Conditions: AIDS-Related Non-Hodgkin Lymphoma Clinical Stage III Cutaneous Melanoma AJCC v8 Clinical Stage IV Cutaneous Melanoma AJCC v8 Hepatocellular Carcinoma HIV Infection Kaposi Sarcoma Locally Advanced Lung Non-Small Cell Carcinoma Locally Advanced Malignant Solid Neoplasm Metastatic Lung Non-Small Cell Carcinoma Metastatic Malignant Solid Neoplasm Metastatic Melanoma Non-Hodgkin Lymphoma Recurrent Classic Hodgkin Lymphoma Recurrent Malignant Neoplasm Refractory Classic Hodgkin Lymphoma Refractory Malignant Neoplasm Stage III Lung Cancer AJCC v8 Stage IV Lung Cancer AJCC v8 Unresectable Melanoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 58
Healthy volunteers: no

Brief summary:
This phase I trial studies the side effects of pembrolizumab in treating patients with human immunodeficiency virus (HIV) and malignant neoplasms that have come back (relapsed), do not respond to treatment (refractory), or have distributed over a large area in the body (disseminated). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of MK-3475 (pembrolizumab) in HIV-infected patients on effective antiretroviral therapy and with relapsed/refractory or disseminated acquired immune deficiency syndrome (AIDS)-defining or non-AIDS defining malignancy.

II. To assess the safety and feasibility of MK-3475 (pembrolizumab) administration as first systemic therapy for HIV associated Kaposi sarcoma in patients on effective antiretroviral therapy.

SECONDARY OBJECTIVES:

I. To obtain preliminary insights into clinical benefit (e.g., tumor shrinkage or stabilization \>= 24 weeks) across a variety of tumors in patients infected with HIV and on effective antiretroviral therapy.

II. To evaluate the response rate in Kaposi sarcoma impacting physical and/or psychological wellbeing and not amenable to local therapy.

EXPLORATORY OBJECTIVES:

I. To assess the correlation of pre-therapy tumor PD-L1 expression and T-cell infiltration on clinical benefit.

II. To assess the effect of MK-3475 (pembrolizumab) on circulating HIV and the HIV viral reservoir in patients on effective combination anti-retroviral therapy (cART), as measured by plasma HIV single copy ribonucleic acid (RNA), CD4+ T-cell associated HIV unspliced RNA, CD4+ T-cell associated integrated HIV deoxyribonucleic acid (DNA) provirus, ratio of HIV unspliced RNA/DNA, "Tat/Rev induced limiting dilution assay" (TILDA), and phylogenetic analysis of HIV-1 molecular evolution.

III. To evaluate the effect of MK-3475 (pembrolizumab) on host gene expression in circulating blood cells.

IV. To evaluate the effect of MK-3475 (pembrolizumab) on circulating HIV-specific CD8+ T-cell cytotoxicity against autologous HIV infected CD4+ T-cells in patients on effective antiretroviral therapy.

V. To evaluate the effect of MK-3475 (pembrolizumab) on circulating lymphocyte and monocyte numbers and phenotypes.

VI. To assess biopsied tumors from participants that progress by immunohistochemistry arrays and gene expression analysis to evaluate potential reasons for the lack of response to MK-3475 (pembrolizumab) or progression such as a lack of T cells within or around tumor.

VII. To evaluate the effect of pembrolizumab on human herpesvirus 8 (KSHV) viral load in the blood, KSHV seroreactivity and KSHV specific CD8+ T-cell activity.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Patients continue receiving their recommended combination antiretroviral therapy orally (PO) once daily (QD). Cycles repeat every 21 days for up to 2 years or 35 doses in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or positron emission tomography (PET)/CT and blood sample collection throughout the trial. Patients may also undergo biopsies during screening and on study.

After completion of study treatment, patients are followed up 30 days and then every 12 weeks up to 1 year.

Arms:
arm 1: Patients receive pembrolizumab IV over 30 minutes on day 1. Patients continue receiving their recommended combination antiretroviral therapy PO QD. Cycles repeat every 21 days for up to 2 years or 35 doses in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or PET/CT and blood sample collection throughout the trial. Patients may also undergo biopsies during screening and on study.

Interventions: intervention 1: Antiretroviral Therapy intervention 2: Biopsy intervention 3: Biospecimen Collection intervention 4: Computed Tomography intervention 5: Pembrolizumab intervention 6: Positron Emission Tomography
Intervention descriptions: intervention 1: Given PO intervention 2: Undergo biopsy intervention 3: Undergo blood sample collection intervention 4: Undergo CT or PET/CT intervention 5: Given IV intervention 6: Undergo PET/CT

Protocol document:
Prot_SAP_000.pdf: 
SUMMARY OF CHANGES – Protocol 
 
For Protocol Amendment 13, version 1.0 to: 
 
NCI Protocol #: CITN-12 
Local Protocol #: CITN-12 
 
NCI Version Date: February 17, 2023 
Protocol Date: February 17, 2023 
 
Protocol Title: Phase I Study of MK-3475 (Pembrolizumab) in Patients with Human 
Immunodeficiency Virus (HIV) and Relapsed/Refractory or Disseminated Malignant 
Neoplasm  
 
 
 
I. 
Changes requested in the RRA from Dr. Elad Sharon, dated February 3, 2023 
# 
Section 
Page(s) 
Comments 
1. 
6.1 
62 
Revision to the dose modification guidelines per RRA dated February 3, 
2023. The following changes are incorporated: 
• 
Deleted:  
• 
General dose modification guidelines for KSHV-associated 
multicentric Castleman disease (MCD) 
• 
Sentence “Please note: prior to restarting the infusion, 
confirm that the 6 hour room temperature stability from the 
time of the IV bag preparation will not be exceeded. 
Otherwise dosing will be held until symptoms resolve and 
the subject should be pre-medicated for the next scheduled 
dose” was removed from Grade 2 infusion related reaction 
treatment.  
 
• 
Updated existing guidelines: 
• 
Added to general instructions: “non-endocrine-related” 
severe irAEs. “Some non-endocrine irAEs do not require 
steroids.”  
• 
Grade 3 or 4 Type 1 diabetes mellitus (T1DM) or 
Hyperglycemia 
• 
Grade 2, 3, or 4 Hypophysitis  
• 
Grade 2, 3, or 4 Hyperthyroidism 
• 
Grade 2, 3 or 4 Nephritis   
• 
Myocarditis updated to Cardiac Events (including 
myocarditis, pericarditis, arrhythmias, impaired ventricular 
function, vasculitis, with new monitoring and follow-up 
guidelines 
• 
Monitoring and follow-up guidelines for Diarrhea/Colitis 


# 
Section 
Page(s) 
Comments 
• 
Treatment and Premedication at subsequent dosing for 
Grade 3 and 4 infusion reactions 
• 
Added new guidelines: 
• 
Grade 1 or 2 Type 1 diabetes mellitus (T1DM) or 
Hyperglycemia  
• 
Confirmed Exfoliative Dermatologic Conditions (SJS, TEN 
or DRESS) 
2. 
7.1.1 
72-76 
Insertion of Revised CAEPR (Version 2.7, December 13, 2022). The 
following changes are incorporated:  
• 
Added New Risk: 
• 
Rare but Serious: Endocrine disorders - Other 
(hypoparathyroidism); Nervous system disorders - Other 
(optic neuritis)  
 
• 
Decrease in Risk Attribution: 
• 
Changed to Also Reported on Pembrolizumab (MK-3475) 
Trials But With Insufficient Evidence for Attribution from 
Less Likely: CPK increased; Joint effusion; Pleuritic pain 
 
• 
Deleted: 
• 
Less Likely: Avascular necrosis; Immune system disorders - 
Other (pseudoprogression/tumor inflammation); Infection; 
Musculoskeletal and connective tissue disorder - Other 
(tenosynovitis) 
• 
Footnote #4 “Infection includes all 75 sites of infection 
under the INFECTIONS AND INFESTATIONS SOC.” is 
deleted. 
 
 
 
II. 
Administrative Changes  
 
# 
Section 
Page(s) 
Change 
1. 
Throughout  
Updated version date throughout the protocol.  


 
NCI Protocol #: 
                              CITN-12 
 
Local Protocol #: 
CITN-12 
ClinicalTrials.gov Identifier:  
NCT02595866 
TITLE:  
Phase I Study of MK-3475 (Pembrolizumab) in Patients 
with Human Immunodeficiency Virus (HIV) and 
Relapsed/Refractory or Disseminated Malignant 
Neoplasm  
Coordinating Center: 
Cancer Immunotherapy Trials Network (CITN), 
Fred Hutchinson Cancer Research Center 
 
Principal Investigator: 
Kathryn A. Lurain, M.D., M.P.H.  
Center for Cancer Research  
National Cancer Institute  
Bethesda, MD 20892-1868 
Kathryn.lurain@nih.gov  
 
Participating organizations: 
CITN – Cancer Immunotherapy Trials Network  


NCI Protocol # CITN-12 
Version Date: February 17, 2023 
 
1 
Statistician: 
 
Study Coordinator: N/A 
 
Bob Salim, PhD 
Axio Research 
2601 4th Ave, Suite 200 
Seattle, WA 98121 
Tel: 1- 206-547-2829 
Email: bob.salim@cytel.com  
 
 
Responsible Research Nurse: N/A 
Responsible Data Manager: N/A 
NCI-Supplied Agent(s):  
MK-3475 (Pembrolizumab, SCH 900475) (NSC # 
776864) 
Other Agent(s): N/A 
 
Protocol Type / Version # / Version Date: Amendment 13 / Version 1.0 / February 17, 2023  
 
IND #:  
IND Sponsor: DCTD, NCI 


NCI Protocol # CITN-12 
Version Date: February 17, 2023 
 
2 
CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data 
submission: 
Regulatory documentation must 
be submitted to the Clinical 
Trials Support Unit (CTSU) via 
the Regulatory Submission 
Portal. 
(Sign in at 
https://www.ctsu.org, and 
select Regulatory > Regulatory 
Submission.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately by phone or email: 
1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878) for regulatory assistance. 
Refer to the patient enrollment section of 
the protocol for instructions on using the 
Oncology Patient Enrollment Network 
(OPEN). OPEN can be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave.  
 
