumab, either as a single agent of in combination with ipilimumab 
or in combination with other immunotherapies or cytotoxic chemotherapies, has 
been studied across all hematological malignancies, in particular Hodgkin and NHL 
[18]. 
Pharmacokinetics 
Pharmacokinetics (PK) of nivolumab was linear in the range of 0.3 to 10 mg/kg, 
with dose-proportional increases in maximum serum concentration (Cmax) and area 
under the concentration-time curve from time zero to infinity (AUC0-∞), with low 
to moderate inter-participant variability observed at each dose level [34]. Clearance 
of nivolumab is independent of dose in the dose range (0.1 to 10 mg/kg) and tumor 
types studied. Body weight normalized dosing showed approximately constant 
trough concentrations over a wide range of body weights. The mean terminal 
elimination half-life of BMS-936558 is 17 to 25 days consistent with the half-life 
of endogenous IgG4. 
Efficacy in solid malignancies 
In a phase 1 (1, 3, and 10 mg/kg nivolumab doses) dose escalation study the 3 
mg/kg dose was chosen for expanded cohorts. Among 236 participants, objective 
responses (ORs) (CR or PR) were seen in NSCLC, melanoma, and RCC. ORs were 
observed at all doses [46]. Median OS was 16.8 months across doses and 20.3 
months at the 3 mg/kg dose. Median OS across all dose cohorts was 9.2 months and 
9.6 months for squamous and non-squamous NSCLC, respectively [47]. In the RCC 
cohort, median duration of response was 12.9 months for both doses with five of 
the ten responses lasting ≥1 year [48]. 
In an advanced melanoma phase 1 study, nivolumab and ipilimumab were 
administered by IV every 3 weeks for four doses followed by nivolumab alone 
every 3 weeks for four doses (concurrent-regimen) [35]. The combined treatment 
was subsequently administered every 12 weeks for up to eight doses. In a sequenced 
regimen, participants previously treated with ipilimumab received nivolumab every 
2 weeks for up to 48 doses. In the concurrent-regimen (53 participants), 53% of 
participants had an OR at doses 1 mg/kg nivolumab and 3 mg/kg ipilimumab, with 

 
AMC #095 (Version 15.0) 24AUG2023 
 
27 
NCI Version Date 24AUG2023 
tumor reduction of 80% or more (modified World Health Organization [mWHO] 
criteria). In the sequenced regimen (33 participants), the objective response rate 
(ORR) was 20%. 
In a phase 1 study of nivolumab plus platinum-based doublet chemotherapy (PT-
doublet) in chemotherapy-naïve NSCLC participants, 43 participants were treated 
with nivolumab + PT-doublet [49]. No dose-limiting toxicities (DLTs) were 
reported and total/confirmed ORRs were 43/33%, 40/33%, and 31/31% in 
nivolumab/gemcitabine/cisplatin, 
nivolumab/pemetrexed/cisplatin, 
and 
nivolumab/carboplatin/paclitaxel arms, respectively. 
Toxicology 
A MTD of nivolumab was not defined [50]. Serious adverse events (SAEs) 
occurred in 32 of 296 participants (11%) similar to the immune-related 
inflammatory events seen with ipilimumab: pneumonitis, vitiligo, colitis, hepatitis, 
hypophysitis, and thyroiditis (with noted pulmonary toxicity resulting in three 
deaths. Renal failure, symptomatic pancreatic and diabetes mellitus (DM), 
neurologic events, and vasculitis have also been reported.). In combination with 
ipilimumab in the concurrent-regimen group [35], grade 3 or 4 treatment-related 
events were noted in 53% of participants. Skin rash represents the majority of these 
events. 
Pharmacodynamics/biomarkers 
Tumor cell expression (melanoma) of PD-L1 was characterized in combination 
with ipilimumab with the use of IHC staining and pharmacodynamics changes in 
the peripheral blood absolute lymphocyte count [35]. With PD-L1 positivity 
defined as expression in at least 5% of tumor cells, biopsy specimens from 21 of 
56 participants (38%) were PD-L1–positive. Among participants treated with the 
concurrent-regimen of nivolumab and ipilimumab, ORs were observed in 
participants with either PD-L1–positive tumor samples (6 of 13 participants) or PD-
L1–negative tumor samples (9 of 22). In the sequenced regimen cohorts, a higher 
number of overall responses was seen among participants with PD-L1–positive 
tumor samples (4 of 8 participants) than among participants with PD-L1–negative 
tumor samples (1 of 13) suggesting the possibility that these tumors have higher 
response rates to the combination. The relationship between PDL-1 expression and 
responses may not be present in participants treated with the combination. Tissue 
expression of PDL-2, interferon-γ (IFN- γ), IDO, and T cell CD8+ are of current 
interest. Until more reliable data based on standardized procedures for tissue 
collection and assays are available, PD-L1 status cannot be used to select patients 
for treatment at this time. 
Efficacy in Hodgkin lymphoma 
Based on the efficacy of PD1 antibody blockade in solid tumors, two phase 1 
studies were conducted in hematological malignancies. The first was a study 
analyzing the safety of single agent nivolumab in relapsed refractory NHL, HL, and 
multiple myeloma [18-20] Doses were escalated from 1 mg/kg to 3 mg/kg. No dose 
limiting toxicities were identified, and the dose used in the expansion cohort of the 

 
AMC #095 (Version 15.0) 24AUG2023 
 
28 
NCI Version Date 24AUG2023 
phase I trial, as well as in the phase II study described below, was 3 mg/kg given 
every 2 weeks until toxicity, progression, or study termination/removal. A second 
study analyzed pembrolizumab, a similar anti- PD-1 antibody [18-21]. As stated 
above, the tumor cell in cHL, hRS, through various mechanisms (e.g., EBV status 
and elevations in 9p24) upregulates PD-L1 expression [18]. The overall response 
rate of relapsed/refractory cHL with single agent nivolumab was 87%, with a CR 
rate of 17% in patients pretreated with multiple lines of therapy, including 
brentuximab vedotin and autologous transplantation [21]. This is higher than any 
solid tumor assessed to date with nivolumab. Eighty-six percent of these patients 
had a PFS of 24 weeks. In the study of nivolumab by Ansell et al., only 22% of the 
patients developed a Grade 3 Adverse event (AE) [21]. 
Recently, a phase II study of single agent nivolumab in patients who failed both 
brentuximab vedotin and autologous bone marrow transplantation was reported. 
Patients received single agent nivolumab at 3 mg/kg every 2 weeks until disease 
progression, death, or toxicity [21]. Of 80 patients treated, 66% achieved an 
objective response, with on average four prior therapies, and nine patients achieved 
a CR. Fifty-eight percent (58%) of the patients achieved a partial remission. At 6 
months, the PFS was 76.9% with an OS of 98% [21]. The median number of 
nivolumab doses received was 17. Of the 80 patients, 29 had to discontinue therapy, 
all due to disease progression and not toxicity. In a recent trial, the combination of 
nivolumab and ipilimumab achieved a similar ORR of 74% in 31 patients with 
relapsed refractory cHL, similar to single agent nivolumab; however, both single 
and combined showed robust activity [22]. 
Toxicity of nivolumab in patients with relapsed refractory Hodgkin lymphoma. 
In the phase I study of nivolumab, 22% of the patients had drug-related grade 3 
AEs. There were no grade 4 or 5 drug-related AEs. In the phase II study, when 
treated with 3 mg/kg, 33% of participants experienced grade 3 AEs and only 8% 
experienced grade 4 AEs. The dose utilized in the phase II study was based on data 
by Ansell et al. The most common drug-related grade 3 or 4 AEs were neutropenia, 
experienced by 5% of participants, and increased serum lipase concentrations in 
5% of participants. The most common SAEs was pyrexia (4%). Three patients died 
during the study though these were not treatment-related [18-21]. 
Pharmacodynamics/biomarkers 
In the phase II trial of patients treated for relapsed refractory HL with single agent 
nivolumab, those analyzed showed that 56% had gain of copies of PD-L1 and PD-
L2 and amplification of 27% of the tumors assessed. In a post- hoc analysis, none 
of the patients with progressive disease had amplification of PD-L1 or PD-L2. In 
addition, correlation between PD-L1 expression was correlated with a greater 
response. All patients who achieved a CR had the highest level of PD-L1 
expression, and progressive disease was only identified in those with the lowest 
staining by immune histochemistry [21]. 
2.2.2 Ipilimumab 
Ipilimumab (BMS-734016, MDX010, MDX-CTLA-4, YervoyTM) is a fully human 

 
AMC #095 (Version 15.0) 24AUG2023 
 
29 
NCI Version Date 24AUG2023 
monoclonal immunoglobulin (Ig) G1κ specific for human cytotoxic T lymphocyte 
antigen 4 (CTLA-4, CD152), which is expressed on a subset of activated T cells 
[51]. CTLA-4 is a negative regulator of T cell activation. Ipilimumab binds to 
CTLA-4 and inhibits its interaction with ligands on antigen-presenting cells 
(APCs). The proposed mechanism of action for ipilimumab’s effects in subjects 
with melanoma is indirect, possibly through T cell potentiation and mediation of 
antitumor immune responses. 
Ipilimumab has been approved for the treatment of unresectable metastatic 
melanoma in over 40 countries including the United States (U.S., March 2011), the 
European Union (July 2011), and Australia (July 2011). 
BMS and Medarex (acquired by BMS in Sep-2009) have co-sponsored an extensive 
clinical development program for ipilimumab, encompassing >13,800 subjects in 
several cancer types in completed and ongoing studies, including a compassionate 
use program [51]. The focus of the clinical program is on melanoma, prostate 
cancer, and lung cancer, with advanced melanoma being the most comprehensively 
studied indication. Ipilimumab is being investigated both as monotherapy and in 
combination with other modalities such as chemotherapy, radiation therapy, and 
other immunotherapies. 
CTEP’s clinical development of ipilimumab focuses on cervical, gastrointestinal, 
ovarian, prostate cancer, chronic lymphocytic leukemia, head and neck squamous 
cell carcinoma, solid tumors, Hodgkin and non-Hodgkin lymphomas, melanoma, 
and myelodysplastic syndrome. 
While the toxicity and clinical responses overlap, mechanisms of immune 
activation and range of responses appear to be different for each of the single 
agents. 
Preclinical data support the combinations of nivolumab and ipilimumab [52]. 
The combination of ipilimumab with nivolumab has been reported to result in 
improved responses in advanced melanoma marked by time to response, number of 
responses, depth, and duration of responses, PFS, and OS compared to single agent 
ipilimumab [35]. 
For RCC results have been reported [53]. 
The combination is being evaluated in other disease settings typically with 3 mg/kg 
nivolumab and 1mg/kg ipilimumab q 3 weeks x 4 induction doses. 
2.3 
Study Design and Rationale 
2.3.1 Preclinical data: combining ipilimumab and nivolumab 
CTLA-4 and PD-1 appear to play complementary roles in regulating adaptive 
immunity. Anti-CTLA-4 can lead to enhanced priming and activation of antigen-
specific T cell and potentially clearance of regulatory T cells from the tumor 
microenvironment. The blocking of PD-1 or its ligand PD-L1 can remove the 
inhibition of cancer cell killing by T cells. In preclinical models, combined 
blockade of PD-1 and CTLA-4 achieved more pronounced antitumor activity than 
blockade of either pathway alone [79]. Combining a CTLA-4 targeted therapy 

 
AMC #095 (Version 15.0) 24AUG2023 
 
30 
NCI Version Date 24AUG2023 
(ipilimumab) with a PD-1-targeted inhibitor (nivolumab) appears to enhance the 
immune activity in patients over either therapy alone. This might be enhanced with 
pretreatment receptor profiling of the tumor. 
2.3.2 Clinical data: combining ipilimumab and nivolumab 
In an early phase study, rapid and deep responses (by modified WHO criteria) were 
observed in participants with melanoma (ORR: 40% [21/72]; CR: 10% [5/72]). 
Immune-related toxicities were also enhanced in their magnitude, frequency, and 
onset (53% Grade 3-4 treatment-related toxicities). Although many of these were 
serious and required treatment, therapy discontinuation, or hospitalization, the 
durable partial and CRs in melanoma may warrant this approach in some patients. 
KS is a likely candidate because of its many similarities to melanoma and because 
it, similarly, as observed in melanoma, tends to regress in response to immune 
modulation. Combination therapy appeared to most dramatically benefit patients 
who were less likely to benefit from PD-L1 or PD-1 inhibition alone, because their 
tumors were PD-L1-negative (6/13 PD-L1-positive and 9/22 PD-L1-negative 
participants responded to combination therapy). 
Successive cohorts of participants with escalating doses of intravenous nivolumab 
and ipilimumab administered concurrently every 3 weeks for four doses, followed 
by nivolumab alone every 3 weeks for four doses (concurrent-regimen group). The 
combined treatment was subsequently continued every 12 weeks for up to eight 
doses. When the two drugs were administered together, nivolumab was 
administered first. Within a cohort, doses of nivolumab and ipilimumab were kept 
constant. The protocol-specified dose levels in the cohorts were as follows. In the 
concurrent-regimen group, cohort 1 was designated to receive 0.3 mg of nivolumab 
per kilogram of body weight and 3 mg of ipilimumab per kilogram; cohort 2, 1 mg 
of nivolumab per kilogram and 3 mg of ipilimumab per kilogram; cohort 2a, 3 mg 
of nivolumab per kilogram and 1 mg of ipilimumab per kilogram; cohort 3, 3 mg 
of nivolumab per kilogram and 3 mg of ipilimumab per kilogram; cohort 4, 10 mg 
of nivolumab per kilogram and 3 mg of ipilimumab; and cohort 5, 10 mg of 
nivolumab per kilogram and 10 mg of ipilimumab per kilogram. 
SAEs related to the treatment were reported in 49% of participants in the 
concurrent-regimen group. Common grade 3 or 4 selected AEs that were related to 
the therapy included hepatic events (in 15% of participants), gastrointestinal events 
(in 9%), and renal events (in 6%). Isolated cases of pneumonitis and uveitis were 
observed, a finding that is consistent with previous experience with monotherapy. 
A total of 11 participants (21%) discontinued therapy owing to treatment-related 
AEs. In the concurrent-regimen cohorts, across all dose levels, confirmed ORs 
according to modified WHO criteria were observed in 21 of 52 participants (40%) 
who had a response that could be evaluated. In addition, four participants had an 
objective response according to immune-related response criteria and two had an 
unconfirmed PR. These participants were not included in the calculation of 
objective response rates. At the maximum doses associated with an acceptable level 
of adverse vents – that is, nivolumab 1 mg/kg and ipilimumab 3 mg/kg – 53% of 
participants had objective response, all with tumor reduction of >80% [80]. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
31 
NCI Version Date 24AUG2023 
Participants with metastatic renal cell cancer were randomized to receive 
nivolumab 3 mg/kg + ipilimumab 1 mg/kg (arm N3 + I1) or nivolumab 1 mg/kg + 
ipilimumab 3 mg/kg (arm N1 + I3) IV Q3W for four doses then nivolumab 3 mg/kg 
IV Q2W until progression/toxicity. The primary objective was to assess 
safety/tolerability; secondary objective was to assess antitumor activity. Treatment-
related AEs were seen in 39/44 pts (89%); 7 pts (16%; N3 + I1: 2; N1 + I3: 5) 
discontinued due to any grade related AEs. Grade 3–4 related AEs occurred in 19 
pts (43%; N3 + I1: 5; N1 + I3: 14), most commonly ↑ lipase (16%, n=7), ↑ ALT 
(11%, n=5), diarrhea (9%, n=4), colitis (5%, n=2), ↑ amylase (5%, n=2). No grade 
3–4 pneumonitis was seen. The ORR was 29% (N3 + I1) and 39% (N1 + I3). 
Duration of response (DOR) was 4.1+ to 22.1+ wks (all six responses ongoing) in 
N3 + I1, and 6.1+ to 18.3+ wks (8/9 responses ongoing) in N1 + I3. Responses 
occurred by first tumor assessment (wk 6) in 67% of responding pts in both N3 + 
I1 and N1 + I3. SD was seen in 7 (33%) pts (N3 + I1) and 9 (39%) pts (N1 + I3) 
[81]. 
Investigators in CheckMate-012 evaluated four administration/dosing schedules for 
the combination of nivolumab and ipilimumab. In arm A, both agents were 
administered at a dose of 1 mg/kg every 3 weeks (Q3W, N = 31). In arm B 
nivolumab was administered at 1 mg/kg every 2 weeks (Q2W) plus ipilimumab 1 
mg/kg every 6 weeks (Q6W; N = 40). Arm C and D dosed nivolumab at 3 mg/kg 
Q2W and ipilimumab 1 mg/kg every 12 weeks (Q12W; N=38) or Q6W (N = 39). 
Across the four groups, the patient cohorts had a median age of 62 to 68, stage IV 
disease in more than 90% of cases, non-squamous histology in more than 80%, and 
ECOG 0-1 performance status. 
All four regimens demonstrated activity, with the arms containing nivolumab at 3 
mg/kg showing the best ORR. In arm C, the ORR was 39% and in arm D the ORR 
was 31%. The ORRs were 25% and 13%, in arm B and arm A, respectively. 
Median PFS ranged from 4.9 months in arm B to 10.6 months in arm A. Median 
PFS was 8 months in arm C and 8.3 months in arm D. The 24-week PFS was 55% 
in arm A, 63% in arm C, and not yet reached in the other two groups. Median OS 
was not yet reached in all four arms (follow-up range, 6.2-16.6 months). 
In those with ≥1 PD-L1 expression by IHC (n = 77; 68%) the ORR was 8%, 24%, 
48%, and 48% in arms A, B, C, and D, respectively. Median PFS across each arm 
were 11.5 weeks, 21.1 weeks, 34.6 weeks, and not reached and the 24-week PFS 
rates were 42%, 40%, 74%, and 65%, respectively. 
Treatment-emergent grade 3/4 adverse AEs occurred in 28% to 35% of patients in 
each group but led to discontinuation in just 3% to 10% of cases. All grade 
treatment-related AEs occurred in 77%, 73%, 74%, and 69% of patients in groups 
A, B, C, and D, respectively. The safety profile was consistent with previous studies 
of the combination, and the discontinuation rate associated with AEs was similar to 
rates observed with nivolumab alone. 
The only grade 3/4 AEs that occurred in as many as 10% of patients were hepatic 
in arm B (10%) and skin-related in arm C and D (13%). Grade 3/4 pulmonary AEs 

 
AMC #095 (Version 15.0) 24AUG2023 
 
32 
NCI Version Date 24AUG2023 
occurred in no more than 3% of patients in any of the groups. There were no 
treatment-related deaths in the trial [82]. 
Given the safety and efficacy profile of nivolumab at 3 mg/kg Q2W and ipilimumab 
1 mg/kg every 12 weeks, this schedule will be evaluated in this study of HIV 
patients with advanced refractory solid tumors. 
2.3.3 Clinical data combining of ipilimumab and nivolumab in relapsed refractory 
classical HL  
The combination of nivolumab and ipilimumab in relapsed refractory HL achieved 
a similar relative response rate, as single agent nivolumab, at 74% [22]. 
Thus, for the relapsed/refractory HIV-cHL cohort, in light of the lack of evidence 
that dual blockade is superior to single agent PD-1 blockade, only single agent 
nivolumab will be used. 
2.3.4 HIV: PD1, CTLA-4, Tregs and immune dysfunction causing cancer 
Up-regulation of inhibitory receptors such as programmed death 1 (PD 1), T cell 
immunoglobulin mucin 3 (TIM-3), lymphocyte activation gene 3(LAG-3), and 
cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) is a characteristic feature 
of exhausted T cells. PD-1, an inhibitory receptor of the CD28 superfamily, is 
highly expressed on exhausted CD8+ T cells during progressive chronic viral 
infections and uncontrolled cancer, making it a major factor in T cell exhaustion. 
However, in chronic infection, the PD-1 pathway mediates pathogen-specific 
CD8+ T cell dysfunction as demonstrated in HIV infection [83-85]. For example, 
the frequency of PD-1+CD8+ T cells is highly elevated in HIV-1 patients where it 
correlates significantly with viral load and declining CD4+ T cell numbers [83, 76]. 
PD-1 is also up-regulated on HIV specific CD4+ T cells [84, 87] and inhibits 
CD4+T cell responses including proliferation. Interestingly, PD-1 levels are 
significantly reduced in HIV-1 progressors who initiate HAART or in long term 
non-progressors (LTNPs), suggesting that antigen persistence drives T cells to 
exhaustion. 
Besides PD-1, other inhibitory receptors such as TIM-3, 2B4 (natural killer cell 
receptor), and LAG-3 are also up-regulated on virus-specific T cells, and the 
expression of multiple inhibitory receptors correlates with a severely dysfunctional 
state [88-90]. For example, co-expression of PD-1 and TIM-3 is associated with 
severely exhausted HIV specific CD8+ T cells [90] and majority of these also co-
express PD-1 and 2B4 [91]. CTLA-4 is another inhibitory receptor expressed by 
activated CD4+ and CD8+ T cells. It has a higher affinity for the B7 ligands (CD80 
and CD86) allowing it to out-compete CD28, hence it is a powerful negative 
regulator of CD28-dependent T cell responses. It is significantly up-regulated on 
CD4+ T cells during HIV-1 and HCV infections where it correlates positively with 
disease progression and negatively with antigen-specific IL-2 production [86, 91]. 
CTLA-4 is abundantly expressed on Treg as it is required for optimum suppressive 
function. 
Increased frequencies of Treg and MDSC are a common feature of persistent 
chronic viral infections, which is well-documented in infections with HIV [93]. For 

 
AMC #095 (Version 15.0) 24AUG2023 
 
33 
NCI Version Date 24AUG2023 
instance, it is postulated that by virtue of their activated nature, Treg express higher 
levels of CCR5 and CXCR4, the co-receptors for HIV-1 thus making them 
preferential targets for HIV-1 infection [94, 95]. Since Foxp3+ Treg represent a 
high proportion of CD4+ T cells (up to 50%) found in mucosal lymphoid organs of 
HIV infected individuals [96], it is plausible that HIV infection can subsequently 
lead to significant depletion of these cells and impaired immuno-regulatory 
functions [97]. 
A number of immuno-regulatory mechanisms triggered to prevent immune 
activation and inflammation also suppress immune effector functions and sustain 
chronic virus persistence. For example, during chronic HIV infection, the 
expansion of Treg [98] with potent suppressive activity within mucosal tissues not 
only contributes to persistence of HIV, but also reduces immune vigilance and 
predisposes to HPV and cervical cancer. 
Therefore, the profound T cell dysfunction, progressive depletion of CD4+ T cells, 
B cell hyper-activation, together with the increased immuno-regulatory 
mechanisms all collude to actively impede tumor immune-surveillance and create 
a permissive environment for cancer initiation and progression. 
2.3.5 In vitro data with anti-PD1 and anti-CTLA-4 in HIV 
In vitro antibody blockade of PD-ligand (L)-1 and IL-10Rα results in increases in 
cytokine expression, including interferon-gamma (IFN-γ) in HIV-1-infected 
patients [99]. PD-1 blockade using PD-1 antibodies led to an increase in HIV 
specific CD8+ T cell proliferation demonstrating that HIV-induced T cell 
exhaustion is reversible in vitro [100]. Memory CD4+ T cells expressing high 
levels of PD-1 contain more proviral DNA than PD-1-low cells and blocking PD-1 
may activate HIV-1 replication and thus facilitate the clearance of these infected 
cells. 
T regulatory cells express high levels of CTLA-4 and are implicated in inhibiting 
immune responses during HIV-1 infection. In vitro experiments using cells from 
healthy and HIV-1-infected individuals showed that CTLA-4 is up-regulated in the 
CD4+ T cells from infected patients and inversely correlated with CD4 counts and 
anti-HIV-1 T cell responses while positively correlating with the percentage of 
activated CD4+ T cells [101]. 
 
 

 
AMC #095 (Version 15.0) 24AUG2023 
 
34 
NCI Version Date 24AUG2023 
2.3.6 Simian studies with anti-PD1 and anti-CTLA-4 
Velu and colleagues presented the first in vivo study to show enhancement of a 
virus-specific immune response through PD-1 blockade using a PD-1 antibody 
[101]. Nine SIV-infected macaques, five in the early phase of infection and four in 
the chronic phase, received an anti-PD-1 antibody while another 5 SIV-infected 
macaques received an isotype control antibody. Their results showed an expansion 
of the Gag-CM9 tetramer specific CD8+ T cells of approximately 2.5 to 11-fold in 
the treated group. Additionally, an enhancement of Gag-specific CD8+ T cell 
function was observed after the blockade as measured by the co-expression of IFNγ, 
interleukin 2 (IL-2), and TNFα. The enhanced immunologic response after anti-
PD-1 treatment corresponded with significant reductions in plasma viremia and 
prolonged survival of the infected macaques. Serum anti-nuclear antibody (ANA) 
levels were unchanged after treatment suggesting no evidence of autoimmune 
disease, which had been observed in murine studies of PD-1 gene disruption. The 
antigen-specific T cell proliferation was significantly elevated until about day 45. 
Similarly, enhancement of HIV specific CD8+ T cell function peaked at around day 
21 and then decreased. These changes reflected a significant reduction in plasma 
viremia initially, which went back to baseline by day 43 post-treatment. The 
transient response was associated with a decline in anti-PD-1 antibody between 
days 14 and 28. 
The results of this study of PD-1 blockade in an SIV-macaque model show promise 
of anti-PD1 antagonists as a novel immunotherapy for HIV. Increasing the immune 
response to the virus, particularly the Gag-specific polyfunctional CD8+ T cells, 
which are associated with control of viremia [27] through PD-1 blockade, may 
allow patients to obtain well-spaced intermittent treatment without being on 
prolonged and continuous antiretroviral regimens. Administration of PD-1 did not 
result in toxic side effects or symptoms of autoimmunity. This is consistent with 
the clinical trial by Berger et al. [102], which showed that administration of 0.2 to 
6.0 mg/kg of CT-011 (a humanized IgG1 monoclonal PD-1 antibody) was well 
tolerated in patients with hematologic malignancies. 
Francheschini et al. [103] showed that PD-L1 negatively regulated Tregs in persons 
chronically infected with HCV. There have been a number of studies showing 
ability of Tregs to suppress the immune response to HIV. Blocking PD-1 will not 
only increase the antiviral function of the CD8+ T cells but may also enhance the 
function of the antigen-specific Tregs, which may negate the antiviral response. 
Although this study has suggested that the transient immune response was 
secondary to declining titers of anti-PD-1 antibody, it is important to look into 
whether an increase in Treg frequency and function is responsible for this transient 
response or whether the possible increase was responsible for bystander 
immunosuppression that prevented autoimmune events from occurring. 
These results suggest that beyond its effects on target-specific immune responses, 
PD-1 blockade may foster immune restoration and/or dampen harmful immune 
dysregulation. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
35 
NCI Version Date 24AUG2023 
In contrast, although CTLA-4 expression was found to be up-regulated in CD4 T 
cells of lymphoid tissues in SIV infection [104], anti-CTLA-4 blockade failed to 
show a benefit in terms of plasma viral load or survival in acutely or chronically 
SIV-infected macaques [101]. Whereas an increase in HIV specific CD4 and CD8 
T cell responses was noted in one study [105], another study did not show an 
expansion of SIV-specific CTL and observed an increase in CD4 T cell activation 
and viral replication at mucosal sites [72]. Further studies are needed to understand 
these contrasting results between blockades of the PD-1 and CTLA-4 networks, 
including profiling the receptors, which is being proposed as a translational 
research component of this clinical trial. Differences between expression and 
function of the PD-1 and CTLA-4 molecules in the CD4 and CD8 T cell subsets 
could contribute to these distinct effects. Because CTLA-4 is crucial for regulatory 
T cell function and findings in HIV infection showed that CTLA-4 is preferentially 
up-regulated on virus-specific CD4 T cells but not CD8 cells, [105], CTLA-4 
blockade might preferentially expand SIV-specific CD4 T cells and increase CD4 
activation, thus providing additional targets for viral infection without 
improvement in CTL function to offset this detrimental effect. 
In a preclinical study in rhesus macaques infected with the pathogenic simian 
immunodeficiency virus SIVmac251 and treated with ART. We tested whether 
vaccination administered together with cytotoxic T lymphocyte associated antigen 
4 (CTLA-4) blockade and treatment with the indoleamine 2,3-dioxygenase (IDO) 
inhibitor 1-methyl-D-tryptophan (D-1mT), decreased immune activation and 
improved vaccine efficacy. The treatment did not augment vaccine 
immunogenicity; rather, it dramatically increased ART-related toxicity, causing all 
treated animals to succumb to acute pancreatitis and hyperglycemic coma. The 
onset of fulminant diabetes was associated with severe lymphocyte infiltration of 
the pancreas and complete loss of the islets of Langerhans. The specific pancreatic 
damage induced by ART, combined with the effect that CTLA-4 and IDO blockade 
may have on immune homeostasis, might have exacerbated autoimmunity to 
pancreatic antigens [107]. 
2.3.7 Clinical experience with nivolumab in patients with Hepatitis C and ipilimumab in 
a HIV patient 
A randomized, modified double-blind placebo-controlled single ascending dose 
study evaluated the safety, pharmacokinetics, and immunogenicity of nivolumab in 
HCV-infected participants. In the high dose group, 3/20 participants, or 15%, 
experienced significant reductions of HCV RNA. Suppression of HCV replication 
persisted more than eight weeks in most participants. Two participants achieved 
HCV RNA below the lower limit of quantitation (25 IU/mL), one of whom (a prior 
null-responder) remained RNA-undetectable 1-year post-study. Transient 
reductions in CD4+, CD8+ and CD19+ cells, including both naïve and memory 
CD4+ and CD8+ subsets, were observed at Day 2 without evidence of immune 
deficit. No clinically relevant changes in immunoglobulin subsets or treatment-
related trends in circulating cytokines were noted. One participant experienced an 
asymptomatic grade 4 ALT elevation coincident with the onset of a 4-log viral load 
reduction. Six participants exhibited immune-related AEs of mild-to-moderate 

 
AMC #095 (Version 15.0) 24AUG2023 
 
36 
NCI Version Date 24AUG2023 
intensity, including two cases of hyperthyroidism consistent with autoimmune 
thyroiditis. This study establishes proof-of-concept that PD-1 blockade with 
nivolumab can lead to persistent suppression of HCV replication in some patients 
with chronic infection. The promising results of this study suggest that further 
exploration of PD-1 pathway blockade is warranted across other chronic viral 
diseases, possibly in combination with other immunomodulatory or direct-acting 
antiviral agents [108]. 
In a case report of a patient with HIV with metastatic melanoma who received ipilimumab, 
the only drug-related adverse effect was a self-limited grade 2 rash. He achieved an 
excellent PR in multiple liver lesions, currently ongoing for more than 8 months 
after completing treatment. There was no adverse effect on HIV viral load or CD4 
cell counts [109].2.3.8 Dosing revision for nivolumab (September 2016) 
In the original version of this protocol, nivolumab was to be administered at a dose 
of 3 mg/kg every 2 weeks for up to 92 weeks of treatment on dose levels 1 and 2 (1 
mg/kg on dose levels -1 and -2). On September 13, 2016, the U.S. Food and Drug 
Administration modified the dosage regimen for nivolumab (Opdivo®, Bristol-
Myers-Squibb Co.) for the currently approved indications for RCC, metastatic 
melanoma, and NSCLC. The currently approved recommended dosage regimens 
were modified to 240 mg intravenously (IV) every two weeks. 
However for cHL, the FDA approved dosing regimen has remained 3 mg/kg given 
every 2 weeks until progression or toxicity. Thus for the expansion cohort of HIV-
cHL in this protocol, the dose of 3 mg/kg given every 2 weeks will be maintained 
for three reasons: 1) no DLT was identified in the trial at dose level 1 in the early 
aspects of this trial, AMC-095, 2) the plethora of clinical data treating non-HIV-
cHL at the 3 mg/kg given every 2 weeks, and 3) the FDA approved dose for this 
indication. 
In addition, the nivolumab dosing regimen in combination with ipilimumab for 
melanoma will remain the same (nivolumab 1 mg/kg IV, followed by ipilimumab 
on the same day, every 3 weeks for four doses). However, after completion of 
ipilimumab, the recommended nivolumab dose will be 240 mg every two weeks 
until disease progression or intolerable toxicity. 
The approval was based on population pharmacokinetics analyses and 
dose/exposure response analyses demonstrating the comparability of the 
pharmacokinetics exposure, safety, and efficacy of the proposed new dosing 
regimen with the previously approved regimen. 
Based on simulations by the population pharmacokinetics model, FDA determined 
that the overall exposure at 240 mg every two weeks flat dose is similar (less than 
6% difference) to 3 mg/kg every two weeks. These differences in exposure are not 
likely to have a clinically meaningful effect on safety and efficacy since 
dose/exposure response relationships appear to be relatively flat in these three 
indications. 
Given the safety and efficacy profile of nivolumab at 240 mg every 2 weeks and 
ipilimumab 1 mg/kg every 6 weeks, this schedule will be evaluated in this study, 

 
AMC #095 (Version 15.0) 24AUG2023 
 
37 
NCI Version Date 24AUG2023 
and has been applied with protocol version 5.0. 
As of May 2017, three evaluable participants completed the safety evaluation 
period for dose level 1 (3 mg/kg q 2 weeks, per protocol versions 1-3) on Stratum 
1 without DLT. Two participants on this cohort discontinued the study for reasons 
other than toxicity prior to completing the safety evaluation period and were 
inevaluable for DLT. Following approval of version 5.0 of the protocol at each 
center, enrollment on dose level 1 for Stratum 1 began in up to three additional 
participants at the original dose of 3 mg/kg q 2 weeks with the combination dose 
level 2 to treat at new dose level 240 mg q 2 weeks. Based on safety of this dose 
observed in the initial dose level among participants with CD4 cell count above 
200, the current experience with single agent nivolumab, and the inclusion of 
participants in this trial who have exhausted standard chemotherapeutic regimens, 
an expansion cohort of up to 24 participants with a CD4 count > 200/mm3 will be 
initiated with protocol version 7.0 to obtain additional data on the safety and 
feasibility of this regimen in HIV positive participants with solid tumors. 
2.3.9 Dosing revision for nivolumab single agent and combination therapy (April 2019) 
In the previous version of this protocol the combination therapy dose was 
nivolumab 240 mg flat dose q 2 week (IV) with ipilimumab 1 mg/kg q 6 week (IV) 
for the duration of the study. This dose was found to be tolerable in Stratum 1 Dose 
Level 2 for participants with a CD4 count above 200 cells/mL. Between May 2017 
and February 2018, the FDA updated the label for OPDIVO® to indicate a dosing 
schedule with only four doses of ipilimumab followed by single agent therapy for 
advanced RCC and colorectal cancer amd single agent therapy has been updated 
for many indications to allow 240 mg q 2 week or 480 mg q 4 week, as equal 
efficacy has been shown for both doses. 
This change will be applied to the combination therapy expansion cohort for which 
tolerability of the original combination therapy has already been established. The 
new combination therapy will remain the same for four cycles of combination 
therapy and will then change to single agent therapy with a flat dose of 480 mg q 4 
week. This change will bring treatment in line with suggested dosing as well as 
reducing the burden on study participant by reducing number of visits required.  
For single agent therapy in participants with classical Hodgkin’s Lymphoma the 
dose was 3 mg/kg q 2 week. The updated label has been changed for this indication, 
to a flat dose of nivolumab of either 240 mg q 2 week or 480 mg q 2 week. The 
protocol dose for the cHL expansion cohort will be updated to 240 mg q 2 week to 
reflect this change. 
Both of these changes will be implemented with version 10.0 of the protocol. 
 