Refer to the data 
submission section of 
the protocol for further 
instructions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU Members’ website (https://www.ctsu.org).  
Access to the CTSU members’ website is managed through the Cancer Therapy Evaluation Program – 
Identity and Access Management (CTEP-IAM) registration and requires log on with CTEP-IAM 
username and password. 
For clinical questions (i.e. patient eligibility or treatment-related): 
Contact the CITN Central Operations and Statistical Center at citn@fhcrc.org  
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or email:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Web site is located at https://www.ctsu.org. 


NCI Protocol # CITN-12 
Version Date: February 17, 2023 
 
3 
SUMMARY 
Title 
Phase I Study of MK-3475 (pembrolizumab) in Patients with Human 
Immunodeficiency Virus (HIV) and Relapsed/Refractory or 
Disseminated Malignant Neoplasm 
Trial Phase 
Phase I 
Clinical Indication 
HIV+ patients on highly effective anti-retroviral therapy (cART) who 
also have cancer  
Trial Type 
Single Arm, Therapeutic 
Type of control 
Nonrandomized trial with primary aim of assessing safety and tolerability 
of MK-3475 (pembrolizumab) in this population. Efficacy endpoints of 
ORR, PFS, DOR and OS may be chronicled and reported for each type of 
cancer. 
Route of administration 
Intravenous (IV)  
Trial Blinding 
None 
Treatment Group  
MK-3475 (pembrolizumab), 200 mg every 3 weeks (q3wks)  
Number of trial patients 
Three or six patients will initially be enrolled into each of the first 3 
cohorts (based on CD4+ T-cell counts), pending safety analysis. If a safe 
dose is established, each cohort may be expanded to 12 patients for a total 
of 36 patients. Additionally, a fourth cohort will be enrolled. Cohort 4 
will consist of 24 patients with HIV associated Kaposi sarcoma.  
Estimated duration of trial 3 years 
Duration of Participation 
Each patient will participate in the trial from the time the Informed 
Consent Form (ICF) is signed through final protocol-specified contact. 
After a screening phase for eligibility, patients will receive MK-3475 
(pembrolizumab) every 3 weeks in addition to ongoing established cART 
regimen.  
Treatment for patients that achieve a stable disease (SD) or a partial 
response (PR) may continue for a maximum of 2 years or 35 doses. 
Patients will be stratified into 3 cohorts based on CD4+T-cell counts 
standard in many HIV therapy trials (cohorts 1-3) or into an additional 
cohort based on KS (cohort 4): 
Cohort 1: 50-199 CD4+ T cells/mcL 
Cohort 2: 200-350 CD4+ T cells/mcL 
Cohort 3: >350 CD4+ T cells/mcL 
Cohort 4: Kaposi sarcoma impacting physical and/or psychological 
wellbeing and not amenable to local therapy. 
Accrual to each cohort (cohorts 1-3) will be based on unacceptable AEs 
experienced during first treatment cycle of 21 days. If 2 or more 
unacceptable AEs occur in the first 6 patients, the cohort will not be 
expanded to 12 patients until the AEs are assessed by the Toxicity 
Evaluation Committee and the Committee approves the expansion.  


NCI Protocol # CITN-12 
Version Date: February 17, 2023 
 
4 
Accrual to Cohort 4 will start after at least 6 subjects in each of Cohorts 
1-3 have completed at least 1 cycle of pembrolizumab and the Toxicity 
Evaluation Committee has reviewed the data. 
MK-3475 (pembrolizumab) will be continued in each patient until 
confirmed progression or the development of an unacceptable AE. Safety 
will be assessed after the initial 3 participants in each cohort have 
completed one cycle of therapy (21 days), and again if 2 unacceptable 
AEs are observed during the first cycle for the first 6 participants 
subsequently treated in the same cohort.  
If 2 or more of the first 6 patients in any individual cohort, and/or ≥1/3 
participants in any individual cohort at any time experience unacceptable 
AEs, the entry into that cohort will be suspended and toxicities assessed 
by the Toxicity Evaluation Committee. The Toxicity Evaluation 
Committee will decide whether accrual should be stopped in that cohort 
or for the entire trial.  
If greater than 1/3 total patients, across all cohorts, develop an 
unacceptable AE in the first cycle of therapy (21 days), the Toxicity 
Evaluation Committee will evaluate the totality of the data to determine 
whether accrual will be suspended in the trial.  
Objective responses and disease progression will be monitored by 
computed tomography (CT) scans and physical examination, scheduled at 
9-week intervals during the first year of treatment and at 12-week 
intervals during the second year of treatment. Responses and progression 
will be assessed by RECIST 1.1, 2014 “Lugano Classification” Response 
Criteria for Malignant Lymphoma, or other relevant tumor-specific 
criteria. 
Administration of MK-3475 (pembrolizumab) will be stopped with: 
documented disease progression warranting alternative systemic therapy, 
unacceptable adverse event(s), intercurrent illness that prevents further 
administration of treatment, investigator’s decision to withdraw the 
patient, patient withdraws consent, pregnancy of the patient, 
noncompliance with trial treatment or procedure requirements, 
completion of 2 years of treatment, or other administrative reasons.  
After the end of treatment, each patient will be followed for 30 days for 
adverse event monitoring and attend a Post-Treatment follow up visit. 
Serious adverse events will be collected for 90 days after the end of 
treatment with investigator attribution as to whether the SAE is 
associated with MK-3475 (pembrolizumab) or subsequent therapies. 
After the Post-Treatment Safety Follow-Up Visit, patients will be seen in 
follow up visits every 3 months for 1 year. 


NCI Protocol # CITN-12 
Version Date: February 17, 2023 
 
5 
Patient Visit Timeline (dosing, disease assessments, and correlative blood draws) (v 1.0) 
 


NCI Protocol # CITN-12 
Version Date: February 17, 2023 
 
6 
TABLE OF CONTENTS 
SUMMARY ..................................................................................................................................................... 3 
1. 
OBJECTIVES .......................................................................................................................................... 8 
1.1 
Primary Objectives ........................................................................................................................... 8 
1.2 
Secondary Objectives ....................................................................................................................... 8 
1.3 
Exploratory Objectives .................................................................................................................... 8 
2. 
BACKGROUND ................................................................................................................................... 10 
2.1 
Cancer in People with HIV ............................................................................................................ 10 
2.2 
CTEP IND Agent: MK-3475 (pembrolizumab) ............................................................................ 25 
2.3 
Other Agent(s): Combination Antiretroviral therapy (cART) ....................................................... 30 
2.4 
Rationale ........................................................................................................................................ 31 
2.5 
Correlative Studies Background .................................................................................................... 31 
3. 
PATIENT SELECTION ........................................................................................................................ 38 
3.1 
Eligibility Criteria .......................................................................................................................... 38 
3.2 
Exclusion Criteria .......................................................................................................................... 42 
3.3 
Inclusion of Women and Minorities .............................................................................................. 44 
4. 
REGISTRATION PROCEDURES ........................................................................................................ 44 
4.1 
Investigator (IVR), Non-Physician Investigator (NPIVR), and Associate Plus (AP) Registration 
with CTEP ............................................................................................................................................... 44 
4.2 
Site Registration ............................................................................................................................. 46 
4.3 
Patient Registration ........................................................................................................................ 48 
4.4 
General Guidelines ......................................................................................................................... 49 
5. 
TREATMENT PLAN ............................................................................................................................ 49 
5.1 
Agent Administration ..................................................................................................................... 50 
5.2 
Safety Monitoring and Definition of Unacceptable Adverse Events (AEs) .................................. 52 
5.3 
General Concomitant Medication and Supportive Care Guidelines .............................................. 55 
5.4 
Duration of Therapy ....................................................................................................................... 57 
5.5 
Duration of Follow Up ................................................................................................................... 58 
5.6 
Criteria for Removal from Study ................................................................................................... 58 
5.7 
Criteria to Resume Treatment ........................................................................................................ 59 
5.8 
Treatment Beyond Progression ...................................................................................................... 59 
5.9 
Criteria for Discontinuing MK-3475 (pembrolizumab) in Patients Achieving a CR .................... 60 
5.10 
Retreating with MK-3475 (pembrolizumab) in Patients with Recurrence ................................ 61 
6. 
DOSING DELAYS/DOSE MODIFICATIONS .................................................................................... 61 
6.1 
MK-3475 (pembrolizumab) Dose Modifications ........................................................................... 61 
6.2 
Delayed Visits for Reasons Other Than Toxicity .......................................................................... 76 
7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .................................................. 77 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ....................................... 77 
7.2 
Adverse Event Characteristics ....................................................................................................... 82 
7.3 
Expedited Adverse Event Reporting .............................................................................................. 82 
7.4 
Routine Adverse Event Reporting ................................................................................................. 84 
7.5 
Secondary Malignancy ................................................................................................................... 84 
7.6 
Second Malignancy ........................................................................................................................ 85 