 

 
AMC #095 (Version 15.0) 24AUG2023 
 
38 
NCI Version Date 24AUG2023 
2.4 
Correlative Studies (Exploratory) 
Unless otherwise noted, specimens will be collected and stored for analysis until funding 
becomes available.  
2.4.1 PD-L1 expression on T cells as a biomarker for response 
PD-L1 and PD-L2 expressed on APCs have been shown to induce T cell anergy or 
apoptosis via PD-1 on T cells, whereas PD-L1 expressed on peripheral tissues 
directly suppress self-reactive lymphocytes [68, 69]. PD-Ls expressed on tumors 
regulate the generation of adaptive Tregs, resulting in tumor-induced immune 
suppression. PD-1 blockade has been shown to enhance the expansion and 
functional capacity of tumor antigen-specific cytotoxic T cells [72]. Additionally, 
given the targets differ between PD-1 and ipilimumab, the combination of an anti-
PD-1 with ipilimumab might also be the preferred clinical strategy, depending on 
the tumor expression profile. There are available antibodies to identify the receptor 
overexpression profile on tumors. Tumor biopsies will be collected by the clinical 
site for submission of tissue to BMS, depending on the availability of material and 
funding for analysis. Samples will be tested using the Dako PD-L1 IHC 28-8 
pharmDx for Autostainer Link 48 assay. 
2.4.2 Role of regulatory T Cells and PD-1 blockage in HIV infection 
The effect of blocking of PD-1/PD-L1 on Treg suppressive function has not been 
clearly defined. In HCV infection, PD-1 expression has been shown to negatively 
regulate CD4+CD25+FOXP3+ Tregs. [84, 97] Therefore, blocking of PD-1/PD-L1 
may potentially increase Treg suppression function thereby further inhibiting HIV-
1-specific responses. In contrast, PD-1 has been shown to be important in the 
peripheral conversion of conventional CD4+ T cells to induced Tregs (iTregs).(96) 
As such, blocking PD-1 may be beneficial in that it will decrease peripheral Treg 
frequency leading to a decrease in T cell suppression. 
We therefore plan to evaluate changes in the Treg frequency after administration of 
nivolumab and ipilimumab. We will also assess PD-1 expression in different Treg 
subsets: CD25+FOXP3+ Tregs, Type 1 regulatory cells (Tr1), as well CD39 
expressing Tregs. 
We will phenotype T cells with antibodies to CD25 and FoxP3 (Tregs), HLA-DR, 
CD38 and CCR5 (T cell activation) and CCR7, CD45RA and CD28 (T cell 
differentiation). Finally, we will use gag peptides and intracellular cytokine staining 
(ICS) to determine if there are any changes in the frequency of HIV specific CD4+ 
and CD8+ T cells following administration of anti-CTLA-4 or anti-PD-1. 
2.4.3 Herpesvirus load 
Approximately 10% of all human CD8 T cells are directed against human 
cytomegalovirus. Standard plasma and PBMC (latent) viral load will be determined 
by real-time qPCR for human cytomegalovirus (HCMV), EBV, and Kaposi 
sarcoma-associated herpesvirus KSHV at the AMC core laboratories as per AMC 
Standard Operating Procedure (SOP) and expanded to estimate the number of 
latently infected CD19+ B cells for EBV and KSHV. Samples will be stored for 
future whole vironome profiling by NextGen sequencing. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
39 
NCI Version Date 24AUG2023 
2.4.4 Role of regulatory T Cells and PD-1 blockage in herpesvirus infections 
As HIV positive participants, and particularly participants with Kaposi sarcoma, 
typically carry latent herpesviruses, including KSHV, we will collect samples in by 
methods to support detailed assessments of herpesvirus-directed T cell responses, 
such as anti-HCMV and anti-KSHV responses as measure by peptide stimulation 
and ICS or ELISPOT. 
2.4.5 HIV viral load and CD4/CD8 T cells 
HIV viral load in plasma will be monitored by FDA approved tests with sensitivity 
to 75 copies/ml or less. CD4/CD8 will be evaluated per institutional standards every 
12 weeks during treatment. Tests for the number of integrated proviruses will be 
conducted by the AMC Core laboratory as per AMC SOP. As HIV viral load 
measurements are still under development, we will preserve additional material for 
future assays in specialized labs. 
2.4.6 Viral transcription in KS tumor biopsies 
Viral transcription in KS tumor samples has been shown to be a sensitive measure 
of the status of the virus and its response to the cellular microenvironment. It also 
serves as surrogate marker for the number of tumor cells. This assay will be 
conducted at the AMC Genomics Core Laboratory per AMC SOP. 
2.4.7 HPV genotyping 
Anal swabs will be used, when feasible, for polymerase chain reaction (PCR) and 
reverse line blot analysis to determine the HPV genotype at the AMC Virology 
Core Laboratory per AMC SOP. 
2.4.8 Characterization of activated T cell responses 
T cell activation status. For example, leukocytes may then be labeled with 
CD3/CD8, ICOS1, CDw137, and E6, E7, HCMV, or KSHV MHC tetramers, for 
analysis by flow cytometry to quantitate and phenotype the percentage of CD8-
tetramer double-positive cells. Alternate immune activation markers may be 
included. 
2.4.9 Latent HIV viral load 
The latent HIV reservoir will be quantified by resting CD4 T cell outgrowth assays 
in participants with hematocrit ≥25 and where enough blood (100 ml) is collected, 
with participant consent. This assay, albeit cumbersome, represents the gold 
standard in the field. This testing will be collected for all participants meeting the 
above criteria. The assay will be conducted at the AMC core laboratories per AMC 
SOP. 
Latent HIV reactivation. Changes in HIV plasma RNA by a highly sensitive HIV 
single copy assay and changes in cell associated HIV unspliced RNA will be 
measured to see if this treatment leads to HIV reactivation. 
Changes in T cell phenotype. Changes in numbers of CD4 and CD8 T cells 
phenotype will be measured as well as changes in at cell surface markers of 
activation, immune exhaustion, and functional response to HIV peptides. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
40 
NCI Version Date 24AUG2023 
2.4.10 Characterization of soluble markers for activated T cell responses 
T cell activation status. For example, serum will be analyzed for IL-2, IL-4, IFN-γ, 
IL-6, TNF-α, CXCL13, IL-10) and immune activation biomarkers (sIL2R-alpha, 
sCD27, sCD30, sTNFR1, sTNFR2) using luminex beads at the AMC core 
laboratories as per AMC SOP. Alternate immune activation markers may be 
included. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
41 
NCI Version Date 24AUG2023 
3.0 
PARTICIPANT SELECTION 
A rostered AMC investigator must document that each protocol participant meets all stated 
eligibility criteria. Participating sites must have documentation that each eligibility 
requirement is satisfied prior to participant enrollment. In compliance with CTEP policy, 
no exceptions to eligibility criteria will be granted under any circumstance. 
NOTE: Institutions may use this section of the protocol as an eligibility checklist for source 
documentation if it has been reviewed, signed, and dated before registration/randomization 
by the study investigator. If used as source documentation, this checklist must be printed, 
the investigator must check each item to document their assessment that the participant 
meets each eligibility criterion, and the completed checklist must be maintained in the 
participant’s chart. All questions regarding eligibility should be directed to the study chair. 
Participant ID Number: 095 - ___ ___ ___ - ___ ___ ___ 
Patient’s Initials (L, F, M): ___ ___ ___ 
3.1 
Eligibility Criteria 
___ 
3.1.1 Participants must have histologically confirmed solid tumor malignancy that is 
metastatic or unresectable and for which standard curative or palliative measures 
do not exist or are no longer effective. Participants with uncontrolled Kaposi 
sarcoma are permitted (KS must be increasing despite HAART and HIV 
suppression for greater than or equal to 2 months, or stable KS despite HAART for 
greater than or equal to 3 months). 
For participants in the 24-participant solid tumor cohort, only those histologies not 
known to respond to single agent nivolumab (such as pancreas, prostate, and MSS 
colorectal cancer) will be excluded. 
For participants in the relapsed refractory HIV-cHL expansion cohort, participants 
must 
have 
histologically 
confirmed, 
relapsed/refractory 
(defined 
as 
relapsed/refractory to one or greater lines of therapy) HIV-associated classical HL. 
___ 
3.1.2 HIV-1 infection, as documented by any federally approved, licensed HIV rapid test 
performed in conjunction with screening (or ELISA, test kit, and confirmed by 
Western blot or other approved test). Alternatively, this documentation may include 
a record demonstrating that another physician has documented the participant's HIV 
status based on either: 1) approved diagnostic tests, or 2) the referring physician's 
written record that HIV infection was documented, with supporting information on 
the participant’s relevant medical history and/or current management of HIV 
infection. 
___ 
3.1.3 Participants must have measurable disease, defined as at least one lesion that can 
be accurately measured in at least one dimension (longest diameter to be recorded 
for non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional 
techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam. 
Scans must have been performed within 4 weeks prior to registration. See Section 
9.1.3 or Section 9.3 for HL for the evaluation of measurable disease. Note: For 
participants with Kaposi sarcoma, the following apply: At least five measurable 
cutaneous KS lesions or any number of lesions with systemic unresectable disease 

 
AMC #095 (Version 15.0) 24AUG2023 
 
42 
NCI Version Date 24AUG2023 
with no previous local radiation, surgical, or intralesional cytotoxic therapy that 
would prevent response assessment. 
___ 
3.1.4 Prior therapy for metastatic disease permitted. At least 4 weeks must have elapsed 
since prior chemotherapy or biological therapy, 6 weeks if the regimen included 
carmustine (BCNU) or mitomycin C; radiotherapy must be completed at least 4 
weeks prior to registration. 
___ 
3.1.5 Age > 18 years, because no dosing or AE data are currently available on the use of 
ipilimumab in combination with nivolumab in participants <18 years of age, 
children are excluded from this study. 
___ 
3.1.6 ECOG performance status ≤ 1 (Karnofsky ≥ 70%, see Appendix III). 
___ 
3.1.7 Participants not on the HL expansion cohort must have organ and marrow function 
within the following parameters within 2 weeks prior to enrollment: 
Leukocytes: ≥ 2,000/mm3 
Absolute neutrophil count (ANC): ≥ 1,000/mm3 
Platelets: ≥ 75,000/mm3 
Total bilirubin: ≤ 1.5× institutional upper limit of normal (ULN) ≤ 3 x ULN for 
participants with Gilbert’s disease or with atazanavir- or indinavir-induced 
unconjugated hyperbilirubinemia without AST or ALT elevation and must have 
a total bilirubin less than 3.0 mg/dL). 
Serum lipase and amylase < 1.5 x ULN 
AST (SGOT) / ALT (SGPT): ≤ 3 x ULN Creatinine: < 1.5 ULN or Cr Cl 
>50ml/min 
Hemoglobin: ≥ 9g/dL 
Serum Albumin ≥2.8g/dL 
___ 
3.1.8 Participants on the HL expansion cohort must have organ and marrow function 
within the following parameters within 2 weeks prior to enrollment. Participants 
may receive GCSF and transfusions to meet these parameters: 
• Leukocyte count: no lower limit 
• Absolute neutrophil count: ≥ 1,000/mm3, unless decreased due to bone marrow 
involvement with lymphoma. 
• Platelets: ≥ 75,000/mm3, unless decreased due to bone marrow involvement 
with lymphoma. 
• Hemoglobin: ≥ 9g/dL unless bone marrow involvement secondary to HL is 
present 
• Total bilirubin: ≤ 1.5× institutional ULN, or ≤ 3 x ULN for participants with 
Gilbert’s disease or with atazanavir- or indinavir-induced unconjugated 
hyperbilirubinemia without AST or ALT elevation, and must have a total 
bilirubin less than 3.0mg/dL) 

 
AMC #095 (Version 15.0) 24AUG2023 
 
43 
NCI Version Date 24AUG2023 
• Serum lipase and amylase < 1.5 x ULN 
• AST (SGOT) / ALT (SGPT): ≤ 3 x ULN 
• Creatinine: <1.5 x UNL or CrCl > 50ml/min 
___ 
3.1.9 HIV Viral load should be well suppressed, defined as below the limit of detection 
of the local assay or below 75 copies/mL) by FDA-approved assays, within 4 weeks 
prior to registration. 
___ 
3.1.10 CD4 Counts: For Stratum 1: CD4+ cell count greater than 200 cells/mm3 obtained 
within 2 weeks prior to enrollment at any U.S. laboratory that has a clinical 
laboratory improvement amendments (CLIA) certification or its equivalent. 
For Stratum 2: CD4 cell count between 100-200 cells/mm3 obtained within 2 weeks 
prior to enrollment at any U.S. laboratory that has a CLIA certification or its 
equivalent. 
Expansion Cohort: CD4 cell count for this cohort will be specified once Stratum 1 
and Stratum 2 have completed enrollment (Section 3.3). 
Solid Tumor Expansion Cohort: CD4+ cell count greater than 200 cells/mm3 
obtained within 2 weeks prior to enrollment at any U.S. laboratory that has a CLIA 
certification or its equivalent. 
cHL Cohort: CD4 cell count of at least 100 cells/mm3. 
___ 
3.1.11 Participants must be PPD negative. Alternatively, the QuantiFERON-TB Gold In-
Tube (QFT-GIT) assay (Cellestis Limited, Carnegie, Australia) can be used. An 
individual is considered positive for M. tuberculosis infection if the IFN-γ response 
to TB antigens is above the test cut-off (after subtracting the background IFN-γ 
response in the negative control). The result must be obtained within 12 weeks prior 
to enrollment. PPD positive (or Quantiferon assay positive) participants are 
permitted if prophylaxis has been completed prior to enrollment. 
___ 
3.1.12 The effects of nivolumab and ipilimumab on the developing human fetus are 
unknown. For this reason and because other therapeutic agents used in this trial are 
known to be teratogenic, women of childbearing potential (WOCBP)1 and men 
must agree to use adequate contraception (hormonal or barrier method of birth 
control; abstinence) prior to study entry and for the duration of study participation. 
WOCBP should use an adequate method to avoid pregnancy for 6 months) after the 
last dose of investigational drug. WOCBP must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
72 hours prior to enrollment and the start of nivolumab. Women must not be 
breastfeeding. Men who are sexually active with WOCBP must use any 
contraceptive method with a failure rate of less than 1% per year. Men receiving 
 
1 Note: Women of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who 
has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. 
Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or 
physiological causes. In addition, women under the age of 55 must have a documented serum follicle stimulating 
hormone (FSH) level less than 40 mIU/mL. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
44 
NCI Version Date 24AUG2023 
nivolumab and who are sexually active with WOCBP will be instructed to adhere 
to contraception for a period of 31 weeks after the last dose of investigational 
product. Women who are not of childbearing potential (i.e., who are 
postmenopausal or surgically sterile as well as azoospermic men) do not require 
contraception. 
WOCBP receiving nivolumab will be instructed to adhere to contraception for a 
period of 6 months after the last dose of investigational product. Men receiving 
nivolumab and who are sexually active with WOCBP will be instructed to adhere 
to contraception for a period of 31 weeks after the last dose of investigational 
product. 
Should a woman become pregnant or suspect she is pregnant while she or her 
partner is participating in this study, she (or the participating partner) should inform 
the treating physician immediately. 
___ 
3.1.13 Participants MUST receive appropriate care and treatment for HIV infection, 
including antiretroviral medications when clinically indicated, and should be under 
the care of a physician experienced in HIV management. Participants will be 
eligible regardless of antiretroviral medication (including no antiretroviral 
medication) provided there is no intention to initiate therapy, or the regimen has 
been stable for at least 4 weeks with no intention to change the regimen within 12 
weeks following enrollment. 
___ 
3.1.14 Participants who have Hepatitis C (both reactive anti-HCV antibody and detectable 
HCV RNA) and Hepatitis B (HBsAg positive and anti-HBc-Total positive), may 
be enrolled, provided total bilirubin is ≤1.5× institutional ULN, AST (SGOT) and 
ALT (SGPT) must be ≤3 X institutional upper limit of normal, and HBV DNA < 
100 IU/mL (if Hepatitis B positive) within 2 weeks prior to enrollment. 
___ 
3.1.14 Ability to understand and to sign a written informed consent document. 
3.2 
Exclusion Criteria 
Participants who do not fulfill the criteria as listed in Section 3.1 above, are ineligible. 
Additionally, the presence of any of the following conditions will exclude a participant 
from study enrollment: 
___ 
3.2.1 Participants who have received any other investigational agents within the 4 weeks 
prior to enrollment. Concurrent radiation therapy is not permitted, except palliative 
(limited-field) radiation therapy, if all of the following criteria are met: 
1) Repeat imaging demonstrates no new sites of bone metastases. 
2) The lesion being considered for palliative radiation is not a target lesion. 
___ 
3.2.2 Participants with known brain metastases or leptomeningeal metastases must be 
excluded unless they qualify for enrollment as described below because of poor 
prognosis and concerns regarding progressive neurologic dysfunction that would 
confound the evaluation of neurologic and other AEs. Participants with brain 
metastases are permitted if metastases have been treated and there is no magnetic 
resonance imaging (MRI) evidence of progression for at least 4 weeks or more after 
treatment is complete and within 4 weeks prior to the first dose of nivolumab 

 
AMC #095 (Version 15.0) 24AUG2023 
 
45 
NCI Version Date 24AUG2023 
administration. 
___ 
3.2.3 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to ipilimumab, nivolumab, or other agents used in study, or 
history of severe hypersensitivity reaction to any monoclonal antibody. 
___ 
3.2.4 Participants should be excluded if they have a condition requiring systemic 
treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other 
immunosuppressive medications within 2 weeks of study drug administration. 
These drugs may interfere with the activity of ipilimumab and nivolumab if 
administered at the time of the first ipilimumab dose. Inhaled or topical steroids 
and adrenal replacement doses ≤10 mg daily prednisone equivalents are permitted 
in the absence of active autoimmune disease. Participants are permitted to use 
topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with 
minimal systemic absorption). Physiologic replacement doses of systemic 
corticosteroids are permitted, even if ≥10 mg/day prednisone equivalents. A brief 
course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment 
of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused 
by contact allergen) is permitted. Use of anabolic steroids is permitted. 
___ 
3.2.5 Participants with clinical or radiographic evidence of pancreatitis are excluded. 
___ 
3.2.6 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
___ 
3.2.7 Participants should be excluded if they have had prior treatment with an anti-PD-1, 
anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug 
specifically targeting T cell co-stimulation or immune checkpoint pathways. Prior 
immune modulating therapy including vaccines may be eligible. Prior immune 
events must be evaluated and the risk for new events, which may represent 
continued sub clinical disease or a new process at previously damaged site or 
immune potentiation (e.g., ipilimumab followed by IL2 causing bowel perforation, 
ipilimumab followed by IDO inhibitor resulting in clinical hypophysitis). Please 
keep in mind that inflammatory events may occur weeks to months following the 
last dose of ipilimumab and possibly nivolumab. 
Assessment of potential effects of prior therapy should include: 
Immune status 
Organ damage 
Risk of autoimmunity 
Immunopotentiation 
___ 
3.2.8 The participant has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity 
due to all prior therapies except ≤ Grade 2 alopecia, neuropathy, and other non-
clinically significant AEs. 
___ 
3.2.9 The participant has a primary brain tumor. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
46 
NCI Version Date 24AUG2023 
___ 
3.2.10 Participant has ≥ grade 2 diarrhea (participants with grade 1 diarrhea are eligible 
provided stool for ova/parasites and stool cryptosporidium studies are negative). 
___ 
3.2.11 Opportunistic infection within the last 3 months. 
___ 
3.2.12 Autoimmune disease: Participants with active autoimmune disease or history of 
autoimmune disease that might recur, which may affect vital organ function or 
require immune suppressive treatment including systemic corticosteroids, should 
be excluded. These include but are not limited to participants with a history of 
immune-related 
neurologic 
disease, 
multiple 
sclerosis, 
autoimmune 
(demyelinating) neuropathy, Guillain-Barré syndrome, myasthenia gravis; 
systemic autoimmune disease such as SLE, connective tissue diseases, 
scleroderma, inflammatory bowel disease (IBD), Crohn’s, ulcerative colitis, 
hepatitis; and participants with a history of toxic epidermal necrolysis (TEN), 
Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because 
of the risk of recurrence or exacerbation of disease. Participants with vitiligo, 
endocrine deficiencies including thyroiditis managed with replacement hormones 
including physiologic corticosteroids are eligible. Participants with rheumatoid 
arthritis and other arthropathies, Sjögren’s syndrome and psoriasis controlled with 
topical medication and participants with positive serology, such as ANA, anti-
thyroid antibodies should be evaluated for the presence of target organ involvement 
and potential need for systemic treatment but should otherwise be eligible. 
Participants are permitted to enroll if they have vitiligo, type I DM, residual 
hypothyroidism due to autoimmune condition only requiring hormone replacement, 
psoriasis not requiring systemic treatment, or conditions not expected to recur in 
the absence of an external trigger (precipitating event). 
___ 
3.2.13 Participants who have had evidence of C. difficile infection, active or acute 
diverticulitis, 
intra-abdominal 
abscess, 
GI 
obstruction 
and 
abdominal 
carcinomatosis, which are known risk factors for bowel perforation, should be 
evaluated for the potential need for additional treatment before coming on study. 
___ 
3.2.14 cHL cohort only: history of allogeneic transplant. 
 
Physician Signature: ______________________________ Date: ___________________ 
(Optional unless this section is used as an eligibility checklist) 
 
3.3 
Criteria for Solid Tumor Expansion and Lymphoma Cohorts 
Inclusion and exclusion criteria for the solid tumor cohorts are the same as above, with the 
following rule for CD4 count based on tolerability in Phase I. If, participants with 
lymphocyte T CD4 count between 100-200/mm3 (Stratum 2) are shown to tolerate 
treatment in the Phase I dose de-escalation portion at the same dose level as those with 
CD4 counts >200/mm3 (Stratum 1), participants in the expansion cohort with CD4 counts 
≥100/mm3 are permitted. Otherwise, the expansion is open to all solid tumor patients 
except those whose tumors are known not to respond to nivolumab (pancreas, prostate and 
MSS colon cancer). For the relapsed refractory HIV-cHL cohort, participants with CD4 

 
AMC #095 (Version 15.0) 24AUG2023 
 
47 
NCI Version Date 24AUG2023 
count ≥ 100/mm3 are permitted. 
3.4 
Number of Participants to be Enrolled 
3.4.1 Proposed sample size 
This study will enroll a minimum of 4 participants and a maximum of 96 
participants (see Section 10.2). 
3.4.2 Accrual rate 
Approximately two participants per month for Phase I, Stratum 1; approximately 
one participant per month for Phase I, Stratum 2. Approximately 2-3 participants 
per month for the combination therapy solid tumor expansion cohort and 
approximately 2-3 participants per month for the single agent solid tumor cohort 
(excluding those histologies not known to respond to single agent nivolumab, i.e., 
pancreas, prostate, MSS colorectal cancer). The cHL cohort will enroll 
approximately 3-4 patients per month.  
3.5 
Participant Enrollment Procedures 
Sites must have this protocol approved by their Institutional Review Boards (IRB) and be 
registered for study participation with the AMC Operations and Data Management Center 
(ODMC) before they may enroll participants. 
After an informed consent form has been signed by the participant and it has been 
determined that the participant is eligible, the participant must be registered on-line via the 
AMC AdvantageEDCSM Internet Data Entry System (AdvantageEDC). Enrollment and 
data collection will occur via the AMC Internet Data Entry System. 
The participating site will ensure a participant meets all eligibility criteria prior to 
completing the protocol-specific eligibility checklist in AdvantageEDC for enrollment. 
Participants will be enrolled on-line via AdvantageEDC no more than 1 week prior to the 
initiation of treatment (enrollment 1 day prior to or on the day of treatment is strongly 
encouraged). It may take up to three business days for sites to receive nivolumab. Once the 
eligibility checklist is submitted, a system-generated confirmation email will be sent to the 
enroller upon successful completion of the participant enrollment. If the on-line system is 
inaccessible, the site should notify the AMC ODMC (via email at amcpm@emmes.com or 
via phone at 301-251-1161) for further instructions. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
48 
NCI Version Date 24AUG2023 
4.0 
TREATMENT PLAN 
4.1 
Treatment Design 
Protocol agents will be administered on an outpatient basis. Reported AEs and potential 
risks for ipilimumab and nivolumab are described in Section 6.0. Appropriate dose 
modifications for ipilimumab and nivolumab are described in Section 5.0, Appendix X. No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant’s malignancy. 
Participants will be studied in separate strata. Stratum 1 will enroll participants with 
lymphocyte T CD4+ count above 200/mm3. Stratum 2 will enroll participants with 
lymphocyte T CD4+ count between 100-200/mm3. Enrollment on Stratum 2 will occur 
sequentially, initially in Stratum 1 at dose level 1, and then in Stratum 2 after Stratum 1 
has completed and an MTD has been determined. Once the MTD is determined in each 
stratum, the MTD will then be studied in a dose expansion cohort of up to 12 participants. 
If the MTDs differ between the two strata, expansion cohorts of six participants each will 
be enrolled. An additional cohort of 12 participants with cHL and lymphocyte T CD4+ 
count ≥ 100/mm3 will be treated with single agent nivolumab. Lastly, an additional 24 
participants with solid tumors will be treated with single agent nivolumab. 
4.2 
Dose De-Escalation Cohorts: Stratum 1 and Stratum 2 
For Stratum 1, the study is a phase I dose de-escalation trial with a rolling six design to 
establish the MTD for single agent nivolumab and then the MTD for combination of 
ipilimumab and nivolumab. Since there are only two dose levels within each single and 
combination therapy, the design requires the full cohort of six participants to be enrolled 
unless two of the first three participants in that cohort experience a DLT, or if two or more 
participants in that cohort experience a DLT. In Stratum 1, two agents will be studied, 
initially nivolumab as a single agent (starting at Dose Level 1) and then the combination 
of ipilimumab and nivolumab (starting at Dose Level 2 or -2). After evaluating single agent 
nivolumab dosing, the next dose level will be 2 if dose level 1 is the MTD for single agent 
nivolumab or dose level -2 if dose level -1 is the single agent MTD. If 2 DLTs are 
experienced at Dose Levels 1 or 2, then one dose de-escalation (Dose Levels of -1 or -2, 
respectively) will be permitted according to the dose de-escalation schedule. Fixed doses 
will be administered according to the dosing schema in the treatment plan. The Phase I 
MTD for single agent or combination therapy is the dose level at which ≤1/6 participants 
experience DLT, with the next higher dose having ≥2 participants encountering DLT 
(unless the MTD is the highest pre-specified dose level). The safety evaluation period is 6 
weeks at a given dose level. No dose escalation will be allowed in an individual participant, 
and participants who have dose limiting AEs or disease progression will discontinue 
therapy. During the period for evaluating DLT, participants who withdraw from the study 
or do not complete the required cycles of treatment owing to reasons other than drug-
related AEs can be replaced. Participants will have blood drawn before each cycle for 
routine safety laboratory monitoring. All participants will be followed every 2 weeks for 
treatment administration, exam, toxicity, response, and compliance assessment for a 
minimum of 8 weeks and up to 92 weeks of treatment. 
 
 

 
AMC #095 (Version 15.0) 24AUG2023 
 
50 
NCI Version Date 24AUG2023 
3. 
If, after completing first 6 weeks for combination of ipilimumab and nivolumab 
(Dose Level 2 or -2), 0/6 or <1/6 exhibits a POSSIBLY, PROBABLY or 
DEFINTELY, study treatment-related DLT then that dose level is the combination-
agent MTD. If a second participant develops a study treatment POSSIBLY, 
PROBABLY or DEFINTELY related DLT, even if it is before there are six total 
participants on that level, then the combination-agent MTD has been exceeded and 
no additional participants should be added to this dose. A total of six participants 
should then be treated on the next lowest dose level (Dose Level -2 if not already 
at the lowest dose) to ensure its tolerability and to better define the MTD. If ≥2 
participants on level -2 experience a POSSIBLY, PROBABLY or DEFINTELY 
related DLT, the MTD will have been exceeded and no additional participants will 
be added at level -2. 
4.2.1 Dosing for Stratum 1 
The study treatment consists of up to 46 intravenous (IV) infusions of nivolumab 
on day 1 of each 2-week cycle for the dose level -1 and 1 cohorts. For dose level 2, 
IV infusions of nivolumab are given on day 1 of each 2-week cycle and ipilimumab 
on day 1 every 6 weeks, i.e., every third cycle of nivolumab (cycles 1, 4, 7, etc.). 
For dose level -2, IV infusions of nivolumab are given on day 1 of each 2-week 
cycle, and ipilimumab is given on day 1 every 12 weeks, i.e., every sixth cycle of 
nivolumab (cycles 1, 7, 13, etc.). 
Participants with an overall response of SD, PR, CR, or unconfirmed PD (refer to 
Section 9.1 for Response Evaluation Criteria in Solid Tumors (RECIST) Criteria at 
the scheduled response visits at week 8 and all subsequent visits day 1 of cycles 6 
and 9 will be eligible to continue to receive study drug treatments provided that 
they also have an Eastern Cooperative Oncology Group (ECOG) performance 
status score of ≤ 2, and did not have a DLT or other safety risk requiring 
discontinuation of the study drugs. Before dosing can continue after the day 1 of 
cycles 5 and each subsequent visit at which response is assessed (every 12 weeks 
thereafter), the results of the scheduled response assessments must be reviewed to 
determine, and document continued eligibility prior to administration of the study 
drugs. 
Participants with an overall response of SD, PR, CR, or unconfirmed PD at the end 
of the first four cycles will continue treatment for up to a total of 46 cycles (refer to 
Section 9.1 for RECIST Criteria). Participants with confirmed PD after the first 
four cycles of therapy will discontinue the study drugs. Participants without 
evidence of confirmed progression after the first four cycles, with either a poor 
performance status (ECOG > 2) or toxicity requiring discontinuation of the study 
drugs will continue treatment until confirmed PD, requiring initiation of a new 
treatment. 
 
 

 
AMC #095 (Version 15.0) 24AUG2023 
 
51 
NCI Version Date 24AUG2023 
4.2.2 Dosing Stratum 2 
After review of AEs in Stratum 1, this will be followed by evaluation of nivolumab 
and ipilimumab in Stratum 2. Stratum 2 single agent dosing will begin after the 
MTD for Stratum 1 single agent therapy has been confirmed (dose level 1 or -1). 
After the Stratum 1 combination therapy MTD is determined (dose level 2 or -2), 
Stratum 2 will begin evaluation of combination therapy at that dose level. Up to six 
participants will be concurrently enrolled at the Stratum 1 MTD, following the dose 
de-escalation rules and treatment plan outlined above in Section 4.2 and 4.2.1. 
Stratum 2 participants will not be allowed to escalate beyond the MTD for Stratum 
1; one dose level de-escalation of the nivolumab and ipilimumab combination or to 
single agent nivolumab will be allowed based on the doses in the schema in the 
treatment plan. The Phase I MTD is the dose level at which ≤1/6 participants 
experience DLT with the next higher dose having ≥2 participants encountering 
DLT (unless the MTD is the highest pre-specified dose level). No dose escalation 
will be allowed in an individual participant, and participants who have dose limiting 
AEs or disease progression will discontinue therapy. During the period for 
evaluating DLT, participants who withdraw from the study or do not complete the 
required cycles of therapy owing to reasons other than drug-related AEs can be 
replaced. During the first four cycles of treatment, participants will have blood 
drawn weekly for routine safety laboratory monitoring. Participants will then be 
followed every 2 weeks for treatment administration, exam, toxicity, response, and 
compliance assessment for a minimum of 8 weeks, and up to 92 weeks. 
4.2.3 Expansion Cohort in Solid Tumors and Lymphoma 
An additional 24 participants with incurable solid tumors will be treated at the 
MTD, according to the treatment schedule defined above for each stratum. If the 
MTDs differ between the two strata, expansion cohorts of six participants each will 
be enrolled. 
Another 24 participants with incurable solid tumors will be treated at single agent 
nivolumab 240 mg every 2 weeks. Only those histologies that are not known to 
respond to single agent nivolumab will be excluded (i.e., pancreas, prostate, MSS 
colorectal cancer, unless results from another clinical trial showing non-response 
in another tumor type become available in the future). 
Participants with HL will be treated at the FDA approved flat dose of 240mg given 
every 2 weeks. 
Participants with an overall response of SD, PR, CR, or unconfirmed PD at the end 
of the first four cycles of nivolumab will continue treatment for up to a total of 46 
cycles of nivolumab (with ipilimumab if receiving dose level 2 or -2) (refer to 
Section 9.1 for RECIST Criteria and Section 9.3 for the 2017 response evaluation 
criteria in lymphoma (RECIL) Criteria for evaluating measurable disease in HIV-
cHL). 
Participants with a confirmed PD will discontinue the study drugs. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
52 
NCI Version Date 24AUG2023 
4.3 
Treatment Plan 
4.3.1 Nivolumab 
For Dose Levels 1 and -1 in Stratum 1 
1 cycle = 14 days 
Treatment: A maximum of 46 cycles of nivolumab will be given every 2 weeks. 
Dose Level 1: Nivolumab 3mg/kg q 2 wk x 46 doses 
Dose Level -1: Nivolumab 1mg/kg q 2 wk x 46 doses 
Nivolumab will be given every two weeks (±2 days) when given as a single agent 
as per the dose de-escalation table in Section 4.2 and will be modified in cohorts of 
up to six participants (as outlined in Section 4.2) based upon the number of 
participants who have a DLT event at each dose level (as defined in Section 4.2) 
during the first cycle of therapy. Participants may be dosed no less than 12 days 
from the previous dose of drug. 
The dosing calculations should be based on the actual body weight. If the 
participant’s weight on the day of dosing differs by >10% from the weight used to 
calculate the original dose, the dose must be recalculated. All doses should be 
rounded to the nearest milligram. There will be no dose modifications allowed. 
Nivolumab is to be administered as a 60-minute IV infusion, using a volumetric 
pump with a 0.2 to 1.2 micron in-line filter at the protocol-specified dose. The drug 
can be diluted with 0.9% normal saline for delivery, but the total drug concentration 
of the solution cannot be below 0.35 mg/mL. It is not to be administered as an IV 
push or bolus injection. At the end of the infusion, flush the line with a sufficient 
quantity of normal saline. 
For the solid tumor expansion cohort, a dose of 240mg of single agent nivolumab 
will be administered every 2 weeks for 46 doses as described above, as a 60-minute 
IV infusion. 
For the cohort of HL, a dose of 240mg flat dose of single agent nivolumab will be 
administered every 2 weeks for 46 doses as described above, as a 60-minute IV 
infusion. 
For nivolumab and ipilimumab combination studies see Section 4.3.2. 
4.3.2 Nivolumab and ipilimumab 
For Dose Levels 2 and -2 in Stratum 1 
1 cycle = 14 days 
Nivolumab treatment: A maximum of 46 cycles of nivolumab will be given every 
2 weeks 
Ipilimumab treatment: A maximum of 16 cycles of ipilimumab given every 6 
weeks (on day 1 of every third nivolumab cycle (cycles 1, 4, 7, etc.)) for Dose Level 
2, and a maximum of eight cycles of ipilimumab given every 12 weeks, (on day 1 
of every sixth nivolumab cycle (cycles 1, 7, 13, etc.)) for Dose Level -2. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
53 
NCI Version Date 24AUG2023 
Dose Level 2: 
▪ Nivolumab 240 mg q 2 wk x 46 doses 
▪ Ipilimumab 1mg/kg q 6 wk x 16 doses (day 1 of nivolumab cycles 1, 4, 7, 10, 
13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, and 46) 
Dose Level -2: 
▪ Nivolumab 1 mg/kg q 2 wk x 46 doses  
▪ Ipilimumab 1mg/kg q 12 wk x 8 doses (day 1 of nivolumab cycles 1, 7, 13, 19, 
25, 31, 37, and 43) 
Toxicity management for the combined agents follows the same template 
guidelines and algorithms that are provided in Appendix X for single agent 
nivolumab. 
Follow the same infusion timing guidelines: nivolumab over 60 minutes and 
ipilimumab over 90 minutes.  
When both nivolumab and ipilimumab are to be administered on the same day, 
separate infusion bags and filters must be used for each infusion. Nivolumab is to 
be administered first. The nivolumab infusion must be promptly followed by a 
saline flush to clear the line of nivolumab before starting the ipilimumab infusion. 
Nivolumab cycles may be repeated every 14 days (± 2 days). Cycles in which 
nivolumab and ipilimumab are administered, per the dosing schedule for the 
assigned dose level 2 or -2, no earlier than 12 days after the last cycle of nivolumab. 
4.3.3 Stratum 2 treatment 
Stratum 2 dosing will begin based on the single agent therapy MTD determined in 
Stratum 1. Stratum 2 will not be allowed to escalate beyond the MTD for Stratum 
1. An expansion cohort will be treated at the MTD for Stratum 1. If the MTDs differ 
between the two strata, expansion cohorts of six participants each will be enrolled. 
4.3.4 Expansion cohorts 
For the solid tumor expansion cohort, a dose of 240 mg of single agent nivolumab 
will be administered every 2 weeks for 46 doses as described above, as a 60-minute 
IV infusion. Inclusion criteria for CD4 count will be managed as noted in Section 
4.1. 
1 nivolumab cycle = 14 days 
A maximum of 46 cycles of nivolumab will be given every 2 weeks. If the 
combination is tolerated, ipilimumab will be given according to the treatment 
instructions for dose level 2 or -2 as above, depending on the MTD for that stratum, 
in a separate solid tumor expansion cohort. 
For the combination solid tumor expansion cohort, the dosing will be 12 
intravenous (IV) infusions of nivolumab, 240 mg, on day 1 of each 2-week cycle 
and ipilimumab on day 1 every 6 weeks with four total ipilumimab cycles, i.e., 
every third cycle (cycles 1, 4, 7, 10). After completion of the 12th cycle of 
nivolumab, the nivolumab dose will change to a flat dose of 480 mg, on day 1 of 