NCI Protocol # CITN-12 
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7 
7.7 
Reporting of Pregnancy and Lactation to the Sponsor ................................................................... 85 
8. 
PHARMACEUTICAL INFORMATION .............................................................................................. 85 
8.1 
CTEP IND Agent ........................................................................................................................... 85 
8.2 
Other Investigational Agent(s): N/A .............................................................................................. 88 
8.3 
Commercial Agent(s): N/A ............................................................................................................ 88 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ............................................................. 88 
9.1 
Integral Laboratory Studies ............................................................................................................ 89 
9.2 
Exploratory/Ancillary Correlative Studies ..................................................................................... 89 
9.3 
Special Studies ............................................................................................................................... 98 
10. 
STUDY CALENDARs ...................................................................................................................... 99 
11. 
MEASUREMENT OF EFFECT ...................................................................................................... 107 
11.1 
Antitumor Effect – Solid Tumors ............................................................................................ 107 
11.2 
Antitumor Effect – Hodgkin Lymphoma and non-Hodgkin Lymphoma ................................ 114 
11.3 
Antitumor Effect - Kaposi Sarcoma ......................................................................................... 119 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ......................................................... 121 
12.1 
Data Reporting ......................................................................................................................... 121 
12.2 
CTEP Multicenter Guidelines .................................................................................................. 123 
12.3 
Collaborative Agreements Language ....................................................................................... 124 
13. 
STATISTICAL CONSIDERATIONS ............................................................................................. 125 
13.1 
Study Design/Endpoints ........................................................................................................... 125 
13.2 
Summaries of Baseline Characteristics, Demographics, and Other Analyses ......................... 129 
13.3 
Sample Size/Accrual Rate - Cohorts 1-3 ................................................................................. 130 
13.4 
Cohort 4 Sample Size ............................................................................................................... 130 
13.5 
Stratification Factors ................................................................................................................ 131 
13.6 
Analysis of Secondary Endpoints ............................................................................................ 132 
14. 
REFERENCES ................................................................................................................................ 133 
APPENDIX A PERFORMANCE STATUS CRITERIA ............................................................................. 148 
APPENDIX B CTEP MULTICENTER GUIDELINES .............................................................................. 149 
APPENDIX C BIOASSAY TEMPLATES .................................................................................................. 151 
APPENDIX D  COMMON SIDE EFFECTS OBSERVED WITH AGENTS PRESCRIBED AS PART OF 
DHHS- RECOMMENDED AND ALTERNATE CART REGIMENS ...................................................... 155 
APPENDIX E  KS CUTANEOUS AND ORAL EXAM AND EVALUATION KS RESPONSE .......... 156 
APPENDIX F  KAPOSI SARCOMA RESPONSE SHEET .................................................................... 171 
 


NCI Protocol # CITN-12 
Version Date: February 17, 2023 
 
8 
1. 
OBJECTIVES 
 
Primary Objectives 
1.1.1 To assess the safety and tolerability of MK-3475 (pembrolizumab) in HIV-infected patients 
on effective antiretroviral therapy and with relapsed/refractory or disseminated AIDS-
defining or non-AIDS defining malignancy. 
Hypothesis: MK-3475 (pembrolizumab) is safe and tolerable in patients with HIV and 
cancer who are on effective antiretroviral therapy. 
1.1.2 To assess the safety and feasibility of MK-3475 (pembrolizumab) administration as first 
systemic therapy for HIV associated Kaposi sarcoma in patients on effective antiretroviral 
therapy. 
Hypothesis: MK-3475 (pembrolizumab) administration will be safe and feasible in this 
patient population with appropriate supportive care. 
 
Secondary Objectives 
1.2.1 To obtain preliminary insights into clinical benefit (e.g., tumor shrinkage or stabilization 
≥24 weeks) across a variety of tumors in patients infected with HIV and on effective 
antiretroviral therapy. 
Hypothesis: MK-3475 (pembrolizumab) will have antitumor activity in some patients with 
HIV and cancer, measurable by clinical response or disease stabilization of ≥24 weeks. 
1.2.2 To evaluate the response rate in Kaposi sarcoma impacting physical and/or psychological 
wellbeing and not amenable to local therapy.  
Hypothesis: MK-3475 (pembrolizumab) will have antitumor activity:  
• As first systemic therapy in treatment naïve patients with HIV associated Kaposi 
sarcoma on effective antiretroviral therapy. 
• As therapy for patients with HIV associated Kaposi sarcoma that has relapsed or 
has had inadequate response to prior therapy. 
 
Exploratory Objectives 
1.3.1 To assess the correlation of pre-therapy tumor PD-L1 expression and T-cell infiltration on 
clinical benefit.  
Hypothesis: MK-3475 (pembrolizumab) activity will be associated with tumor PD-L1 
expression and T-cell infiltration. 


NCI Protocol # CITN-12 
Version Date: February 17, 2023 
 
9 
1.3.2 To assess the effect of MK-3475 (pembrolizumab) on circulating HIV and the HIV viral 
reservoir in patients on effective cART (defined in Section 3.1.4), as measured by plasma 
HIV single copy RNA, CD4+ T-cell associated HIV unspliced RNA, CD4+ T-cell 
associated integrated HIV DNA provirus, ratio of HIV unspliced RNA/DNA, “Tat/Rev 
Induced Limiting Dilution Assay” (TILDA), and phylogenetic analysis of HIV-1 molecular 
evolution.  
Hypothesis: In patients on effective cART, MK-3475 (pembrolizumab) will lead to latency 
reversal and associated short-term increases in HIV RNA in plasma and CD4+ T-cells, but 
over time will lead to a decrease in the HIV viral reservoir and alterations in HIV-1 genetic 
variation.  
1.3.3 To evaluate the effect of MK-3475 (pembrolizumab) on host gene expression in circulating 
blood cells. 
Hypothesis: MK-3475 (pembrolizumab) will alter gene expression in circulating blood 
cells to a yet unknown extent. 
1.3.4 To evaluate the effect of MK-3475 (pembrolizumab) on circulating HIV-specific CD8+ T-
cell cytotoxicity against autologous HIV infected CD4+ T-cells in patients on effective 
antiretroviral therapy. 
Hypothesis: MK-3475 (pembrolizumab) will improve HIV virus-specific CD8+ T-cell 
cytotoxicity in HIV-infected participants. 
1.3.5 To evaluate the effect of MK-3475 (pembrolizumab) on circulating lymphocyte and 
monocyte numbers and phenotypes. 
Hypothesis: Pembrolizumab will perturbate circulating lymphocyte and monocyte numbers 
and phenotypes to a yet unknown extent. 
1.3.6 To assess biopsied tumors from participants that progress by immunohistochemistry arrays 
and gene expression analysis to evaluate potential reasons for the lack of response to MK-
3475 (pembrolizumab) or progression such as a lack of T cells within or around tumor. 
Hypothesis: Lack or loss of a response to MK-3475 (pembrolizumab) will occur as a result 
of a lack of infiltrating T cells and/or alternative immune suppressive pathways, as 
measured by immune gene expression profiling panel. 
1.3.7 To evaluate the effect of pembrolizumab on KSHV viral load in the blood, KSHV 
seroreactivity and KSHV specific CD8+ T-cell activity 
Hypothesis: Pembrolizumab will perturb KSHV reservoirs and immune response to a yet 
unknown extent. 


NCI Protocol # CITN-12 
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10 
2. 
BACKGROUND 
 
Cancer in People with HIV 
2.1.1 Rationale and Background: 
Human immunodeficiency virus (HIV)-infected individuals with cancer are often excluded 
from clinical trials that test novel agents. Improving access to clinical trials for this 
population is an ongoing focus of the Division of Cancer Treatment and 
Diagnosis/National Cancer Institute (DCTD/NCI), and these efforts have been funded in 
part by funds to Cancer Therapy Evaluation Program (CTEP) from the Office of Acquired 
Immunodeficiency Syndrome (AIDS) Research. This joint proposal from the Cancer 
Immunotherapy Trials Network (CITN) and the NIH Center for Cancer Research HIV and 
AIDS Malignancy Branch is primarily aimed at showing the feasibility of administering 
MK-3475 (pembrolizumab) to individuals with both HIV infection and cancer. If this trial 
shows that the agent can be safely given in this setting, exclusion from other trials using 
this agent then will have no medical basis for exclusion based solely on HIV infection in 
patients otherwise meeting protocol eligibility criteria. Thus, a major public health intent of 
this trial is to further the public health mission of the NCI in providing access to clinical 
trials for the American population regardless of HIV serostatus. To accomplish this goal, 
we propose to evaluate the safety and tolerability and to establish the tolerated dose of MK-
3475 (pembrolizumab) in a phase I study adequately sized to provide confidence of the 
safety of administering MK-3475 (pembrolizumab) in patients with HIV and cancer.  
This study may also inform future studies of MK-3475 (pembrolizumab) in specific 
cancers, such as HIV-associated lung cancer or HIV-associated classic Hodgkin lymphoma 
(cHL), where there is strong rationale for disease-specific clinical studies. Indeed, the NCI 
Board of Scientific Advisors (BSA) Ad Hoc Subcommittee on HIV and AIDS Malignancy 
recently identified the study of agents that target the programmed cell death-1 (PD-1) 
checkpoint in lung cancer as a research priority. It will also provide prospective safety data 
for its use in patients with HIV who have malignancies for which the drug has approval 
from the US Food and Drug Administration (FDA). Lastly, the proposed trial is expected to 
provide important virologic and immunologic correlative science related to the effect of 
checkpoint blockade in patients with HIV and cancer. 
2.1.2 The Growing Burden of Cancer in People with HIV 
HIV and associated immune suppression has been strongly associated with several mature 
B-cell lymphomas and Kaposi sarcoma (KS) since the beginning of the AIDS epidemic. 
Although the incidence of these cancers have decreased in relative terms since the 
introduction of effective combination antiretroviral therapy (cART), the relative incidence 
for these tumors remains dramatically elevated compared to the general population. It is 
increasingly recognized that several additional cancers occur with increased frequency in 
people with HIV, most importantly lung cancer, cancers associated with human 
papillomavirus (HPV; anal cancer, cervical cancer, oropharyngeal cancer), cHL, and 
hepatocellular carcinoma (HCC) (Table 1). In addition to occurring with increased 
frequency, some epidemiologic data suggests that the natural history of many of these 
tumors may be somewhat different in patients with HIV.(Shiels 2010)  