 
AMC #095 (Version 15.0) 24AUG2023 
 
54 
NCI Version Date 24AUG2023 
each 4-week cycle without ipilimumab. Participants with an overall response of SD, 
PR, CR, or unconfirmed PD at week 8 will continue treatment (Refer to Section 9.1 
for RECIST Criteria) for up to 84 weeks. For participants with HIV-cHL, single 
agent nivolumab will be given as a flat dose of 240 mg every 2 weeks as described 
in Section 4.3.1. 
4.3.5 Study procedures by visit and treatment cycle 
Note that results of all safety laboratory test (that is, all chemistry and all 
hematology results) must be obtained and reviewed before ipilimumab 
administration, as applicable. All laboratory results must be within the established 
range before ipilimumab is administered. All laboratory samples for the first four 
cycles of nivolumab must be collected within a window of up to 3 days before 
administration of nivolumab and/or ipilimumab. Laboratory evaluations using a 
local laboratory must be performed and the result examined by the investigator 
before administration of each dose of nivolumab and/or ipilimumab. 
4.4 
Definition of DLT 
Nivolumab has the potential to be synergistic with ipilimumab and augment the rate and 
duration of clinical responses. It also, however, has the potential to augment the frequency 
and severity of previously characterized ipilimumab-related immune-related adverse 
events (irAE), as well as to generate new study drug-related irAEs or toxicities. It will be 
important to differentiate between irAEs expected from ipilimumab toxicity as opposed to 
an increase in frequency or a worsening of severity of irAEs as an indicator of unacceptable 
toxicity related to the combination. 
The MTD to define the optimal dose. The MTD itself is determined by DLT, i.e., 
toxicity/severity that limits the possibility to treat a participant at the planned dose. DLT is 
traditionally defined as any grade 3-4 non-hematological or grade 4 hematological toxicity 
at least possibly related to the treatment, occurring during the first cycle of treatment. DLTs 
will be defined by drug-related AEs that meet the criteria below as evaluated by NCI 
Common Terminology Criteria for AEs version 5 (CTCAE v5.0), unless clearly unrelated 
to study drugs (e.g., disease progression) defined based on DLTs that occur during the first 
6 weeks for single agent nivolumab (Dose Levels 1 and -1) and 6 weeks for the nivolumab 
and ipilimumab combination (Dose Levels 2 and -2). 
Note: DLT and other toxicities are discussed among the Study Chair, Co-Chairs, the Phase 
I Committee Chair, the AMC Medical Monitor, and the AMC Biostatistician. The 
discussions are the basis for the decisions regarding dose de-escalation according to the 
rules of the protocol and opening of Stratum 2 to enrollment. 
• Permanently stopping protocol treatment during the DLT period (defined as 6 weeks 
from the first dose) for either arm is considered a DLT. 
• Any drug-related death is a DLT. 
• Grade 3 or 4 events requiring permanent discontinuation of nivolumab or ipilimumab, 
including those that will require long term, high dose corticosteroids. 
Management and dose modifications associated with the above AEs are outlined in Section 
5.0 and Appendix X. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
55 
NCI Version Date 24AUG2023 
4.5 
Dose Adjustments, Dose Delays, and Missed Doses 
There will be no dose adjustments allowed except for weight changes (± 10% from the 
baseline weight measurement) at visits that require weight measurements. If it is 
determined that a dose level combination exceeds the MTD, participants tolerating that 
dose level combination will receive subsequent doses at the next lower dose level 
combination. 
During treatment for all dose levels, if there is a dose delay between 1 and 5 days, the 
procedures at the original scheduled visit should be performed as soon as possible. If the 
delay is more than 5 days, the visit and dose will be considered missed; the procedures at 
the next scheduled visit should be performed, and subsequent visits will follow every 2 
weeks. 
If treatment is delayed for > 35 days for participants on dose levels 1 or -1, or > 42 days 
for participants on dose levels 2 or -2 (> 56 days for participants on a steroid taper), the 
participant must be permanently discontinued from study therapy, except as specified in 
Section 4.7 (Duration of Therapy). 
4.6 
General Concomitant Medication and Supportive Care Guidelines 
4.6.1 Supportive care 
All supportive measures consistent with optimal patient care will be given 
throughout the study. 
See Appendix X for supportive care considerations for nivolumab and nivolumab 
and ipilimumab combination administration. 
If the confirmed viral load of a participant is > 1,000, the treating physician is 
advised to make changes to the ART regimen, preferably after consultation with an 
HIV specialist. If the participant is not receiving ART at the time of study initiation 
and his/her viral load becomes detectable during study participation, ART initiation 
may be recommended, at an HIV specialist’s direction for the participant’s medical 
care. 
Participants requiring chemotherapy or radiation therapy during the study will be 
taken off study treatment. Any exceptions must be discussed with the study chair. 
Palliative (limited-field) radiation therapy is permitted if all of the following criteria 
are met: 
1) Repeat imaging demonstrates no new sites of bone metastases. 
2) The lesion being considered for palliative radiation is not a target lesion. 
4.6.2 Other medications 
Participants MUST receive medically appropriate care and treatment for HIV 
infection, including antiretroviral medications when clinically indicated. 
Suspension or modification of an antiretroviral regimen during study participation 
will be permitted (after 8 weeks from study entry) at the discretion of the physician 
providing HIV care, provided the change and its rationale are carefully 
documented. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
56 
NCI Version Date 24AUG2023 
Recommended prophylaxis for opportunistic infections is listed in Appendix VIII. 
Participants must be instructed to inform the investigators of the current or planned 
use or all other medications during the study (including prescription medications, 
over-the-counter medications, vitamins, and herbal and nutritional supplements). It 
is the responsibility of the investigator to ensure that details regarding all 
medications are documented. Only prescription medications will be recorded in the 
case report forms. Bisphosphonates started prior to screening activities or initiated 
during the course of the study to control bone pain may be used with caution. 
As the study will identify DLTs of this treatment regimen during the initial cycle 
of therapy, prophylactic growth factor (G-CSF) administration is not 
recommended. Based on observed toxicities, protocol-specified dose modification 
guidelines should be followed for subsequent therapy cycles. Management of 
anemia will be at the discretion of the treating physician. No concurrent 
investigational agents are permitted. 
4.6.3 Prohibited therapies 
Participants in this study may use standard vaccines. Participants in this study may 
not use vaccines for the treatment of cancer for up to one month pre- and post-
dosing with ipilimumab. Concomitant systemic or local anti-cancer medications 
including biologics or radiation therapy treatments are prohibited in this study while 
receiving ipilimumab and nivolumab. 
Where possible, routine vaccination for influenza, pneumococcal pneumonia 
should be given prior to the start of therapy but may be administered during 
treatment when clinically indicated. Vaccination should be given when there is 
enough separation to distinguish any vaccine reactions from drug toxicity. There is 
no experience using live attenuated vaccination during ipilimumab therapy, so that 
live vaccine should be used cautiously during treatment. 
Concomitant systemic or local anti-cancer medications or treatments are prohibited 
in this study while receiving ipilimumab treatments. 
Participants may not use any of the following therapies during the study: 
• Any non-study anti-cancer agent (investigational or non-investigational) 
• Any other investigational agents 
• Any other CTLA-4 inhibitors or agonists 
• CD137 agonists, PD-1 inhibitors 
• Immunosuppressive agents, unless indicated to manage study therapy induced 
irAEs 
• Chronic systemic corticosteroids, unless indicated to manage study therapy 
induced irAEs or chronic GVHD at a stable dose prior to study entry 
• Any non-oncology vaccine therapies used for the prevention of infectious 
diseases (for up to 30 days prior to or after any dose of study drug; however, it 
is suggested that routine vaccinations, including seasonal influenza, be given at 

 
AMC #095 (Version 15.0) 24AUG2023 
 
57 
NCI Version Date 24AUG2023 
least 2 weeks prior to study treatment). 
4.6.4 Precautions 
Combination therapy may result in unexpected toxicity especially in novel 
combinations with other immune modifying agents. A striking example in 
macaques is presented in Vaccari, et al. 2012. 
Please note that while unproven, there is a suggestion that autoimmune events, 
including hepatitis, may occur more frequently at sites of metastases or prior injury. 
Caution is advised when considering treatment with high dose IL-2 in participants 
who have previously been administered ipilimumab, particularly in participants 
who 
experienced 
ipilimumab-related 
diarrhea/colitis. 
Colonoscopy 
or 
sigmoidoscopy with biopsy may be advisable prior to IL-2 administration once the 
participant is no longer receiving ipilimumab. 
Participants who have received ipilimumab may potentially develop autoimmune 
disease with subsequent therapy including the appearance of colitis, hypophysitis, 
or adrenal insufficiency. 
4.7 
Duration of Therapy 
In the absence of treatment delays due to AE(s), treatment may continue 92 weeks of 
nivolumab (with ipilimumab, if receiving dose level 2 or -2) until one of the following 
criteria applies: 
• The development of progression (confirmed PD by RECIST Criteria or PD by the KS 
evaluation criteria in Section 9.2 or per Section 9.3, utilizing the consensus RECIL 
(2017). Participants will remain on study treatment until progression is confirmed, 
• Pregnancy 
o All WOCBP should be instructed to contact the investigator immediately if they 
suspect they might be pregnant (e.g., missed, or late menstrual period) at any time 
during study participation. Institutional policy and local regulations should 
determine the frequency of on study pregnancy tests for WOCBP enrolled in the 
study. 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a study participant. 
• Intercurrent illness that prevents further administration of treatment. 
• Unacceptable AE(s) which include the following (see also Section 6.0 and specific 
algorithms in Appendix X): 
o Any grade 4 events except as noted below. 
o Grade 3 drug-related autoimmune or inflammatory events including uveitis, 
pneumonitis, diarrhea, colitis, neurologic AEs, hypersensitivity reaction, or 
infusion reaction of any duration requires discontinuation except as noted below: 
o Any other grade 3 non-skin, drug-related AE lasting >7 days including fatigue. 
o Any grade 3 or 4 drug-related laboratory abnormality or electrolyte abnormality, 

 
AMC #095 (Version 15.0) 24AUG2023 
 
58 
NCI Version Date 24AUG2023 
not associated with underlying organ pathology that does not require treatment 
except for electrolyte replacements does not require treatment discontinuation. 
o Grade 3 or 4 amylase or lipase abnormalities that are not associated with DM, 
associated liver or gall bladder inflammation clinical manifestations of pancreatitis 
and which decrease to < Grade 2 within 1 week of onset may resume study 
treatment when resolved. 
• Any grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period 
OR requires systemic treatment. 
o Participants requiring > two dose delays for the same type of event should go off 
protocol therapy. 
o Any AE, laboratory abnormality, or intercurrent illness, which, in the judgment of 
the investigator, presents a substantial clinical risk to the participant with continued 
study drug dosing. 
• Any participants who require additional immune suppressive treatment beyond steroids 
should go off study treatment. 
• In participants with HIV-cHL, any participant who requires consolidative therapy with 
high dose chemotherapy followed by stem cell transplantation will be permitted to go 
off study therapy. 
• Withdrawal of informed consent (participant’s decision to withdraw for any reason). 
• General or specific changes in the participant's condition, or any clinical AE, laboratory 
abnormality or intercurrent illness, which, in the opinion of the investigator, indicate 
that continued treatment with study therapy is not in the best interest of the participant. 
• Termination of the study by sponsor. 
• Participants treated with systemic steroids, except for a short course of tapered steroids 
for grade 3 rash and physiologic replacement doses, should be off study. 
o Participants who have been treated with steroids and who do not have an 
immunologically based event (e.g., infectious pneumonia rather than lymphocytic 
pneumonitis) may be restarted on treatment if asymptomatic after 2 weeks off all 
steroids. 
o Tumor assessments should continue as per protocol even if dosing is interrupted. 
4.8 
Duration of Follow-Up 
Participants will be followed for 16 weeks or 112 days (based on five half-lives) after 
removal from study treatment, or until death, whichever occurs first. Participants removed 
from study for unacceptable AE(s) will be followed until resolution or stabilization of the 
AE. 
4.9 
Criteria for Removal from Treatment 
Participants will be removed from study when any of the applicable criteria, including PD, 
AEs, participant withdrawal, or inability to follow study protocol as listed in Section 4.7. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
59 
NCI Version Date 24AUG2023 
The reason for study removal and the date the participant was removed must be 
documented in the Case Report Form. 
4.10 
Criteria to Resume Treatment 
Restarting applies only to grade 2 events and some grade 3 events (skin rash and 
thyroiditis). The protocol chairs emphasize stopping treatment and starting steroids earlier 
to obtain resolution with the possibility for restarting rather than waiting for higher grade 
events. 
For non-autoimmune or non-inflammatory events, participants may resume treatment with 
study drug when the drug-related AE(s) resolve to Grade ≤1 or baseline value, with the 
following exceptions: 
• Participants may resume treatment in the presence of Grade 2 fatigue 
• Evaluation to exclude any additional immune-mediated events endocrine, GI, and 
liver/pancreas function as clinically indicated must be made prior to restarting. 
• Non-drug-related toxicity including hepatic, pulmonary toxicity, diarrhea, or colitis, 
must have resolved to baseline before treatment is resumed. 
If the criteria to resume treatment are met, the participant should restart treatment no sooner 
than the next scheduled time point per protocol. However, if the treatment is delayed past 
the next scheduled time point per protocol the treatment should resume at the earliest 
convenient point that is within the six-week delay period. 
If treatment is delayed for > 35 days for participants on dose levels 1 or -1, or > 42 days 
for participants on dose levels 2 or -2 (> 56 days for participants on a steroid taper), the 
participant must be permanently discontinued from study therapy, except as specified in 
Section 4.7 (Duration of Therapy). 
4.11 
Treatment of Nivolumab-Related and Ipilimumab Combination Infusion Reactions 
Since ipilimumab and nivolumab contain only human immunoglobulin or immunoglobulin 
protein sequences, these agents are unlikely to be immunogenic and induce infusion or 
hypersensitivity reactions. However, if such a reaction were to occur, it might manifest 
with fever, chills, rigors, headache, rash, urticaria, angioedema, pruritus, arthralgia, hypo- 
or hypertension, bronchospasm, or other symptoms. 
All Grade 3 or 4 infusion reactions should be reported as a SAE if criteria are met. Infusion 
reactions should be graded according to NCI CTCAE version 5.0 guidelines. 
Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines as medically appropriate: 
4.11.1 For Grade 1 symptoms 
Mild reaction: infusion interruption not indicated; intervention not indicated. 
Remain at bedside and monitor participant until recovery from symptoms. Infusion 
rate may be slowed. If the infusion is interrupted, then restart the infusion at 50% 
of the original infusion rate when symptoms resolve; if no further complications 
ensue after 30 minutes, the rate may be increased to 100% of the original infusion 
rate. Monitor participant closely. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
60 
NCI Version Date 24AUG2023 
The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen) at least 30 minutes before additional nivolumab administrations, 
slowing infusion rate as above. 
4.11.2 For Grade 2 symptoms 
Moderate reaction requires therapy or infusion interruption but responds promptly 
to symptomatic treatment (e.g., antihistamines, non-steroidal anti-inflammatory 
drugs, narcotics, corticosteroids, bronchodilators, IV fluids); close observation for 
recurrence and treatment medications may need to be continued for 24-48 hours. 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the 
participant with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 
to 1000 mg (acetaminophen); remain at bedside and monitor participant until 
resolution of symptoms. Corticosteroid or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, then restart the infusion 
at 50% of the original infusion rate when symptoms resolve; if no further 
complications ensue after 30 minutes, the rate may be increased to 100% of the 
original infusion rate. Monitor participant closely. If symptoms recur, then no 
further nivolumab will be administered at that visit. Administer diphenhydramine 
50 mg IV and remain at bedside and monitor the participant until resolution of 
symptoms. The amount of study drug infused must be recorded on the electronic 
case report form (eCRF). The following prophylactic premedication’s are 
recommended for future infusions: diphenhydramine 50 mg (or equivalent) and 
acetaminophen or paracetamol 325 to 1000 mg should be administered at least 30 
minutes before additional nivolumab administrations. If necessary, corticosteroids 
(recommended dose: up to 25 mg of IV hydrocortisone or equivalent) may be used. 
4.11.3 For Grade 3 or Grade 4 symptoms 
Severe reaction, Grade 3 symptoms: prolonged (i.e., not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion); recurrence of 
symptoms following initial improvement; hospitalization indicated for other 
clinical sequelae (e.g., renal impairment, pulmonary infiltrates). 
Grade 4 symptoms: life threatening; pressor or ventilatory support indicated. 
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal 
saline, and treat the participant as follows. Recommend bronchodilators, 
epinephrine 0.2 to 1 mg of a 1:1,000 solution for subcutaneous administration or 
0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV administration, and/or 
diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or equivalent), as 
needed. Participant should be monitored until the investigator is comfortable that 
the symptoms will not recur. Nivolumab will be permanently discontinued. 
Investigators should follow their institutional guidelines for the treatment of 
anaphylaxis. Remain at bedside and monitor participant until recovery from 
symptoms. In the case of late-occurring hypersensitivity symptoms (e.g., 
appearance of a localized or generalized pruritus within 1 week after treatment), 
symptomatic treatment may be given (e.g., oral antihistamine, or corticosteroids). 

 
AMC #095 (Version 15.0) 24AUG2023 
 
68 
NCI Version Date 24AUG2023 
of ipilimumab will induce a cytokine release syndrome that could be evidenced by 
fever, chills, rigors, rash, pruritus, hypotension, hypertension, bronchospasm, or 
other symptoms. No prophylactic pre-medication should be given unless indicated 
by previous experience in an individual participant. Reactions should be treated 
based upon the following recommendations. 
• For mild symptoms (e.g., localized cutaneous reactions such as mild pruritus, 
flushing, rash): 
o Decrease the rate of infusion until recovery from symptoms, remain at 
bedside, and monitor participant. 
o Complete the ipilimumab infusion at the initial planned rate. 
o Diphenhydramine 50 mg IV may be administered at the discretion of the 
treating physician and participants may receive additional doses with close 
monitoring. 
o Premedication with diphenhydramine may be given at the discretion of the 
investigator for subsequent doses of ipilimumab. 
• For moderate symptoms (any symptom not listed above [mild symptoms] or 
below [severe symptoms] such as generalized pruritus, flushing, rash, dyspnea, 
hypotension with systolic BP >80 mmHg): 
o Interrupt ipilimumab. 
o Administer diphenhydramine 50 mg IV. 
o Monitor participant closely until resolution of symptoms. 
o Corticosteroids may abrogate any beneficial immunologic effect but may 
be administered at the discretion of the treating physician. 
o Resume ipilimumab infusion after recovery of symptoms. 
o At the discretion of the treating physician, ipilimumab infusion may be 
resumed at one-half the initial infusion rate, then increased incrementally to 
the initial infusion rate. 
o If symptoms develop after resumption of the infusion, the infusion should 
be discontinued and no additional ipilimumab should be administered that 
day. 
o The next dose of ipilimumab will be administered at its next scheduled time 
and may be given with pre-medication (diphenhydramine and 
acetaminophen) and careful monitoring, following the same treatment 
guidelines outlined above. 
o At the discretion of the treating physician additional oral or IV antihistamine 
may be administered prior to dosing with ipilimumab. 
• For severe symptoms (e.g., any reaction such as bronchospasm, generalized 
urticaria, systolic blood pressure 80 mm Hg, or angioedema): 
o Immediately discontinue infusion of ipilimumab and disconnect infusion 

 
AMC #095 (Version 15.0) 24AUG2023 
 
69 
NCI Version Date 24AUG2023 
tubing from the participant. 
o Consider bronchodilators, epinephrine 1 mg IV or subcutaneously, and/or 
diphenhydramine 50 mg IV, with solumedrol 100 mg IV, as needed. 
o Participants should be monitored until the investigator is comfortable that 
the symptoms will not recur. 
o No further ipilimumab will be administered. 
• In case of late-occurring hypersensitivity symptoms (e.g., appearance within 
one week after treatment of a localized or generalized pruritus), symptomatic 
treatment may be given (e.g., oral antihistamine, or corticosteroids). 
5.2.2 Treatment of ipilimumab-related isolated drug fever 
In the event of isolated drug fever, the investigator must use clinical judgment to 
determine if the fever is related to the ipilimumab or to an infectious etiology. If a 
participant experiences isolated drug fever, for the next dose, pre-treatment with 
acetaminophen or non-steroidal anti-inflammatory agent (investigator discretion) 
should be instituted and a repeated antipyretic dose at 6 and 12 hours after 
ipilimumab infusion, should be administered. The infusion rate will remain 
unchanged for future doses. If a participant experiences recurrent isolated drug 
fever following premedication and post-dosing with an appropriate antipyretic, the 
infusion rate for subsequent dosing should be decreased to 50% of the previous 
rate. If fever recurs following infusion rate change, the investigator should assess 
the participant’s level of discomfort with the event and use clinical judgment to 
determine if the participant should receive further ipilimumab. 
5.2.3 Monitoring and management of immune-mediated adverse reactions 
Immune-mediated enterocolitis 
The clinical presentation of GI immune-related AEs included diarrhea, increase in 
the frequency of bowel movements, abdominal pain, or hematochezia, with or 
without fever. However, inflammation may occur in any part of the GI tract 
including esophagitis and gastritis. Fatalities due to GI perforation have been 
reported in clinical trials of ipilimumab. Participants should be carefully monitored 
for GI symptoms that may be indicative of immune-related colitis, diarrhea, or GI 
perforation. Diarrhea or colitis occurring after initiation of ipilimumab therapy 
should be evaluated to exclude infectious or alternate etiologies. In clinical trials, 
immune-related colitis was associated with evidence of mucosal inflammation, 
with or without ulcerations, and lymphocytic infiltration. 
Monitor participants for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, mucus, or blood in stool, with or without fever) and bowel 
perforation (such as peritoneal signs and ileus). In symptomatic participants, rule 
out infectious etiologies and consider endoscopic evaluation to establish etiology 
and for persistent or severe symptoms. C. difficile toxin has been detected in several 
participants with colitis and may be an independent entity or may co-exist with 
ipilimumab induced inflammatory colitis. 
Withhold ipilimumab dosing for any participants with enterocolitis pending 

 
AMC #095 (Version 15.0) 24AUG2023 
 
70 
NCI Version Date 24AUG2023 
evaluation; administer anti-diarrheal treatment and, if persistent evaluate with 
colonoscopy and initiate systemic corticosteroids at a dose of 0.5 mg/kg/day 
prednisone or equivalent. 
Permanently discontinue ipilimumab in participants with severe enterocolitis and 
initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or 
equivalent. Upon improvement to grade 1 or less, initiate corticosteroid taper and 
continue to taper over at least one month. In clinical trials, rapid corticosteroid 
tapering has resulted in recurrence or worsening symptoms of enterocolitis in some 
participants. 
Participants have been treated with anti-TNF agents for persistent colitis not 
responding to steroids. 
Please note autoimmune pancreatitis may cause abdominal pain and should be 
included in all evaluations. Enteritis may occur occasionally with other 
autoimmune events including hepatitis, pancreatitis, and endocrine insufficiency, 
which should be evaluated as clinically indicated. 
Immune-mediated hepatitis and pancreatitis 
Hepatic immune-related AEs were mostly clinically silent and manifested as 
transaminase or bilirubin laboratory abnormalities. Fatal hepatic failure has been 
reported in clinical trials of ipilimumab. Serum transaminase, bilirubin, and lipase 
levels must be evaluated before each dose of ipilimumab as early laboratory 
changes may be indicative of emerging immune-related hepatitis/ pancreatitis and 
elevations in liver function tests (LFTs) may develop in the absence of clinical 
symptoms. Increase in LFT or total bilirubin should be evaluated to exclude other 
causes of hepatic injury, including infections, disease progression, or other 
medications, and monitored until resolution. Liver biopsies from participants who 
had immune-related hepatotoxicity showed evidence of acute inflammation 
(neutrophils, lymphocytes, and macrophages). 
Monitor LFTs (hepatic transaminase and bilirubin levels, lipase) and assess 
participants for signs and symptoms of hepatotoxicity/ pancreatitis before each dose 
of ipilimumab. In participants with hepatotoxicity, rule out infectious or malignant 
causes and increase frequency of liver function test monitoring until resolution. 
Withhold ipilimumab in participants with grade 2 hepatotoxicity. 
Permanently 
discontinue 
ipilimumab 
in 
participants 
with 
grade 
3-5 
hepatotoxicity/pancreatitis and administer systemic corticosteroids at a dose of 1 to 
2 mg/kg/day of prednisone or equivalent. When LFTs show sustained improvement 
or return to baseline, initiate corticosteroid tapering and continue to taper over 1 
month. Across the clinical development program for ipilimumab, mycophenolate 
treatment has been administered in participants who have persistent severe hepatitis 
despite high dose corticosteroids. 
Immune-mediated dermatitis 
Skin immune-related AEs presented mostly frequently as a rash and/or pruritus. 
Some participants reported vitiligo associated with ipilimumab administration. 
Fatal TEN has been reported in clinical trials of ipilimumab. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
71 
NCI Version Date 24AUG2023 
Monitor participants for signs and symptoms of dermatitis such as rash and pruritus. 
Unless an alternate etiology has been identified, signs or symptoms of dermatitis 
should be considered immune-mediated. 
Permanently discontinue ipilimumab in participants with Stevens-Johnson 
syndrome, TEN, or rash complicated by full thickness dermal ulceration, or 
necrotic, 
bullous, 
or 
hemorrhagic 
manifestations. 
Administer 
systemic 
corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When 
dermatitis is controlled, corticosteroid tapering should occur over a period of at 
least 1 month. Withhold ipilimumab dosing in participants with moderate to severe 
signs and symptoms. 
For mild-to-moderate dermatitis, such as grade 2 localized rash and pruritus, treat 
symptomatically. For persistent grade 2, grade 3, or greater, topical steroids may 
be administered. Administer topical or systemic corticosteroids as indicated if there 
is no improvement of symptoms within 1 week. 
Immune-related neurological events 
Fatal Guillain-Barré syndrome has been reported in clinical trials of ipilimumab. 
Participants may present with muscle weakness and myasthenia gravis, cranial 
nerve palsy (n VII Bell’s palsy), and aseptic meningitis, encephalopathy. 
Unexplained motor neuropathy, muscle weakness, or sensory neuropathy lasting 
more than 4 days should be evaluated and non-inflammatory causes such as disease 
progression, infections, metabolic syndromes, nerve entrapment, and medications 
should be excluded as causes. 
Withhold ipilimumab dosing in participants with any evidence of neuropathy 
pending evaluation. 
Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral 
weakness, sensory alterations, or paresthesia. Permanently discontinue ipilimumab 
in participants with severe neuropathy (interfering with daily activities) such as 
Guillain-Barré-like syndromes. Institute medical intervention as appropriate for 
management of neuropathy and other neurologic events. Consider initiation of 
systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for 
severe neuropathies. 
Immune-mediated endocrinopathies 
Ipilimumab can cause inflammation of endocrine organs including thyroid 
(Hashimoto’s thryroiditis with positive antibodies) and adrenal glands, 
hypophysitis, hypopituitarism, and resulting thyroid and adrenal insufficiency, low 
ADH, prolactin, FSH, LH. Hyperthyroid with Graves’ disease and positive 
antibody has been reported. Participants may present with subtle and nonspecific 
symptoms. The most common clinical presentation includes headache and fatigue. 
Symptoms may also include visual field defects, behavioral changes, and 
electrolyte disturbances including hyponatremia and hypotension. Adrenal crisis as 
a cause of the participant’s symptoms should be excluded. Based on the available 
data with known outcome, most of the participants symptomatically improved with 
hormone replacement therapy. Long term hormone replacement therapy with HC 

 
AMC #095 (Version 15.0) 24AUG2023 
 
72 
NCI Version Date 24AUG2023 
and synthroid will typically be required for participants developing 
hypophysitis/hypopituitarism after treatment with ipilimumab. Some participants 
have regained partial function following steroid treatment. 
Monitor participants for clinical signs and symptoms of hypophysitis, adrenal 
insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Headache is 
often the first symptoms of hypophysitis. Participants may present with fatigue, 
headache, mental status changes, loss of libido, abdominal pain, unusual bowel 
habits, and hypotension, or nonspecific symptoms, which may resemble other 
causes such as brain metastasis or underlying disease. Unless an alternate etiology 
has been identified, signs or symptoms of endocrinopathies should be considered 
immune-mediated and drug withheld pending evaluation. Participants may 
demonstrate both central (hypophysitis) and peripheral adrenal and thyroid 
insufficiency. Evaluation of hypophysitis should include pituitary MRI. 
Endocrine evaluation, including TSH, should be performed at baseline prior to 
initial treatment 
Monitor thyroid function tests and clinical chemistries at the start of treatment for 
baseline function and anti-thyroid antibodies. Endocrine function will be evaluated 
every 12 weeks by monitoring TSH, free T4, TPO, morning ACTH, and morning 
cortisol if ACTH is abnormal. The package insert for ipilimumab includes a 
recommendation for monitoring TSH prior to each infusion; as an early indication 
for pituitary dysfunction and hypophysitis, clinical monitoring of symptoms may 
be equally or more sensitive as an initial presentation. In a limited number of 
participants, hypophysitis was diagnosed by imaging studies through enlargement 
of the pituitary gland. 
Withhold ipilimumab dosing in participants symptomatic for hypophysitis. Initiate 
systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent 
and initiate appropriate hormone replacement therapy. 
Other immune-mediated adverse reactions, including ocular manifestations 
Ocular inflammation, manifested as grade 2 or grade 3 episcleritis or uveitis, was 
associated with concomitant diarrhea in a few participants (<1%) and occasionally 
occurred in the absence of clinically apparent GI symptoms. Other presumed 
immune-related AEs reported include, but were not limited to, arthritis/arthralgias, 
pneumonitis, pancreatitis, autoimmune (aseptic) meningitis, autoimmune nephritis, 
pure red cell aplasia, noninfective myocarditis, polymyositis, and myasthenia 
gravis, of which were individually reported for <1% of participants. 
The following clinically significant immune-mediated adverse reactions were seen 
in less than 1% of ipilimumab-treated participants in Study 1: nephritis, 
pneumonitis, 
pulmonary 
granuloma 
resembling 
sarcoidosis, 
meningitis, 
pericarditis, uveitis, iritis, ITP, neutropenia, and hemolytic anemia. 
Across the clinical development program for ipilimumab, the following likely 
immune-mediated adverse reactions were also reported with less than 1% 
incidence: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia 
rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic 

 
AMC #095 (Version 15.0) 24AUG2023 
 
73 
NCI Version Date 24AUG2023 
vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune 
thyroiditis. 
Permanently discontinue ipilimumab for clinically significant or severe immune-
mediated adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 
mg/kg/day prednisone or equivalent for severe immune-mediated adverse 
reactions. 
Administer corticosteroid eye drops to participants who develop uveitis, iritis, or 
episcleritis. Permanently discontinue ipilimumab for immune-mediated ocular 
disease that is unresponsive to local immunosuppressive therapy. 
Overall, immune-related AEs commonly started within 3 to 10 weeks from first 
dose, were successfully managed in most instances by omitting doses, 
discontinuing 
dosing, 
and/or 
through 
administering 
symptomatic 
or 
immunosuppressive therapy, including corticosteroids, as mentioned above, and 
detailed in this section. Immune-related AEs generally resolved within days to 
weeks in the majority of participants. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
78 
NCI Version Date 24AUG2023 
EAR AND LABYRINTH DISORDERS - Vestibular disorder 
EYE DISORDERS - Eye disorders - Other (iridocyclitis); Optic nerve disorder; Periorbital edema 
GASTROINTESTINAL 
DISORDERS 
- 
Constipation; 
Duodenal 
ulcer; 
Flatulence; 
Gastrointestinal disorders - Other (mouth sores); Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema 
limbs; Malaise; Pain 
HEPATOBILIARY DISORDERS - Bile duct stenosis  
IMMUNE SYSTEM DISORDERS - Anaphylaxis; Immune system disorders - Other 
(autoimmune thrombotic microangiopathy); Immune system disorders - Other (limbic 
encephalitis) 
INFECTIONS AND INFESTATIONS - Bronchial infection; Lung infection; Sepsis; Upper 
respiratory infection 
INVESTIGATIONS - Blood lactate dehydrogenase increased; GGT increased; Investigations - 
Other (protein total decreased); Lymphocyte count increased; Weight loss  
METABOLISM 
AND 
NUTRITION 
DISORDERS 
- 
Dehydration; 
Hyperuricemia; 
Hypoalbuminemia; Hypocalcemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; 
Musculoskeletal and connective tissue disorder - Other (musculoskeletal pain); Musculoskeletal 
and connective tissue disorder - Other (polymyalgia rheumatica); Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Neoplasms benign, malignant, and unspecified (incl cysts and polyps) - Other 
(histiocytic necrotizing lymphadenitis) 
NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Intracranial hemorrhage 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS - Hematuria; Renal and urinary disorders - Other 
(tubulointerstitial nephritis) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchospasm; 
Cough; Dyspnea; Hypoxia 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; 
Pain of skin; Photosensitivity; Rash acneiform; Skin and subcutaneous tissue disorders - Other 
(rosacea) 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Vasculitis 
Note: Nivolumab in combination with other agents could cause an exacerbation of any AE 
currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
6.1.2 CAEPR for ipilimumab (MDX-010, NSCs 732442 and 720801) 

 
AMC #095 (Version 15.0) 24AUG2023 
 
82 
NCI Version Date 24AUG2023 
4Complications including hyperacute graft-versus-host disease (GVHD), may occur in patients receving allo stem cell 
transplant (SCT) after receiving Ipilimumab (MDX-010). These complications may occur despite intervening therapy 
between receiving Ipilimumab (MDX-010) and allo-SCT. 
5In rare cases diplopia (double vision) has occurred as a result of muscle weakness (Myasthenia gravis). 
6Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal 
hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal 
hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, 
Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal 
hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
7Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
Adverse events reported on ipilimumab (MDX-010) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that ipilimumab (MDX-010) 
caused the AE: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Blood and lymphatic system 
disorders - Other (pure red cell aplasia)2; Febrile neutropenia 
CARDIAC DISORDERS - Conduction disorder; Restrictive cardiomyopathy 
EYE DISORDERS - Extraocular muscle paresis5; Eye disorders - Other (retinal pigment changes) 
GASTROINTESTINAL DISORDERS - Colonic ulcer; Dyspepsia; Dysphagia; Gastrointestinal 
disorders - Other (gastroenteritis); Gastrointestinal hemorrhage6; Proctitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like 
symptoms; Non-cardiac chest pain 
HEPATOBILIARY DISORDERS - Hepatic failure2 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INFECTIONS AND INFESTATIONS - Infection7 
INVESTIGATIONS - Creatinine increased; Investigations - Other (rheumatoid factor); Lipase 
increased; Platelet count decreased; Serum amylase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Joint 
range of motion decreased; Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysphasia; Ischemia cerebrovascular; Seizure 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia 
RENAL AND URINARY DISORDERS - Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; 
Cough; Dyspnea; Laryngospasm 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; 
Skin hypopigmentation 

 
AMC #095 (Version 15.0) 24AUG2023 
 
83 
NCI Version Date 24AUG2023 
VASCULAR DISORDERS - Flushing; Hypertension; Vascular disorders - Other (temporal 
arteritis) 
Note: Ipilimumab (BMS-734016; MDX-010 Transfectoma-derived) in combination with other 
agents could cause an exacerbation of any AE currently known to be caused by the other agent, or 
the combination may result in events never previously associated with either agent. 
6.2 
Classification of AEs by Severity and Relationship to Study Drug Administration 
6.2.1 AE: Any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a medical 
treatment or procedure regardless of whether it is considered related to the medical 
treatment or procedure (attribution of unrelated, unlikely, possible, probable, or 
definite). 
6.2.2 Life threatening Adverse Event: Any AE that places the participant or participant, 
in view of the Investigator, at immediate risk of death from the reaction. 
6.2.3 Serious Adverse Event (SAE): Any AE occurring at any dose that results in any of 
the following outcomes: Death, a life threatening AE, inpatient hospitalization, or 
prolongation of existing hospitalization, a persistent or significant disability/ 
incapacity, or a congenital anomaly/birth defect. 
6.2.4 Please note for hospitalization – All hospitalizations (or prolongation of existing 
hospitalization) for medical events equivalent to CTCAE Grade 3, 4, 5 must be 
reported regardless of the requirements for Phase of study, expected or unexpected, 
and attribution. For example, do not report an admission for pharmacokinetic 
sampling, but do report an admission for a myocardial infarction. 
6.2.5 Toxicity: Toxicity is a term NOT clearly defined by regulatory organizations. 
Toxicity has been described as an AE that has an attribution of possibly, probably, 
or definitely related to investigational treatment. To minimize confusion the NCI 
would recommend that the term toxicity NOT be utilized for AE reporting 
purposes. The CTCAE continues to use the term ‘toxicity’ because of familiarity. 
6.2.6 Unexpected Adverse Event: Any AE that is not listed in available sources including 
the package insert, the Investigator’s Brochure, or the protocol. 
6.2.7 CTEP Adverse Event Reporting System (CTEP-AERS): An electronic system for 
expedited submission of AE reports. 
6.2.8 Attribution: The determination of whether an AE is related to a medical treatment 
or procedure. Attribution categories: 
Definite – The AE is clearly related to the investigational agent. 
Probable – The AE is likely related to the investigational agent. 
Possible – The AE may be related to the investigational agent. 
Unlikely – The AE is doubtfully related to the investigational agent. 
Unrelated – The AE is clearly NOT related to the investigational agent. 
6.3 
Expedited AE Reporting 

 
AMC #095 (Version 15.0) 24AUG2023 
 
84 
NCI Version Date 24AUG2023 
6.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP home page (http://ctep.cancer.gov). 
The reporting procedures to be followed are presented in the “CTEP, NCI 
Guidelines: Adverse Event Reporting Requirements” which can be downloaded 
from the CTEP home page (http://ctep.cancer.gov). These requirements are 
briefly outlined in the table below (Section 6.3.3). 
A 24-hour notification is to be made to CTEP by telephone at 301-897-7497, only 
when Internet connectivity is disrupted. Once Internet connectivity is restored, a 
24-hour notification phoned in must be entered electronically into CTEP-AERS by 
the original submitter at the site. 
6.3.2 CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals: Study Coordinator of the Lead Organization, Principal 
Investigator, and the local treating physician. CTEP-AERS provides a copy feature 
for other e-mail recipients. 
6.3.3 Expedited Reporting Guidelines 
Use the NCI protocol number and the protocol-specific participant ID assigned 
during trial registration on all reports. 
Note: A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below. Attribution to treatment or other cause must be 
provided. 
Death due to PD should be reported as Grade 5 “General disorders and 
administration site conditions - Disease Progression.” Evidence that the death 
was a manifestation of underlying disease (e.g., radiological changes suggesting 
tumor growth or progression: clinical deterioration associated with a disease 
process) should be submitted. 
Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for AEs that Occur 
on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An AE is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life threatening AE 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
• 
A congenital anomaly/birth defect. 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the participant or participant and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 
312.32; ICH E2A and ICH E6). 