NCI Protocol # CITN-12 
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11 
With the introduction of effective antiretroviral therapy, infectious mortality has decreased 
dramatically in this patient population, and malignancies have become a leading cause of 
morbidity and mortality. In the United States, an estimated 1.2 million people have HIV 
infection. As this population ages, the burden of certain cancers such as lung cancer, anal 
cancer, and cHL continues to increase.(Shiels 2011) Cancer is estimated to be responsible 
for over one-third of all deaths in this patient population.(Bonnet 2009) A recent report 
from the French Mortalite 2010 survey of deaths in 82,000 HIV-infected patients looked at 
the underlying causes of over 700 deaths from 2000 to 2010. AIDS-defining malignancies 
were the cause of death in 10% of patients. Non-AIDS defining malignancies (NADM) 
were the cause of death in 26% of the patients in the most recent period, doubling from 
2000. Of the 193 NADM deaths, the commonest were bronchopulmonary malignancies 
(32%), HCC (17%), head and neck cancers (8%), and anal cancer (8%).(Morlat 2014) 
Lymphoma, lung cancer, and liver cancer are currently the leading causes of death from 
cancer in patients with HIV.(Bonnet 2009, Simard 2010, Achenbach 2011) In addition, 
more than 35 million people are infected with HIV globally, and with rapidly expanding 
HIV treatment programs, cancer in people with HIV is becoming a major global health 
issue.  
At the same time as cancers are becoming a leading cause of morbidity and mortality 
among people with HIV, disparities in the treatment and outcomes of patients with HIV 
and cancer persisting in the cART era have been reported and are most notable for 
disparities in lymphoma and lung cancer.(Suneja 2014, Uldrick 2014) For these tumors, 
HIV-infected patients are less likely to receive chemotherapy or surgery. HIV infection in 
patients with non-small lung cancer (NSCLC) is associated with a higher cancer-specific 
mortality. Decreasing these disparities requires the implementation of effective therapies, 
and the inclusion of patients with HIV in clinical trials for diseases without good treatment 
options.  
Advances in cancer therapeutics are urgently needed for several viral-associated tumors, 
lung cancer, and refractory lymphomas in people with HIV.(Persad 2008, Suneja 2014) For 
some of these tumors, immunotherapy might be more active in patients with HIV than in 
the general population. Recent advances in the treatment of diffuse large B-cell lymphoma, 
Burkitt lymphoma, and cHL (Dunleavy 2010, Montoto 2012, Dunleavy 2013) have 
demonstrated that with appropriate management of HIV, patients with HIV and cancer can 
tolerate standard regimens. Nonetheless, specific attention to the safety of immunotherapy 
in patients with HIV and activity of immunotherapy in certain common tumors occurring in 
this setting is required. In addition, correlative studies that evaluate the dysregulation of 
checkpoint inhibition in HIV infection are likely to advance our understanding of control of 
chronic viral infections and perhaps malignancies in people with HIV. 


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Table 1: Common Malignancies in People with HIV in the cART Era (Engels 2006, Engels 
2008, Shiels 2011, Shiels 2011, Robbins 2014)  
Malignancies 
Standard 
Incidence Ratio 
(HIV only/AIDS) 
Recent 
Incidence  
in HIV (per 
100,000 person-
yrs.) 
Estimated % of 
all cancers 2004-
2007 in HIV/AIDS 
in US 
Viral 
Associations 
AIDS-Defining Malignancies 
Non-Hodgkin 
lymphoma* 
 
 
 
 
Systemic 
10-15/30-60 
>153* 
25.9% 
EBV, KSHV 
Primary CNS 
lymphoma 
250/1,020 
27 
3% 
EBV 
Kaposi sarcoma 
1,300/3,640 
110 
18.5% 
KSHV 
Cervical cancer 
2.9/5.3 
47 
2.4% 
HPV 
Non-AIDS Defining Malignancies 
Lung cancer 
2.6/2.6 
78 
10% 
- 
Anal cancer 
9.2/20 
59 
5.7% 
HPV 
cHL 
5.6/14 
33 
4.4% 
EBV 
Oropharyngeal 
carcinoma 
1.7/2.1 
22 
2.5% 
HPV 
HCC 
2.7/3.3 
32 
2.3% 
HBV, HCV 
Abbreviations: cHL, classic Hodgkin lymphoma; EBV, Epstein-Barr virus; HBV, hepatitis B virus; HCC, 
hepatocellular carcinoma; HCV, hepatitis C virus; HPV, human papillomavirus; KSHV, Kaposi sarcoma–associated 
herpes virus; US, United States. 
*Includes diffuse large B-cell lymphoma and Burkitt lymphoma, but not other rarer histologies 
 
2.1.3 PD-1/PD-L1 Checkpoint Blockade 
Programmed cell death-1 (PD-1) is a co-inhibitor receptor that negatively regulates antigen 
receptor signaling of CD8+ effector T cells.(Nishimura 1999, Brahmer 2012) PD-1 is 
expressed on the surface of T-cells (Ishida 1992, Agata 1996, Vibhakar 1997) as well as on 
other immune cells such as monocytes and macrophages.(Ma 2011) Program cell death 
ligand 1 (PD-L1) is a cell-surface glycoprotein and one of the ligands of PD-1. PD-L1 is 
expressed on the surface of many tumor cells and antigen-presenting cells.(Dong 2002, 
Iwai 2002, Zou 2008) Binding of PD-L1 to PD-1 leads to the inhibition of T-cell–mediated 
lymphocyte proliferation and cytokine secretion, resulting in T-cell exhaustion and 
hampering of immune responses.(Freeman 2000) Targeting and inhibiting the interaction of 
PD-L1 with PD-1 releases the immune checkpoint blockade and may elicit antitumor 
activity for some cancers.(Dong 2002, Iwai 2002) 
2.1.4 Chronic Viral Infections, Including HIV and the PD-1/PD-L1 Pathway 
Chronic viral infections, including HIV, generate “exhausted” CD8+ T cells with a 
diminished capacity to both produce cytokines and lyse infected cells. In the setting of 


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chronic antigenic stimulation, this diminished immune function is associated with T-cell 
upregulation of messenger RNA (mRNA) encoding PD-1. In viral infections, PD-1 and 
PD-L1 are also upregulated by interferons in various cell types, including monocytes and 
antigen-presenting cells.(Cheng 2007, Ma 2011, Teijaro 2013) Additional viral-specific 
mechanisms are poorly understood; however one recent mechanistic study demonstrated 
that the HIV gene nef appears necessary for PD-1 upregulation and that PD-1 upregulation 
can be decreased by the phosphatidylinositol 3-kinase and protein kinase B (PI3K/Akt) 
pathway or inhibitors of the p38 mitogen-activated protein kinase (MAPK) 
pathway.(Muthumani 2008, Muthumani 2011) Additional viral- and tissue-specific 
mechanisms are possible. Dysregulation of PD-1 in the setting of HIV may be relevant to 
both the natural history of cancer and the maintenance of viral reservoirs in these patients. 
In mice, blockade of the PD-1 receptor caused an increase in virus-specific CD8+ T-cell 
proliferation and enhanced the clearance of the chronic viral infection.(Barber 2006) PD-
L1 knockout mice also have increased clearance of viral infection with lymphocytic 
choriomeningitis virus, further supporting a role for the PD-1/PD-L1 pathway in chronic 
viral infections. However, in this setting, PD-L1 knockout mice also have increased 
inflammation in the lung and liver when exposed to viruses than wild-type mice.(Mueller 
2010) 
In HIV infection, PD-1 expression on HIV-specific CD8+ cells is associated with disease 
progression, an increase in plasma viral load, and a decrease in CD4+ T-cell counts.(Day 
2006) In a prospective study of HIV-infected patients treated with highly active 
antiretroviral therapy (cART), T-cell activation (CD38+HLADR+) and immune exhaustion 
parameters (PD-1+) were measured upon the initiation of therapy. T-cell exhaustion 
(CD4+PD-1+ and CD8+PD-1+ T cells) was significantly associated with suboptimal CD4 
reconstitution and persisted despite long-term sustained HIV-RNA viral 
suppression.(Nakanjako 2011) Interestingly, blockade of PD-1 reversed HIV-induced T-
cell exhaustion in vitro, enhanced a virus-specific immune response, and decreased viral 
load in vivo in humanized mice and macaques infected with simian immunodeficiency 
virus (SIV).(Trautmann 2006, Seung 2013),(Velu 2009, Zhou 2013),(Palmer 2013) 
Recently, Cubas et al proposed a model in which HIV infection may drive the expansion of 
both T follicular cell helper (Tfh) cells and germinal center B cells (GCBs), as corroborated 
by the findings of an increased frequency of PD-L1 in GCBs. That, in turn, led to excessive 
triggering of PD-1 on Tfh cells and affected their capacity to provide GCB help and 
decreased B-cell antibody responses. Thus, blocking PD-1 enhanced HIV-specific 
immunoglobulin production in vitro.(Cubas 2013) 
In addition to HIV, increased PD-1 on virus-specific CD8+ T cells is associated with T-cell 
exhaustion in hepatitis C virus (HCV) and is also associated with tolerance in virus-specific 
T-cells against Epstein Barr virus (EBV) and cytomegalovirus (CMV).(Day 2006, 
Duraiswamy 2007, Radziewicz 2007) 
Therapy with the antibody to PD-1 (anti-PD-1) has been evaluated in the setting of chronic 
HCV. BMS-936558 (nivolumab), a humanized anti-PD-1 monoclonal antibody, was 
evaluated in a phase I study of 42 patients with chronic HCV who were previously treated 
with interferon. A total of 35 patients received BMS-936558 doses from 0.03–10 mg/kg, 


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and 7 patients received placebo. The most frequent adverse events (AEs; mostly grade 1 to 
2) were fatigue, headache, diarrhea, and pharyngeal pain. Transient decreases in CD4+, 
CD8+, and CD19+ cells were noted. Six patients had probable reversible grade 1–2 
immune-related AEs (irAEs), including hypothyroidism, diarrhea, and rash, and 2 had 
possible irAEs (thyroid and worsening glycemic control) (Gardiner 2013). Interestingly, 1 
patient had grade 4 aspartate aminotransferase/alanine aminotransferase (AST/ALT) 
abnormalities associated with anti-HCV response. A total of 5 patients who received the 
study drug and 1 patient receiving placebo had a reduction in HCV RNA ≥0.5 log10 IU/mL 
on at least 2 consecutive visits; 3 patients had a >4 log10 reduction. Preliminary results 
from an ongoing study of nivolumab in 19 hepatitis virus-infected patients with HCC 
suggests that anti-PD-1 therapy is safe and tolerable, with no dose limiting toxicity AE 
reported, and with few and reversible Grade 3 and 4 elevation of liver enzymes (5-12%) 
(El-Khoueiry 2015). 
In addition to having a chronic viral infection that may benefit from anti-PD-1 therapy, 
patients with HIV and AIDS are at risk of developing several virally associated tumors that 
may be particularly suitable for treatment with immunotherapy. However, specific safety 
data are needed for this approach, as some HIV-infected patients develop immune 
reconstitution inflammatory syndrome (IRIS) against infectious agents upon T-cell 
expansion after initiating cART.(DeSimone 2000, French 2000) IRIS consists of an 
exacerbation of inflammatory disorders with paradoxical worsening of preexisting 
infectious processes in the setting of improving immunologic function. Patients who 
develop IRIS are typically successfully managed with glucocorticoid therapy. For patients 
with HIV, IRIS itself is associated with increased PD-1 expression on CD4+ and CD8+ T 
cells. (Antonelli 2010) The effect of PD-1–PD-L1 checkpoint blockade in this setting is 
unknown. 
2.1.5 PD-L1 Expression in Lung cancer, Classical Hodgkin lymphoma, and other Virally-
Associated NADMs 
Upregulation of PD-L1 has been noted in many virus-associated tumors, and associated 
immune evasion may play a role in tumorigenesis. PD-L1 expression in tumors is 
associated with the treatment effect of anti-PD-1 therapy. PD-1 is a particularly interesting 
target in patients with HIV and cancer, as many tumors are virally related. Furthermore, 
patients with HIV are also at an increased risk for lung cancer independent of smoking, 
which may be in part also related to chronic immune activation and inflammation 
associated with HIV,(Giorgi 1993, Fulop 2010) although PD-L1 has not been formally 
evaluated in this setting. As chronic HIV itself is associated with T-cell exhaustion through 
the upregulation of PD-1, (Day 2006) we hypothesize that PD-1 blockade may lead to 
improved antitumor responses in the setting of HIV in malignancies amenable to 
immunotherapy. 
Based on recent NSCLC tumor responses to both anti-PD-L1 and anti-PD-1 antibodies, 
(Brahmer 2010, Brahmer 2012, Topalian 2012, Sznol 2013) there is increasing interest in 
identifying possible predictors of response and prognostic markers to these therapies. In 
situ mRNA hybridization techniques and quantitative fluorescence approaches were used to 
measure PD-L1 in 2 cohorts of patients with NSCLC. PD-L1 protein expression was 


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identified in 25% and 36% in the 2 cohorts. The authors also showed that the expression of 
PD-L1 protein or mRNA was associated with better outcome.(Velcheti 2014) However, the 
literature is controversial on this topic, as other series showed that higher expression of PD-
L1 may portend a worse prognosis.(Mu 2011) Overall the expression of PD-L1 in NSCLC 
tumors is present in around 25–50% of the cases depending on the series and method of 
PD-L1 measurement.(Chen 2012, Velcheti 2014) Validated predictive biomarkers are 
required. 
PD-L1 expression has also been evaluated in other tumor types. A series of 654 tumor 
samples from 19 types of solid tumors was analyzed using a commercially available PD-L1 
immunohistochemistry (IHC) assay (Dako). PD-L1 was positive (≥5% frequency) in 14% 
of the tumors. Highest PD-L1 frequencies were seen in several tumors with increased in 
incidence in patients with HIV, including head and neck cancers (17/54 [31%]), cervical 
cancer (10/34 [29%]), and HCC (6/41 [15%]), among others.(Joseph Grosso 2013) 
In malignancies associated with the gamma herpesvirus, which are common in patients 
with HIV/AIDS, PD-L1 expression is often detected in the virally infected malignant cells. 
In particular, PD-L1 can be expressed by Reed-Sternberg (RS) cells in cHL and by 
malignant B cells of EBV-positive post-transplant lymphoproliferative disorders 
(PTLD),(Chen 2013) and in HIV-associated diffuse large B cell lymphoma (DLBCL) 
cells.(Kutok 2006, Taylor 2011) A recent series used a rabbit anti-PD-L1 monoclonal 
antibody (Sino Biological) to measure IHC-stained sections of selected hematologic and 
virus-associated malignancies. PD-L1 was highly expressed (defined as ≥5% malignant 
cells positive) in 33/87 cHL cases, 16/16 EBV-associated DLBCL, 7/7 EBV- and 
immunodeficiency-associated DLBCL, 6/10 EBV+ PTLD cases, and 4/9 plasmablastic 
lymphomas. However, PD-L1 was not expressed on any of the 7 EBV+ Burkitt lymphoma 
cases.(Chen 2013) 
Of clinical interest, patients without HIV with relapsed/refractory cHL treated with a 
different PD-1 inhibitor, nivolumab, (Ansell 2014) had a response rate of 87%, with a 
complete response occurring in 4 patients. A subgroup analysis of 10 patients with 
available tumor samples was also evaluated. In all tumors analyzed by fluorescence in situ 
(FISH), tumor cells had 3 to 15 copies of PD-L1 characterized by amplification, relative 
copy gain, or polysomy of chromosome 9p24. In all the samples, RS cells expressed PD-
L1. In patients with HIV-associated cHL, the RS cells are generally EBV infected. One 
analysis of cHL tumor samples suggests that PD-L1 upregulation in EBV-infected RS cells 
may occur through virally mediated upregulation of PD-L1 rather than through 9p24 
amplification.(Green 2012) Evaluating MK-3475 (pembrolizumab) in this patient 
population is of particular interest. 
HPV-associated tumors include cervical carcinoma, squamous cell carcinomas of the head 
and neck, and anal canal carcinomas. HPV-associated squamous cell carcinomas of the 
head and neck have improved clinical outcomes compared to tobacco-associated 
counterparts.(Gillison 2008, Mueller 2010) PD-L1 expression in HPV-associated head and 
neck cancers was found in 14/20 tumor samples and was noted on both tumor cells and 
tumor-associated macrophages, while tumor-infiltrating CD8+ T lymphocytes from the 
same specimens expressed high levels of PD-1.(Lyford-Pike 2013) In addition, PD-L1 was 


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expressed in 22/115 tumor samples of unselected patients with cervical adenocarcinomas 
although PD-1 was highly expressed in infiltrating lymphocytes (Karim 2009). PD-L1 may 
also play an important role in the pathogenesis of HPV-associated premalignant lesions, 
such as cervical intraepithelial neoplasia (CIN) (Insinga 2011) or anal intraepithelial 
neoplasia (AIN). Increased expression of PD-1 and PD-L1 have been associated with CIN 
in women with high-risk HPV, and PD-L1 expression correlated positively with CIN 
grade.(Yang 2013) This suggests that PD-1 blockade modulation may have a beneficial 
effect on in situ premalignant HPV-associated lesions.  
Lastly, Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous tumor, and in 
most patients is associated with Merkel cell polyomavirus (MCPV). In 49 patients with 
MCC, PD-L1 expression in tumor cells was present in 49% (Lipson 2013), with expression 
limited to tumors where MCPV was detectable. A smaller series of 18 patients with MCC 
also showed tumor PD-L1 expression in 9/13 samples.(Afanasiev 2013) These findings add 
to the mounting evidence that viral antigens create a local inflammatory response leading to 
PD-L1 expression.  
2.1.6 Rationale for pembrolizumab as first systemic therapy in HIV-associated Kaposi sarcoma 
Kaposi sarcoma has become less common in the U.S. after the introduction of ART, but 
remains the second most common cancer in people with HIV. The most recent estimate of 
incidence is of 76:100,000 in the HIV/AIDS Cancer Match Study (personal 
communication, Meredith Shiels). It also remains among the most common cancers in Sub-
Saharan Africa (SSA) despite now broad use of ART. To our knowledge there are no other 
studies of checkpoint inhibitors for KS and none using checkpoint inhibitors as first 
systemic therapy. 
The success of current standard therapy for KS is dismal in both the USA and resource 
poor countries (see below) and limited by cumulative toxicities and lack of availability in 
resource poor settings. There are several reasons to believe that KS will respond to 
pembrolizumab as the first systemic therapy. Most importantly, the biology of KS shares 
similarities with the biology of Merkel Cell Carcinoma (MCC) in which high response 
rates have been shown (see below). The biological features common between MCC and KS 
include: (1) the cancer is induced by an oncogenic virus, (2) tumors continue to express 
virus, (3) patient immune-incompetence is a co-factor in tumor induction, (4) tumors often 
contain many T cells, some of which are specific for virus, and (5) there is substantial 
evidence that boosting T-cell responses can have therapeutic benefit.  
The response of MCC to pembrolizumab as first systemic therapy is the highest of any 
solid tumor, (Kaufman 2016, Nghiem 2016) and pembrolizumab is now considered by 
many as therapy of choice for advanced MCC. In the small initial trial of pembrolizumab 
as first systemic therapy for MCC the response rate was 62% in virus positive tumors. 
Many of the initial responses are durable and are continuing at greater than a year. 
Approximately 50% of patients with MCC respond to chemotherapy, but the median 
duration of response is only about 3 months. A trial of anti-PD-L1 as second or third line 
therapy for MCC provided benefit for some patients, but appeared to be less effective than 
first line pembrolizumab (Kaufman 2016). The difference is likely to be related to the use 