 
AMC #095 (Version 15.0) 24AUG2023 
 
86 
NCI Version Date 24AUG2023 
4. 
Is associated with clinical signs or symptoms, which may suggest a disease 
and/or organ toxicity, or may represent a new condition or worsening of a 
baseline condition 
5. 
Is associated with a SAEs, or is otherwise judged by the Investigator to be of 
significant clinical impact 
In general, a laboratory abnormality that is not clinically significant will be 
consistent with CTCAE grade 1 (mild) or 2 (moderate) severity, as categorized by 
the relevant severity description in the Investigations System Organ Class (SOC) 
or Metabolism and Nutrition Disorders SOC. Investigators may not designate 
laboratory abnormalities that are consistent with grade 3 or greater severity as not 
clinically significant. 
All laboratory values deemed clinically significant will be subsequently reported as 
AEs unless the result is a sign of a clinical diagnosis that is reported as an AE. 
6.5 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation, or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm. 
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to 
describe the event: 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML]) 
• Myelodysplastic syndrome (MDS) 
• Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol. 
6.6 
Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy). Second malignancies require ONLY routine AE 
reporting. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
87 
NCI Version Date 24AUG2023 
7.0 
PHARMACEUTICAL INFORMATION 
A list of the AEs and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 6.1. 
7.1 
Nivolumab (NSC 748726) 
Amino Acid Sequence: Four polypeptide chains, which include two identical heavy chains 
with 440 amino acids and two identical light chains. 
Other Names: BMS-936558, MDX1106 
Classification: Anti-PD-1MAb 
M.W.: 146,221 daltons 
Mode of Action: Nivolumab targets the programmed death–1 (PD-1, cluster of 
differentiation 279 [CD279]) cell surface membrane receptor. PD-1 is a negative regulatory 
receptor expressed by activated T and B lymphocytes. Binding of PD-1 to its ligands, 
programmed death–ligand 1 (PD-L1) and 2 (PD-L2), results in the down-regulation of 
lymphocyte activation. Nivolumab inhibits the binding of PD-1 to PD-L1 and PD-L2. 
Inhibition of the interaction between PD-1 and its ligands promotes immune responses and 
antigen-specific T cell responses to both foreign antigens as well as self-antigens. 
Description: Nivolumab injection is a clear to opalescent, colorless to pale yellow liquid; 
light (few) particulates may be present. The drug product is a sterile, nonpyrogenic, single-
use, isotonic aqueous solution formulated in sodium citrate, sodium chloride, mannitol, 
diethylenetriamine pentacetic acid (pentetic acid) and polysorbate 80 (Tween® 80), and 
water for injection. Dilute solutions of hydrochloric acid and/or sodium hydroxide may be 
used for pH adjustment (pH 5.5-6.5). 
How Supplied: Nivolumab is supplied by Bristol-Myers-Squibb and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI as 100 mg vials (10 mg/mL) with 
a 0.7 mL overfill. It is supplied in 10 mL type I flint glass vials, with fluoropolymer film-
laminated rubber stoppers and aluminum seals. 
Preparation: Nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 
0.9% Sodium Chloride Injection, USP or 5% Dextrose, USP to concentrations no less than 
0.35 mg/mL. When the dose is fixed (eg, 240 mg, 360 mg, or 480 mg flat dose), nivolumab 
injection can be infused undiluted or diluted so as not to exceed a total infusion volume of 
160 mL. For patients weighing less than 40 kilograms (kg), the total volume of infusion 
must not exceed 4 mL per kg of patient weight. During drug product preparation and 
handling, vigorous mixing or shaking is to be avoided. 
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin 
containers and infusion sets, and glass bottles.  
Storage: Vials of nivolumab injection must be stored at 2°-8°C (36°-46°F) and protected 
from light, freezing, and shaking. The unopened vials can be stored at room temperature 
(up to 25°C, 77°F) and room light for up to 48 hours 
Stability: Shelf-life surveillance of the intact vials is ongoing. 
The administration of undiluted and diluted solutions of nivolumab must be completed 

 
AMC #095 (Version 15.0) 24AUG2023 
 
88 
NCI Version Date 24AUG2023 
within 24 hours of preparation. If not used immediately, the infusion solution may be stored 
up to 24 hours in a refrigerator at 2°-8°C (36°-46°F) and a maximum of 4 hours of the total 
24 hours can be at room temperature (20°-25°C, 68°-77°F) and room light. The maximum 
4-hour period under room temperature and room light conditions includes the product 
administration period. 
CAUTION: The single-use dosage form contains no antibacterial preservative or 
bacteriostatic agent. Therefore, it is advised that the product be discarded 8 hours after 
initial entry. 
Route of Administration: Intravenous infusion over 30 minutes. Do not administer as an 
IV push or bolus injection. See Section 4.3 for dosing instructions. 
Method of Administration: Administer through a 0.2 micron to 1.2 micron pore size, low-
protein binding polyethersulfone membrane in-line filter. 
Potential Drug Interactions: No incompatibilities between nivolumab injection and 
polyvinyl 
chloride 
(PVC), 
non-PVC/non-DEHP 
(di[2-ethylhexyl]phthalate) 
IV 
components, or glass bottles have been observed. 
Availability: Nivolumab is an investigational agent supplied to investigators by the 
Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
Nivolumab is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Appendix II). 
7.2 
Ipilimumab (NSC 732442) 
Chemical Name or Amino Acid Sequence: Four polypeptide chains, two identical heavy 
chains with 447 amino acids and two identical light chains consisting of 215 amino acids. 
Other Names: Anti-CTLA-4 monoclonal antibody, MDX-010, Yervoy™ 
Classification: Human monoclonal antibody 
M.W.: 147,991 Daltons 
Mode of Action: Ipilimumab is specific for the CTLA-4 antigen expressed on a subset of 
activated T cells. CTLA-4 interaction with the B7 molecule, one of its ligands expressed 
on professional antigen-presenting cells, can down-regulate T cell response. Ipilimumab 
is, thought to act by blocking the interaction of CTLA-4 with the B7 ligand, resulting in a 
blockade of the inhibitory effect of T cell activation. The CTLA-4/B7 creates the 
interaction. 
Description: Ipilimumab is a fully human immunoglobulin (IgG1) with two 
manufacturing processes – ongoing trials have been using substances manufactured using 
Process B. New clinical trials will be using ipilimumab that is manufactured by Process C. 
The Process C has been developed using a higher producing sub-clone of the current 
Master Cell Bank, and modified cell culture and purification steps. 
How Supplied: Bristol-Myers-Squibb (BMS) supplies Ipilimumab to the DCTD/NCI. 
Ipilimumab injection, 200 mg/40 mL (5 mg/mL), is formulated as a clear to slightly 
opalescent, colorless to pale yellow, sterile, nonpyrogenic, single-use, isotonic aqueous 
solution that may contain particles. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
90 
NCI Version Date 24AUG2023 
Method of Administration: Can use a volumetric pump to infuse ipilimumab at the 
protocol-specific dose(s) and rate(s) via a PVC IV infusion set with an in-line, sterile, non-
pyrogenic, low-protein-binding filter (0.2 micron to 1.2 micron). 
Patient Care Implications: Monitor participants for immune-related AEs, e.g., 
rash/vitiligo, diarrhea/colitis, uveitis/episcleritis, hepatitis, and hypothyroidism. If you 
suspect toxicity, refer to the protocol guidelines for ruling out other causes. 
7.3 
Agent Ordering and Agent Accountability 
NCI-supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution. Pharmaceutical Management Branch (PMB) 
policy requires that agent be shipped directly to the institution where the participant is to 
be treated. PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained). The CTEP-assigned protocol number must be used for 
ordering all CTEP-supplied investigational agents. The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF). If there 
are several participating investigators at one institution, CTEP-supplied investigational 
agents for the study should be ordered under the name of one lead investigator at that 
institution. In general, sites may order initial agent supplies when a participant is being 
screened for enrollment onto the study. 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application. Access to OAOP requires the establishment of a CTEP 
Identity and Access Management (IAM) account and the maintenance of an “active” 
account status and a “current” password. For questions about drug orders, transfers, returns, 
or accountability, call or email PMB at any time. Refer to the PMB’s website for specific 
policies and guidelines related to agent management. 
7.4 
Agent Inventory Records 
The Investigator, or a responsible party designated by the Investigator, must maintain a 
careful record of the inventory and disposition of all drugs received using the NCI Drug 
Accountability Record Form (DARF) (available on the CTEP home page 
(http://ctep.cancer.gov) or by calling the PMB at 240-276-6575). The DARFs document 
the drug delivery date to the site, inventory at the site, use by each study participant, and 
disposal of the drug (if applicable). A site-specific accountability record, either manual or 
electronic, may be used if it includes all the information required on the NCI Investigational 
Drug Accountability Record and if the paper printout is identical to the NCI accountability 
record. A separate DARF is required for each protocol using the same agent. The 
investigator will ensure that the drugs are used only in accordance with this protocol. 
7.5 
Useful Links and Contacts 
CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
NCI CTEP Investigator Registration: PMBRegPend@ctep.nci.nih.gov 
PMB policies and guidelines: 

 
AMC #095 (Version 15.0) 24AUG2023 
 
91 
NCI Version Date 24AUG2023 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
PMB OAOP application: https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx  
CTEP IAM account: https://eapps-ctep.nci.nih.gov/iam/ 
CTEP Associate Registration and IAM account help: ctepreghelp@ctep.nci.nih.gov  
PMB email: PMBAfterHours@mail.nih.gov 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 
am and 4:30 pm (ET) 

 
AMC #095 (Version 15.0) 24AUG2023 
 
92 
NCI Version Date 24AUG2023 
8.0 
CLINICAL AND LABORATORY EVALUATIONS  
A Study Calendar of the evaluations described below is provided in Appendix I. 
8.1 
Pre-Study Evaluations (Visit -1) 
Pre-study evaluations may be performed (or existing results obtained for the purpose of 
documenting eligibility) after the participant provides informed consent. 
8.1.1 Complete medical history, to include CDC HIV risk categories and history of 
AIDS-defining conditions, documentation of HIV infection with duration of HIV 
and AIDS diagnoses, history of opportunistic illnesses, history of prior treatment 
for the study malignancy, history of any other prior malignancies and treatment, 
and history of other autoimmune conditions per Section 3.2.12. 
8.1.2 Complete physical examination, including ECOG score or KPS (Appendix III), 
vital signs, weight, and height. 
8.1.3 AE assessment (from any prior therapies). Recovery to CTCAE ≤ grade 1 from 
toxicity from prior therapies is required for all AEs except alopecia, neuropathy, 
and other non-clinically significant AEs. AEs from prior therapies present at 
baseline should be documented in the source only. Assessment of effects of prior 
therapy should include evaluation of immune status, organ damage, risk of 
autoimmunity, and immunopotentiation. 
8.1.4 List of all concurrent medications taken for the 3 months prior to enrollment, 
including ART regimen. 
8.1.5 Laboratory studies within 2 weeks prior to enrollment (unless otherwise noted), 
including: 
a) CBC with differential and platelet count: Hematology labs are to include 
hemoglobin, hematocrit, red blood cell count, WBC, ANC, platelets (direct 
platelet count), and total and differential CBC counts. 
b) Serum chemistry analysis, to include albumin, urea or BUN, creatinine, ALT, 
AST, LDH, serum alkaline phosphatase, direct and total bilirubin, glucose, total 
protein, sodium, potassium, chloride, HCO3 (CO2; venous blood), calcium, 
phosphorous. 
c) Serum amylase and lipase 
d) EKG. EKG and echocardiogram (ECHO) for any patients with a history of 
congestive heart failure (CHF) or at risk because of underlying cardiovascular 
disease or exposure to cardiotoxic drugs as clinically indicated. For patients 
with evidence of CHF, MI, cardiomyopathy, or myositis cardiac evaluation 
including lab tests and cardiology consultations as clinically indicated including 
EKG, CPK, troponin, echocardiogram. 
e) PPD (or Quantiferon assay) within 12 weeks prior to enrollment if known PPD 
negative. If PPD positive, the participant must complete prophylaxis before 
enrollment. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
93 
NCI Version Date 24AUG2023 
f) HIV viral load will be performed using an assay with a limit of detection of 75 
copies/ml or less within 4 weeks prior to enrollment 
g) CD4/CD8 count within 2 weeks prior to enrollment 
h) Hepatitis B antigen, and Hepatitis C antibody tests within 2 weeks prior to 
enrollment 
i) Pregnancy test will be performed (and results obtained) within 72 hours of 
enrollment (WOCBP) 
j) Immunologic labs consisting of: rheumatoid factor, C-reactive protein, and 
ANA, SPEP, quantitative immunoglobulins and free light chains to be 
completed within 4 weeks prior to enrollment. 
k) Endocrine labs consisting of: TSH, free T4, TPO, morning ACTH, and morning 
cortisol if ACTH is abnormal. 
8.1.6 Radiologic evaluation, including studies to assess all measurable or non-
measurable sites of disease must be done within 4 weeks prior to registration. 
For participants with known KS, chest X-ray to determine pulmonary involvement. 
Pulmonary KS must be asymptomatic or minimally symptomatic and not require 
systemic cytotoxic therapy in the judgment of the investigator. KS participants with 
a positive chest X-ray or symptoms suggestive of pulmonary disease must have a 
chest CT performed before study entry. 
Participants with KS must also have tumor assessments with a photographic record 
performed within 7 days before initiating study treatment. Tumor assessments and 
photographs should be performed as outlined in the AMC’s Kaposi’s Sarcoma (KS) 
Tumor Assessment Manual of Procedures (MOP). 
8.1.7 Participants with HL: PET/CT scans are required to be completed within 4 weeks 
of starting nivolumab. A combined FDG-PET/CT or FDG-PET + CT scan with and 
without IV contrast is required for this study. If a participant has an allergy to IV 
contrast, a non-IV contrast CT scan will be permitted. To ensure consistency 
between all centers, FDG-PET/CT scans at diagnosis should be conducted no more 
than 28 days before enrollment. 
If the CT scan of a PET/CT hybrid is performed with both oral and IV contrast with 
contrast enhancement in the arterial and/or portal venous phase, with at least a 2-
slice CT, and is acquired with at least 80 mAs and CT scans are obtained with 
contiguous sections (with a maximum of 5 mm slice thickness), then the pre-
treatment PET/CT scan alone will suffice for participants enrolled on this trial. If 
no contrast is used in the FDG-PET/CT, an additional CT scan with contrast is 
required of the neck, chest, abdomen, and pelvis. 
8.1.8 Bone marrow biopsy for histology and determination of percent bone marrow 
involvement for HL participants. If bone marrow involvement by lymphoma has 
already been documented after bone marrow biopsy performed more than 6 weeks 
prior to registration, the biopsy does not have to be repeated. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
94 
NCI Version Date 24AUG2023 
8.1.9 Optional donation to the AIDS and Cancer Specimen Resource (ACSR). (See 
Appendix V for ACSR Informed Consent Form and Appendix IV for ACSR 
Specimen Preparation and Shipping Instructions). 
8.1.10 Biological sample submissions for correlative studies 
The collection procedures for correlative studies are described in analyte-specific 
appendices to this protocol and based on validated AMC SOPs. The guiding 
principles are to be consistent across past and future AMC trials, coordinating with 
other clinical trials with these agents. They involve the AMC Biorepository as the 
central laboratory to manage all samples for this study. 
a) Blood draw: 
• Collect two 6 ml red top tubes for assessment of circulating levels of pro-
inflammatory molecules (Appendix XV). 
• Collect twelve 8.5 mL yellow top (ACD) tubes for the HIV latent reservoir 
assay and viral outgrowth assay for participants with hematocrit ≥ 25 who 
provide consent for this optional sample. The sample will be collected at 
baseline (within 7 days before starting treatment and must be collected after 
enrollment in AdvantageEDC). These samples will be shipped directly to 
the AMC Biorepository via priority overnight service for processing. See 
Appendix XVI for collection and shipping instructions. Material from these 
samples will also be used for herpesvirus load and latent virus studies 
(Appendix XIV). 
• If a participant has not consented to the HIV latent reservoir testing blood 
draw, two 8.5 mL yellow top tubes will be collected for herpesvirus load 
and latent virus studies (Appendix XIV and Appendix XVI). 
b) The collection, shipping, and storage of 2x2 mm biopsies in RNALater and 
formalin is described in Appendix XIV (optional for KS cases only, with 
participant consent). 
c) The collection, shipping, and storage of anal swabs is described in Appendix 
XVII (optional for anal cancer cases only, with participant consent). 
d) Collect four 4 micron thick unstained slides from the initial diagnostic biopsy 
and store at the AMC Biorepository for PDL-1 testing at the AMC Pathology 
Core Lab.. 
8.2 
Cycle 1, Day 1 
Unless noted otherwise below, the evaluations may be performed up to three days prior to 
treatment initiation. Pre-visit requirements may be combined with the pre-dose Cycle 1 
Day 1 requirements provided that the evaluation is within the stated window for visits, and 
all required pre-study evaluation results have been evaluated by an investigator prior to 
enrollment in AdvantageEDC. 
8.2.1 Review of medical history since pre-study visit 
8.2.2 Physical examination (vital signs, weight, performance status) 

 
AMC #095 (Version 15.0) 24AUG2023 
 
95 
NCI Version Date 24AUG2023 
8.2.3 Review of changes in concurrent medications 
8.2.4 Laboratory studies (as defined in Section 8.1.5) 
a) CBC with differential and platelet count within 2 days prior to treatment 
b) Serum chemistries 
c) Serum amylase and lipase 
d) Serum or urine pregnancy test for WOCBP within 72 hours prior to treatment 
8.2.5 Biological sample submissions for correlative studies (as defined in Section 8.1.10) 
must be collected at any time prior to starting treatment on Day 1. The samples 
below must be collected at the time points provided below. 
a) Blood draw: Five 8.5mL ACD tubes for assays (HIV DNA, HIV RNA, single 
copy assays (SCA), and phenotypic/ICS for all participants with hematocrit ≥ 
25 to be collected within 2 days before the Day 1 dose, and Day 1 of Cycle 1 
post-dose. (Appendix XVI). The pre-dose sample and the Day 1 Cycle 1 sample 
must be drawn on different calendar days and should be collected at least 12 
hours apart. The post-dose sample must be drawn between 12 and 36 hours after 
the infusion has been completed. Every effort should be made to process 
samples for viable PBMC and plasma on site within 6 hours of collection. The 
samples will be shipped to the AMC Biorepository via priority overnight service 
for processing if this cannot occur on site. 
8.2.6 First dose of study drug(s) (if receiving). Vital signs will be obtained before the 
infusion and every 15 minutes from the start of the infusion until 60 minutes post-
completion. When slowing or restarting an infusion due to an infusion reaction, 
vital signs should be monitored every 15 minutes or as directed by the Investigator 
until the infusion is completed and/or the participant is stabilized. See Section 4.11 
for dosing information and instructions regarding management of nivolumab 
infusion reactions, and Section 5.1 for management of ipilimumab infusion 
reactions. 
8.2.7 AE assessment 
8.3 
Cycle 1, Day 8 
Unless noted otherwise below, the evaluations may be performed up to three days prior. 
8.3.1 Review of medical history since last visit 
8.3.2 Physical examination (vital signs, weight, performance status) 
8.3.3 Review of changes in concurrent medications 
8.3.4 Laboratory studies (as defined in Section 8.1.5) 
a) CBC with differential and platelet count within 2 days prior to treatment 
b) Serum chemistries 
c) Serum amylase and lipase 
8.3.5 AE assessment 

 
AMC #095 (Version 15.0) 24AUG2023 
 
96 
NCI Version Date 24AUG2023 
8.3.6 Blood draw: Five 8.5 mL yellow ACD tubes for assays (HIV DNA, HIV RNA, 
SCA, and Pheno/ICS) for all participants with hematocrit ≥ 25 to be collected 
(Appendix XVI). Every effort should be made to process samples for viable 
PBMC and plasma on site within 6 hours of collection. The samples will be 
shipped to the AMC Biorepository via priority overnight service for processing if 
this cannot occur on site. 
8.4 
Cycles 2-4, Day 1 
Unless noted otherwise below, the evaluations may be performed up to three days prior to 
treatment. 
8.4.1 Review of medical history since last visit 
8.4.2 Physical examination (vital signs, weight, performance status) 
8.4.3 Review of changes in concurrent medications 
8.4.4 Laboratory studies (as defined in Section 8.1.5) 
a) CBC with differential and platelet count within 2 days prior to treatment 
b) Serum chemistries 
c) Serum amylase and lipase 
d) Serum or urine pregnancy test for WOCBP within 72 hours prior to treatment 
8.4.5 AE assessment 
8.4.6 For participants with KS, tumor, and response assessment with photographic 
documentation at cycle 3 before receiving treatment, as outlined in the KS Tumor 
Assessment MOP. Response of KS to treatment is described in Section 9.2. 
8.4.7 Dose of nivolumab. Vital signs will be monitored as per Section 8.2.6). 
Prophylactic preinfusion medications should be given if infusion reactions were 
observed during prior infusions. 
8.4.8 Blood draw: At cycle 4 only, collect five 8.5 mL yellow ACD tubes for assays (HIV 
DNA, HIV RNA, SCA, and Pheno/ICS) for all participants on dose levels 1 
(including 240 mg q 2 weeks) or 2 with hematocrit ≥ 25, to be collected at the 
following time points: pre-dose on Day 1, post-dose on Day 1, and on day 8 
(Appendix XVI). The pre-dose sample and the Day 1 Cycle 1 sample must be drawn 
on different calendar days and should be collected at least 12 hours apart. The post-
dose sample must be drawn between 12 and 36 hours after the infusion has been 
completed. Every effort should be made to process samples for viable PBMC and 
plasma on site within 6 hours of collection. The samples will be shipped to the 
AMC Biorepository via priority overnight service for processing if this cannot occur 
on site. 
8.5 
Cycles 5-46, Day 1 
Unless noted otherwise below, the evaluations may be performed up to three days prior to 
treatment. 
8.5.1 Review of medical history since last visit 

 
AMC #095 (Version 15.0) 24AUG2023 
 
97 
NCI Version Date 24AUG2023 
8.5.2 Physical examination (vital signs, weight, performance status) 
8.5.3 Review of changes in concurrent medications 
8.5.4 Laboratory studies (as defined in Section 8.1.5) 
a) CBC with differential and platelet count within 2 days prior to treatment 
b) Serum chemistries (odd # cycles only 5, 7, 9, etc.) 
c) Serum amylase and lipase (odd # cycles only 5, 7, 9, etc.) 
d) Serum or urine pregnancy test for WOCBP at Cycle 5 Day 1 and every 12 weeks 
thereafter 
e) HIV viral load and CD4/CD8 count at Cycle 5 Day 1 and every 12 weeks 
thereafter: Viral load studies will be performed using an assay with a limit of 
detection of 75 copies/ml or less. Repeat Hepatitis B antigen and/or Hepatitis C 
antibody if positive at baseline. 
f) Immunologic labs at Cycle 5 Day 1 and every 12 weeks thereafter after 
consisting of: rheumatoid factor, C-reactive protein, ANA, SPEP, 
immunoglobulins, and free light chains (FLC). 
g) Endocrine labs at Cycle 5 Day 1 and every 12 weeks thereafter consisting of: 
TSH, free T4, TPO, morning ACTH, and morning cortisol if ACTH is abnormal 
8.5.5 AE assessment 
8.5.6 Biological sample submissions for correlative studies. Samples will be collected as 
defined in Section 8.1.10, unless otherwise noted. 
a) Collect two 6 ml red top tubes for assessment of circulating levels of pro-
inflammatory molecules before cycle 5. Collection, shipping, and storage 
methods are described in Appendix XV. 
b) Collect 2x2 mm biopsies in RNALater and formalin before cycle 5 as described 
in Appendix XIV (optional for KS cases only, with participant consent). 
c) Collect anal swabs before cycle 5 as described in Appendix XVII (optional for 
anal cancer cases only, with participant consent). 
d) Blood draw: Five 8.5mL ACD tubes for assays (HIV DNA, HIV RNA, SCA, 
and Pheno/ICS) for participants on dose levels 1 (including 240 mg q 2 weeks) 
or 2 with hematocrit ≥ 25, to be collected pre-dose on Day 1, post-dose on 
Day 1, and on Day 8 of Cycles 7, 10, 13, 19, 22, 25, 28, 31, 34, 37, 40, 43 and 
46 (Appendix XIV). The pre-dose sample and the Day 1 Cycle 1 sample must 
be drawn on different calendar days and should be collected at least 12 hours 
apart. The post-dose sample must be drawn between 12 and 36 hours after the 
infusion has been completed. Every effort should be made to process samples 
for viable PBMC and plasma on site within 6 hours of collection. The samples 
will be shipped to the AMC Biorepository via priority overnight service for 
processing if this cannot occur on site. 
Five 8.5 mL ACD tubes for assays (HIV DNA, HIV RNA, SCA, and 
Pheno/ICS) for participants on dose levels -1 or -2 with hematocrit ≥ 25, to be 

 
AMC #095 (Version 15.0) 24AUG2023 
 
98 
NCI Version Date 24AUG2023 
collected pre-dose on Day 1, post-dose on Day 1, and on Day 8 of Cycles 7, 
13, 19, 25, 31, 37, and 43 (Appendix XIV). The pre-dose sample and the Day 
1 Cycle 1 sample must be drawn on different calendar days and should be 
collected at least 12 hours apart. The post-dose sample must be drawn between 
12 and 36 hours after the infusion has been completed. Every effort should be 
made to process samples for viable PBMC and plasma on site within 6 hours 
of collection. The samples will be shipped to the AMC Biorepository via priority 
overnight service for processing if this cannot occur on site. 
e) Blood draw: Twelve 8.5mL ACD tubes for assays (latent reservoir and VOA) 
for all participants who consent to this optional draw with hematocrit ≥ 25 to 
be collected on day 1 of cycle 16. These tubes will be shipped directly to the 
AMC Biorepository for processing (Appendix XVI). 
f) If a participant has not consented to the HIV latent reservoir testing blood draw, 
two 8.5 yellow top tubes will be collected for herpesvirus load and latent virus 
studies on day 1 of cycle 16 (Appendix XIV and Appendix XVI). 
8.5.7 Radiologic assessment of response before cycle 5, and thereafter every 12 weeks. 
All imaging studies or CT scans should be performed in an identical way to the 
baseline scan with the same scanner, same scan direction, and consistent arm 
pointing. Confirmatory scans should also be obtained 4 weeks following initial 
documentation of objective response. If tumor flare is suspected, the participant 
must undergo a second scan within a month of the first scan and the case must be 
discussed with the principal investigator. If progression is documented at that time, 
participant must come off study. For all cohorts and disease types if a scheduled 
response assessment is missed, an assessment must be completed and documented 
prior to drug administration for the next cycle. 
For participants with KS, tumor, and response assessment with photographic 
documentation before odd numbered cycles (5, 7, 9, etc.), as outlined in the KS 
Tumor Assessment MOP. Response of KS to treatment is described in Section 9.2. 
Scans will not be required for participants with KS unless clinically indicated. 
In participants with HIV-cHL, F-FDG-PET/CT scans will be done at cycles 9 and 
13 (weeks 17 and 25). At cycle 24 (week 49), a F-FDG-PET/CT scan will be 
required for participants who do not have two consecutive negative scans before 
this time point. A combined FDG-PET/CT or FDG-PET + CT scan with and 
without IV contrast is required for this study. If a participant has an allergy to IV 
contrast, a non-IV contrast CT scan will be permitted. If the CT scan of a PET/CT 
hybrid is performed with both oral and IV contrast with contrast enhancement in 
the arterial and/or portal venous phase, with at least a 2-slice CT, and is acquired 
with at least 80 mAs and CT scans are obtained with contiguous sections (with a 
maximum of 5 mm slice thickness), then the PET/CT scan alone will suffice. If no 
contrast is used in the FDG-PET/CT, an additional CT scan with contrast is required 
of the neck, chest, abdomen, and pelvis, see Section 8.1.7. 
 
 

 
AMC #095 (Version 15.0) 24AUG2023 
 
99 
NCI Version Date 24AUG2023 
8.5.8 Dose of nivolumab (or nivolumab and ipilimumab). Prophylactic preinfusion 
medications should be given if infusion reactions were observed during prior 
infusions. Vital signs will be monitored pre-infusion and every 30 minutes (+/- 10 
minutes) during dosing, and 1-hour post-completion for participants with prior 
infusion reactions. Participants with no prior infusion reactions may have vital signs 
monitor pre- and post-infusion only. 
8.6 
Combination Therapy Solid Tumor Expansion Cohort: Cycle 5-23 Day 1 
Unless noted otherwise below, the evaluations may be performed up to three days 
prior to treatment. 
8.6.1 Review of medical history since last visit 
8.6.2 Physical examination (vital signs, weight, performance status) 
8.6.3 Review of changes in concurrent medications 
8.6.4 Laboratory studies (as defined in Section 8.1.5) 
a) CBC with differential and platelet count within 2 days prior to treatment 
b) Serum chemistries Serum amylase and lipase  
c) Serum or urine pregnancy test for WOCBP at Cycle 5 Day 1 and every 12 weeks 
thereafter 
d) HIV viral load and CD4/CD8 count at Cycle 5 Day 1 and every 12 weeks 
thereafter: Viral load studies will be performed using an assay with a limit of 
detection of 75 copies/ml or less. Repeat Hepatitis B antigen and/or Hepatitis C 
antibody if positive at baseline. 
e) Immunologic labs at Cycle 5 Day 1 and every 12 weeks thereafter after 
consisting of: rheumatoid factor, C-reactive protein, ANA, SPEP, 
immunoglobulins, and FLC. 
f) Endocrine labs at Cycle 5 Day 1 and every 12 weeks thereafter consisting of: 
TSH, free T4, TPO, morning ACTH, and morning cortisol if ACTH is abnormal 
8.6.5 AE assessment 
Biological sample submissions for correlative studies. Samples will be collected as defined 
in Section 8.1.10, unless otherwise noted. 
a) Collect two 6 ml red top tubes for assessment of circulating levels of pro-
inflammatory molecules before cycle 5. Collection, shipping, and storage 
methods are described in Appendix XV. 
b) Collect anal swabs before cycle 5 as described in Appendix XVII (optional for 
anal cancer cases only, with participant consent). 
c) Blood draw: Five 8.5mL ACD tubes for assays (HIV DNA, HIV RNA, SCA, 
and Pheno/ICS) with hematocrit ≥ 25, to be collected pre-dose on Day 1, post-
dose on Day 1, and on Day 8 of Cycles 7, 10, (Appendix XIV). The pre-dose 
sample and the Day 1 Cycle 1 sample must be drawn on different calendar days 
and should be collected at least 12 hours apart. The post-dose sample must be 

 
AMC #095 (Version 15.0) 24AUG2023 
 
100 
NCI Version Date 24AUG2023 
drawn between 12 and 36 hours after the infusion has been completed. Every 
effort should be made to process samples for viable PBMC and plasma on 
site within 6 hours of collection. The samples will be shipped to the AMC 
Biorepository via priority overnight service for processing if this cannot occur 
on site. 
d) Blood draw: Twelve 8.5mL ACD tubes for assays (latent reservoir and VOA) 
for all participants who consent to this optional draw with hematocrit ≥ 25 to 
be collected on day 1 of cycle 15. These tubes will be shipped directly to the 
AMC Biorepository for processing (Appendix XVI). 
e) If a participant has not consented to the HIV latent reservoir testing blood draw, 
two 8.5 yellow top tubes will be collected for herpesvirus load and latent virus 
studies on day 1 of cycle 15 (Appendix XIV and Appendix XVI). 
8.6.7 Radiologic assessment of response before cycle 5, and thereafter every 12 weeks. 
All imaging studies or CT scans should be performed in an identical way to the 
baseline scan with the same scanner, same scan direction, and consistent arm 
pointing. Confirmatory scans should also be obtained 4 weeks following initial 
documentation of objective response. If tumor flare is suspected, the participant 
must undergo a second scan within a month of the first scan and the case must be 
discussed with the principal investigator. If progression is documented at that time, 
participant must come off study. If a scheduled response assessment is missed, an 
assessment must be completed and documented prior to drug administration for the 
next cycle. 
 
8.7 
Treatment Discontinuation Evaluations 
End of study assessments will be done at 6 weeks (± 1 week) and at 16 weeks (± 1 week) 
of the last dose of study treatment, unless otherwise noted. 
Participants with ongoing toxicities should be seen more often as clinically indicated. The 
schedule of clinical follow-up for these participants will be at the discretion of the treating 
physicians and according to established Standard of Care. AEs Assessment on the study, 
including assessment of immune-mediated AEs and SAEs, will continue for all participants 
until 90 days after the last study drug administration. 
8.6.1 Review of medical history since last visit 
8.6.2 Physical examination (vital signs, weight, performance status) 
8.6.3 Review of changes in concurrent medications 
8.6.4 Laboratory studies (as defined in Section 8.1.5) 
a) CBC with differential and platelet count 
b) Serum chemistries 
c) Serum amylase and lipase 
d) Serum or urine pregnancy test for WOCBP 

 
AMC #095 (Version 15.0) 24AUG2023 
 
101 
NCI Version Date 24AUG2023 
e) HIV viral load, performed using an assay with a limit of detection of 75 
copies/ml or less, CD4/CD8, and repeat Hepatitis B antigen and/or Hepatitis C 
antibody if positive at baseline 
f) Immunologic labs consisting of rheumatoid factor, C-reactive protein, and 
ANA 
g) Endocrine labs consisting of: TSH, free T4, TPO, morning ACTH, and morning 
cortisol if ACTH is abnormal 
h) For participants with HIV-cHL and with bone marrow involvement at 
screening, a bone marrow biopsy will be required to confirm complete 
remission. 
8.6.5 AE assessment 
8.6.6 Biological sample submissions for correlative studies (as defined in Section 
8.1.10), within 6 weeks (± 1 week) of the last dose of study treatment only 
a) Collect two 6 ml red top tubes for assessment of circulating levels of pro-
inflammatory molecules (Appendix XV). 
b) The collection, shipping, and storage of 2x2 mm biopsies in RNALater and 
formalin is described in Appendix XIV (optional for KS cases only, with 
participant consent). 
c) The collection, shipping, and storage of anal swabs is described in Appendix 
XVII (optional for anal cancer cases only, with participant consent). 
d) Blood draw: Twelve 8.5mL ACD tubes for assays (HIV DNA, HIV RNA, SCA, 
and Pheno/ICS) for all participants who consent to this optional draw with 
hematocrit ≥ 25. These tubes will be shipped directly to the AMC Biorepository 
for processing (Appendix XVI). 
e) If a participant has not consented to the HIV latent reservoir testing blood draw, 
two 8.5 yellow top tubes will be collected for herpesvirus load and latent virus 
studies (Appendix XIV). 
8.6.7 Radiologic assessment of response, as applicable per Section 9.0. 
For participants with KS, tumor, and response assessment with photographic 
documentation, as outlined in the KS Tumor Assessment MOP. Response of KS to 
treatment is described in Section 9.2. Scans will not be required for participants 
with KS unless clinically indicated. 
In participants with HIV-cHL, F-FDG-PET/CT scans will be done at treatment 
completion. A combined FDG-PET/CT or FDG-PET + CT scan with and without 
IV contrast is required for this study. If a participant has an allergy to IV contrast, 
a non-IV contrast CT scan will be permitted. If the CT scan of a PET/CT hybrid is 
performed with both oral and IV contrast with contrast enhancement in the arterial 
and/or portal venous phase, with at least a 2-slice CT, and is acquired with at least 
80 mAs and CT scans are obtained with contiguous sections (with a maximum of 
5 mm slice thickness), then the PET/CT scan alone will suffice. If no contrast is 

 
AMC #095 (Version 15.0) 24AUG2023 
 
102 
NCI Version Date 24AUG2023 
used in the FDG-PET/CT, an additional CT scan with contrast is required of the 
neck, chest, abdomen, and pelvis, see Section 8.1.7. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
103 
NCI Version Date 24AUG2023 
9.0 
MEASUREMENT OF EFFECT 
Although response is not the primary endpoint of this trial, participants with measurable 
disease will be assessed by standard criteria. For the purposes of this study, participants 
should be evaluated for response after cycle 4, and then re-evaluated every 12 weeks. In 
addition to a baseline scan, confirmatory scans will also be obtained 4 weeks following 
initial documentation of an objective response. Participants with KS will be evaluated for 
response before odd numbered cycles (5, 7, 9, etc.). Scans will not be required for 
participants with KS unless clinically indicated. Response of KS to treatment is described 
in Section 9.2. In participants with HIV-cHL, F-FDG-PET/CT scans will be done at cycles 
9 and 13 (weeks 17 and 25). At cycle 24 (week 49), a F-FDG-PET/CT scan will be required 
for participants who do not have two consecutive negative scans before this time point. 
Refer to Section 9.3 for the 2017 RECIL Criteria for evaluating measurable disease in HIV-
cHL. 
9.1 
Antitumor Effect – Solid Tumors 
For the purposes of this study, participants should be evaluated for response after 
completing four cycles of therapy and re-evaluated for response every 12 weeks. In 
addition to a baseline scan, confirmatory scans should also be obtained 4 weeks following 
initial documentation of objective response. 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised RECIST guideline (version 1.1) [Eur J Ca 45:228-247, 
2009]. Changes in the largest diameter (unidimensional measurement) of the tumor lesions 
and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
For progression to visceral disease in participants with KS, see Section 9.2.4, 
Noncutaneous Progression. 
9.1.1 Definitions 
Evaluable for Toxicity: All participants will be evaluable for toxicity from the time 
of their first treatment with nivolumab and/or ipilimumab. 
Evaluable for Objective Response: Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for response. These 
participants will have their response classified according to the definitions stated 
below. (Note: Participants who exhibit objective disease progression prior to the 
end of cycle 1 will also be considered evaluable.) 
Evaluable Non-Target Disease Response: Participants who have lesions present 
at baseline that are evaluable but do not meet the definitions of measurable disease, 
have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for non-target disease. The response assessment is 
based on the presence, absence, or unequivocal progression of the lesions. 
9.1.2 Disease Parameters 
Measurable Disease: Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm 

 
AMC #095 (Version 15.0) 24AUG2023 
 
104 
NCI Version Date 24AUG2023 
by chest x-ray, as ≥10 mm with CT scan, or ≥10 mm with calipers by clinical exam. 
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
Note: Tumor lesions that are situated in a previously irradiated area might or might 
not be considered measurable. Such lesions should be considered measurable only 
if evidence of disease progression has been observed in this site. Disease present 
only in a previously irradiated field should have biopsy confirmation. 
Malignant Lymph Nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15 mm in short axis when assessed by CT scan 
(CT scan slice thickness recommended to be no greater than 5 mm). At baseline 
and in follow-up, only the short axis will be measured and followed. 
Non-measurable Disease: All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 
mm short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same participant, these are 
preferred for selection as target lesions. 
Target Lesions: All measurable lesions up to a maximum of two lesions per organ 
and five lesions in total, representative of all involved organs, should be identified 
as target lesions and recorded and measured at baseline. Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly 
should be selected. A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
Non-target Lesions: All other lesions (or sites of disease) including any measurable 
lesions over and above the five target lesions should be identified as non-target 
lesions and should also be recorded at baseline. Measurements of these lesions are 
not required, but the presence, absence, or in rare cases unequivocal progression of 
each should be noted throughout follow-up. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
105 
NCI Version Date 24AUG2023 
9.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
Clinical Lesions: Clinical lesions will only be considered measurable when they 
are superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter 
as assessed using calipers (e.g., skin nodules). In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the 
lesion, is recommended. 
Chest X-ray: Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung. However, CT is preferable. 
Conventional CT and MRI: This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness. MRI is also acceptable in certain 
situations (e.g. for body scans). 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables involved 
in MRI, which greatly impact image quality, lesion conspicuity, and measurement. 
Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences used should be 
optimized for the evaluation of the type and site of disease. Furthermore, as with 
CT, the modality used at follow-up should be the same as was used at baseline and 
the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases. Ideally, the same type of 
scanner should be used, and the image acquisition protocol should be followed as 
closely as possible to prior scans. Body scans should be performed with breath-hold 
scanning techniques, if possible. 
PET-CT: At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements. However, if the site can document that the CT performed 
as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV 
and oral contrast), then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET portion of the CT 
introduces additional data, which may bias an investigator if it is not routinely or 
serially performed. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
106 
NCI Version Date 24AUG2023 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. Ultrasound examinations cannot be reproduced 
in their entirety for independent review at a later date and because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will 
be taken from one assessment to the next. If new lesions are identified by ultrasound 
in the course of the study, confirmation by CT or MRI is advised. If there is concern 
about radiation exposure at CT, MRI may be used instead of CT in selected 
instances. 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to determine relapse 
in trials where recurrence following CR or surgical resection is an endpoint. 
Tumor Markers: Tumor markers alone cannot be used to assess response. If 
markers are initially above the upper normal limit, they must normalize for a 
participant to be considered in complete clinical response. Specific guidelines for 
both CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent 
prostate cancer) have been published [JNCI 96:487-488, 2004; J Clin Oncol 17, 
3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008]. In addition, the Gynecologic 
Cancer Intergroup has developed CA-125 progression criteria, which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian 
cancer [JNCI 92:1534-1535, 2000]. 
Cytology, Histology: These techniques can be used to differentiate between PR and 
CR in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or SD is mandatory to differentiate between response or SD (an effusion 
may be a side effect of the treatment) and PD. 
FDG-PET: While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement 
CT scanning in assessment of progression (particularly possible 'new' disease). 
New lesions on the basis of FDG-PET imaging can be identified according to the 
following algorithm:  
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. However, as this may not necessarily represent a new 
tumor lesion for individuals with ongoing HIV replication, new lesions on FDG-
PET MUST be confirmed by CT scan to document PD. 
No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up 