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of checkpoint inhibition as first systemic therapy vs. therapy following lympholytic 
chemotherapy. Based in part on the overwhelming need in SSA and the tremendous effect 
of pembrolizumab on MCC as first systemic therapy, we now propose to administer 
pembrolizumab as first systemic therapy for KS.  
a) KS is a significant global health problem. Kaposi Sarcoma (KS) is an 
angioproliferative tumor caused by Kaposi sarcoma-associated herpes virus (KSHV, 
also known as human herpesvirus 8 or “HHV-8”)(Chang 1994, Gao 1996, Biggar 
2007). Human immunodeficiency virus (HIV) infection substantially increases KS risk 
(Engels 2008) and accounts for greater than 80% of KS in the United States (Shiels 
2011). In the era of effective ART, KS can occur at a broad range of CD4+ T-cell 
counts (Yanik 2016). Due in part to the high prevalence of HIV and HHV-8 co-
infection, KS is the second most common cancer in Uganda, the fourth most common 
cancer in SSA and the second most common in men (Mosam 2009, Ferlay J 2013). 
From 2007-2012, the incidence of Kaposi sarcoma in East Africa among people with 
HIV is estimated to be 334/100,000 person years (Semeere 2016) by the International 
Epidemiologic Databases to Evaluate AIDS (IeDEA). In Uganda, which has one of the 
highest rates of KS in the world, KS is the most common malignancy in men and 
women combined (Wabinga 2000, Gondos 2005). KS rates have remained high in 
Africa despite the scale-up of ART over the last several years(U.S. State Department 
2010). The reasons for these persistently high rates are unclear, but these data suggest 
that KS will likely remain a significant health problem in SSA in the near future and 
underscore the need for innovative research in Africa to address this malignancy that is 
associated with substantial morbidity and mortality. 
b) Current benefits of KS treatment are limited. Current therapy for KS is often limited 
by poor response and toxicity(Krown 2004). In HIV-associated KS, antiretroviral 
therapy (ART) is indicated, but may be insufficient. A stage-stratified approach 
recommends ART alone for limited cutaneous KS (Stage T0), but includes ART and 
chemotherapy for patients with more advanced KS (Stage T1) (Bower 2014). For 
patients with advanced KS in the US, FDA-approved liposomal anthracyclines are 
generally used as initial therapy (Gill 1996, Northfelt 1998, Stewart 1998, Cooley 2007, 
Cianfrocca 2010). Paclitaxel is approved by the FDA for patients who fail or do not 
tolerate this initial approach (Welles 1998, Tulpule 2002). In sub-Saharan Africa, 
advanced KS is often treated with ART and combination bleomycin and vincristine or 
paclitaxel, but the optimal approach to treating advanced KS in resource limited 
settings is unknown (Krown 2014). 
Patients with KS often require treatment for many years. Current limitations of 
providing chemotherapy in resource limited settings include cumulative toxicities (i.e. 
bone marrow toxicities that may require growth factor support; cardiotoxicity from 
anthracyclines, drug-drug interactions between protease inhibitors and vinca alkaloids, 
immunosuppression from chemotherapy or radiation therapy, risk of secondary 
malignancies), and an ultimate poor outcome with few long-term survivors (Mosam 
2012).  


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While treatment of KS in the US and Europe is associated with clinical improvement 
rates of 50-80%, more than half of patients fail to achieve complete resolution of 
disease and up to 20% experience disease relapse within 1 year.(Dupin 1999, Antman 
2000, Nunez 2001, Bihl 2007, Nguyen 2008). The 5-year survival rate of HIV-
associated KS is only 54% in the US and less than 9% in Uganda (Gondos 2005, 
Armstrong 2013). A South African study reported 77% 1-year survival among HIV-
associated KS patients receiving ART with or without chemotherapy (Mosam 2012). 
Data from the Uganda Cancer Institute (UCI), the country’s national referral cancer 
center, have observed 50% 1-year mortality despite optimized treatment with ART and 
chemotherapy (Figure 1) (Phipps 2015). To improve these poor KS response and 
survival outcomes, new effective and less toxic treatment approaches are urgently 
needed. 
c) Immunotherapy may be a promising treatment strategy for KS. Kaposi sarcoma is 
a tumor often associated with changes in immune function. Several lines of evidence 
suggest that KS oncogenesis is associated with loss of T-cell mediated control of 
KSHV, the viral cause of KS. First, there are strong epidemiologic associations 
between KS incidence and immune suppression, with the risk of KS increased several 
thousand-fold in the setting of HIV and organ transplantation(Grulich 2007). Second, 
improvement and resolution of KS is associated with restoration of immune function, 
through the reversal of iatrogenic immune suppression in patients with transplant-
related KS or the initiation of ART and subsequent immune reconstitution in a subset of 
patients with HIV-associated KS (Penn 1995, Euvrard 2003). Third, restoration of T-
cell immunity with ART is accompanied by increases in T-cell responses against 
KSHV, which in turn is associated with resolution of KS(Bihl 2009).  
KSHV is a large DNA virus that encodes many potentially immunogenic proteins (See 
below). Our group has shown that high plasma KSHV is frequently detected in patients 
with KS(Johnston 2009) and that KSHV transcripts are commonly expressed in KS 
tumors(Phipps 2010). These observations suggest that inadequate adaptive immune 
control of KSHV is critical to the development and progression of KS. Consequently, 
we hypothesize that superior response and survival in KS will be associated with 
the activation and expansion of tumor-reactive T-cells and/or KSHV-reactive T 
cells, and immunotherapeutic approaches to enhance that response could 
significantly improve KS outcomes. 
To our knowledge, checkpoint inhibition has not been tested in patients with KS. There 
are several standard immunotherapy regimens used to treat patients with KS, but none 
with the potential checkpoint inhibition has shown in other immunogenic cancers. 
Interferon-alpha 2b (Intron A®) is FDA approved for AIDS-associated KS. Response 
rates at a dose of 30 million units intramuscularly three times a week range from 29% 
to 71%, and increase with increasing CD4+ T-cell counts higher CD4+/CD8+ T-cell 
ratios. Use of Intron-A is limited due to common adverse events such as “flu-like 
symptoms” including fevers, headache, myalgia and fatigue, as well as severe 
depression in some cases. Interferon-alpha is most effective in patients with a CD4+ T-
cell count > 150 cells/uL (Krown 2002). More recently, pomalidomide has been shown 
to have a 73% response rate a heavily pre-treated patient population in a Phase I/II 


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study (Polizzotto MN 2014, Polizzotto 2015). Its activity in part appears to be through 
an immune mechanism.  
Figure 1: 1-year survival of HIV/KS patients at Uganda Cancer Institute 
 
Expression of KSHV genes and T cell infiltration and T cell clonality  
a) KSHV genes and markers of immune exhaustion are highly expressed in KS 
tumors. Warren Phipps and Edus Warren of Fred Hutchinson Cancer Research Center 
have evaluated gene expression in 39 pre-treatment KS tumors from Ugandan patients 
participating in the “HHV-8 in Presentation and Prognosis Observational Study” 
(HIPPOS) using RNA-seq (Figure 2). High levels of both latent and lytic HHV-8 
transcripts were detected in all samples, including transcripts of many of the structural 
and oncogenic viral genes that encode antigenic peptides recognized by T cells in North 
American/European patients with KS. It is highly likely that the proteins encoded by 
these viral genes are recognizable by T cells from African patients, and that expansion 
or “release” of this T-cell response may be a critical step in tumor resolution. The 
RNAseq data showed uniformly high levels of expression of molecules associated with 
immune exhaustion (including PD-1, CTLA-4, LAG-3) across all KS tumor samples. 
As expected, others have noted PD-L1 expression on inflammatory cells in the 
microenvironment (Chen 2013, Paydas 2016).  