 
AMC #095 (Version 15.0) 24AUG2023 
 
107 
NCI Version Date 24AUG2023 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring. The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication. However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity. 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG-avid with an 
uptake greater than twice that of the surrounding tissue on the attenuation corrected 
image. 
9.1.4 Response Criteria 
9.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters 
of target lesions, taking as reference the baseline sum diameters 
Progressive Disease (PD): At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on study). In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions 
is also considered progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
diameters while on study 
9.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non-
pathological in size (<10 mm short axis) 
Note: If tumor markers are initially above the upper normal limit, they must 
normalize for a participant to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. Unequivocal 
progression should not normally trump target lesion status. It must be 
representative of overall disease status change, not a single lesion increase. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
110 
NCI Version Date 24AUG2023 
9.2.1 Complete response (CR) is defined as the absence of any detectable residual 
disease, including tumor-associated edema, persisting for at least 4 weeks. 
Participants in whom pigmented (brown or tan) macular skin lesions persist after 
apparent complete response, biopsy of at least one representative lesion is required 
in order to document the absence of malignant cells. Participants without visceral 
disease are not required to undergo radiographic measurements. In participants 
known to have had visceral disease, an assessment at restaging with appropriate 
endoscopic or radiographic procedures should be made. 
9.2.2 Partial response (PR) is defined as no new lesions (skin or oral), or new visceral 
sites of involvement (or the appearance or worsening of tumor-associated edema or 
effusions); AND 
• A 50% or greater decrease in the number of all previously existing lesions 
lasting for at least 4 weeks; OR 
• Complete flattening of at least 50% of all previously raised lesions (i.e., 50% of 
all previously nodular or plaque-like lesion become macules); OR 
• A 50% decrease in the sum of the products of the largest perpendicular 
diameters of the marker lesions 
Note: Participants with residual tumor-associated edema or effusion who otherwise 
meet the criteria for complete response will be classified as having a partial 
response. 
9.2.3 Stable disease (SD) is defined as any response not meeting the criteria for CR, PR, 
or PD. 
9.2.4 Progressive disease (PD) is defined as follows: 
For participants with ≤ 50 cutaneous lesions 
• ≥ 25% increase in the sum of perpendicular diameters of the indicator lesions, 
OR  
• ≥ 25% increase in the total lesion count, or a minimum of five new lesions, 
whichever is greater, OR 
• ≥ 25% increase in the number of raised lesions (minimum of five new raised 
lesions if there are very few raised lesions, for example  8), whichever is 
greater. 
Note: There are body sites where disease is particularly difficult to evaluate, and a 
few new lesions may be counted in spite of the fact that a participant is not actually 
progressing. For example, lesions of the foot, particularly those which are flat, are 
difficult to evaluate because their intensity may be variable based on how much 
edema is present, how much the person walked the day before, how long their feet 
have been in a dependent position prior to the physical exam, etc. 
For participants with >50 cutaneous lesions 
• 25% increase in the sum of the perpendicular diameters of the indicator lesions, 
OR 

 
AMC #095 (Version 15.0) 24AUG2023 
 
111 
NCI Version Date 24AUG2023 
• 25% increase in the total number of lesions in the prospectively defined 
anatomic sites containing representative numbers of lesions, OR 
• A total of five new lesions in anatomic sites which were previously documented 
as having no evidence of cutaneous disease on the whole-body diagram, OR 
• 25% increase in the number of raised lesions (minimum of five raised lesions if 
there are very few raised lesions, for example <8) whichever is greater. 
Photographic documentation of “gross” or significant progression, particularly 
in areas that were not being followed, will be of particular value. 
In order to classify a response as PR, the participant must have at least a PR in 
either the cutaneous or noncutaneous sites of disease, and no evidence of 
progression as defined in the above criteria. In order to classify a response as a CR, 
the participant must have a CR in both the cutaneous (if applicable) and 
noncutaneous (if applicable) sites of disease and no evidence of progression as 
defined by the above criteria. 
Noncutaneous Progression 
Progressive disease includes new visceral sites of involvement or progression of 
visceral disease or the development of new or increasing tumor-associated edema 
or effusion lasting at least 1 week, which interferes with the participant’s normal 
activities. Progressive visceral disease, for measurable and evaluable disease, 
should be analogous to non-KS response criteria (RECIST; see Section 9.1). 
9.2.5 Recurrent disease is defined as the appearance of tumor following documentation 
of a complete remission. 
9.2.6 Time to response is defined as time from the first dose of chemotherapy until 
documentation of first response. 
9.2.7 Time to progression is defined as time from initiation of chemotherapy to 
documentation of first progression. 
9.2.8 Response duration is defined as the time from first documentation of response to 
documentation of first progression. 
9.3 
Evaluation of Response for Participants with HIV-Associated Hodgkin Lymphoma 
9.3.1 Definition of Response 
The response definitions used for this study are the 2017 International Working 
Group Consensus RECIL 2017) [23]. This is similar to the Lugano criteria of 2014 
where response is determined by a combination of Deauville score and CT scan 
criteria; however, only three lymph node targets are required in this evaluation 
criteria [23]. See table below. 
9.3.2 Complete Response (CR) 
1. Complete disappearance of all detectable clinical evidence of disease and 
disease-related symptoms if present before therapy. 
2a. Typically FDG-avid lymphoma: In participants with no pretreatment PET scan 
or when the PET scan was positive before therapy, a post-treatment residual 

 
AMC #095 (Version 15.0) 24AUG2023 
 
112 
NCI Version Date 24AUG2023 
mass of any size is permitted as long as it is PET negative. PET negative is 
defined as a Deauville score of less than 4. 
2b. Variably FDG-avid lymphomas/FDG-avidity unknown: In participants without 
a pretreatment PET scan, or if a pretreatment PET scan was negative, all lymph 
nodes and nodal masses must have regressed on CT to normal size (1.0 cm in 
their greatest transverse diameter for nodes > 1.5 cm before therapy). 
Previously involved nodes that were 1.1 to 1.5 cm in their long axis and more 
than 1.0 cm in their short axis before treatment must have decreased to 1.0 cm 
in their short axis after treatment. 
3. The spleen and/or liver, if considered enlarged before therapy on the basis of a 
physical examination or CT scan, should not be palpable on physical 
examination and should be considered normal size by imaging studies, and 
nodules related to lymphoma should disappear. However, determination of 
splenic involvement is not always reliable because a spleen considered normal 
in size may still contain lymphoma, whereas an enlarged spleen may reflect 
variations in anatomy, blood volume, the use of hematopoietic growth factors, 
or causes other than lymphoma. 
4. If the bone marrow was involved by lymphoma before treatment, the infiltrate 
must have cleared on repeat bone marrow biopsy. The biopsy sample on which 
this determination is made must be adequate (with a goal of > 20 mm unilateral 
core). If the sample is indeterminate by morphology, it should be negative by 
immunohistochemistry. 
9.3.3 Partial Response (PR) requires all of the following 
1. At least a less than or equal to a 30% decrease in sum of the product of the 
longest diameters (SLD) of up to three of the largest dominant nodes or nodal 
masses. These nodes or masses should be selected according to all of the 
following: they should be clearly measurable in at least two perpendicular 
dimensions; if possible, they should be from disparate regions of the body; and 
they should include mediastinal and retroperitoneal areas of disease whenever 
these sites are involved. 
2. No increase should be observed in the size of other nodes, liver, or spleen.  
3. Splenic and hepatic nodules must regress by 30% in their SLD or, for single 
nodules, in the greatest transverse diameter.  
4. With the exception of splenic and hepatic nodules, involvement of other organs 
is usually assessable, and no measurable disease should be present.  
5. Participants who achieve a CR by the above criteria, but who have persistent 
morphologic bone marrow involvement will be considered partial responders. 
When the bone marrow was involved before therapy and a clinical CR was 
achieved, but with no bone marrow assessment after treatment, participants 
should be considered partial responders. 
6. No new sites of disease should be observed. 
7. Typically FDG-avid lymphoma: for a participant with no pretreatment PET 

 
AMC #095 (Version 15.0) 24AUG2023 
 
113 
NCI Version Date 24AUG2023 
scan or if the PET scan was positive before therapy, the post-treatment PET 
should be positive in at least one previously involved site. 
8. Variably FDG-avid lymphomas/FDG-avidity unknown: if a pretreatment PET 
scan was negative, CT criteria should be used. 
9.3.4 Minor Response (MR) 
Minor Response (MR) is defined as the following A participant is considered to 
have MR when he or she fails to attain the criteria needed for a CR or PR, less than 
or equal to10% decrease or less than or equal to 20% increase in the sum of longest 
diameters of the target lesions. Typically FGD-avid lymphomas: the PET should 
be positive at prior sites of disease with no new areas of involvement on the post- 
treatment CT or PET. 
9.3.5 Stable Disease (SD) is defined as the following A participant is considered to have 
SD when he or she fails to attain the criteria needed for a CR or PR, <10% decrease 
or less than or equal to 20% increase in the sum of longest diameters of target 
lesions. Typically FGD-avid lymphomas: the PET should be positive at prior sites 
of disease with no new areas of involvement on the post- treatment CT or PET.  
Variably FDG-avid lymphomas/FDG-avidity unknown: if the pretreatment PET 
was negative, there must be no change in the size of the previous lesions on the 
post-treatment CT scan.  
9.3.6 Relapsed Disease (RD) (after CR)/Progressive Disease (PD) (after PR, SD) 
Lymph nodes should be considered abnormal if the long axis is more than 1.0 cm 
regardless of the short axis. >20% increase in the sum of longest diameters of target 
lesions. For small lymph nodes measuring <15mm post-therapy, a minimum 
absolute increase of 5mm and the long diameter should exceed 15mm or the 
appearance of a new lesion will enough define the participant with RD or PD. 
If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered 
abnormal if its short axis is more than 1.0. Lymph nodes 1.0 x 1.0 cm will not be 
considered as abnormal for relapse or PD.  
Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size. Increased FDG uptake in a 
previously unaffected site should only be considered relapsed or progressive 
disease after confirmation with other modalities. In participants with no prior 
history of pulmonary lymphoma, new lung nodules identified by CT are mostly 
benign. Thus, a therapeutic decision should not be made solely on the basis of the 
PET without histologic confirmation.  
9.3.7 Recurrent Disease is defined as the appearance of tumor following documentation 
of a complete remission.  
9.3.8 Time to Response is defined as time from the first dose of chemotherapy until 
documentation of first response.  
9.3.9 Time to Progression is defined as time from initiation of chemotherapy to 
documentation of first progression.  

 
AMC #095 (Version 15.0) 24AUG2023 
 
115 
NCI Version Date 24AUG2023 
10.0 
STATISTICAL CONSIDERATIONS 
10.1 
Study Design/Endpoints 
This is a phase I dose de-escalation trial of ipilimumab and nivolumab in advanced HIV-
associated solid tumors implemented as a rolling six design that first establishes the MTD 
for single agent nivolumab and then the MTD for combination of ipilimumab and 
nivolumab. Since there are only two dose levels within each single and combination 
therapy, the design requires the full cohort of six participants be enrolled unless two or 
more experience a DLT. The design is stratified by lymphocyte T CD4+ count (above 
200/mm3 for Stratum 1 and 100-200/mm3 for Stratum 2). Please see Section 4.2 and Section 
4.3 of the Treatment Plan for the dose levels of ipilimumab and nivolumab, and Section 
4.4 for the definition of DLT. After the combination therapy MTD has been determined, 
an expansion cohort in HIV-associated solid tumors will be enrolled. An expansion cohort 
in solid tumors, excluding those histologies not known to respond to single agent 
nivolumab (i.e. pancreas, prostate, MSS colorectal cancer) with CD4 counts > 200/mm3 
will also be enrolled and treated with single agent nivolumab. An additional cohort of 
participants with relapsed refractory cHL will be treated with single agent nivolumab. No 
intra-participant dose escalations will be allowed. Overall study duration including 
completion of evaluation of the final participant is projected to be 5 years. 
10.1.1 Primary endpoints 
Dose De-Escalation Strata: To demonstrate safety and feasibility of ipilimumab and 
nivolumab at the standard doses of drug in solid tumor participants with HIV 
infection given the possibility of increased toxicity based on immune activation, 
co-morbidity, or interference with HAART therapy. The purpose for this would be 
to provide appropriate experience and guidelines, if necessary, to allow participants 
with HIV infections to participate in ongoing trials. 
10.1.2 Analysis of primary objective 
Please see Section 4.2 of the Treatment Plan for the dose de-escalation decision 
rule. In summary, the primary goal in this phase I study is to determine the safety 
and feasibility of ipilimumab and nivolumab in combination therapy in participants 
with advanced HIV-associated solid tumors, and to determine the maximum 
tolerated dose (MTD) in this participant population. A rolling design will be used, 
where successive cohorts of two to six participants will be enrolled into specified 
dose levels. Dosing from nivolumab alone to nivolumab in combination with 
ipilimumab will occur according to the scheme in the treatment plan; the safety 
evaluation period is 6 weeks. The MTD for single agent or combination therapy is 
the starting dose level at which ≤1/6 participants experience DLT with the next 
higher dose having at least ≥2 participants encountering DLT (unless the MTD is 
the highest pre-specified dose level). DLTs for this protocol are defined in Section 
4.4. Given the potential susceptibility of participants with CD4+ counts ≤200/mm3, 
the dose de-escalation will initially occur in participants with counts >200/mm3 
(Stratum 1), and then participants in Stratum 2 (100-200/mm3 CD4 counts) will be 
evaluated starting at the MTD determined in Stratum 1 after reviewing the safety 
profile for Stratum 1. For Stratum 2, participants will be enrolled starting at the 
Stratum 1 DLT in cohorts of 2-6 participants. Stratum 2 participants will not be 

 
AMC #095 (Version 15.0) 24AUG2023 
 
116 
NCI Version Date 24AUG2023 
allowed to escalate beyond the MTD for Stratum 1; one dose level de-escalation 
will be allowed based on the criteria in the treatment plan. 
If a DLT occurs in none or one participant in Stratum 1 at a particular dose level, a 
total of six participants will be enrolled to that cohort. If a second participant 
experiences a DLT, the MTD will have been exceeded. If 2 DLTs are experienced 
at the first cohort, one dose de-escalation (Dose Level -1) will be permitted 
according to the study schema in the treatment plan. Similarly, if 2 DLTs are 
experienced at dose level 2, a dose de-escalation (Dose Level -2) will be permitted. 
Thus, the MTD is the dose level at which ≤1/6 participants experience DLT with 
the next higher dose having ≥2 participants encountering DLT (unless the MTD is 
the highest pre-specified dose level) during the safety evaluation period. 
To better estimate the preliminary efficacy of treatment, an expansion cohort of 12 
participants will be treated at the MTD for single agent nivolumab or combination 
therapy with ipilimumab and nivolumab (depending on the results of the Phase I 
portion). If the MTDs differ between the two strata then there will be two expansion 
cohorts of 18 participants with a CD4 count >200 cells/mL and six participants with 
a CD4 count between 100 and 200 cell/mL. Also, to better estimate preliminary 
safety (secondary objective) in HIV infected individuals, a cohort of 24 participants 
with solid tumors (excluding histologies not known to respond to single agent 
nivolumab) and a cohort of 12 participants with cHL will be treated with single 
agent nivolumab. 
All participants will be evaluable for toxicity from the time of nivolumab (which is 
administered first when there is concurrent treatment with ipilimumab). The details 
of toxicity grading and reporting may be found in Section 6.0. Toxicity data will 
be presented by type and severity for each dose group and overall; the incidence of 
toxicity related dose reductions and treatment discontinuations will be summarized. 
10.2 
Sample Size/Accrual Rate 
For phase I, Stratum 1, a minimum of four to a maximum of 18 participants will be enrolled. 
For phase I, Stratum 2, a minimum of zero to a maximum of 18 participants will be 
enrolled. An expansion cohort of 24 participants will be treated at the combination therapy 
MTD, and an expansion cohort of 24 participants with solid tumors, excluding those 
histologies not known to respond to single agent nivolumab (i.e. pancreas, prostate, MSS 
colorectal cancer) will be treated with single agent nivolumab. Also, 12 participants with 
relapsed refractory cHL will be treated with single agent nivolumab. Therefore, in total, 
this study will enroll a minimum of four participants and a maximum of 96 participants. 
Considering precision, 12 participants in the additional cHL cohort would yield an exact 
95% confidence interval of 38% to 92% when the ORR is 70%, and 24 participants in the 
additional solid tumor cohort would yield an exact 95% confidence interval of 48% to 87%, 
such that these estimates would be considered preliminary. 
Accrual will be approximately two participants per month for phase I, Stratum 1; 
approximately one participant per month for phase I, Stratum 2; and approximately 2-3 
participants per month for each of the two solid tumor expansion cohorts. And, 3-4 
participants per month for the cHL cohort. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
117 
NCI Version Date 24AUG2023 
10.3 
Stratification Factors 
Participants will be studied in separate strata. Stratum 1 will first enroll participants with 
lymphocyte T CD4+ count above 200/mm3. After Stratum 1 single agent therapy 
completes, Stratum 2 will enroll participants with lymphocyte T CD4+ count between 100-
200/mm3. Stratum 2 will be evaluated starting at the single agent therapy MTD determined 
in Stratum 1, after reviewing the safety profile for Stratum 1. Stratum 2 participants will 
not be allowed to escalate beyond the MTD for Stratum 1; one dose level de-escalation will 
be allowed based on the doses in the schema in the treatment plan. 
10.4 
Analysis of Secondary Endpoints 
10.4.1 Preliminary objective response rates 
The proportion of participants achieving ORs (by RECIST criteria or KS response 
criteria, which includes RECIST for visceral disease, or by RECIL for cHL) and 
their corresponding 95% confidence intervals (calculated using exact Binomial) 
will be reported separately for solid tumor and cHL according to treatment 
(combination therapy and single agent) using response criteria designated in 
Section 9.0. Participants in the expansion cohort and those treated at any Dose 
Level in the dose de-escalation cohorts will be included. Disease-specific outcomes 
will be estimated for histologies with > 5 participants. For participants who fail 
therapy, the proportion with loco-regional vs. distant progression will be 
summarized. Descriptive statistics will also be compiled for DOR. 
10.4.2 Immune function and other parameters  
Descriptive statistics will be generated to evaluate the effects of single agent 
nivolumab, and the combination of ipilimumab and nivolumab, on immune 
function (HIV viral load, CD4 and CD8 cells). 
Depending on the number of dose levels tested, immune status and HIV viral load 
will be summarized overall and according to dose level at pre-study and end of 
study. In an explorative fashion, change in these parameters from pre-study to the 
end of study will be examined using a nonparametric Wilcoxon signed-rank test. 
Due to the small number of participants, no adjustments for multiple testing are 
planned. 
10.5 
Exploratory Objectives 
All exploratory objectives will addressed in batch at the completion of enrollment/study as 
applicable. Some measures are only applicable to disease subsets. 
10.5.1 Understand the immune response to agent in the context of ART, of altered immune 
function, and repertoire due to prior HIV infection 
10.5.1.1 To evaluate the effects of single agent nivolumab, and the combination of 
ipilimumab and nivolumab, on intratumor immune cells by IHC such as 
PD1, PDL-1, and others. 
10.5.1.2 To evaluate the effects of single agent nivolumab, and the combination of 
ipilimumab and nivolumab on circulating cytokine markers by multiplex 
assay. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
118 
NCI Version Date 24AUG2023 
10.5.2 To understand the response of human tumor viruses (HPV, EBV, and KSHV) to 
agent 
10.5.2.1 To evaluate the effects of single agent nivolumab, and the combination of 
ipilimumab and nivolumab on herpesvirus loads (EBV, KSHV, CMV) in 
plasma. 
10.5.2.2 To evaluate the effects of single agent nivolumab, and the combination of 
ipilimumab and nivolumab on latent herpesvirus (EBV, KSHV, CMV) in 
PBMC. 
10.5.2.3 To evaluate the effects of single agent nivolumab, and the combination of 
ipilimumab and nivolumab on herpesvirus specific CD8 and CD4 T cells 
in PBMC. 
10.5.2.4 In cases of KS, to evaluate the effects of single agent nivolumab, and the 
combination of ipilimumab and nivolumab on viral transcription in tumor 
biopsies. 
10.5.2.5 In cases of anal cancer, to evaluate the effects of single agent nivolumab, 
and the combination of ipilimumab and nivolumab on HPV types in anal 
swabs, when feasible. 
10.5.3 Understand the response of HIV to agent 
10.5.3.1. To evaluate the effects of single agent nivolumab, and the combination of 
ipilimumab and nivolumab on latent HIV loads in PBMC using outgrowth 
assay. 
10.5.3.2. To evaluate the effects of single agent nivolumab, and the combination of 
ipilimumab and nivolumab on HIV reactive T cells. 
10.5.3.3. Descriptive statistics will be generated for the above measures. Changes 
from pre-study to end of study will be explored using nonparametric 
Wilcoxon signed-rank test. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
119 
NCI Version Date 24AUG2023 
11.0 
ROLE OF DATA MANAGEMENT 
11.1 
CRF Instructions 
Access to the internet data entry system for this study, AdvantageEDCSM, and instructions 
for recording of study data on CRFs will be provided by the AMC ODMC at 
www.AIDSCancer.org. Participating institutions are responsible for submitting data 
and/or data forms via AdvantageEDC in accordance with the AMC Data Entry Guide and 
specific form instructions, within the timelines specified by the AMC’s Standards of 
Procedure for Site Performance Measures. 
11.2 
Data Quality 
It is the responsibility of the AMC ODMC to assure the quality of data for the study (See 
Appendix VI, AMC Data and Safety Monitoring Plan). This role extends from protocol 
development to generation of the final study database. 
11.3 
Data Monitoring 
This study will be monitored in compliance with AMC policies and by the Clinical Data 
Update System (CDUS) Version 3.0. Cumulative protocol- and participant-specific CDUS 
data will be submitted electronically to CTEP on a quarterly basis. Reports are due January 
31, April 30, July 31, and October 31. Instructions for submitting data using the CDUS can 
be found on the CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html). 
The AMC ODMC is responsible for compiling and submitting CDUS data to CTEP for all 
participants and for providing the data to the Principal Investigator for review. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
120 
NCI Version Date 24AUG2023 
12.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
IRB Approval and Informed Consent 
The principles of Institutional Review Board (IRB) approval and informed consent 
described in the Food and Drug Administration (FDA) regulations (21 CFR Part 50 and 
56) and Department of Health and Human Services (DHHS) regulations for the Protection 
of Human Participants regulations (45 CFR Part 46) must be followed. IRB approval of 
the protocol and the informed consent form must be given in writing. 
The sponsor’s designee (AMC ODMC) must receive a copy of the letter of approval from 
the IRB, which specifically approves the protocol and informed consent, before participant 
enrollment. The IRB must also approve any significant changes to the protocol and 
documentation of this approval must be sent to the AMC ODMC. The IRB must review 
the research project at least once every 365 days during the duration of the project. 
Continuing approval of the project must also be given in writing and provided to the AMC 
ODMC. 
Records of all study review and approval documents must be kept on file by the 
Investigator and are participant to inspection during or after completion of the study. AEs 
must be reported to the IRB according to local procedures. The IRB should receive 
notification of completion of the study and final report within 3 months of study completion 
and termination. The Investigator will maintain an accurate and complete record of all 
submissions made to the IRB, including a list of all reports and documents submitted. 
Written informed consent will be obtained from the participant. The nature, significance, 
and risks associated with the study must be explained to the participant. The informed 
consent will describe the purpose of the study, the procedures to be followed, the risks, and 
benefits of participation, all risks of the investigational agent(s) and/or study participation 
as listed in the model informed consent form, and all other elements of informed consent 
as required by regulation. A copy of the consent form will be given to the participant to 
keep. 
In addition, any institution(s) conducting research according to the guidelines of this 
protocol is required to adhere to local and national laws and regulations governing the 
confidentiality and disclosure of health information. 
12.2 
Changes to the Protocol 
Any change or addition to this protocol requires a written protocol amendment that must 
be approved by CTEP and the Investigator before implementation. All amendments require 
approval by the IRB/IEC of the treating institution. A copy of the written approval of the 
IRB/IEC must be sent to the ODMC. 
12.3 
Women and Minorities 
This study is being conducted by the NCI-sponsored AIDS Malignancy Consortium 
(AMC). As part of their contractual obligations, each participating site within the AMC 
and the AMC as a whole is required to assure that the participation of women and minority 
participants reflects the percentage representation of these populations in their geographic 
region and, for the AMC, the United States as a whole. As such, it is expected that the 

 
AMC #095 (Version 15.0) 24AUG2023 
 
122 
NCI Version Date 24AUG2023 
13.0 
REFERENCES 
1. 
Rubinstein PG, Aboulafia DM, Zloza A. Malignancies in HIV/AIDS: from epidemiology to 
therapeutic challenges. AIDS. 2014 Feb;28(4):453-65. 
2. 
Carbone A, Vaccher E, Gloghini A, Pantanowitz L, Abayomi A, de Paoli P, Franceschi S. 
Diagnosis and management of lymphomas and other cancers in HIV-infected patients. Nat 
Rev Clin Oncol. 2014;11(4):223. 
3. 
Pantanowitz L, Schlecht HP, Dezube BJ. The growing problem of non-AIDS-defining 
malignancies in HIV. Curr Opin Oncol 2006; 18: 469-478. 
4. 
Bower M, Collins S, Cottrill C, Cwynarski K, Montoto S, Nelson M, Nwokolo N, Powles T, 
Stebbing J, Wales N, Webb A, AIDS Malignancy Subcommittee. British HIV Association 
guidelines for HIV-associated malignancies 2008. HIV Med. 2008;9(6):336. 
5. 
Deeken JF, Tjen-A-Looi A, Rudek MA, Okuliar C, Young M, Little RF, Dezube BJ. The 
rising challenge of non-AIDS-defining cancers in HIV-infected patients. Clin Infect Dis. 
2012;55(9):1228. 
6. 
Ramsdell F, Fowlkes BJ. Maintenance of in vivo tolerance by persistence of antigen. Science 
(1992) 257(5073):1130–410.1126/science.257.5073.1130. 
7. 
Utzschneider DT, Legat A, Fuertes Marraco SA, Carrie L, Luescher I, Speiser DE, et al. T 
cells maintain an exhausted phenotype after antigen withdrawal and population 
reexpansion. Nat Immunol (2013) 14(6):603–1010.1038/ni.2606. 
8. 
Virgin HW, Wherry EJ, Ahmed R. Redefining chronic viral infection. Cell (2009) 
138(1):30–5010.1016/j.cell.2009.06.036. 
9. 
Critchlow CW, Surawicz CM, Holmes KK, Kuypers J, Daling JR, Hawes SE, et al. (1995). 
Prospective study of high grade anal squamous intraepithelial neoplasia in a cohort of 
homosexual men: influence of HIV infection, immunosuppression and human 
papillomavirus infection. AIDS 9:1255-1262. 
10. Frisch M, Glimelius B, van den Brule AJ, Wohlfahrt J, Meijer CJ, Walboomers JM, Goldman 
S, Svensson C, Adami HO, Melbye M. Sexually transmitted infection as a cause of anal 
cancer. N Engl J Med 1997; 337: 1350-1358. 
11. Palefsky JM, Holly EA, Ralston ML, Da Costa M, Bonner H, Jay N, et al. (2001b). Effect of 
highly active antiretroviral therapy on the natural history of anal squamous intraepithelial 
lesions and anal human papillomavirus infection. J Acquir Immune Defic Syndr 28:422-
428. 
12. Bedani PL, Risichella IS, Strumia R, Cavazzini L, Gilli P, Calastrini C, Verzola A, Stabellini 
G. Kaposi's sarcoma in renal transplant recipients: pathogenetic relation between the 
reduced density of Langerhans cells and cyclosporin-A therapy. J Nephrol. 1999 May-
Jun;12(3):193-6. PubMed PMID:10440518. 
13. Maurer T, Ponte M, Leslie K. HIV-associated Kaposi's sarcoma with a high CD4 count and 
a low viral load. N Engl J Med. 2007 Sep 27;357(13):1352-3. 
14. Bihl F, Berger C, Chisholm JV 3rd, Henry LM, Bertisch B, Trojan A, Nadal D, Speck RF, 
Flepp M, Brander C, Mueller NJ; Swiss HIV Cohort Study. Cellular immune responses 

 
AMC #095 (Version 15.0) 24AUG2023 
 
123 
NCI Version Date 24AUG2023 
and disease control in acute AIDS-associated Kaposi's sarcoma. AIDS. 2009 Sep 
10;23(14):1918-22. doi: 10.1097/QAD.0b013e3283300a91. PubMed PMID: 19609199. 
15. Lepone L, Rappocciolo G, Knowlton E, Jais M, Piazza P, Jenkins FJ, Rinaldo CR. 
Monofunctional and polyfunctional CD8+ T cell responses to human herpes virus 8 lytic 
and latency proteins. Clin Vaccine Immunol. 2010 Oct;17(10):1507-16. 
16. Skinnider BF, Elia AJ, Gascoyne RD, Patterson B, Trumper L, Kapp U, et al. Signal 
transducer and activator of transcription 6 is frequently activated in Hodgkin and Reed-
Sternberg cells of Hodgkin lymphoma. Blood 2002,99:618-626. 
17. Skinnider BF, Mak TW. The role of cytokines in classical Hodgkin lymphoma. Blood 
2002:4283-4297. 
18. Armand P. Immune checkpoint blockade in hematologic malignancies. Blood. 
2015;125:3393-400. 
19. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or 
refractory Hodgkin’s lymphoma. N Engl JMed. 2015;372(4): 311-319. 
20. Moskowitz CH, Ribrag V, Michot J-M, et al. PD-1 blockade with the monoclonal antibody 
pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after 
brentuximab vedotin failure: preliminary results from a phase 1b study (KEYNOTE-013) 
[abstract]. Blood. 2014 
21. Younes A, Santoro A, Shipp M, Zinzani PL, Timmerman JM, Ansell S et al. Nivolumab for 
classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation 
and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet 
Oncol. 2016;17:1283-94. 
22. Ansell S , Gutierrez ME , Shipp MA , Gladstone D , Moskowitz A, Borello I et al. A Phase 
1 Study of Nivolumab in Combination with Ipilimumab for Relapsed or Refractory 
Hematologic Malignancies (CheckMate 039). Blood 2016 128:183. 
23. Younes A, Hilden P, Coiffier B, Hagenbeek A, Salles G, Wilson W et al. International 
Working Group consensus response evaluation criteria in lymphoma (RECIL 2017). Ann 
Oncol. 2017 Apr 3. [Epub ahead of print]. 
24. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, et al. PD-1 expression 
on HIV-specific T cells is associated with T-cell exhaustion and disease progression. 
Nature (2006) 443(7109):350–410.1038/nature05115. 
25. Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, Bessette B, et al. Upregulation 
of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. 
Nat Med (2006) 12(10):1198–20210.1038/nm1106-1329b. 
26. Zhang JY, Zhang Z, Wang X, Fu JL, Yao J, Jiao Y, et al. PD-1 up-regulation is correlated 
with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-
term nonprogressors. Blood (2007) 109(11):4671–810.1182/blood-2006-09-044826. 
27.  Maier H, Isogawa M, Freeman GJ, Chisari FV. PD-1:PD-L1 interactions contribute to the 
functional suppression of virus-specific CD8+ T lymphocytes in the liver. J Immunol 
(2007) 178(5):2714–20. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
124 
NCI Version Date 24AUG2023 
28. Golden-Mason L, Palmer B, Klarquist J, Mengshol JA, Castelblanco N, Rosen HR. 
Upregulation of PD-1 expression on circulating and intrahepatic hepatitis C virus-specific 
CD8+ T cells associated with reversible immune dysfunction. J Virol (2007) 
81(17):9249–5810.1128/JVI.00409-07. 
29. Zhang Z, Zhang JY, Wherry EJ, Jin B, Xu B, Zou ZS, et al. Dynamic programmed death 1 
expression by virus-specific CD8 T cells correlates with the outcome of acute hepatitis B. 
Gastroenterology (2008) 134(7):1938–4910.1053/j.gastro.2008.03.037. 
30. Petrovas C, Casazza JP, Brenchley JM, Price DA, Gostick E, Adams WC, et al. PD-1 is a 
regulator of virus-specific CD8+ T cell survival in HIV infection. J Exp Med (2006) 
203(10):2281–9210.1084/jem.20061496. 
31. Kaufmann DE, Kavanagh DG, Pereyra F, Zaunders JJ, Mackey EW, Miura T, et al. 
Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease 
progression and defines a reversible immune dysfunction. Nat Immunol (2007) 
8(11):1246–5410.1038/ni1515. 
32. Swann JB, Smyth MJ. Immune surveillance of tumors. J Clin Invest. 2007;117: 1137-1146. 
33. Drake CG, Jaffee E, Pardoll DM. Mechanisms of immune evasion by tumors. Adv Immunol. 
2006;90:51-81. 
34. Investigator Brochure. (2014). Nivolumab, BMS-936558, MDX1106. Version 13, 21 July 
2014. Bristol-Myers Squibb. Lawrenceville, NJ. 
35. Wolchok, J.D., H. Kluger, M.K. Callahan, et al. (2013). Nivolumab plus ipilimumab in 
advanced melanoma. N Engl J Med. 369:122-133. 
36. Woo, S.R., M.E. Turnis, M.V. Goldberg, et al. (2012). Immune inhibitory molecules LAG-
3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. 
Cancer Res. 72:917-927. 
37. Taube, J.M., R.A. Anders, G.D. Young, et al. (2012). Colocalization of inflammatory 
response with B7-H1 expression in human melanocytic lesions supports an adaptive 
resistance mechanism of immune escape. Sci Transl Med. 4:127ra137. 
38. Thompson, R.H., M.D. Gillett, J.C. Cheville, et al. (2004). Costimulatory B7-H1 in renal cell 
carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. 
Proc Natl Acad Sci U S A. 101:17174-17179. 
39. Thompson, R.H., M.D. Gillett, J.C. Cheville, et al. (2005). Costimulatory molecule B7-H1 
in primary and metastatic clear cell renal cell carcinoma. Cancer. 104:2084-2091. 
40. Thompson, R.H., S.M. Kuntz, B.C. Leibovich, et al. (2006). Tumor B7-H1 is associated with 
poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res. 
66:3381-3385. 
41. Ohigashi, Y., M. Sho, Y. Yamada, et al. (2005). Clinical significance of programmed death-
1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin 
Cancer Res. 11:2947-2953. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
125 
NCI Version Date 24AUG2023 
42. Wu, C., Y. Zhu, J. Jiang, et al. (2006). Immunohistochemical localization of programmed 
death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta 
Histochem. 108:19-24. 
43. Dong, H., and L. Chen. (2003). B7-H1 pathway and its role in the evasion of tumor immunity. 
J Mol Med (Berl). 81:281-287. 
44. Nomi, T., M. Sho, T. Akahori, et al. (2007). Clinical significance and therapeutic potential 
of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic 
cancer. Clin Cancer Res. 13:2151-2157. 
45. Zitvogel, L., A. Tesniere, and G. Kroemer. (2006). Cancer despite immunosurveillance: 
immunoselection and immunosubversion. Nat Rev Immunol. 6:715-727. 
46. Sznol, M., H.M. Kluger, F.S. Hodi, et al. (2013). Survival and long-term follow-up of safety 
and response in patients (pts) with advanced melanoma (MEL) in a phase I trial of 
nivolumab (anti-PD-1; BMS-936558; ONO-4538). J Clin Oncol. 31:ACRA9006. 
47. Brahmer, J.R., L. Horn, S.J. Antonia, et al. (2013). Survival and long-term follow-up of the 
phase I trial of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with 
previously treated advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 
31:A8030. 
48. Drake, C.G., D.F. McDermott, M. Sznol, et al. (2013). Survival, safety, and response 
duration results of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in a phase I trial in 
patients with previously treated metastatic renal cell carcinoma (mRCC): Long-term 
patient follow-up. J Clin Oncol. 31:A4514. 
49. Rizvi, N.A., S.J. Antonia, L.Q.M. Chow, et al. (2013). A phase I study of nivolumab (anti-
PD-1; BMS-936558, ONO-4538) plus platinum-based doublet chemotherapy (PT-
doublet) in chemotherapy-naive non-small cell lung cancer (NSCLC) patients (pts). J Clin 
Oncol. 31:A8072. 
50. Topalian, S.L., F.S. Hodi, J.R. Brahmer, et al. (2012). Safety, activity, and immune correlates 
of anti-PD-1 antibody in cancer. N Engl J Med. 366:2443-2454. 
51. Ipilimumab Investigator Brochure. (2014). BMS-734016, MDX010. Version 17, 10 March 
2014. Bristol-Myers Squibb. Wallingford, CT.  
52. Curran, MA, Montalvo W, Yagita H, et al. (2010). PD-1 and CTLA-4 combination blockade 
expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 
melanoma tumors. Proc Natl Acad Sci U S A. 107: 4275-80. 
53. Hammers, HJ, Plimack ER, Infante JR, et al. (2014). Phase I study of nivolumab in 
combination with ipilimumab in metastatic renal cell carcinoma (mRCC). J Clin Oncol. 
32:A4504. 
54. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-
4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing 
a critical negative regulatory role of CTLA-4. Immunity. Nov 1995;3(5):541-547. 
55. Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early 
lethality in mice deficient in Ctla-4. Science. Nov 10 1995;270(5238):985-988. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
126 
NCI Version Date 24AUG2023 
56. Chambers CA, Sullivan TJ, Allison JP. Lymphoproliferation in CTLA-4-deficient mice is 
mediated by costimulation-dependent activation of CD4+ T cells. Immunity. Dec 
1997;7(6):885 895. 
57. Tchekmedyian S, Glaspy J, Korman A, et al. MDX-010 (human anti-CTLA4): a phase I trial 
in malignant melanoma. In: Programs and abstracts of The American Society of Clinical 
Oncology Annual Meeting. Orlando, Florida, May 18–21, 2002 [abstract: 56]. 
58. Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by 
cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic 
melanoma. Proc Natl Acad Sci U S A 2003;100:8372–7. 
59. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated 
advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging 
study. Lancet Oncol 2010;11:155–64. 
60. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients 
with metastatic melanoma. N Engl J Med 2010;363:711–23. 
61. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously 
untreated metastatic melanoma. N Engl J Med 2011;364:2517–26. 
62. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of 
the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative 
regulation of lymphocyte activation. J Exp Med. 2000; 192:1027-1034. 
63. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor 
cells in the escape from host immune system and tumor immunotherapy by PD-L1 
blockade. Proc Natl Acad Sci U S A. 2002;99:12293-12297 
64. Parekh VV, Lalani S, Kim S, Halder R, Azuma M, Yagita H, et al. PD-1/PD-L blockade 
prevents anergy induction and enhances the anti-tumor activities of glycolipid- activated 
invariant NKT cells. J Immunol. 2009;182:2816-2826. 
65. Talay O, Shen CH, Chen L, Chen J. B7-H1 (PD-L1) on T cells is required for T-cell-mediated 
conditioning of dendritic cell maturation. Proc Natl Acad Sci USA. 2009;106:2741-2746. 
66. Wang L, Pino-Lagos K, de Vries VC, Guleria I, Sayegh MH, Noelle RJ. Programmed death 
1 ligand signaling regulates the generation of adaptive Foxp3þCD4þ regulatory T cells. 
Proc Natl Acad Sci U S A. 2008;105:9331-9336. 
67. Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 
and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 
2005;65:1089-1096. 
68. Azuma T, Yao S, Zhu G, Flies AS, Flies SJ, Chen L. B7-H1 is a ubiquitous antiapoptotic 
receptor on cancer cells. Blood. 2008; 111:3635. 
69. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Ann Rev 
Immunol.2005;23:515. 
70. Okazaki T, Honjo T. The PD-1-PD-L pathway in immunological tolerance. Trends Immunol. 
2006;27:195-201. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
127 
NCI Version Date 24AUG2023 
71. Velu, V., K. Titanji, B. Zhu, S. Husain, A. Pladevega, L. Lai, T. H. Vanderford, L. 
Chennareddi, G. Silvestri, G. J. Freeman, et al. 2009. Enhancing SIV-specific immunity 
in vivo by PD-1 blockade. Nature 458: 206–210. 
72. Boasso, A., M. Vaccari, A. Hryniewicz, D. Fuchs, J. Nacsa, V. Cecchinato, J. Andersson, G. 
Franchini, G. M. Shearer, and C. Chougnet. 2007. Regulatory T-cell markers, indoleamine 
2,3-dioxygenase, and virus levels in spleen and gut during progressive simian 
immunodeficiency virus infection. J. Virol. 81: 11593–11603. 
73. Brahmer JR, Drake CG, Wollner I, 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 28:3167-3175, 2010 
74. Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-
PD-1 antibody in cancer. N Engl J Med 366:2443-2453, 2012. 
75. Sznol, M., H.M. Kluger, F.S. Hodi, et al. (2013). Survival and long-term follow-up of safety 
and response in patients (pts) with advanced melanoma (MEL) in a phase I trial of 
nivolumab (anti-PD-1; BMS-936558; ONO-4538). J Clin Oncol. 31:ACRA9006 
76. Drake, C.G., D.F. McDermott, M. Sznol, et al. (2013). Survival, safety, and response 
duration results of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in a phase I trial in 
patients with previously treated metastatic renal cell carcinoma (mRCC): Long-term 
patient follow-up. J Clin Oncol. 31:A4514. 
77. Rizvi, N.A., S.J. Antonia, L.Q.M. Chow, et al. (2013). A phase I study of nivolumab (anti-
PD-1; BMS-936558, ONO-4538) plus platinum-based doublet chemotherapy (PT-
doublet) in chemotherapy-naive non-small cell lung cancer (NSCLC) patients (pts). J Clin 
Oncol. 31:A8072. 
78. Topalian, S.L., F.S. Hodi, J.R. Brahmer, et al. (2012). Safety, activity, and immune correlates 
of anti-PD-1 antibody in cancer. N Engl J Med. 366:2443-2454. 
79. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade 
expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 
melanoma tumors. Proc Natl Acad Sci U S A 2010;107:4275-80. 
80. Wolchok JD, Kluger H, Callahan MK et al. Nivolumab plus ipilimumab in advanced 
melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33. doi: 10.1056/NEJMoa1302369. 
Epub 2013 Jun 2. 
81. Hammers HJ., Plimack ER, Infante JR., Ernstoff MS et al. Clin Oncol 32:5s, 2014 (suppl; 
abstr 4504) Phase I study of nivolumab in combination with ipilimumab in metastatic 
renal cell carcinoma (mRCC).  
82. Rizvi NA, Gettinger SN, Goldman MD, et al. Safety and Efficacy of First-Line Nivolumab 
(NIVO; Anti-Programmed Death-1 [PD-1]) and Ipilimumab in Non-Small Cell Lung 
Cancer (NSCLC). Presented at: 16th World Conference on Lung Cancer; September 6-9; 
Denver, CO. Abstract 786. 
83. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, et al. PD-1 expression 
on HIV-specific T cells is associated with T-cell exhaustion and disease progression. 
Nature (2006) 443(7109):350–410.1038/nature05115  

 
AMC #095 (Version 15.0) 24AUG2023 
 
128 
NCI Version Date 24AUG2023 
84. Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, Bessette B, et al. Upregulation 
of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. 
Nat Med (2006) 12(10):1198–20210.1038/nm1106-1329b [ 
85. Zhang JY, Zhang Z, Wang X, Fu JL, Yao J, Jiao Y, et al. PD-1 up-regulation is correlated 
with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-
term nonprogressors. Blood (2007) 109(11):4671–810.1182/blood-2006-09-044826  
86. D’Souza M, Fontenot AP, Mack DG, Lozupone C, Dillon S, Meditz A, et al. Programmed 
death 1 expression on HIV-specific CD4+ T cells is driven by viral replication and 
associated with T cell dysfunction. J Immunol (2007) 179(3):1979–87  
87. Kaufmann DE, Kavanagh DG, Pereyra F, Zaunders JJ, Mackey EW, Miura T, et al. 
Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease 
progression and defines a reversible immune dysfunction. Nat Immunol (2007) 
8(11):1246–5410.1038/ni1515  
88. Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, et al. Coregulation of 
CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. 
Nat Immunol (2009) 10(1):29–3710.1038/ni.1679  
89. Jones RB, Ndhlovu LC, Barbour JD, Sheth PM, Jha AR, Long BR, et al. Tim-3 expression 
defines a novel population of dysfunctional T cells with highly elevated frequencies in 
progressive HIV-1 infection. J Exp Med (2008) 205(12):2763–7910.1084/jem.20081398  
90. Jin HT, Anderson AC, Tan WG, West EE, Ha SJ, Araki K, et al. Cooperation of Tim-3 and 
PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc Natl Acad Sci U S A 
(2010) 107(33):14733–810.1073/pnas.1009731107  
91. Yamamoto T, Price DA, Casazza JP, Ferrari G, Nason M, Chattopadhyay PK, et al. Surface 
expression patterns of negative regulatory molecules identify determinants of virus-
specific CD8+ T-cell exhaustion in HIV infection. Blood (2011) 117(18):4805–
1510.1182/blood-2010-11-317297  
92. Nakamoto N, Cho H, Shaked A, Olthoff K, Valiga ME, Kaminski M, et al. Synergistic 
reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-
4 blockade. PLoS Pathog (2009) 5(2):e1000313.10.1371/journal.ppat.1000313  
93. Manches O, Munn D, Fallahi A, Lifson J, Chaperot L, Plumas J, et al. HIV-activated human 
plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase-dependent 
mechanism. J Clin Invest (2008) 118(10):3431–910.1172/JCI34823  
94. Moreno-Fernandez ME, Zapata W, Blackard JT, Franchini G, Chougnet CA. Human 
regulatory T cells are targets for human immunodeficiency virus (HIV) infection, and their 
susceptibility differs depending on the HIV type 1 strain. J Virol (2009) 83(24):12925–
3310.1128/JVI.01352-09 [PMC free article] [PubMed] [Cross Ref] 
95. Jiang Q, Zhang L, Wang R, Jeffrey J, Washburn ML, Brouwer D, et al. FoxP3+CD4+ 
regulatory T cells play an important role in acute HIV-1 infection in humanized Rag2-/-
gammaC-/- mice in vivo. Blood (2008) 112(7):2858–6810.1182/blood-2008-03-145946 

 
AMC #095 (Version 15.0) 24AUG2023 
 
129 
NCI Version Date 24AUG2023 
96. Nilsson J, Boasso A, Velilla PA, Zhang R, Vaccari M, Franchini G, et al. HIV-1-driven 
regulatory T-cell accumulation in lymphoid tissues is associated with disease progression 
in HIV/AIDS. Blood (2006) 108(12):3808–1710.1182/blood-2006-05-021576  
97. Kinter AL, Hennessey M, Bell A, Kern S, Lin Y, Daucher M, et al. CD25(+)CD4(+) 
regulatory T cells from the peripheral blood of asymptomatic HIV-infected individuals 
regulate CD4(+) and CD8(+) HIV-specific T cell immune responses in vitro and are 
associated with favorable clinical markers of disease status. J Exp Med (2004) 
200(3):331–4310.1084/jem.20032069  
98. Weiss L, Donkova-Petrini V, Caccavelli L, Balbo M, Carbonneil C, Levy Y. Human 
immunodeficiency virus-driven expansion of CD4+CD25+ regulatory T cells, which 
suppress HIV-specific CD4 T-cell responses in HIV- infected patients. Blood (2004) 
104(10):3249–5610.1182/blood-2004-01-0365 
99. Porichis F, Hart MG, Zupkosky J, Barblu L, Kwon DS, McMullen A, Brennan T, Ahmed R, 
Freeman GJ, Kavanagh DG, Kaufmann DE: Differential impact of PD-1 and/or IL-10 
blockade on HIV-1- specific CD4 T cell and antigen-presenting cell functions. J Virol 
2013, 88:2508-18. 
100. Trautmann L, Janbazian L, Chomont N, et al. Upregulation of PD-1 expression on HIV-
specific CD8 + T cells leads to reversible immune dysfunction. Nat Med Oct; 2006 
12(10):1198–1202. [PubMed:16917489] 
101. Hryniewicz A, Boasso A, Edghill-Smith Y, Vaccari M, Fuchs D, Venzon D, Nacsa J, Betts 
MR, Tsai WP, Heraud JM, Beer B, Blanset D, Chougnet C, Lowy I, Shearer GM, 
Franchini G: CTLA-4 blockade decreases TGF-beta, IDO, and viral RNA expression in 
tissues of SIVmac251-infected macaques. Blood 2006, 108: 3834-42. 
102. Velu V, Titanji K, Zhu B, et al. Enhancing SIV-specific immunity in vivo by PD-1 blockade. 
Nature Mar 12;2009 458(7235):206–210. [PubMed: 19078956] 
103. Berger R, Roten-Yehudar R, Slama G, et al. Phase I safety and pharmacokinetic study of 
CT-011, a humanized antibody interacting with PD-1, in patients with advanced 
hematologic malignancies. Clin Cancer Res May;2008 14(10):3044–3051. [PubMed: 
18483370] 
104. Franceschini D, Paroli M, Francavilla V, et al. PD-L1 negatively regulates 
CD4+CD25+Foxp3+ Tregs by limiting STAT-5 phosphorylation in patients chronically 
infected with HCV. J Clin Invest Mar; 2009 119(3):551–564. [PubMed: 19229109] 
105. Okazaki T, Honjo T. The PD-1-PD-L pathway in immunological tolerance. Trends Immunol. 
2006;27:195-201. 
106. Hryniewicz, A., A. Boasso, Y. Edghill-Smith, M. Vaccari, D. Fuchs, D. Venzon, J. Nacsa, 
M. R. Betts, W. P. Tsai, J. M. Heraud, et al. 2006. CTLA-4 blockade decreases TGF-_, 
indoleamine 2,3- dioxygenase, and viral RNA expression in tissues of SIVmac251-
infected macaques. Blood 108: 3834–3842. 
107. Cecchinato, V., E. Tryniszewska, Z. M. Ma, M. Vaccari, A. Boasso, W. P. Tsai, C. Petrovas, 
D. Fuchs, J. M. Heraud, D. Venzon, et al. 2008. Immune activation driven by CTLA-4 
blockade augments viral replication at mucosal sites in simian immunodeficiency virus 
infection. J. Immunol. 180: 5439–5447. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
130 
NCI Version Date 24AUG2023 
108. Vaccari M, Boasso A, Fenizia C, Fuchs D, Hryniewicz A, Morgan T, Weiss D, Doster MN, 
Heraud JM, Shearer GM, Franchini G. Fatal pancreatitis in simian immunodeficiency 
virus SIV(mac251)-infected macaques treated with 2',3'-dideoxyinosine and stavudine 
following cytotoxic-T-lymphocyte-associated antigen 4 and indoleamine 2,3-dioxygenase 
blockade. J Virol. 2012 Jan;86(1):108-13. doi: 10.1128/JVI.05609-11. Epub 2011 Oct 19. 
PubMed PMID:22013040; PubMed Central PMCID: PMC3255892. 
109. Gardiner D, Lalezari J, Lawitz E, DiMicco M, Ghalib R, Reddy KR, Chang KM, Sulkowski 
M, Marro SO, Anderson J, He B, Kansra V, McPhee F, Wind-Rotolo M, Grasela D, Selby 
M, Korman AJ, Lowy I. A randomized, double-blind, placebo-controlled assessment of 
BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD-1), in 
patients with chronic hepatitis C virus infection. PLoS One. 2013 May 22;8(5):e63818. 
doi: 10.1371/journal.pone.0063818. Print 2013. PubMed PMID: 23717490; PubMed 
Central PMCID: PMC3661719. 
110. Burke MM, Kluger HM, Golden M, Heller KN, Hoos A, Sznol M. Case Report: Response 
to Ipilimumab in a Patient With HIV With Metastatic Melanoma J Clin Oncol. 2011 Nov 
10;29(32):e792-4. doi: 10.1200/JCO.2011.36.9199. Epub 2011 Oct 11 
111. Zang X, et al. (Tumor associated endothelial expression of B7-H3 predicts survival in 
ovarian carcinomas. (Translated from eng) Mod Pathol 23(8):1104-1112 (in eng). 
112. Zang X, et al. (2007) B7-H3 and B7x are highly expressed in human prostate cancer and 
associated with disease spread and poor outcome. Proc Natl Acad Sci U S A 
104(49):19458-19463. 
113. Wei L, et al. (Identification and testing of reference genes for Sesame gene expression 
analysis by quantitative real-time PCR. Planta 237(3):873-889. 
114. Zhao R & al. e (2013) HHLA2 is a member of the B7 family and inhibits human CD4 and 
CD8 T cell function. Proc Natl Acad Sci U S A 2013 Jun 11;110(24):9879-84 
115. Loi S, et al. (Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III 
randomized adjuvant breast cancer trial in node-positive breast cancer comparing the 
addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. 
J Clin Oncol 31(7):860-867 
116. Eggena MP, Barugahare B, Jones N, Okello M, Mutalya S, Kityo C, Mugyenyi P, Cao H. 
Depletion of regulatory T cells in HIV infection is associated with immune activation. 
Journal of immunology. 2005;174(7):4407-14. PubMed PMID: 15778406. 
117. Ndhlovu LC, Loo CP, Spotts G, Nixon DF, Hecht FM. FOXP3 expressing CD127lo CD4+ 
T cells inversely correlate with CD38+ CD8+ T cell activation levels in primary HIV-1 
infection. Journal of leukocyte biology. 2008;83(2):254-62. doi: 10.1189/jlb.0507281. 
PubMed PMID: 17982112. 
118. Kinter A, McNally J, Riggin L, Jackson R, Roby G, Fauci AS. Suppression of HIV-specific 
T cell activity by lymph node CD25+ regulatory T cells from HIV-infected individuals. 
Proceedings of the National Academy of Sciences of the United States of America. 
2007;104(9):3390-5. doi: 10.1073/pnas.0611423104. PubMed PMID: 17360656 PMCID: 
PMC1805624. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
131 
NCI Version Date 24AUG2023 
119. Angin M, King M, Altfeld M, Walker BD, Wucherpfennig KW, Addo MM. Identification 
of HIV-1-specific regulatory T-cells using HLA class II tetramers. Aids. 
2012;26(16):2112-5. doi: 10.1097/QAD.0b013e328358cc75. PubMed PMID: 22874519 
PMCID: PMC3825094. 
120. Macatangay BJ, Szajnik ME, Whiteside TL, Riddler SA, Rinaldo CR. Regulatory T cell 
suppression of Gag-specific CD8 T cell polyfunctional response after therapeutic 
vaccination of HIV-1-infected patients on ART. PloS one. 2010;5(3):e9852. doi: 
10.1371/journal.pone.0009852. PubMed PMID: 20352042 PMCID: PMC2844424. 
121. Chen X, Fosco D, Kline DE, Meng L, Nishi S, Savage PA, Kline J. PD-1 regulates 
extrathymic regulatory T-cell differentiation. European journal of immunology. 2014. doi: 
10.1002/eji.201344423. PubMed PMID: 2497512. 
122. Radziewicz H, Dunham RM, Grakoui A. PD-1 tempers Tregs in chronic HCV infection. The 
Journal of clinical investigation. 2009;119(3):450-3. PubMed PMID: 19306502 PMCID: 
PMC2648682. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
134 
NCI Version Date 24AUG2023 
b. All study procedures including, blood samples collected for pretreatment laboratory tests may be collected and analyzed no more 
than 2 days prior to dosing. Chemistry results must be reviewed and confirm that participant’s LFTs and other safety labs still meet 
inclusion criteria prior to administration of nivolumab dose. Baseline pregnancy exam must be performed within 72 hours of 
beginning nivolumab dosing and determined to be negative. They should be seen and evaluated more often if clinically indicated for 
the management of toxicities, at the discretion of the treating physician investigator. Hormonal studies and immunologic labs are 
required for monitoring at the specified time points and as clinically indicated. The results of these tests (hormonal studies and 
immunologic labs) are not required for dosing unless there are clinical indications and/or associated AEs as described under Section 
5.0 and Appendix X, Dose and Schedule Modifications for ipilimumab and nivolumab. 
c. During C1-4 on days when a participant will receive a nivolumab and an ipilimumab infusion, vital signs will be obtained before 
the nivolumab infusion and every 15 minutes until 60 minutes post-completion of the ipilimumab infusion. On days when a 
participant will only receive a nivolumab infusion, vital signs will be obtained before the BMS nivolumab infusion, every 15 minutes 
during the infusion, and at 15, 30, 45, and 60 minutes post-infusion. When slowing or restarting an infusion due to an infusion 
reaction, vital signs should be monitored every 15 minutes or as directed by the Investigator until the infusion is completed and/or 
the participant is stabilized. If a participant has an infusion reaction with nivolumab, the ipilimumab infusion can be given (without 
prophylactic medications) if the infusion reaction resolves within 3 hours. For scheduling purposes after a nivolumab infusion 
reaction, the ipilimumab infusion may be given the next day. Prophylactic preinfusion medications should be given prior to all 
subsequent nivolumab. For subsequent infusions, vital signs should be collected prior to dosing. For subsequent infusions, vital signs 
should be collected prior to dosing, every 30 minutes (-/+ 10 minutes) during dosing, and 1 hour post-dosing. For cycles 5 and 
beyond, for participants receiving nivolumab alone, who have never had a documented infusion reaction, pre and post-dosing vital 
signs may be obtained. 
d. Hematology labs to include hemoglobin, hematocrit, red blood cell count, white blood cell count, platelets (direct platelet count), as 
well as total and differential CBC counts. These labs must be done and reviewed before ipilimumab and nivolumab infusion. These 
labs are required to be done throughout follow-up regardless if the participant goes off treatment early for anything other than 
recurrence. Once recurrence occurs, these labs are no longer required to be completed. 
e. Serum chemistry laboratory analysis includes albumin, urea or BUN, creatinine, ALT, AST, LDH, serum alkaline phosphatase, 
direct and total bilirubin, glucose, total protein, sodium, potassium, chloride, HCO3 (CO2; venous blood), calcium, phosphorous. 
These labs must be done 2 weeks before enrollment for eligibility purposes, and within 48 hours before drug infusion (See 8.2). 
These labs are required to be done throughout follow-up regardless if the participant goes off treatment early for anything other than 
recurrence. Once recurrence occurs, these labs are no longer required to be completed. WOCBP must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 4 weeks prior to registration. Serum or urine 
pregnancy test must be done within 72 hours prior to Day 1 of cycles 1-5 and then every 12 weeks thereafter. 
f. At screening, testing should be performed for HIV antibody (refer to eligibility criteria 3.1.2), hepatitis C antibody, and Hepatitis B 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
135 
NCI Version Date 24AUG2023 
antigen utilizing local standard informed consent procedures prior to this laboratory collection. Viral load for HIV and if positive 
for Hepatitis C/Hepatitis B should repeated prior to cycle 5 and every 12 weeks thereafter till participant off study. Refer to eligibility 
criteria at 3.1.12 and 3.1.13. 
g. The following immunologic labs are to be done at baseline (within 4 weeks of starting the study drug) prior to cycle 5 and then every 
12 weeks: rheumatoid factor, C-reactive protein and ANA, SPEP, quantitative immunoglobulins and FLC. These labs must be 
repeated prior to cycle 5 and then every 12 weeks after that until the participant goes off study. 
h. Endocrine labs: To be done at the indicated visits. These include TSH, free T4, TPO, morning ACTH, morning cortisol if ACTH is 
abnormal. 
i. All AEs must be collected whether they occur on treatment or non-treatment weeks and must be submitted utilizing the corresponding 
AE Forms, covering all time periods specified on the forms. AE assessment must include assessment of immune-mediated AEs. 
j. Scans will be performed at baseline, before cycle 5, and thereafter every 12 weeks. It is critical that all imaging studies or CT scans 
be performed in an identical way to the baseline scan with the same scanner, same scan direction, and consistent arm pointing. 
Confirmatory scans should also be obtained 4 weeks following initial documentation of objective response. If tumor flare is 
suspected, the participant must undergo a second scan within a month of the first scan and the case must be discussed with the 
principal investigator. If progression is documented at that time, participant must come off study. If a participant has a history of 
brain metastasis, a brain MRI at baseline is required. Participants with KS will be evaluated for response before odd numbered cycles 
(5, 7, 9, etc.). Scans will not be required for participants with KS unless clinically indicated. 
For participants with relapsed refractory HIV-cHL, F-FDG-PET /CT scans will be done at baseline, and weeks 17 and 25. At week 
49, an F-FDG-PET/CT scan is required for patients who did not have two consecutive negative scans before this time point. If F-
FDG-PET/CT scans are done without contrast, a full scan with and without contrast will be required unless there is an allergy to IV 
contrast. CT with and without contrast will follow the same schedule as stated above. For patients with bone marrow involvement 
at screening, a bone marrow biopsy was required to confirm complete remission. 
k. Participants with ongoing toxicities should be seen more often as clinically indicated. AEs Assessment on the study will continue 
for all participants until 90 days after the last study drug administration. End of Study Assessment will be done within 6 weeks (±1 
week) and at 16 weeks (± 1 week) of the last dose of study treatment. 
l. For participants with KS, tumor assessments with photographic record must be performed within 7 days prior to initiating treatment. 
Tumor assessments and photographs should be performed as outlined in the AMC Kaposi’s Sarcoma (KS) Tumor Assessment MOP. 
KS tumor assessment will occur every 4 weeks during study participation. 
m. For participants with classical HL who had bone marrow involvement at baseline only. 
 
 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
136 
NCI Version Date 24AUG2023 
Biological Sample Submissions for Correlative Studies 
Specimens are to be submitted as outlined in Section 8. All samples will be submitted to the AMC Biorepository unless noted otherwise. 
All blood tubes are to be filled completely. 
 
Visit 
-1 
C1 
Pre D1 
Post D1 
D8 
C4 
Pre D1 
Post D1 
D8 
Pre C5 
D1 
C7 and 
Pre D1 
Post D1 
D8 
C10 
Pre D1 
Post D1 
D8 
C13 
Pre D1 
Post D1 
D8 
C16 
D1 
C19, C25, 
C31, C37, 
and C43 
Pre D1 
Post D1 
D8 
C22, C28, 
C34, C40, 
and C46 
Pre D1 
Post D1 
D8 
After 
Completion 
of Therapy/ 
Off Study9 
MANDATORY 
Two 6 mL red top tubes 
X 
 
 
X 
 
 
 
 
 
 
X 
Twelve 8.5 mL ACD tubes1,3 
OR two 8.5 mL ACD tubes1 
Ship to AMC Biorepository 
X 
 
 
 
 
 
 
X 
 
 
X 
Five 8.5 mL ACD tubes2, 3, 7 
Ship to AMC Biorepository 
 
X 
X10 
 
X 
X10 
X 
 
X 
X10 
 
Four 4 micron thick unstained slides 
from initial biopsy6,8 
X 
 
 
 
 
 
 
 
 
 
 
ADDITIONAL BIOPSIES DEPENDING ON TUMOR TYPE 
Submit from participants who answer “Yes” to “I agree to participate in the laboratory research studies that are being done as part of this clinical trial.” 
Tumor Tissue Biopsy if participants 
have KS4 
OR 
Anal swab for participants with anal 
cancer5 
X 
 
 
X 
 
 
 
 
 
 
X 
1. If consenting to participate in the HIV latent reservoirs study and hematocrit ≥ 25. To be shipped unprocessed. If a participant 
has not consented to the HIV latent reservoir testing blood draw, two 8.5 yellow top tubes will be collected for herpesvirus load 
and latent virus studies (Appendix XIV and Appendix XVI). 
2. To be processed on site for viable PBMC and plasma within 6 hours of collection. If processing cannot be completed on site, 
specimens should be shipped via priority overnight service. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
137 
NCI Version Date 24AUG2023 
3. Only to be completed for participants with hematocrit ≥ 25. 
4. Two 2x2 mm biopsies in RNALater and formalin as described in Appendix XIV. The AMC Genomics Core Laboratory will 
provide kits for 2x2 punch biopsy collection and shipping samples. 
5. Anal swabs as described in Appendix XVII. 
6. Representative tumor tissue from the initial diagnostic biopsies or repeat diagnostic biopsy prior to initiating treatment and 
related pathology reports are to be submitted within one (1) month following registration or collection as outlined in Appendix 
XIV. 
7. Collect within 2 days prior to day 1 of each cycle for pre-dose samples, and on day 1 for post-dose samples. The pre-dose sample 
and the Day 1 Cycle 1 sample must be drawn on different calendar days, and should be collected at least 12 hours apart. All 
samples on day 8 of a given cycle may be collected up to 3 days prior to day 8. 
8. A minimum of four unstained sections (or three unstained sections plus one H&E), adhered to positively charged slides, and cut 
at a thickness of four microns are preferred for testing. Slides should be stored refrigerated if possible. 
9. Samples are to be collected within 6 weeks (± 1 week) of the last dose of study treatment only. 
10. For dose levels 1 (including 240 mg q 2 weeks) and 2 only. 
 
 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
139 
NCI Version Date 24AUG2023 
Therapeutic Parameters 
1. Prestudy PPD testing (only if known to be negative) is only required within the last 12 weeks before enrollment. The Quantiferon 
assay is an acceptable alternative to PPD testing. If PPD positive, prophylaxis must be complete before enrollment. 
2. Prestudy scans and x-rays used to assess all measurable or non-measurable sites of disease must be done ≤ 4 weeks prior to 
registration. 
3. Prestudy CBC (with differential and platelet count) should be done ≤ 2 weeks prior to registration. 
4. All required prestudy chemistries, as outlined in Section 8.1.5, should be done ≤ 2 weeks prior to registration – unless specifically 
required within 48 hours before starting treatment as per protocol. 
5. Baseline Hepatitis B and C testing and viral load studies (HIV, if indicated Hepatitis B and C studies) should be done ≤ 2 weeks 
prior to registration. 
6. See Table below regarding biologic sample submissions. 
7. EKG. EKG and echocardiogram (ECHO) for any patients with a history of CHF or at risk because of underlying cardiovascular 
disease or exposure to cardiotoxic drugs as clinically indicated. For patients with evidence of CHF, MI, cardiomyopathy, or myositis 
cardiac evaluation including lab tests and cardiology consultations as clinically indicated including EKG, CPK, troponin, 
echocardiogram. 
In the event that the participant’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation 
of the next cycle of therapy. 
a. CBCs (with differential and platelet count) which includes WBC, ANC, platelets, Hgb, and Hct required for protocol therapy must 
be done within 2 weeks of enrollment for eligibility, and < 48 hours prior to the treatment cycle. See 8.2 for instructions on 
performing these evaluations once prior to eligibility and treatment. 
b. All study procedures including, blood samples collected for pretreatment laboratory tests may be collected and analyzed no more 
than 2 days prior to dosing. Chemistry results must be reviewed and confirm that participant’s LFTs and other safety labs still meet 
inclusion criteria prior to administration of nivolumab dose. Baseline pregnancy exam must be performed within 72 hours of 
beginning nivolumab dosing and determined to be negative. They should be seen and evaluated more often if clinically indicated for 
the management of toxicities, at the discretion of the treating physician investigator. Hormonal studies and immunologic labs are 
required for monitoring at the specified time points and as clinically indicated. The results of these tests (hormonal studies and 
immunologic labs) are not required for dosing unless there are clinical indications and/or associated AEs as described under Section 
5.0 and Appendix X, Dose and Schedule Modifications for ipilimumab and nivolumab. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
140 
NCI Version Date 24AUG2023 
c. During C1-4 on days when a participant will receive a nivolumab and an ipilimumab infusion, vital signs will be obtained before 
the nivolumab infusion and every 15 minutes until 60 minutes post-completion of the ipilimumab infusion. On days when a 
participant will only receive a nivolumab infusion, vital signs will be obtained before the BMS nivolumab infusion, every 15 minutes 
during the infusion, and at 15, 30, 45, and 60 minutes post-infusion. When slowing or restarting an infusion due to an infusion 
reaction, vital signs should be monitored every 15 minutes or as directed by the Investigator until the infusion is completed and/or 
the participant is stabilized. If a participant has an infusion reaction with nivolumab, the ipilimumab infusion can be given (without 
prophylactic medications) if the infusion reaction resolves within 3 hours. For scheduling purposes after a nivolumab infusion 
reaction, the ipilimumab infusion may be given the next day. Prophylactic preinfusion medications should be given prior to all 
subsequent nivolumab. For subsequent infusions, vital signs should be collected prior to dosing. For subsequent infusions, vital signs 
should be collected prior to dosing, every 30 minutes (-/+ 10 minutes) during dosing, and 1 hour post-dosing. For cycles 5 and 
beyond, for participants receiving nivolumab alone, who have never had a documented infusion reaction, pre and post-dosing vital 
signs may be obtained. 
d. Hematology labs to include hemoglobin, hematocrit, red blood cell count, white blood cell count, platelets (direct platelet count), as 
well as total and differential CBC counts. These labs must be done and reviewed before ipilimumab and nivolumab infusion. These 
labs are required to be done throughout follow-up regardless if the participant goes off treatment early for anything other than 
recurrence. Once recurrence occurs, these labs are no longer required to be completed. 
e. Serum chemistry laboratory analysis includes albumin, urea or BUN, creatinine, ALT, AST, LDH, serum alkaline phosphatase, 
direct and total bilirubin, glucose, total protein, sodium, potassium, chloride, HCO3 (CO2; venous blood), calcium, phosphorous. 
These labs must be done 2 weeks before enrollment for eligibility purposes, and within 48 hours before drug infusion (See 8.2). 
These labs are required to be done throughout follow-up regardless if the participant goes off treatment early for anything other than 
recurrence. Once recurrence occurs, these labs are no longer required to be completed. WOCBP must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 4 weeks prior to registration. Serum or urine 
pregnancy test must be done within 72 hours prior to Day 1 of cycles 1-5 and then every 12 weeks thereafter. 
f. At screening, testing should be performed for HIV antibody (refer to eligibility criteria 3.1.2), hepatitis C antibody, and Hepatitis B 
antigen utilizing local standard informed consent procedures prior to this laboratory collection. Viral load for HIV and if positive 
for Hepatitis C/Hepatitis B should repeated prior to cycle 5 and every 12 weeks thereafter till participant off study. Refer to eligibility 
criteria at 3.1.12 and 3.1.13. 
g. The following immunologic labs are to be done at baseline (within 4 weeks of starting the study drug) prior to cycle 5 and then every 
12 weeks: rheumatoid factor, C-reactive protein and ANA, SPEP, quantitative immunoglobulins and FLC. These labs must be 
repeated prior to cycle 5 and then every 12 weeks after that until the participant goes off study. 
h. Endocrine labs: To be done at the indicated visits. These include TSH, free T4, TPO, morning ACTH, morning cortisol if ACTH is 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
141 
NCI Version Date 24AUG2023 
abnormal. 
i. All AEs must be collected whether they occur on treatment or non-treatment weeks and must be submitted utilizing the corresponding 
AE Forms, covering all time periods specified on the forms. AE assessment must include assessment of immune-mediated AEs. 
j. Scans will be performed at baseline, before cycle 5, and thereafter every 12 weeks. It is critical that all imaging studies or CT scans 
be performed in an identical way to the baseline scan with the same scanner, same scan direction, and consistent arm pointing. 
Confirmatory scans should also be obtained 4 weeks following initial documentation of objective response. If tumor flare is 
suspected, the participant must undergo a second scan within a month of the first scan and the case must be discussed with the 
principal investigator. If progression is documented at that time, participant must come off study. If a participant has a history of 
brain metastasis, a brain MRI at baseline is required. Participants with KS will be evaluated for response before odd numbered cycles 
(5, 7, 9, etc.). Scans will not be required for participants with KS unless clinically indicated. 
For participants with relapsed refractory HIV-cHL, F-FDG-PET /CT scans will be done at baseline, and weeks 17 and 25. At week 
49, an F-FDG-PET/CT scan is required for patients who did not have two consecutive negative scans before this time point. If F-
FDG-PET/CT scans are done without contrast, a full scan with and without contrast will be required unless there is an allergy to IV 
contrast. CT with and without contrast will follow the same schedule as stated above. For patients with bone marrow involvement 
at screening, a bone marrow biopsy was required to confirm complete remission. 
k. Participants with ongoing toxicities should be seen more often as clinically indicated. AEs Assessment on the study will continue 
for all participants until 90 days after the last study drug administration. End of Study Assessment will be done within 6 weeks (±1 
week) and at 16 weeks (± 1 week) of the last dose of study treatment. 
l. For participants with KS, tumor assessments with photographic record must be performed within 7 days prior to initiating treatment. 
Tumor assessments and photographs should be performed as outlined in the AMC Kaposi’s Sarcoma (KS) Tumor Assessment MOP. 
KS tumor assessment will occur every 4 weeks during study participation. 
 
 
 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
142 
NCI Version Date 24AUG2023 
Biological Sample Submissions for Correlative Studies for participants on combination therapy solid tumor expansion cohort 
Specimens are to be submitted as outlined in Section 8. All samples will be submitted to the AMC Biorepository unless noted otherwise. 
All blood tubes are to be filled completely. 
 