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Figure 2: Heat map of KSHV gene expression (y-axis) in 24 KS tumor samples (x-axis) 
 
b) CD4+ and CD8+ T cells Infiltrate KS tumors. Detection of CD3, CD4, and CD8 cells 
was evaluated by immunohistochemistry in pretreatment tumors from 5 KS patients. 
CD4+ T cells (Figure 3) and CD8+ T cells (data not shown) were observed in all 
tumors. Characterizing T-cell phenotype, density and location within tumor may 
augment current KS staging and provide prognostic information concerning response to 
checkpoint inhibition, as has been demonstrated in other cancers (Tumeh 2014, Nghiem 
2016). 
Figure 3: T-cell Infiltration in KS Tumors  
 
c) Clonality of the TIL repertoire in pre-treatment KS tumors may be associated 
with treatment response and 1-year survival. Preliminary assessment of the clonal 
composition of the tumor infiltrating lymphocytes (TIL) in KS tumors was evaluated by 
high-throughput sequencing of the T-cell receptor  chain (TRB) repertoire in 12 
pretreatment tumors from a subset of subjects on the HIPPOS study who collectively 
demonstrated a wide range of treatment response. The sequence yield from the 12 


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tumors was excellent (median number of sequences 2419, range 330-4401), consistent 
with our immunohistochemistry findings that KS tumors contain a significant number 
of infiltrating T cells. Using a specific metric termed “clonality” that captures the clonal 
diversity of complex T cell populations and ranges from 0 (maximally diverse) to 1 
(monoclonal), we found that the clonal diversity of the TIL repertoires was quite 
variable (median 0.12; range 0.035 to 0.25). The TRB sequence datasets with higher 
clonality were uniformly characterized by the presence of a small number of sequences 
present at high frequency, up to 7.3% of the total, which indicates preferential 
migration into and/or significant expansion of antigen-specific T cell clones within the 
tumor microenvironment.  
Figure 4: KS Response by TCR Clonality 
 
The presumption is that TRB sequencing of KS tumors identifies candidate tumor-
reactive T cells. It is likely that the higher clonality values observed in some 
pretreatment tumors reflects the increased representation of a population of tumor-
reactive T cells, which is rescued with initiation of ART, and subsequently mediates 
tumor regression. To explore the relationship between clonality of the TIL repertoire 
and KS response and survival, we dichotomized the tumor samples into 2 groups 
defined by clonality values above and below the median value. This analysis revealed 
that complete or partial KS response to ART and chemotherapy (combination 
bleomycin and vincristine) was significantly associated with higher clonality (p=0.01) 
(Figure 4).  
We hypothesize that the higher clonality values observed in some pretreatment tumors 
reflects the expansion of a population of tumor-reactive T cells, which is rescued with 
initiation of ART, and subsequently mediates tumor regression. Multiple studies 
characterizing distinct T-cell subsets in cancer patients at baseline and after immune 
checkpoint blockade support the hypothesis that activation and expansion of pre-
existing tumor-reactive T-cells is required for clinical response to checkpoint inhibitors. 
(Cha 2014, Gubin 2014, Snyder 2014, Tumeh 2014, Rizvi 2015, McGranahan 2016, 


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Nghiem 2016) Based on these observations, we further hypothesize that treatment with 
anti-PD-1 therapy could similarly, and perhaps more effectively, unleash the presumed 
endogenous tumor reactive immune responses we have observed in KS tumors.  
In summary, evaluation of immunotherapeutic approaches in the first line setting with 
advanced KS is warranted and may lead to changes in the standard of care, as well as 
provide data for approaches for KS in HIV uninfected patients. An anti-PD-1 approach 
in this patient population warrants investigation due to the upregulation of the PD-
1/PD-L1 pathway in the setting of HIV. 
d) TRB sequencing of KS tumors identifies candidate tumor-reactive T cells. TRB 
sequencing was also performed on additional pre-treatment and post-treatment KS 
tumors from the same 12 HIV+KS HIPPOS subjects, one of whom (008-030) achieved 
a durable complete response (CR) to therapy. We hypothesize that this subject mounted 
an effective anti-KS immune response. Sequencing of 3 tumor biopsies from different 
sites from this subject, 2 obtained pretreatment and the other obtained posttreatment, 
was particularly informative. Of 3,858 unique TRB sequences identified in the 3 
tumors, 382 sequences (9%) were observed in 2 or more tumors, and 86 (2.2%) were 
observed in all 3 tumors (Figure 5). We hypothesize that these shared sequences are 
carried in tumor-reactive T cell clones. TRB sequencing of a normal skin biopsy 
obtained from this subject with the pretreatment KS biopsies is currently in progress.  
Figure 5: TCR Sequences shared by TIL in 3 KS Tumors 
 
Analysis of the frequency with which the shared sequences were observed in the 3 
biopsies suggested that achievement of CR was associated with expansion within the 
tumor of specific T cell clones (Figure 5).  
e) Experience in CITN-12 in patients with heavily pretreated KS 
To date, 6 KS patients have been enrolled in cohorts 1-3 on CITN-12. These patients 
were heavily pretreated, having received a range of 1-8 (median 3) previous lines of 
systemic therapy. In addition, 50% of these patients had received prior radiation 


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therapy. At the time of this report, two patients achieved a partial response and one has 
had stable disease for > 6 months. In addition, two patients treated for primary effusion 
lymphoma who also had concurrent KS have been treated. One of these two had 
improvement in KS documented by photography, but not officially measured, as well 
as a meaningful PR to his underlying lymphoma that lasted 13 cycles until the patient 
was censored at time of allogeneic stem cell transplant. 
Two patients had immune related AEs at least possibly attributed to pembrolizumab. 
One had grade 2 joint pain in shoulders and wrists that improved with steroids, but 
prohibited additional therapy. One had Grade 5 KSHV-lymphoproliferative disease 
involving liver, spleen, lungs, and kidneys that likely represented unmasking of KSHV-
associated multicentric Castleman disease. This patient had a history of KSHV viremia 
that likely represented undiagnosed multicentric Castleman disease (MCD). Protocol 
amendment 6 included changes to the eligibility criteria for Cohort 4 that substantially 
decreased the risk of enrolling future patients with MCD and also provided 
management guidelines should MCD emerge.  
In summary, evaluation of immunotherapeutic approaches in the first line setting with 
advanced KS is warranted and may lead to changes in the standard of care, as well as 
provide data for approaches for KS in HIV uninfected patients. An anti-PD-1 approach 
in this patient population warrants investigation due to the upregulation of the PD-
1/PD-L1 pathway in the setting of HIV. 
2.1.7 Correlation of PD-L1 Expression and Response to Treatment 
Attempts have been made to identify biomarkers to predict response to immunotherapies. 
The relationship between PD-L1 expression and response to PD-1/PD-L1 antibodies 
remains unclear at this time. However, in a phase 1 trial of MK-3475 (pembrolizumab), a 
humanized monoclonal immunoglobulin G4 (IgG4) antibody against PD-1, tumor 
responses and progression-free-survival correlated with expression levels of PD-L1.(Daud 
2014) In another study in patients with NSCLC using the same monoclonal antibody, 
antitumor activity correlated with PD-L1 expression.(Gandhi 2014) PD-L1 expression also 
has been shown to correlate with response in a small series of patients treated with the PD-
1 antibody.(Topalian 2012, Sznol 2013) The threshold of staining and whether to stain 
tumor cells, tumor-infiltrating cells, or stromal cells are still unresolved, however, positive 
staining—even at 1–5% level for staining of malignant or infiltrating tumor or stromal 
cells—seems to correlate with response.(Dong 2002, Taube 2012, Topalian 2012, Chen 
2013) 
2.1.8 Evaluation of HIV in Patients on cART with Undetectable Viral Load Using Commercial 
Assays 
During effective antiretroviral therapy, HIV persists in a reservoir of cells, and the 
additional effects of various immunomodulatory agents are currently under investigation. 
In such patients, the majority of HIV exists as integrated proviral DNA with CD4+ T-cells 
and other cells. Although persistent plasma viremia remains detectable using sensitive 
assays during cART, it is not known whether the virus is the product of complete cycles of 


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replication or is the product of long-lived cells with integrated proviruses. The distinction 
between these possibilities is critical for understanding HIV pathogenesis and for designing 
strategies for HIV eradication. For instance, if persistent viremia is the result of complete 
ongoing cycles of replication, then current antiretroviral therapy, which targets active 
infection, requires improvement.(Chun 2008, Buzon 2010) In contrast, if persistent viremia 
is derived from long-lived cells with integrated proviruses, then current antiretroviral 
therapy is maximally suppressive, and alternative strategies are necessary to eliminate virus 
infection.(Dinoso 2009, McMahon 2010) Several approaches have been useful in 
determining the nature of HIV viremia on therapy. The NCI HIV Drug Resistance Program 
has developed a sensitive real-time reverse transcription polymerase chain reaction (RT-
PCR) assay for HIV with a limit of sensitivity of approximately 0.3 copies/mL 
plasma,(Palmer 2003) as well as assays for evaluating cell associated integrated provirus. 
Analysis of viremia during standard and intensive antiretroviral therapy has yielded useful 
insights on the source of persistent viremia. In addition, techniques to amplify genetic 
sequences from low-level viremia have enabled detailed phylogenetic analysis of HIV 
genetic diversity and molecular evolution.(Kearny 2010) Additional methods have also 
been recently employed to evaluate HIV latency reversal, and include kinetic evaluation of 
plasma HIV RNA and CD4+ T-cell unspliced HIV RNA(Elliott 2014) as well as estimate 
the size of the HIV reservoir through quantitation of inducible HIV producing cells using a 
“Tat/Rev Induced Limiting Dilution Assay” (TILDA) developed by Nicolas Chomont from 
the University of Montreal. 
We will gain new insights in the proposed studies by analyzing HIV viremia before, 
during, and after treatment with MK-3475 (pembrolizumab). In addition, genetic analysis 
of persistent viremia should identify molecular evolution and provide novel insights into 
the clonality of long-lived HIV infected cells. If we find no effect of immune checkpoint 
blockade on the levels of HIV viremia, estimates of the cellular reservoir, or on population 
genetic characteristics, then persistent viremia may be the result of either long-lived cells 
that do not undergo frequent cell division that are not modifiable by PD-1 blockade. 
Modest increases in viremia during therapy may be the result of induced replication. 
Analysis of both the kinetics of viremia using single copy assay and population genetics 
will help distinguish these possibilities, as new active cycles of replication may result in 
ongoing accumulation of new mutations or shifts in the population structure. In addition, 
assays evaluating HIV-specific CD8+ T-cell cytotoxic activity against autologous targets 
have been developed in the Intramural Program in the laboratory of Mark Connors, MD, at 
the National Institute of Allergy and Infectious Diseases (NIAID) and will be employed to 
evaluate the effect of PD-1 blockade on anti-HIV CD8+ T-cell activity.(Migueles 2009) 
2.1.9 Cancer Genome Characterization Initiative for HIV-Associated Cancers 
The Office of Cancer Genomics (OCG), along with the Office of HIV and AIDS 
Malignancies (OHAM), initiated the HIV+ Tumor Molecular Characterization Project 
(HTMCP) to gain insight into the genetic events driving HIV-associated cancers and to 
determine why certain cancers have higher incidences in HIV-positive patients and why 
others do not. Understanding the molecular causes of these tumors may translate into 
improved therapies for a growing population of patients doubly afflicted with HIV and 
cancer. HTMCP is presently accruing tissues of cervical cancer, diffuse large B cell 