Visit -1 
C1 
Pre D1 
Post D1 
D8 
C4 
Pre D1 
Post D1 
D8 
Pre C5 
D1 
C7 and 
Pre D1 
Post D1 
D8 
C10 
Pre D1 
Post D1 
D8 
C15 D1 
After Completion of 
Therapy/ Off Study9 
MANDATORY 
Two 6 mL red top tubes 
X 
 
 
X 
 
 
 
X 
Twelve 8.5 mL ACD tubes1,3 
OR two 8.5 mL ACD tubes1 
Ship to AMC Biorepository 
X 
 
 
 
 
 
X 
X 
Five 8.5 mL ACD tubes2, 3, 7 
Ship to AMC Biorepository 
 
X 
X 
 
X 
X 
 
 
Four 4 micron thick unstained slides 
from initial biopsy6,8 
X 
 
 
 
 
 
 
 
ADDITIONAL BIOPSIES DEPENDING ON TUMOR TYPE 
Submit from participants who answer “Yes” to “I agree to participate in the laboratory research studies that are being done as part of this clinical trial.” 
Tumor Tissue Biopsy if participants 
have KS4 
OR 
Anal swab for participants with anal 
cancer5 
X 
 
 
X 
 
 
 
X 
 
1. If consenting to participate in the HIV latent reservoirs study and hematocrit ≥ 25. To be shipped unprocessed. If a participant 
has not consented to the HIV latent reservoir testing blood draw, two 8.5 yellow top tubes will be collected for herpesvirus load 
and latent virus studies (Appendix XIV and Appendix XVI). 
2. To be processed on site for viable PBMC and plasma within 6 hours of collection. If processing cannot be completed on site, 
specimens should be shipped via priority overnight service. 
3. Only to be completed for participants with hematocrit ≥ 25. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
143 
NCI Version Date 24AUG2023 
4. Two 2x2 mm biopsies in RNALater and formalin as described in Appendix XIV. The AMC Genomics Core Laboratory will 
provide kits for 2x2 punch biopsy collection and shipping samples. 
5. Anal swabs as described in Appendix XVII. 
6. Representative tumor tissue from the initial diagnostic biopsies or repeat diagnostic biopsy prior to initiating treatment and 
related pathology reports are to be submitted within one (1) month following registration or collection as outlined in Appendix 
XIV. 
7. Collect within 2 days prior to day 1 of each cycle for pre-dose samples, and on day 1 for post-dose samples. The pre-dose sample 
and the Day 1 Cycle 1 sample must be drawn on different calendar days, and should be collected at least 12 hours apart. All 
samples on day 8 of a given cycle may be collected up to 3 days prior to day 8. 
8. A minimum of four unstained sections (or three unstained sections plus one H&E), adhered to positively charged slides, and cut 
at a thickness of four microns are preferred for testing. Slides should be stored refrigerated if possible. 
9. Samples are to be collected within 6 weeks (± 1 week) of the last dose of study treatment only. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
144 
NCI Version Date 24AUG2023 
APPENDIX II: COLLABORATIVE RESEARCH AGREEMENT 
The agents, ipilimumab and nivolumab (hereinafter referred to as “Agent(s)”), supplied by 
CTEP, DCTD, NCI used in this protocol is provided to the NCI under a Collaborative 
Agreement (CRADA, CTA, CSA) between BMS (hereinafter referred to as Collaborator(s)) 
and the NCI Division of Cancer Treatment and Diagnosis. Therefore, the following 
obligations/guidelines, in addition to the provisions in the Intellectual Property  
Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within 
the terms of award, apply to the use of the Agent(s) in this study: 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) 
be transferred or licensed to any party not participating in the clinical study. Collaborator(s) 
data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as 
such by the investigators. The protocol documents for studies utilizing investigational Agents 
contain confidential information and should not be shared or distributed without the permission 
of the NCI. If a copy of this protocol is requested by a participant or participant’s family member 
participating on the study, the individual should sign a confidentiality agreement. A suitable 
model agreement can be downloaded from: http://ctep.cancer.gov. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the participant of different collaborative agreements, 
the access to and use of data by each Collaborator shall be as follows (data pertaining to such 
combination use shall hereinafter be referred to as "Multi-Party Data.): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, the design of the proposed 
combination protocol, and the existence of any obligations that would tend to restrict NCI's 
participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator to 
develop, obtain regulatory approval or commercialize its own investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree 
in writing prior to the commencement of the trials that it will use the Multi-Party Data solely 
for development, regulatory approval, and commercialization of its own investigational 
Agent. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will 
be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate and 
unless additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
145 
NCI Version Date 24AUG2023 
• When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-Cooperative 
Group studies for immediate delivery to Collaborator(s) for advisory review and comment prior 
to submission for publication. Collaborator(s) will have 30 days from the date of receipt for 
review. Collaborator shall have the right to request that publication be delayed for up to an 
additional 30 days in order to ensure that Collaborator’s confidential and proprietary data, in 
addition to Collaborator(s)’s intellectual property rights, are protected. Copies of abstracts must 
be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible 
and preferably at least three (3) days prior to submission, but in any case, prior to presentation 
at the meeting or publication in the proceedings. Press releases and other media presentations 
must also be forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or 
press release/ media presentation should be sent to: 
Email: ncicteppubs@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
147 
NCI Version Date 24AUG2023 
APPENDIX IV: AIDS AND CANCER SPECIMEN RESOURCE (ACSR) SPECIMEN 
PREPARATION AND SHIPPING INSTRUCTIONS 
A. 
GENERAL 
To ship blood specimens, use a diagnostic shipper approved for a volume of at least 30 
cc. The use of the SAF-T-PAK STP 210 diagnostic cardboard shipper is recommended. 
These shippers may be ordered at the SAF-T-PAK website: www.saftpak.com. The 
following instructions below are for use with the recommended STP-210 shipper. If 
using another federally approved diagnostic shipper, please follow instructions provided 
for that specific shipper. 
 
NOTE: Specimens MUST BE SHIPPED Mondays through Thursday as an 
OVERNIGHT PRIORITY shipment. Specimens are NOT ACCEPTED ON 
SATURDAYS OR SUNDAYS in the ACSR. 
 
B. 
SPECIMEN PREPARATION, PACKAGING, AND SHIPMENT 
Blood Specimens 
Draw two 8.5 mL yellow top [acid citrate dextrose (ACD)] tubes from study participant. 
With a black, water resistant, sharpie pen, label each specimen with the following 
information: 
• AMC Protocol # 095 
• AMC Participant ID# 
• Date and time of collection 
• Specimen type, i.e., WB=Whole Blood, P=Plasma, S=Serum, or Tissue 
• Specimen purpose: Donation 
Specimen Shipment 
• Seal the tops of the two 10 ml yellow tops with parafilm. 
• Place the two sealed tubes into bubble wrap (provided in STP-210 kit). 
• Tape around the bubble wrap so that the roll stays together and the tubes cannot fall 
out or break. 
• Place absorbent material sheet around the bubble wrapped tubes and slip into a 
biohazard poly-bag and “self-seal.” 
• Place poly-bag containing tubes into the white TYVEK bag and seal. 
• Place the TYVEK bag into the STP-210 diagnostic cardboard shipper. Seal the 
cardboard shipper with clear packing/shipping tape. 
• Affix the FED-EX airbill on blank side of the shipper making sure that it is marked 
“FED-EX PRIORITY OVERNIGHT.” 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
148 
NCI Version Date 24AUG2023 
• Mark “OTHER” in the airbill under “Packaging.” Please refer to the MOP and the 
AMC Operations website’s (www.AIDSCancer.org) Shipping tab for more 
information and the FedEx account details.Under airbill section “Special Handling” 
indicate “YES-SHIPPERS DECLARATION NOT REQUIRED.” 
• Place “From/To” information onto areas provided on the shipper. 
Blood specimens should be shipped by overnight express at room temperature to: 
Jeff Bethony, PhD 
AMC Biorepository 
George Washington Medical Center 
Ross Hall, Room 118 
2300 I Street, NW 
Washington, DC 20037 
Tel: (202) 994-2945 
Fax: (202) 994-5056 
Email: amc-bio@emmes.com 
• Make certain that shipper is already either pre-labeled with ‘UN#3373’ stamp, or 
make a paper label with ‘UN#3373” and affix it to the shipper. 
• Make certain that the net volume of the specimen being shipped is written in the 
space provided on the shipper or make a separate label with the volume in ml and 
affix to the shipper. 
• Affix airbill to shipper so that the ‘UN’ and ‘VOLUME’ labels are visible. 
• RETAIN THE TOP COPY OF THE AIRWAY BILL FOR YOUR RECORDS. 
• Place the box in the FedEx pickup area at your site or call to request a package 
pickup. 
Please Note: The shippers will be mailed back to each AMC site. 
INSTRUCTIONS FOR BLOOD SPECIMENS COLLECTED ON FRIDAY OR 
SATURDAY 
Preparation of Plasma and Mononuclear Cells 
Refer to the ACSR’s SOP on Separation of Plasma and Mononuclear Cells on the AMC 
Operations web site for instructions on preparing plasma and PBMC aliquots. It is 
preferable that separation occurs as soon as possible. If necessary, whole blood in ACD 
(yellow top tubes) can be held at room temperature for no more than 24 hours. 
Freeze the cell suspension in 0.5 ml aliquots in sterile NUNC vials by placing the NUNC 
tubes in a room temperature, alcohol saturated, control rate freezer container and store 
in the -80°C freezer overnight. Transfer the cell suspension into the liquid nitrogen 
temperature freezer for long term storage the next working day. 
***PLEASE DOUBLE CHECK PACKAGING OF SHIPPER AND DO NOT 
DEVIATE FROM REQUESTED LABELING. Shipping frozen aliquots 
requires the use of packaging acceptable for dry ice and Class 9 label with 
weight of dry ice written on package. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
149 
NCI Version Date 24AUG2023 
PREPARATION OF TISSUE SAMPLES 
Tissue specimens to be fresh frozen should be placed in OCT and then on dry ice 
immediately. The specimens may stay on dry ice until being transferred to a -80ºC 
freezer. 
Tissue specimens for donation may be batched for shipping after storage in -80ºC 
freezer. *NOTE: Specimens can only be accepted Monday through Friday. Therefore, 
specimens can only be shipped Sunday-Thursday for delivery the next day. Shipping 
frozen tissue requires the use of packaging acceptable for dry ice and Class 9 label with 
weight of dry ice written on package. 
TISSUE specimens should be shipped by overnight express to: 
Jeff Bethony, PhD 
AMC Biorepository 
George Washington Medical Center 
Ross Hall, Room 118 
2300 I Street, NW 
Washington, DC 20037 
Tel: (202) 994-2945 
Fax: (202) 994-5056 
Email: amc-bio@emmes.com 
C. 
RECORD OF SPECIMENS 
This study will track specimens via GlobalTraceSM, a component of the AMC 
AdvantageEDCSM system. The GlobalTraceSM shipment manifest must accompany all 
specimen shipments. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
150 
NCI Version Date 24AUG2023 
APPENDIX V: ACSR INFORMED CONSENT 
Study Title for Study Participants: Collecting Blood and Tissue Sample Donations for 
Research for HIV/AIDS-Related Cancers 
Official Study Title: 
Biospecimen Collection and Donation to the AIDS  
and Cancer Specimen Resource (ACSR) 
What is the usual approach to donate blood and/or tissue to the ACSR? 
You are being asked to donate blood and/or tissue for future research. You are being asked to 
donate your blood and/or tissue samples to the ACSR because you have HIV infection and are 
being considered for participation in an AIDS Malignancy Consortium (AMC) clinical trial. 
The AMC works with the ACSR to collect donated samples from persons with HIV infection 
for research studies. People who do not take part in an AMC clinical trial can also donate 
samples to the ACSR. 
What are my other choices if I do not take part in this study? 
It is your choice to donate or not donate your blood and/or tissue samples. You may still take 
part in the AMC clinical study if you choose not to donate blood or biopsy samples to the ACSR.  
You may also choose to donate: 
• Blood but not tissue, or 
• Tissue but not blood. 
What is the AIDS and Cancer Specimen Resource (ACSR)? 
The ACSR is a biorepository (biobank) that collects human biological specimens (samples) 
from persons who have HIV or cancers related to HIV/AIDS. The ACSR stores the samples 
and some of the donor’s medical information for use by researchers in future research studies. 
The National Cancer Institute (NCI) has set up the ACSR to assist researchers locate samples 
needed for their studies. 
The ACSR has an independent research panel that approves researchers’ requests to use the 
ACSR’s stored samples for research studies. The ACSR only gives samples and medical 
information to researchers after their projects have been approved. Researchers may use the 
samples to study cancers and other diseases associated with HIV disease. This information may 
help us learn more about the causes of HIV-related diseases and cancers and to develop better 
ways to screen, diagnose, and treat them. 
Why is this study being done? 
The purpose of this study is to collect samples for the ACSR for future research studies. 
Researchers may study samples from the ACSR in combination with hundreds or thousands of 
other samples to explore how biologic or genetic factors may be related to HIV-related diseases 
and cancer. The information might help doctors in the future to identify who will or will not 
benefit from treatment. The samples may be used to learn more about how HIV-related diseases 
and cancers develop. The samples may also lead to new tests or discoveries. Finally, researchers 
may use the samples to study the genetic material from your cancer tissue and compare it to the 
material from your normal tissue (blood) to try to find the differences that exist. These studies 
could make it possible to identify many of the changes that are associated with diseases such as 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
151 
NCI Version Date 24AUG2023 
cancers. It may also help us tailor treatments to a patient's unique genetic make-up and/or to the 
genetic markers of the tumors. 
What extra tests and procedures will I have if I take part in this study? 
1. If you agree to donate blood, the medical team will draw about 2 tablespoons of blood to 
give to the ACSR. This takes about 10 minutes. 
2. If you agree to donate tissue, your leftover tissue biopsy material will be donated to and 
stored by the ACSR. 
3. Some of your clinical information will be released to the ACSR and entered into their 
database. The information given to the ACSR will not include your name or any information 
that could personally identify you. 
We will only give the ACSR tissue that is left over after making decisions about your treatment 
or diagnosis. The study doctor will not take any extra biopsies just for the ACSR. 
We cannot tell you right now what future research these samples would be used for. Instead, 
we are asking that you give approval to give your samples for future testing without contacting 
you again. The results of whatever research is done on your samples will not be told to you or 
your doctor. The results of the tests will not be placed in your study records. 
How long will ACSR keep my samples? 
Your blood and/or tissue sample will be stored until it is used for research. The samples may be 
stored indefinitely. 
What possible risks can I expect from taking part in this study? 
• Blood Draw: The risks of drawing blood include temporary discomfort from the needle 
stick, bruising, and, rarely, infection. 
• Confidentiality: The ACSR will receive study samples with code numbers. There will be no 
personal identifiers on the samples. Then the samples will be re-labeled with a barcode and 
stored for future testing. While the ACSR and researchers who study ACSR samples will 
have no information that could identify you, there is a risk that someone could use 
information from genetic studies to trace your samples back to you. The researchers believe 
the chance that someone will identify you is very small, but the risk may change in the future 
as people come up with new ways of tracing information. In some cases, this information 
could be used to make it harder for you to get or keep a job. There are laws against misuse 
of genetic information, but they may not give full protection. The researchers believe the 
chance these things will happen is very small, but cannot promise that they will not occur. 
Let your study doctor know of any questions you have about these possible risks. You can ask 
the study doctor questions about side effects at any time. 
What possible benefits can I expect from taking part in this study? 
This study is unlikely to help you. This study may help us learn things that may help people in 
the future. 
The information may help to identify those who are at increased risk and those who may benefit 
from targeted treatment and screening. In turn, these studies could help find ways to prevent or 
improve treatments for HIV-related diseases and AIDS-related cancers. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
152 
NCI Version Date 24AUG2023 
Can I stop taking part in this study? 
Yes, you may withdraw your samples from the ACSR at any time. You may contact your AMC 
study coordinator if you would like to withdraw your samples. The coordinator can ask in 
writing that your sample be removed from research use and that any identifiable sample and 
information still in their possession be destroyed. However, if any research has already been 
done using some of your samples, the data will be kept and analyzed as part of those studies. 
What are my rights in this study? 
Taking part in this study is your choice. No matter what decision you make, and even if your 
decision changes, there will be no penalty to you. You will not lose medical care or any legal 
rights. 
For questions about your rights while in this study, call the ________________________ 
(insert name of center) Institutional Review Board at __________________ (insert telephone 
number). (Note to Local Investigator: Contact information for patient representatives or other 
individuals at a local institution who are not on the IRB or research team but take calls 
regarding clinical trial questions can also be listed here.) 
What are the costs of taking part in this study? 
There will be no cost to you for donating your samples to the ACSR. You will not be paid for 
taking part in this study. 
What happens if I am injured or hurt because I took part in this study? 
If you are injured or hurt as a result of taking part in this study and need medical treatment, 
please tell your study doctor. The AMC will not offer to pay for medical treatment for injury. 
Your insurance company may not be willing to pay for study-related injury. If you have no 
insurance, you would be responsible for any costs. 
If you feel this injury was a result of medical error, you keep all your legal rights to seek 
payment for injury even though you are in a study. 
Who will see my medical information? 
Your privacy is very important to us and the researchers will make every effort to protect it. 
Your information may be given out if required by law. For example, certain states require 
doctors to report to health boards if they find a disease like tuberculosis. However, the 
researchers will do their best to make sure that any information that is released will not identify 
you. Some of your health information, and/or information about your specimen, from this study 
will be kept in a central database for research. Your name or contact information will not be put 
in the database. 
There are organizations that may inspect your records. These organizations are required to make 
sure your information is kept private, unless required by law to provide information. Some of 
these organizations are: 
• The AIDS Malignancy Consortium (AMC) 
• The Institutional Review Board, IRB, is a group of people who review the research with the 
goal of protecting the people who take part in the study. 
• The Office for Human Research Protections and the National Cancer Institute in the U.S. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
153 
NCI Version Date 24AUG2023 
To protect your privacy, the AMC does not keep identifying information that links study 
participants to specific samples. As a result, the AMC and ACSR will not be able to link the 
results from studies that use your samples back to you. Thus, information, including genetic 
information, that researchers may obtain in studies that use your samples may not be directly 
linked to you and will not be placed in your medical record. However, some clinical and basic 
information obtained confidentially from the AMC will be attached with these data. It is 
possible that findings may one day help, for example, people of the same race or sex as you. It 
also is possible that genetic factors might come to be associated with people who have HIV and 
cancer through these kinds of studies. 
Where can I get more information? 
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or 
general information about cancer. You may also call the NCI Cancer Information Service to get 
the same information at 1-800-4-CANCER (1-800-422-6237). 
Who can answer my questions about this study? 
You can talk to the study doctor about any questions or concerns you have about this study or 
to report side effects or injuries. Contact the study doctor __________________ (insert name 
of study doctor[s]) at __________________ (insert telephone number). 
 
Please circle your answer to show whether or not you would like to take part in each option: 
 
1. I agree to donate my blood to the ACSR for future research that may be used to learn 
about, prevent, diagnose, or treat HIV-related diseases and cancer. 
YES 
 
NO 
2. I agree to donate my blood to the ACSR for future research that may include genetic 
testing to learn about, prevent, diagnose, or treat HIV-related diseases and cancer.  
YES 
 
NO 
3. I agree to donate some of my tissue biopsy material that is not required for my 
treatment or diagnosis to the ACSR for future research that may be used to learn 
about, prevent, diagnose, or treat HIV-related diseases and cancer. 
YES 
 
NO 
4. I agree to donate some of my tissue biopsy material to the ACSR for future research 
that may include genetic testing to learn about, prevent, diagnose, or treat HIV-related 
diseases and cancer.  
YES 
 
NO 
 
 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
154 
NCI Version Date 24AUG2023 
My Signature Agreeing to Take Part in the Study 
I have read this consent form or had it read to me. I have discussed it with the study doctor and 
my questions have been answered. I will be given a signed copy of this form. I agree to take 
part in the optional study.  
 
Participant’s signature
 
 
Date of signature_____________________________________ 
 
 
Signature of person(s) conducting the informed consent discussion
 
 
Date of signature_____________________________________ 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
155 
NCI Version Date 24AUG2023 
APPENDIX VI: AMC DATA AND SAFETY MONITORING PLAN 
(Version 9.0 October 6, 2020) 
 
Introduction 
The AMC Data and Safety Monitoring Plan (DSMP) outlines the measures employed by the 
group to monitor the safety of participants and ensure the data validity and integrity for all 
clinical trials it conducts. This includes methods to: 1) monitor the progress of trials and the 
safety of participants; 2) comply with regulatory requirements for adverse event (AE) reporting; 
3) processes for trial termination or temporary suspension and major modifications; and 4) plans 
for ensuring data accuracy and protocol compliance. As the AMC conducts protocols of varying 
research phase, region of conduct (which may include trials conducted in the U.S., international 
sites, or both), IND sponsor (AMC investigator, CTEP, or industry-sponsored) and clinical data 
entry system use, this plan addresses broad processes applying to the range of trial designs and 
requirements. Refer to the individual AMC protocol to identify the applicable study 
characteristics for the relevant requirements described in this plan. 
Monitoring the Progress of Trials and the Safety of Participants 
Routine and expedited AE reporting 
All AMC protocols that collect safety data adhere to the National Cancer Institute (NCI), 
Cancer Therapy Evaluation Program (CTEP) Guidelines: Adverse Event Reporting 
Requirements 
(https://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm), 
as 
applicable to the clinical protocol. AEs are to be recorded in the source documents, assessed by 
a clinical investigator for the AE reporting criteria, and promptly reported in the clinical data 
entry system as required by each protocol. For AMC trials conducted under a CTEP IND and 
AMC trials conducted within the U.S., all AEs that meet the NCI’s expedited reporting 
requirements are reported to the NCI via the CTEP Adverse Event Reporting System (CTEP-
AERS) web application, either directly or through integration with Medidata Rave where this 
system is employed for AMC protocols. Use of this system ensures notification to the protocol 
chair and Investigational Drug Branch (IDB) at CTEP, as required for trials conducted under a 
CTEP IND, and a uniform expedited reporting and safety review process for AMC domestic 
trials. The system may also be programmed to include sponsor notification as required for trials 
with industry support. Alternate process for expedited AE reporting to the AMC protocol chairs 
and AMC Operations and Data Management Center (ODMC) within the clinical data entry 
system (AdvantageEDC or Advantage eClinical only) may be defined in the protocol for select 
trials (international studies and The ANCHOR Study). 
All serious adverse events (SAEs) received by the AMC ODMC will be reviewed by the AMC 
medical monitor at the AMC ODMC for consideration of individual participant safety, safe trial 
conduct, data reporting quality for AE term selection, and appropriate application of the 
regulatory criteria for seriousness, expectedness, and relatedness to the investigational therapy. 
If alternate procedures are followed for SAE review, the process for adequate medical 
monitoring will be defined in the AMC protocol and the Transfer of Regulatory Obligations 
(TORO) with the sponsor. AMC medical monitor review includes review of the CTEP-AERS 
report before CTEP submission for IDB review (if applicable), or review of the SAE report in 
the data entry system for trials not using CTEP-AERS for expedited reporting. The IND sponsor 
or its designee will issue the determination as to whether the AE requires IND safety reporting 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
156 
NCI Version Date 24AUG2023 
to FDA as a serious and unexpected suspected adverse drug reaction (SUSAR). For protocols 
not conducted under an IND, in the event of disagreement between the reporting physician and 
the AMC medical monitor regarding the relationship of the AE to the investigational agent(s) 
(i.e., determination of whether the attribution is unrelated or unlikely, or possible, probable, or 
definite), the AMC medical monitor will provide the final determination of the relationship. 
IND safety reporting to FDA is performed by CTEP for trials conducted under a CTEP IND; 
IND safety reporting is performed by the sponsor or sponsor’s designee (AMC ODMC or other 
party defined in the study agreement or TORO) for IND studies sponsored by AMC 
investigators or industry sponsors. 
Expedited reporting to the Institutional Review Board (IRB) 
The requirements for IRB review will be identified in the protocol section on ethical and 
regulatory obligations. All AMC trials initiated before September 1, 2020 and all international 
sites for all AMC studies are subject to local IRB review; only U.S. sites are subject to the NCI 
requirement to use a single IRB for protocols initiated on or after September 1, 2020. For trials 
subject to local IRB review, the site principal investigator is responsible for ensuring that 
expedited AE reports for its trial participants and any unanticipated problems that affect the 
local institution only are submitted to the local IRB of the reporting institution, per the local 
IRB’s requirements for such reporting. For studies reviewed by the single IRB, the protocol 
chair will render a determination as to whether a SAE or other problem constitutes a trial-wide 
unanticipated problem that requires reporting to that IRB, in accordance with its standards of 
procedure. 
To comply with investigator notification requirements for IND studies under 21 CFR 312.32 
and 312.55, IND safety reports from all trials the AMC conducts and reports from external 
sponsors investigating the same agents are made available to all investigators upon receipt from 
the sponsor or its designee, either via the password-protected section of the AMC Operations 
web site (AMC trials subject to local IRB review only) or the CTSU website (U.S. trials subject 
to single IRB review/CTEP IND agents). The site clinical investigator responsible for the 
applicable AMC protocol(s) is responsible for reviewing any IND safety reports received and 
documenting submission to the IRB of record (if required by local policy) within the timeline 
defined by the Clinical Trials Monitoring Branch (CTMB) audit guidelines. 
Procedures for monitoring trial progress and pharmacovigilance 
For trials using AdvantageEDC or Advantage eClinical for clinical data entry, the AMC ODMC 
provides on demand tabular listings of all reported AEs and SAEs on a participant level to the 
protocol chair and co-chair(s) for review via the password-protected section of the AMC 
Operations web site, www.AIDScancer.org. For trials using OPEN and Medidata Rave for 
clinical data collection, data listing will be made available using that system. Summary reports 
of AEs by frequency and relationship to the investigational agent(s) are provided to all AMC 
investigators and their staff It is the responsibility of each site to provide trial-specific AE 
listings to their respective IRB, if required by its policies. For blinded studies, the AE and SAE 
listings are reviewed and tabulated without treatment assignment. 
Accrual summaries for each AMC trial are updated nightly on the password-protected section 
of the AMC web site. The progress of each AMC trial is reviewed regularly by the protocol 
chair and also by the appropriate Scientific Working Group (SWG) during scheduled 
conference calls (monthly SWG calls and as required, protocol-specific monitoring conference 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
157 
NCI Version Date 24AUG2023 
calls). Summary accrual, summary AE, and individual SAE reports are provided to SWG 
leadership and protocol chairs to monitor participant safety during these monthly calls. 
The AMC medical monitor reviews listings of all reported AEs on a quarterly basis for assuring 
compliance with the protocol requirements for AE reporting and the identification of any safety 
concerns (individual AE or increased frequency/severity of expected AEs) for the agents under 
investigation. Findings from these reviews are communicated to the protocol chairs and all 
AMC investigators, and posted to the AMC Operations web site. 
Data and Safety Monitoring Board Review (DSMB) review 
The AMC has formed an independent Data and Safety Monitoring Board (DSMB) for AMC 
trials and for the ANCHOR Study. As required by NCI policy, the AMC requires DSMB review 
for all phase III randomized trials. All other clinical trials that the AMC initiates will be 
reviewed by the AMC ODMC and AMC Statistical Center during protocol development to issue 
a recommendation as to whether the study requires DSMB oversight, which will require the 
approval of the AMC Executive Committee. This determination will be based on the phase of 
the study, experimental design, risk posed by the investigational approach, extent of data 
available on the safety of an investigational agent, risk posed by the natural course of the health 
condition under research, and the categories of vulnerable populations involved. The 
involvement of a DSMB in reviewing an AMC protocol will be identified in each clinical 
protocol as approved by CTEP and, as applicable, required by the IRB of record. 
Regarding the composition of the AMC DSMB, voting members usually include physicians, 
statisticians, an ethicist, and a patient advocate. All voting members have no other affiliation to 
the AMC and are appointed by the AMC Executive Committee with the approval of the OHAM 
Director. Nonvoting members are the AMC group statistician, the protocol statistician, an AMC 
ODMC staff member, two representatives (normally a clinician or statistician) from CTEP, and 
the grant program directors from the NCI Office of HIV and AIDS Malignancy (OHAM). 
The DSMB reviews all applicable AMC studies in accordance with the National Cancer 
Institute’s Policy for Data and Safety Monitoring. Confidential reports of all trials under review 
are prepared by the AMC group statistician with support from the AMC ODMC. A written 
report containing the current status of each trial monitored, and when appropriate, any toxicity 
and outcome data, are sent to DSMB members by the AMC ODMC within the timelines 
specified by the DSMB charter. This report addresses specific toxicity issues and any other 
concerns about the conduct of the trial, as defined by the protocol plan for DSMB review. The 
report may contain information for the DSMB to render determinations for participant safety, 
early trial termination, results reporting, or continuing accrual or follow-up. 
The results of each DSMB meeting are summarized in a formal report sent by the DSMB chair 
to the AMC group chair and AMC ODMC. The DSMB report contains recommendations on 
whether to close each study reviewed, whether to report the results, and whether to continue 
accrual or follow-up. A primary recommendation (e.g., continue with no change; recommended 
or required modification; stop) must be included in the document. The group chair or designee 
is then responsible for notifying the protocol chair and relevant SWG chair before the 
recommendations of the DSMB are carried out. In the unlikely event that the protocol chair 
does not concur with the DSMB, then the OHAM program directors and the NCI division 
director or designee must be informed of the reason for the disagreement. The protocol chair, 
relevant SWG chair, group chair, DSMB chair, and NCI division director or designee will be 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
158 
NCI Version Date 24AUG2023 
responsible for reaching a mutually acceptable decision about the study. CTEP approval of a 
protocol amendment will be required prior to any implementation of a change to the study. 
Following a DSMB meeting, the DSMB’s recommendations are provided to all AMC 
investigators and staff. It is each site principal investigator’s responsibility for conveying this 
information to its local IRB as relevant for its protocol participation. For trials reviewed by a 
single IRB, the AMC ODMC will support notification to the IRB as required per its procedures. 
Cohort trial reviews not subject to DSMB review 
For phase I dose escalation trials, dose escalation (or dose de-escalation) is based on the rules 
in the protocol and the protocol chair, AMC medical monitor, and protocol statistician 
determine whether these criteria have been met based on a review of all safety data for the 
protocol-defined evaluation period. If applicable for phase II trials, stopping the trial for toxicity 
or efficacy, or suspending enrollment pending observation of responses in a multi-stage phase 
II trial, is based on meeting criteria stated in the protocol, and the protocol chair, AMC medical 
monitor, and protocol statistician determine whether these criteria have been met. 
Plans for Assuring Compliance with Requirements Regarding AE Reporting 
The protocol chair, AMC group chair, and the AMC ODMC share responsibility in assuring 
that participating investigators comply with applicable regulatory and protocol requirements for 
AE reporting. The AMC site principal investigator certifies compliance with NCI and FDA 
requirements for trial conduct by signing the site subaward agreement for the grant and the 
AMC Adherence Statement for site membership; clinical investigators also certify compliance 
in completing the protocol signature page for each protocol active at the site, and Form FDA-
1572 for CTEP investigator registration, and also for AMC IND studies sponsored by AMC 
investigators or industry sponsors. Protocol compliance with AE identification, assessment and 
reporting requirements is assessed by the AMC ODMC using several methods: 1) programmed 
system checks and messages to instruct the site to complete routine and/or expedited reporting 
when certain criteria are reported in the clinical data entry system; 2) programmed data reports 
provided to the protocol chairs that identify reports requiring expedited AE reporting; 3) remote 
review of data entry or data reports to ensure compliance with protocol and NCI AE reporting 
requirements; 4) AMC medical monitor review described in the section above; and, 5) routine 
site audits by reviewing the site’s source documentation. 
The clinical data entry systems used for AMC studies include the Oncology Patient Enrollment 
Network, OPEN for enrollment, and Medidata Rave for clinical data entry for enrolled 
participants; trials activated before September 1, 2020 or that involve only AMC international 
sites may be reported in AdvantageEDC/Advantage eClinical, a web-based data entry and 
enrollment system. These data entry systems are programmed to notify the site investigator, 
protocol chair, AMC medical monitor, and AMC ODMC via e-mail in the event that a site 
reports an AE that meets expedited reporting criteria to NCI and/or FDA. Additional reporting 
conditions may be programmed depending on the sponsor reporting requirements of a given 
protocol (e.g., adverse events of special interest [AESI]). If the site does not follow with an 
expedited report, the AMC ODMC contacts sites to request compliance with reporting 
requirements. Additionally, the protocol chair, AMC ODMC, and the AMC medical monitor 
review reported AEs on a routine basis to identify AEs reported by sites that require expedited 
reporting. The protocol chair, AMC SWG chairs, AMC group chair, and IND sponsors have 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
159 
NCI Version Date 24AUG2023 
general oversight for assuring that routine and expedited adverse reporting requirements are met 
by the responsible parties. 
For studies monitored by CTEP using the Data Mapping Utility (DMU), cumulative protocol- 
and participant-specific data will be submitted weekly to CTEP electronically via the DMU. 
For trials monitored by the NCI’s Clinical Data Update System (CDUS), AE information is 
transmitted electronically to NCI on a quarterly basis. For trials monitored by NCI’s Clinical 
Trials Monitoring Service (CTMS), AE information is transmitted electronically to NCI every 
two weeks. 
Plans for Assuring that any Action Resulting in a Temporary or Permanent Suspension 
of an NCI-Funded Clinical Trial is Reported to the NCI Grant Program Director 
Responsible for the Grant 
In the event that temporary or permanent suspension of a trial, or major modification to the 
protocol is under consideration, the protocol chair will convene the AMC ODMC, AMC 
Statistical Center, and SWG chair by conference call to discuss the options. Suspension actions 
will also be reviewed by the AMC Executive Committee for program oversight and direct 
communication of the action with the OHAM program directors. For phase III trials, closure 
decisions are typically rendered by the AMC DSMB; if the trial in question is under AMC 
DSMB oversight but rendered by the AMC investigators, the AMC DSMB will be notified of 
the suspension and the reason. For phase I and II trials, the protocol chair also has the option of 
asking the DSMB to review the study. The AMC ODMC will inform the CTEP Protocol 
Information Office (PIO), with copy to OHAM Directors, when studies are temporarily or 
permanently closed. In the event of major trial modification, CTEP must approve all protocol 
amendments prior to distributing to the AMC sites. 
Plans for Assuring Data Accuracy and Protocol Compliance 
All study data for AMC clinical trials are entered directly by AMC clinical site staff into the 
applicable clinical data entry system for the trial. During data entry, the system performs 
validation checks on many fields and performs consistency checks between select fields. Range 
checks are placed on each field to eliminate entry of out-of-range values. Edit check programs 
are run on the database on a set schedule to identify and resolve inconsistencies between forms 
or data collected at different points in time. Submitted data entry forms are reviewed for 
compliance with the protocol and data entry instructions according to the AMC ODMC’s 
standards for data quality processes. AMC ODMC staff routinely interacts with site staff to 
resolve any data submission problems. 
In accordance with NCI guidelines, the AMC ODMC conducts audits at the AMC sites to 
evaluate compliance with regulatory issues, and to review data for specific cases by checking 
source documents. These reports are sent to the site principal investigator and to the NCI. In the 
event that major violations are identified, sites are asked to provide a written corrective and 
preventative action plan to correct deficiencies. If needed, a repeat site audit is conducted. In 
the event that a site does not correct deficiencies in a pre-determined time frame, the AMC 
Executive Committee has the option to implement remedial action(s) for the site. Possible 
actions include, but are not limited to, suspending enrollment of new participants to AMC trials 
until deficiencies are corrected; recommending a decrease in funding to the site; and requiring 
specific training for site investigators or staff members. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
160 
NCI Version Date 24AUG2023 
APPENDIX VII: LIST OF PROHIBITED MEDICATIONS 
The following medications may not be taken while participating on this study through 6 weeks 
after the last dose of protocol treatment: 
• Any non-study anti-cancer agent (investigational or non-investigational) 
• Any other investigational agents 
• Any other CTLA-4 inhibitors or agonists 
• CD137 agonists, PD-1 inhibitors 
• Immunosuppressive agents, unless indicated to manage study therapy induced irAEs 
• Chronic systemic corticosteroids, unless indicated to manage study therapy induced irAEs 
or chronic GVHD at a stable dose prior to study entry 
• Any non-oncology vaccine therapies used for the prevention of infectious diseases (for up 
to 30 days prior to or after any dose of study drug, however it is suggested that routine 
vaccinations, including seasonal influenza, be given at least 2 weeks prior to study 
treatment) 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
162 
NCI Version Date 24AUG2023 
APPENDIX IX: IMAGING METHODOLOGIES 
Contrast enhanced CT or enhanced MRI are the preferred imaging modalities to be used. Chest 
x-rays performed during the screening phase (and repeated at anytime during the study if 
clinically indicated) may be used as supportive data, as an accessory to the CT chest scans. 
The same imaging techniques used at screening MUST be used at all subsequent time points to 
permit accurate, comparable measurement of lesions. All imaging data are to be collected on 
film or in digital format. 
CT/MRI of the Chest/Abdomen/Pelvis 
CT/MRI imaging of the chest, abdomen and pelvis is required at Screening and at each tumor 
assessment visit as indicated in Table 1, Table 2, and Table 3, regardless of the location of 
known metastases. In addition, CT/MRI scans must be obtained of anatomic regions not covered 
by the chest, abdomen and pelvic scans, in participants where there is clinical suspicion of deep 
soft tissue metastases (e.g., lesions in the thigh). Such additional CT/MRIs will be required at 
Screening only when deep soft tissue disease is known/suspected and must be consistently 
repeated at all subsequent tumor assessment visits. 
Brain MRI/CT 
Brain scans (MRI or CT) are required at Screening. Brain scans should be conducted during the 
course of the study if the Screening scan was positive as per study protocol or as clinically 
indicated. 
Non-radiographic Assessments/Digital Photography 
These should be made at the sites and recorded in the source documents. Visible skin lesions 
should be measured clinically and documented digitally using standardized photographic 
images, including a ruler for scale as part of the image. 
Image Acquisition Guidelines 
Similar methods of tumor assessment and similar techniques must be used to characterize each 
identified and reported lesion at screening and during all subsequent response assessments. All 
measurable and non-measurable lesions should be assessed at screening and at the defined 
tumor assessment time points (see Table 1, Table 2, and Table 3). Additional assessments may 
be performed, as clinically indicated, if there is a suspicion of progression or for confirmation 
of response. The Investigator will base response to treatment on the RC (Section 9.1). Imaging-
based evaluation is preferred to physical examination. Helical (spiral) CT scans of chest, 
abdomen and pelvis are preferred. If not available, conventional (non-helical, non-spiral CT) 
should be used. 
IV contrast should be used for all CT scans. If IV contrast is contraindicated, CT may be 
performed without contrast. Alternatively, MRI can be used to assess lesions in the participant. 
Participants who develop contrast allergy after study enrollment may be followed by MRI for 
subsequent tumor measurements. Sections should be contiguous, similarly sized and consistent 
from visit-to-visit. Section thickness must be based on institutional standards (e.g., from 5 to 8 
mm; 10 mm cuts are not recommended). Chest x-ray, ultrasound, and PET scans are not 
acceptable methods to measure disease for the purposes of this study. 
 

 
AMC #095 (Version 15.0) 24AUG2023 
 
 
163 
NCI Version Date 24AUG2023 
APPENDIX X: NIVOLUMAB: MANAGEMENT ALGORITHMS FOR 
ENDOCRINOPATHY, GASTROINTESTINAL, HEPATIC, NEUROLOGICAL, 
PULMONARY, RENAL, AND SKIN ADVERSE EVENTS 
Management algorithms for the above-mentioned AEs are provided on the following pages. 
 

 
AMC #095 (Version 15.0) 24AUG2023 
 
164 
NCI Version Date 24AUG2023 

 
AMC #095 (Version 15.0) 24AUG2023 
 
165 
NCI Version Date 24AUG2023 
 

 
AMC #095 (Version 15.0) 24AUG2023 
 
166 
NCI Version Date 24AUG2023 

 
AMC #095 (Version 15.0) 24AUG2023 
 
167 
NCI Version Date 24AUG2023 

AMC #095 (Version 15.0)24AUG2023 
 
168 
NCI Version Date 24AUG2023 

 
AMC #095 (Version 15.0)24AUG2023 
 
169 
NCI Version Date 24AUG2023 
 

 
AMC #095 (Version 15.0)24AUG2023 
 
170 
NCI Version Date 24AUG2023 
 
 

 
AMC #095 (Version 15.0) 24AUG2023 
 
171 
NCI Version Date 24AUG2023 
APPENDIX XI: DEFINITION OF AIDS INDICATOR CONDITIONS 
 
• Aspergillosis, invasive * 
• Bartonella henselae infection, disseminated (bacillary angiomatosis, peliosis hepatis)* 
• Candidiasis of bronchi, trachea, or lungs * 
• Candidiasis, esophageal * 
• Cervical cancer, invasive * 
• Coccidioidomycosis, disseminated or extrapulmonary * 
• Cryptococcosis, extrapulmonary * 
• Cryptosporidiosis, chronic intestinal (> 1 month's duration) * 
• Cytomegalovirus disease, invasive * 
• Cytomegalovirus retinitis * 
• Encephalopathy, HIV-related * 
• Herpes simplex: chronic ulcer(s) (> 1 month's duration), bronchitis, pneumonitis, or 
esophagitis * 
• Histoplasmosis, disseminated or extrapulmonary * 
• Isosporiasis, chronic intestinal (> 1 month's duration) * 
• Kaposi's sarcoma (progression to visceral disease) 
• Lymphoma, Burkitt's (or equivalent term) * 
• Lymphoma, immunoblastic (or equivalent term) * 
• Lymphoma, primary, of brain * 
• Microsporidiosis, diarrhea > 1 month or disseminated * 
• Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary * 
• Mycobacterium tuberculosis, any site (pulmonary1 or extrapulmonary) * 
• Mycobacterium, other species or unidentified species, disseminated or extrapulmonary * 
• Nocardiosis, pulmonary, brain or disseminated * 
• Pneumocystis jirovecii pneumonia (new or recurrent diagnosis) 
• Progressive multifocal leukoencephalopathy * 
• Salmonella septicemia, recurrent * 
• Toxoplasmosis of brain * 
• Wasting syndrome due to HIV * 
• New Diagnosis * 
 
 

 
AMC #095 (Version 15.0) 24AUG2023 
 
172 
NCI Version Date 24AUG2023 
APPENDIX XII: PHOTOGRAPHIC RECORD OF KS LESIONS 
Photographs will be taken to assist in documentation of the diagnosis of KS and for clinical 
monitoring purposes. The difficulty in standardizing these photographs is acknowledged. 
In all participants, photographs will be needed of the five marker lesions. The five markers lesions 
must be labeled in the photographs #1-#5. The same lesions must be consistently labeled 
throughout the trial. For each lesion, two photos will be taken. The first photo will be a close-up 
of the lesion. A millimeter ruler should be included in the photograph to demonstrate the size of 
the lesion. The second photo will be a larger view of the photo that will show the lesion’s location 
on the body. 
All participants will also need photos of larger views of the back, chest, arms (front and back), 
legs (front and back), feet (including soles), whether involved with KS or not. In addition, photos 
should be taken of any other area with significant involvement at baseline (e.g., the face) 
In participants with >50 cutaneous lesions, photographs will be taken of the three representative 
areas (each with ≥ 5 lesions), defined at study enrollment and used for clinical assessment of 
response.  
Photographic documentation will be completed at each visit when the KS response category 
changes (as described in Section 9.2). For example, if a participant’s KS response category changes 
from no response to PR, the site will take photos of this to document the category change. If there 
was no change in the KS response category, no photos are required 
Photographs will be stored electronically under the participant ID number and back-up electronic 
storage will be kept. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
174 
NCI Version Date 24AUG2023 
APPENDIX XIV: AMC BIOREPOSITORY SPECIMEN PREPARATION AND 
SHIPPING INSTRUCTIONS 
Regimen: Required study specimens are included in Appendix I. Unless otherwise specified (HIV 
latent reservoir and viral outgrowth assays requiring twelve 8.5 ACD tubes, or two 8.5 ACD tubes 
where consent for larger draw was not obtained), all specimens will be shipped to and banked at 
the AMC Biorepository, which will serve as a tissue source site for processing samples for all 
AMC sites, for future testing at AMC core labs and outside labs. Tests will be conducted at the 
end of enrollment for each phase or within one year of acquisition of samples. 
Assays procedures are described in the Network Core Laboratories’ Manual of Operation(s) and 
available from the network core laboratories. Assays details may change as technology progresses.  
Assays as proposed in exploratory objectives: 
• Plasma for herpesvirus (HCMV, EBV, KSHV) viral load and PBMC for herpesvirus (HCMV, 
EBV, KSHV) latent virus will be provided to the AMC Virology Core Laboratory and the 
Lewin Laboratory at the University of Melbournefrom the material collected under Appendix 
XVI (10 million PBMC and plasma from all time points where 12 ACD tubes are collected 
(submitted by the site directly to the AMC Biorepository), or 2 ACD tubes where consent for 
larger blood draw was not obtained 
• Four 4 micron unstained slides for PD-L1 testing (AMC Pathology Core Lab) 
• For KS participants: Tissue (skin of KS) biopsies: RNALater for gene expression profiling 
(AMC Biomarker Core Laboratory) 
• Tissue (skin of KS) biopsies: formalin for IHC (PD1, PDL-1, LANA, orf59, CD4, CD8, other 
immune cell populations) 
• Serum for Luminex multiplex cytokine assay(s) (AMC Biomarker Core Laboratory) (See 
Appendix XV) 
• For anal cancer participants: anal swabs for HPV type determination (AMC HPV Virology 
Core Laboratory, see Appendix XVII). 
GENERAL 
A. 
To ship blood specimens, use a diagnostic shipper approved for a volume of at least 30 cc. 
The use of the SAF-T-PAK STP 210 diagnostic cardboard shipper is recommended. These 
shippers may be ordered at the SAF-T-PAK website: www.saftpak.com. The following 
instructions below are for use with the recommended STP-210 shipper. If using another 
federally approved diagnostic shipper, please follow instructions provided for that specific 
shipper. 
NOTE: Specimens MUST BE SHIPPED Sunday through Thursday as an OVERNIGHT 
PRIORITY shipment. Specimens are NOT ACCEPTED ON SATURDAYS OR 
SUNDAYS in the AMC Biorepository. 
B. 
SPECIMEN PREPARATION, PACKAGING, AND SHIPMENT 
Instructions for Peripheral Blood Specimens (Sunday – Thursday) 
From study participant, draw: 

 
AMC #095 (Version 15.0) 24AUG2023 
 
175 
NCI Version Date 24AUG2023 
Five 8.5 ml yellow top [ACD] tubes for HIV studies at: To be collected within two days 
before the Day 1 dose, post-dose Day 1, and Day 8 on the indicated cycles. 
• For participants on dose levels 1 (including 240 mg every 2 weeks) 2, collect at the 
following cycles: Cycles 1, 4, 7, 10, 13, 19, 22, 25, 28, 31, 34, 37, 40, 43, and 46. 
• For participants on dose levels -1 and -2, collect at the following cycles: Cycles 1, 7, 10, 
19, 25, 31, 37, and 43. 
• For participants on the combination therapy solid tumor expansion cohort collect at the 
following cycles: Cycles 1, 4, 7, and 10. 
• The pre-dose sample and the Day 1 Cycle 1 sample must be drawn on different calendar 
days, and should be collected at least 12 hours apart. 
• With a black, water resistant, sharpie pen, label each specimen with the following 
information: 
o AMC Protocol # 095 
o AMC Participant ID# 
o Date and time of collection 
o Specimen type, i.e., WB=Whole Blood, P=Plasma, PBMCs=Peripheral blood 
mononuclear cells 
o Specimen purpose: HIV and Herpesvirus Viral Load Studies 
Specimen Shipment 
• Seal the tops of the tube(s) with parafilm. 
• Place the sealed tube(s) into bubble wrap (provided in STP-210 kit). 
• Tape around the bubble wrap so that the roll stays together and the tubes cannot fall out or 
break. 
• Place absorbent material sheet around the bubble wrapped tubes and slip into a biohazard 
poly-bag and “self-seal.” 
• Place poly-bag containing tubes into the white TYVEK bag and seal. 
• Place the TYVEK bag into the STP-210 diagnostic cardboard shipper. Seal the cardboard 
shipper with clear packing/shipping tape. 
• Affix the FED-EX airbill on blank side of the shipper making sure that it is marked “FED-
EX PRIORITY OVERNIGHT.” 
• Mark “OTHER” in the airbill under “Packaging.” Please refer to the MOP and the AMC 
Operations website’s (www.AIDSCancer.org) Shipping tab for more information and the 
FedEx account details.Under airbill section “Special Handling” indicate “YES-SHIPPERS 
DECLARATION NOT REQUIRED.” 
• Place “From/To” information onto areas provided on the shipper. 
 

 
AMC #095 (Version 15.0) 24AUG2023 
 
176 
NCI Version Date 24AUG2023 
C. 
BLOOD SPECIMENS should be shipped by overnight express at room temperature 
to: 
AMC Biorepository at GWU 
Jeff Bethony, PhD 
George Washington University Medical Center 
Ross Hall, Room 118 
2300 I Street NW 
Washington, DC 20037 
Tel: (202) 994-3422 
Fax: (202) 994-5056 
Email: amc-bio@emmes.com 
• Make certain that shipper is already either pre-labeled with ‘UN#3373’ stamp, or make a 
paper label with ‘UN#3373” and affix it to the shipper. 
• Make certain that the net volume of the specimen being shipped is written in the space 
provided on the shipper or make a separate label with the volume in ml and affix to the 
shipper. 
• Affix airbill to shipper so that the ‘UN’ and ‘VOLUME’ labels are visible. 
• RETAIN THE TOP COPY OF THE AIRWAY BILL FOR YOUR RECORDS. 
• Place the box in the FedEx pickup area at your site or call to request a package pickup. 
Please Note: The shippers will be mailed back to each AMC site. 
Specimens should be sent by 24-hour shipment at room temperature. If collecting on a 
Thursday through Saturday where 24-hour shipment is not possible, please see Section 
below for instructions regarding separation of PBMCs from blood. In this case separation 
will need to occur on site and within 6 hours of blood collection. 
D. 
INSTRUCTIONS FOR SEPARATION OF BLOOD FOR PBMCS (FOR RESEARCH) 
COLLECTED ON SUNDAY – THURSDAY AND PERIPHERAL BLOOD 
COLLECTED ON FRIDAY - SATURDAY 
From study participant, draw: 
Five 8.5 ml yellow top (ACD) tubes for PBMCs (see Appendix XVI for PBMC separation 
directions) at the time points described in Appendix I. 
With a black, water resistant, sharpie pen, label each specimen with the following 
information: 
• AMC Protocol # 095 
• AMC Participant ID# 
• Date and time of collection 
• Specimen type, i.e., P=Plasma, PBMCs=Peripheral blood mononuclear cells 
• Specimen purpose: HIV and herpesvirus assays 
Specimen Shipment 
• Seal the tops of the tube(s) with parafilm. 
• Place the sealed tube(s) into bubble wrap (provided in STP-210 kit). 

 
AMC #095 (Version 15.0) 24AUG2023 
 
177 
NCI Version Date 24AUG2023 
• Tape around the bubble wrap so that the roll stays together and the tubes cannot fall out or 
break. 
• Place absorbent material sheet around the bubble wrapped tubes and slip into a biohazard poly-
bag and “self-seal.” 
• Place poly-bag containing tubes into the white TYVEK bag and seal. 
• Place the TYVEK bag into the STP-210 diagnostic cardboard shipper. Seal the cardboard 
shipper with clear packing/shipping tape. 
• Affix the FED-EX airbill on blank side of the shipper making sure that it is marked “FED-EX 
PRIORITY OVERNIGHT.” 
• Mark “OTHER” in the airbill under “Packaging.” Please refer to the MOP and the AMC 
Operations website’s (www.AIDSCancer.org) Shipping tab for more information and the 
FedEx account details.Under airbill section “Special Handling” indicate “YES-SHIPPERS 
DECLARATION NOT REQUIRED.” 
• Place “From/To” information onto areas provided on the shipper. 
Preparation of Peripheral Blood Mononuclear Cells 
Refer to Appendix XVI for instructions. 
 
***PLEASE DOUBLE CHECK PACKAGING OF SHIPPER AND DO NOT DEVIATE 
FROM REQUESTED LABELING. Shipping frozen aliquots requires the use of 
packaging acceptable for dry ice and Class 9 label with weight of dry ice written on 
package. 
E. 
PREPARATION OF TISSUE SAMPLES 
• From all participants, obtain four 4 micron unstained tissue slides from the diagnostic 
biopsy. 
• From KS study participant, obtain: 
o Skin biopsy; formalin-fixed. Biopsy will be obtained at baseline/Day 1 of Cycle 1, 
Day 1 of Cycle 5, and at treatment discontinuation. 
o Skin biopsy; RNALater. Biopsy will be obtained at baseline/Day 1 of Cycle 1, Day 
1 of Cycle 5, and at treatment discontinuation. RNALater biopsy must be kept at -
20°C or lower, -80°C is preferred. 
o Tissue specimens (punch biopsies) should be placed (a) into no more than 5 mL 
buffered formalin and (b) 1 ml RNALater provided by the AMC Core Lab in 
batches to each site. 
*NOTE: Specimens can only be accepted Monday through Friday. Therefore, specimens 
can only be shipped Sunday-Thursday for delivery the next day. Samples in RNALater 
are to be shipped on dry ice, and tissue slides and samples in formalin are to be shipped in 
ambient temperature. 
 
TISSUE specimens should be shipped to: 

 
AMC #095 (Version 15.0) 24AUG2023 
 
178 
NCI Version Date 24AUG2023 
Jeff Bethony, PhD 
AMC Biorepository 
George Washington Medical Center 
Ross Hall, Room 118 
2300 I Street, NW 
Washington, DC 20037 
Tel: (202) 994-2945 
Fax: (202) 994-5056 
Email: amc-bio@emmes.com 
F. 
BILLING 
Please refer to the MOP and the AMC Operations website’s (www.AIDSCancer.org) 
Shipping tab for more information and the FedEx account details.. It is only to be used for 
billing shipment of specimens to the lab where the sample is processed and/or stored. 
G. 
RECORD OF SPECIMENS 
This study will track specimens via GlobalTraceSM, a component of the AMC 
AdvantageEDCSM system. The GlobalTraceSM shipment manifest must accompany all 
specimen shipments. 
H. 
TECHNICAL QUESTIONS 
Questions regarding these specimens may be directed to Dr. Jeff Bethony using the above 
contact information. Available hours: Monday-Friday (9AM-5PM EST) 
 
 

 
AMC #095 (Version 15.0) 24AUG2023 
 
179 
NCI Version Date 24AUG2023 
APPENDIX XV: COLLECTION AND SHIPPING INSTRUCTIONS FOR PERIPHERAL 
BLOOD FOR IMMUNE RESPONSE (CYTOKINES AND SOLUBLE RECEPTORS) 
1.0 
OBJECTIVES 
The aim of this proposed pilot study is to evaluate the effect of therapy with ipilimumab 
(anti-CTLA-4) and nivolumab (anti-PD-1) on plasma levels of biomarkers of immune 
activation, at baseline/day 1 of cycle 1, day 1 of cycle 5, and treatment discontinuation, to 
identify the clinical correlates with regard to tumor response and disease free survival. 
2.0 
BACKGROUND 
Ipilimumab and nivolumab, monoclonal antibody-based therapeutics for the treatment of 
cancer, work by enhancing T cell activation and effector functions. They do this by 
reversing the inhibition of T cell activation and effector functions due to ligation of CTLA-
4 and PD-1. Therefore, measurement of biomarkers of T cell activation, including 
cytokines, soluble cytokine receptors, and biomarkers of immune activation, may provide 
insights into the biological effects of treatment with these agents, and may provide 
prognostic information regarding responses to treatment. These molecules are products of 
activated T cells, including TH1, TH2, TH17, T follicular helper, and regulatory T cells. 
3.0 
RATIONALE 
Inhibition of T cell activation and effector functions has the potential to contribute to the 
growth of cancers in HIV infected persons, by allowing these cancers to evade host immune 
responses. Reversal of T cell inhibition mediated by CTLA-4 and/or PD-1 ligation by 
ipilimumab and nivolumab may lead to potent antitumor immune responses. Additionally, 
enhanced T cell immunity following treatment may provide more effective responses to 
HIV infection or to other viral infections. However, there is little information available on 
the effect of treatment with these agents on serum levels of cytokines and immune 
activation biomarkers, nor on the prognostic significance of such biomarkers. 
The recent availability of multiplexed immunometric assays has made possible the 
simultaneous assessment of several of these immune activation and inflammation-
associated factors, using small volumes (<500 l) of serum or plasma. 
The results of this study will provide information on immune activation/inflammation-
associated biomarker plasma levels in HIV+ cancer participants treated with ipilimumab 
and nivolumab. 
4.0 
EVALUATIONS 
Serum levels of cytokines and inflammation-associated molecules will be determined at 
the following study visits: pre-study (entry), and prior to Cycle 5 of therapy, and then at 
the off study or early discontinuation visit. 
5.0 
ANALYSES 
The working hypothesis that will be tested is that participants who are treated with 
ipilimumab and nivolumab will display elevated levels of T cell-produced cytokines 
following treatment initiation, and that the level of T cell cytokine responses will diminish 
with time, following the conclusion of therapy. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
180 
NCI Version Date 24AUG2023 
Levels of cytokines and inflammation-associated biomarkers will be determined using two 
multiplexed (Luminex platform) panels. The first is a high-sensitivity cytokine panel that 
can detect human IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, TNF, and IFN. The second 
is a soluble receptor/inflammatory cytokine panel: sCD14, sIL-6R, sIL-2R, sTNFR1, 
sTNFR2, CXCL13, IP10, and sCD30. Both of these panels are produced by R&D Systems, 
and we have used variations of these assays extensively in prior epidemiologic studies. The 
cytokine panel has yielded results that compare well to ELISA results for IL-6 and IL-10. 
The soluble receptor/inflammation panel yields detectable results for these biomarkers in 
the majority of persons tested. 
2 ml of serum in 0.5 ml aliquots should be sent in batch at the end of the study to the 
Martinez-Maza laboratory. 
6.0 
SHIPPING INSTRUCTIONS AND SAMPLE PROCESSING 
A. GENERAL 
To ship blood specimens, use a diagnostic shipper approved for a volume of at least 30 
cc. The use of the SAF-T-PAK STP 210 diagnostic cardboard shipper is recommended. 
These shippers may be ordered at the SAF-T-PAK website www.saftpak.com. The 
following instructions below are for use with the recommended STP-210 shipper. If 
using another federally approved diagnostic shipper, please follow instructions 
provided for that specific shipper. 
NOTE: Specimens MUST BE SHIPPED Monday through Thursday as an 
OVERNIGHT PRIORITY shipment. Specimens are NOT ACCEPTED ON 
SATURDAY OR SUNDAY in the AMC BIOREPOSITORY.  
Should the site collect specimens on Friday through Saturday, samples should be 
processed for serum according to the procedures in Section C below for serum 
separation. At least four 0.5 ml aliquots of serum are required. Aliquots should be 
frozen at -80 C and shipped on dry ice to the AMC Biorepository the following week. 
B. SPECIMEN PREPARATION AND PACKAGING FOR SAME DAY SHIPMENT 
Draw two 6 ml red top (uncoated) tubes from study participant. Seal the tops of the 
tubes with parafilm. Individually wrap the sealed tubes in bubble wrap (provided in 
STP-210 kit) and tape around the bubble wrap so that the tubes are secured and the 
tubes cannot fall out or break. Place an absorbent material sheet around the bubble 
wrapped tubes and slip into a biohazard poly-bag and “self-seal.” Place poly-bag 
containing tubes into the white TYVEK bag and seal. Place the TYVEK bag into the 
STP-210 diagnostic cardboard shipper. Seal the cardboard shipper with clear 
packing/shipping tape. 
Affix the FedEx airbill on blank side of the shipper making sure that it is marked 
“FedEx PRIORITY OVERNIGHT.” Mark “OTHER” in the airbill under “Packaging.” 
Under airbill section “Special Handling,” indicate “YES-SHIPPERS DECLARATION 
NOT REQUIRED.” Place “From/To” information onto areas provided on the shipper. 
 
 

 
AMC #095 (Version 15.0) 24AUG2023 
 
181 
NCI Version Date 24AUG2023 
Blood specimens should be shipped by overnight express at room temperature to: 
Jeff Bethony, PhD 
AMC Biorepository 
George Washington Medical Center 
Ross Hall, Room 118 
2300 I Street, NW 
Washington, DC 20037 
Tel: (202) 994-2945 
Fax: (202) 994-5056 
Email: amc-bio@emmes.com 
Make certain that shipper is already either pre-labeled with ‘UN#3373’ stamp. Make 
certain that the net volume of the specimen being shipped is written in the space 
provided on the shipper or make a separate label with the volume in ml and affix to the 
shipper. Affix airbill to shipper so that the ‘UN’ and ‘VOLUME’ labels are visible. 
RETAIN THE TOP COPY OF THE AIRWAY BILL FOR YOUR RECORDS. Place 
the box in the FedEx pickup area at your site or call to request a package pickup. 
C. SERUM SEPARATION SPECIMEN PREPARATION AND PACKAGING FOR 
DELAYED SHIPMENT 
• For immediate processing, after blood is drawn, gently invert collection tubes five 
times and allow the blood to clot 60 minutes at room temperature, leaving the tube 
in an undisturbed upright position during the clotting process. Once clotted, the 
collection tube should not be allowed to sit at room temperature for more than 1 
hour prior to centrifugation and separation of the serum from the clot. 
• If the site would like to hold the sample for processing later the same day, store the 
sample at 4°C until ready to invert the tube and clot the sample. 
• Centrifuge the collection tube for 10 minutes at 1000 x g. After separation, the 
serum should be clear and free from all blood cells. Using a clean serological pipette 
tip for each sample, dispense the serum into a minimum of four 0.5 ml aliquots in 
cryovials 
• Discard the red top tube and residual blood fraction in accordance with local 
procedures for medical waste. 
• Label each serum aliquot tube with an AMC GlobalTrace specimen label. Specify 
the specimen type as “Serum” when entering each sample into GlobalTrace. With 
a black, water resistant, sharpie pen, label each specimen with the following 
information: 
o AMC Protocol # 095 
o AMC Participant ID# 
o Date and time of collection 
o Specimen type, i.e., S=Serum 
o Specimen purpose: Cytokine assays 

 
AMC #095 (Version 15.0) 24AUG2023 
 
182 
NCI Version Date 24AUG2023 
• Separated sera aliquots must be stored frozen until ready for shipment to the AMC 
Biorepository on next operating day (no longer than 72 hours after collection). 
Once sera aliquots are frozen at -80°C, sera must be shipped on dry ice to avoid thawing 
during shipment. Specimens should be placed on dry ice immediately. The specimens 
must stay on dry ice until being transferred to a -80ºC freezer. 
Specimens may be batched for shipping after storage in -80ºC freezer. *NOTE: 
Specimens can only be accepted Monday through Friday. Therefore, specimens can 
only be shipped Sunday-Thursday for delivery the next day. Shipping frozen 
specimens requires the use of packaging acceptable for dry ice and Class 9 label with 
weight of dry ice written on package. 
Billing 
Please refer to the MOP and the AMC Operations website’s (www.AIDSCancer.org) 
Shipping tab for more information and the FedEx account details.It is only to be used 
for billing shipment of specimens to the lab where the sample is processed and/or 
stored. 
Contact for Site Questions (9AM-5PM Pacific Time) 
Lab Manager: Larry Magpantay (lmagpantay@mednet.ucla.edu) 
Lab phone: 310-206-6846 
Oto Martinez-Maza’s office phone: 310-825-2542 
7.0 
AMC BIOREPOSITORY INSTRUCTIONS ONLY 
The AMC Biorepository will separate the whole blood samples, aliquot the serum into as 
many 0.5 ml aliquots until the sample is used as per AMC Biorepository SOPs, and store 
at -80C. Specimens should be sent in batch at the end of the study to: 
Larry Magpantay 
BSRB 173 
UCLA AIDS Institute 
615 Charles Young Drive 
Los Angeles, CA 90095-7363 
Phone: 310-206-6846 
Fax: 310-206-5387 
Email: lmagpantay@mednet.ucla.edu 
 
 

 
AMC #095 (Version 15.0) 24AUG2023 
 
183 
NCI Version Date 24AUG2023 
APPENDIX XVI: HIV LATENT RESERVOIR AND VIRAL OUTGROWTH ASSAY 
SPECIMEN PREPARATION AND SHIPPING INSTRUCTIONS 
Blood samples for HIV latent reservoir testing should only be collected for participants with 
hematocrit ≥ 25. 
Latent Reservoir Quantification 
To ship blood for latent reservoir quantitation, place twelve (or two) 8.5 mL yellow top (ACD) 
tubes into a canister of a STP-100 SAF-T-PAK shipper (VWR# 11217-163) wrapping each tube 
in bubble wrap and using the absorbent paper at the bottom of the canister. Each sample tube 
should be labeled using a Sharpie pen with the following information: 
• Protocol #: AMC-095 
• 9 digit Participant # 
• Date and time of collection 
• Specimen type: “Whole Blood” 
• Specimen purpose: “HIV latent reservoir” 
Specimen Shipment. Specimens are accepted TUESDAY through FRIDAY. All specimens 
should be shipped to: 
AMC Biorepository at GWU 
Jeff Bethony, PhD 
George Washington University Medical Center 
Ross Hall, Room 118 
2300 I Street NW 
Washington, DC 20037 
Tel: (202) 994-3422 
Fax: (202) 994-5056 
• Email: amc-bio@emmes.comPlease refer to the MOP and the AMC Operations website’s 
(www.AIDSCancer.org) Shipping tab for more information and the FedEx account details.It 
is only to be used for billing shipment of specimens to the lab where the sample is processed 
and/or stored.It is the responsibility of the Primary Investigator to ensure that all staff personnel 
who will be handling, packaging, and/or shipping clinical specimens act in conformance with 
International Air Transport Association (IATA) regulations (IATA Packing Instruction 650) 
relating to the handling and shipping of hazardous goods. (IATA Packing Instruction 650 is 
located on the AMC web site.) 
• Use a federally approved shipper for biological substance shipment (Category B). Label the 
shipper with the "Infectious substance" diamond-shaped label. On one side, in black marker 
write “Biological Substance, Category B, UN 3373”, your name or name of responsible person, 
date of collection, and phone number of the person responsible for the package. Package and 
label the shipment in accordance with the instructions provided for that specific shipper. 
• A Shipper’s Declaration for Dangerous Goods is not required. If shipping separated 
specimens on dry ice, the following information must be shown in sequence on the airway bill 
in the “Nature and Quality of Goods” box: Dry Ice, 9, UN1845, number of boxes being 
shipped, net weight of dry ice per box. 
Please Note: The shipper will be mailed back to the AMC site. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
184 
NCI Version Date 24AUG2023 
The STP-100 SAF-T-PAK shipper (VWR Cat #11217-163) is a complete shipment kit. To reuse 
the shipper, there is a refurbishment kit with sufficient replacement materials (STP102) (VWR Cat 
# 11217-166) for 15 mailings. 
INSTRUCTIONS BELOW FOR BLOODS COLLECTED ON FRIDAY: 
In the event that blood samples are drawn on Friday, the samples must be processed into plasma 
and PBMC immediately to maintain their viability for analysis, frozen over the weekend, and 
shipped to the lab on Monday. The HIV latent reservoir assay will be conducted using frozen 
PBMC and the single copy HIV viral load assay will be conducted using frozen plasma specimens. 
Preparation of Plasma and PBMCs 
Blood is to be processed on site within 6 hours of collection. 
Materials 
• Lymphocyte Separation Medium (LSM Solution, Ficoll-Hypaque - sterile) 
• 15 ml conical centrifuge tubes (sterile) 
• PBS (sterile) 
• 1 ml, 5 ml and 10 ml serologic pipettes (sterile) 
• 1.5 ml NUNC tubes 
• Alcohol saturated, control rate freezer container 
• DMSO freezing media 
• 50% Cryoprotective Medium, Cambrex (catalog no.:12-132A) 
• 50% Heat Inactivated Fetal Bovine Serum 
Plasma Separation and Freezing Procedures 
1. The 10 ml tubes of whole blood in ACD should be rotated gently two or three times before 
being centrifuged. Do not transfer before centrifugation. 
2. Separate the cells by centrifugation at 500 g for 10 minutes. 
3. Remove 0.5 ml aliquots of plasma and put into separate 1.5 ml NUNC tubes and transfer to 
liquid nitrogen storage. 
PBMC Separation and Freezing Procedures 
1. The cells and plasma remaining from the previous step are transferred into a 15 ml conical tube 
or 50 ml centrifuge tube depending on volume. 
2. Sterile PBS should be added to the suspended whole blood cells in an equal volume and 
pipetted up and down to mix (1:1). 
3. The whole blood-PBS mixture should be carefully overlaid onto 4-5 ml of room temperature 
LSM or Ficoll-Hypaque solution in a sterile 15 ml conical centrifuge tube. A sharp interface 
should exist between the LSM and the whole blood mixture. (If the layer of LSM gets mixed 
with the blood-PBS, the tube should be gently rotated to mix the blood, PBS, and LSM, and 
transfer to a 50 ml sterile conical tube. An equal volume of PBS is added, and the cells are 
separated at 600 g for 15 minutes. After removal of LSM-PBS supernatant, return to Step 2). 

 
AMC #095 (Version 15.0) 24AUG2023 
 
185 
NCI Version Date 24AUG2023 
4. Centrifuge the 15 ml conical tube for 30 minutes at 900 g at room temperature. The 
mononuclear leukocytes (principally lymphocytes and monocytes) will band at plasma/LSM 
interface. 
5. The fluffy white layer just below the plasma layer should be aspirated off and transferred to an 
appropriately labeled 15 ml sterile conical centrifuge tube. Be careful to remove only the 
interface and a minimum amount of the LSM or Ficoll-Hypaque. 
6. Add three volumes of PBS to the cell suspension and or enough to fill conical and mix by 
pipetting up and down. 
7. Centrifuge at 500 g for 10 minutes. 
8. Aspirate off and discard supernatant, taking care not to disturb pellet. 
9. Resuspend in 12 ml of PBS. Take 10 
l of suspension for cell counting (dilute accordingly 
whether using a hemocytometer or automated cell counter). Centrifuge again for 10 minutes at 
500g to wash cells. 
10. Using a 1 ml pipette, the *DMSO freezing mixture should be added dropwise to the cell pellet 
suspension. Gently finger-tap between drops to resuspend cells. If the cell pellet is small, only 
0.5 ml of freezing media is added (and only one aliquot of cells is frozen). If the cell pellet is 
large, up to 2 ml of freezing media can be added in a drop wise fashion. (Cell densities of 1-
10 million PBMC/ml are best for cryopreservation. If a hemocytometer is available, the 
optimal concentration is 5 x 106 PBMC/ml). 
*Important: Do not put the DMSO containing media on the cell button all at once. 
Freeze the cell suspension in 0.5 ml aliquots in sterile NUNC vials by placing the NUNC tubes 
in a room temperature, alcohol saturated, control rate freezer container and store in the -80°C 
freezer overnight. Transfer the cell suspension into the liquid nitrogen temperature freezer for 
long term storage the next working day. 
RECORD OF SPECIMENS 
This study will track specimens via GlobalTraceSM, a component of the AMC AdvantageEDCSM 
system. The GlobalTraceSM shipment manifest must accompany all specimen shipments. 
TECHNICAL QUESTIONS 
AMC Biorepository at GWU 
Jeff Bethony, PhD 
George Washington University Medical Center 
Ross Hall, Room 118 
2300 I Street NW 
Washington, DC 20037 
Tel: (202) 994-3422 
Fax: (202) 994-5056 
Email: amc-bio@emmes.com 
 

 
AMC #095 (Version 15.0) 24AUG2023 
 
186 
NCI Version Date 24AUG2023 
APPENDIX XVII: PROCEDURE FOR INTRA-ANAL HPV DNA PCR SAMPLE 
COLLECTION, PACKAGING, AND SHIPPING 
All HPV DNA PCR specimens will be collected at the local institution and shipped to the 
AMC Biorepository. Specimens will be shipped to the Joel Palefsky Laboratory at the end of 
the study for testing. 
PROCEDURE FOR OBTAINING INTRA-ANAL HPV DNA PCR SAMPLE 
The subject should undress from the waist down, and either bend over the exam table or lay on his 
side in the fetal position. The examiner should use one hand to spread the buttocks and expose the 
anoderm. A Dacron or polyester (not cotton, and not scored) swab moistened in sterile saline will 
then be inserted as far as is comfortable into the anus, a minimum of 2-3 inches. Do not use the 
swab provided with the Digene kit as it is scored to break easily into the collection tube and can 
break in the anus. If there is difficulty inserting the swab, the subject should also retract their 
buttocks. With pressure on the distal end of the swab, rotate it gently and slowly in a circular 
fashion as it is withdrawn over 15 to 30 seconds. Do not retract the buttocks when the swab is 
close to the verge to ensure that it is sampled as well. 
Immediately immerse the swab into a tube containing 1 mL of Specimen Transport Medium 
(Digene Female Swab Specimen Collection Kit, Qiagen Catalog #5123-1220, 1-800-426-8157), 
agitating vigorously over 10 to 15 seconds to disperse the cells. 
The swab should be placed in the collection vial and cut with sterile or single-use scissors to allow 
the swab to fit in the vial. The cap should then be replaced securely. 
Note: Specimens will be processed for HPV DNA PCR, not Digene HCII. 
SAMPLE LABELING 
Each sample must be labeled with the following information using AMC GlobalTrace labels. Each 
label is preprinted with a 9-digit specimen ID number: 
• 
Nine (9) Digit Subject ID: 095-XXX-XXX 
• 
Specimen Type: "Anal Swab”  
• 
Specimen Purpose: “HPV DNA PCR” 
• 
Date of Sample Collection: MM/DD/YYYY 
STORAGE 
Anal specimens obtained for HPV DNA testing should be stored at -80 C until they are ready to 
be shipped. All specimens will be batch shipped quarterly on dry ice by overnight delivery to the 
AMC Biorepository. 
If the site does not have a -80 C freezer, the site must store the specimens in refrigeration if 
possible (2-8 C) and ship the specimens to the AMC Biorepository within two weeks of 
collection. 
SHIPPING 
Please note that the shipment of these samples requires certified training in IATA 
regulations. All shipping materials can be ordered from SAF-T-PAK at www.saftpak.com.  

 
AMC #095 (Version 15.0) 24AUG2023 
 
187 
NCI Version Date 24AUG2023 
 
1. Please use the Saf-T-Pak STP 320 shipper (each tube must be sealed with moisture-resistant 
tape or parafilm under current IATA rules). Place securely fastened tubes in the clear biohazard 
bag with the absorbent strip. Seal bag. 
2. Place clear biohazard bag into the white TYVEK bag and seal bag. 
3. Place white TYVEK bag into inner box. 
4. Place the inner box into the STP 320 insulated box and place 5 lbs of dry ice in the insulated 
box around each side of the inner box. For sites shipping refrigerated specimens, use four 
frozen cold packs instead of dry ice, each placed in the space between the inner box and the 
inner wall of the insulated box. 
5. Place the lid on the insulated box. Place the GlobalTrace shipping manifest on top of the lid. 
6. Seal the box and place your FedEx airbill on the outside. 
7. Please refer to the MOP and the AMC Operations website’s (www.AIDSCancer.org) Shipping 
tab for more information and the FedEx account details.It is only to be used for billing shipment 
of specimens to the lab where the sample is processed and/or stored.Include a return FedEx 
Express or Ground Airbill charged to the AMC FedEx account for the return of shippers. 
8. Specimens should be shipped by overnight express to: 
Jeff Bethony, PhD 
AMC Biorepository 
George Washington Medical Center 
Ross Hall, Room 118 
2300 I Street, NW 
Washington, DC 20037 
Tel: (202) 994-2945 
Fax: (202) 994-5056 
Email: amc-bio@emmes.com 
***PLEASE DOUBLE CHECK PACKAGING OF SHIPPER AND DO NOT DEVIATE FROM 
REQUESTED LABELING. Shipping frozen aliquots requires the use of packaging acceptable for 
dry ice and Class 9 label with weight of dry ice written on package. STP-320 will come pre-printed 
with: Biological Substance Category B Marking, Exempt Human/Animal Specimen Marking, 
UN3373 Marking, Orientation Arrows, Class 9 Label and UN1845 Dry Ice Marking 
RECORD OF SPECIMENS 
This study will track specimens via GlobalTraceSM, a component of the AMC AdvantageEDCSM 
system. The GlobalTraceSM shipment manifest must accompany all specimen shipments. 
AMC BIOREPOSITORY INSTRUCTIONS 
Specimens will be frozen at -80C and stored until the end of the trial. Following receipt of the last 
specimens, the Biorepository will ship all specimens on dry ice to the Joel Palefsky Laboratory. 

 
AMC #095 (Version 15.0) 24AUG2023 
 
188 
NCI Version Date 24AUG2023 
Joel Palefsky Laboratory 
C/o Maria Da Costa 
University of California, San Francisco 
513 Parnassus Ave., Room S-420 
San Francisco, CA 94143 
Tel: 415-476-8885 
Email: Maria.DaCosta@ucsf.edu 
Specimens must only be shipped on Mondays and Tuesdays and not during the week of a federal 
holiday. 
TECHNICAL QUESTIONS 
Questions regarding these specimens may be directed to Maria Da Costa using the above contact 
information for the Palefsky Laboratory.