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lymphoma, and lung cancer (and matched controls). Whole exome and transcriptome 
(mRNA and microRNA [miRNA]) sequencing are being performed on each case with the 
ultimate goal to produce comprehensive molecular profiles of 3 tumor types from both 
HIV-positive and HIV-negative patients. Tissue obtained from our proposed trial will be 
shared with the HTMCP. 
Genomic characterization is of particular interest for lung cancer. Several factors may be 
associated with the increase incidence in lung cancer in patients with HIV. The higher rates 
of tobacco use (as high as 70%, compared to 20% in the general population) is one major 
contributor.(Burkhalter 2005) Cigarette smoke contains more than 60 known carcinogens. 
High mutational burden signatures with transcriptional strand bias, which are probably an 
imprint of the DNA adducts generated by polycyclic hydrocarbons found in tobacco 
smoke, have been observed in NSCLC,(Pfeifer 2002, Alexandrov 2013) and this high 
mutational burden may contribute to the antigenicity in some cases of lung cancer. Data 
suggest that lung cancers in HIV-positive persons have a high number of microsatellite 
alterations, reflecting a wide genomic instability, and increased DNA methylation of cancer 
suppressor genes.(Wistuba 1998) However, a much better understanding of the mutational 
signature of lung cancer in patients with HIV is of utmost importance, and it will be of 
particular interest in the setting of MK-3475 (pembrolizumab) therapy. 
 
CTEP IND Agent: MK-3475 (pembrolizumab) 
MK-3475 (pembrolizumab) (previously known as SCH 900475) is a potent and highly selective 
humanized mAb of the IgG4/kappa isotype.  
PD-1 is an immune-checkpoint receptor expressed on T cells that can suppress antitumor immunity 
when bound to either of its ligands, PD-L1 or PD-L2. PD-L1 and PD-L2 are transmembrane 
proteins that play a major role in suppressing the immune system. In chronic T cell driven immune 
responses, PD-L1 expression is upregulated on T cells, NK cells, macrophages, myeloid DCs, B 
cells, epithelial cells, and vascular endothelial cell upon IFN-γ stimulation. In addition, some 
tumor cells upregulate the PD-L1 to evade active T-cell immune surveillance. MK-3475 
(pembrolizumab) designed to directly block the interaction between PD-1 and its ligands, thereby 
enhancing tumor regression and ultimately immune rejection.  
Thus, the PD-1 receptor-ligand interaction is a major normal pathway designed to limit or dampen 
down T-cell responses and also is a pathway hijacked by tumors to suppress immune control. The 
normal function of PD-1, expressed on the cell surface of activated T cells under healthy 
conditions, is to downmodulate unwanted or excessive immune responses, including autoimmune 
reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to CD28 and 
cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4), which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
(Usubutun 1998) (Talmadge 2007). 
The structure of murine PD-1 has been resolved (Al-Shibli 2008). PD-1 and family members are 
type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible 
for ligand binding and a cytoplasmic tail, which is responsible for the binding of signaling 
molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 


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immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based 
switch motif (ITSM). After T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector 
molecules such as CD3ζ, PKCθ, and ZAP70, which are involved in the CD3 T-cell signaling 
cascade (Diez 1998, Galon 2006, Talmadge 2007, Deschoolmeester 2010).  
The mechanism by which PD-1 down-modulates T-cell responses is similar to, but distinct from, 
that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins (Nobili 2008, 
Hiraoka 2010). PD-1 was shown to be expressed on activated lymphocytes including peripheral 
CD4+ and CD8+ T cells, B cells, T regulatory cells (T regs), and natural killer (NK) cells (Kloor 
2009, Hodi 2010). Expression has also been shown during thymic development on CD4-CD8- 
(double negative) T cells as well as subsets of macrophages and dendritic cells (Hillen 2008). The 
ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of 
cell types, including nonhematopoietic tissues as well as in various tumor (Nishimura 2000, Lee 
2008, Leffers 2009, Hiraoka 2010). Both ligands are type I transmembrane receptors containing 
both IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic regions 
with no known signaling motifs. Binding of either PD-1 ligand to PD-1 inhibits T-cell activation 
triggered through the T-cell receptor. PD-L1 is expressed at low levels on various 
nonhematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is only 
detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory 
environments. PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas 
PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues (Hiraoka 2010). 
Although healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to 
express abundant levels of this T-cell inhibitor. PD-1 has been suggested to regulate tumor-specific 
T-cell expansion in patients with melanoma. This suggests that the PD-1/PD-L1 pathway plays a 
critical role in tumor immune evasion and should be considered as an attractive target for 
therapeutic intervention.  
In mouse models, blockade of the PD-1 pathway effectively promoted CD8+ T-cell infiltration 
into the tumor and the presence of IFN-γ, granzyme B, and perforin, indicating that the mechanism 
of action involved local infiltration and activation of effector T-cell function in vivo (Korman 
2007). In addition, the combination of gemcitabine and anti-PD-L1 mAb demonstrated synergy in 
the rejection of pancreatic mouse tumors (Nomi 2007). Merck in-house experiments have 
confirmed the in vivo efficacy of PD-1 blockade as a monotherapy. Therapeutic studies in mouse 
models show that administration of antibodies blocking PD-1/PD-L1 interaction enhances 
infiltration of tumor-specific CD8+ T cells and leads ultimately to tumor rejection, either as a 
monotherapy or in combination with other treatment modalities. Anti-mouse PD-1 or anti-mouse 
PD-L1 have demonstrated antitumor responses as a monotherapy in models of squamous cell 
carcinoma, pancreatic carcinoma, melanoma, and colorectal carcinoma. Blockade of the PD-1 
pathway effectively unleashes a T-cell response when used alone as well as in combination with 
chemotherapy in syngeneic mouse tumor models.  
MK-3475 (pembrolizumab) is a humanized IgG4 anti-PD-1 mAb with similar preclinical 
characteristics as BMS-936558. Both MK-3475 (pembrolizumab) and BMS-936558 contain the 
S228P stabilizing mutation. MK-3475 (pembrolizumab) is a pure PD-1 antagonist. MK-3475 
(pembrolizumab) potency in PD-1 binding, inhibition of ligand binding, and inhibition of PD-1 
function has been similar or up to several-fold higher than that of an analogue of BMS-936558. 


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Modeling of MK-3475 (pembrolizumab) pharmacokinetics (PK) in monkeys vs BMS-936558 PK 
reported in humans suggested comparable concentration-time curves at various dose levels. A 1 
month, repeat-dose, Good Laboratory Practice toxicity study with 4-month observation after 
dosing of MK-3475 (pembrolizumab) revealed no major safety findings. The “No observed 
adverse effect level” (NOAEL) was ≥200 mg/kg.  
Recent data of MK-3475 (pembrolizumab) have validated PD-1 as an attractive target for clinical 
intervention and have provided proof of concept for anti-PD-1 mAbs in melanoma (Hamid 2013). 
Patients with advanced melanoma were treated with MK-3575 with 10 mg/kg every 2 or 3 weeks. 
The response rate by RECIST was 38%. Responses were durable in the majority of patients 
(median follow-up, 11 months among patients who had a response); 81% of the patients who had a 
response (42 of 52) were still receiving treatment at the time of last published analysis in March 
2013. The overall median PFS among the 135 patients was longer than 7 months. Common 
adverse events (AEs) attributed to treatment were fatigue, rash, pruritus, and diarrhea; most of the 
AEs were low grade (Trial detailed below in Section 2.2.1.1). On September 14, 2014, the US 
Food and Drug Administration (FDA) granted accelerated approval of pembrolizumab for the 
treatment of patients with unresectable or metastatic melanoma and disease progression following 
ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
These data are similar to data in melanoma and renal carcinoma published for a similar agent, 
BMS-936558 (Sznol 2010). BMS-936558 has shown an overall response rate of approximately 
30% in patients with advanced melanoma and RCC who had failed prior therapy. Responses were 
of long duration, and the agent was generally well tolerated. 
2.2.1 MK-3475 (pembrolizumab)  
MK-3475 (pembrolizumab) (SCH 900475) is a humanized immunoglobulin (Ig) G4 
monoclonal antibody (mAb) which binds the programmed death 1 (PD-1) receptor, thus 
inhibiting the interaction with its ligands, PD-L1 or PD-L2 (Merck & Co. 2014). PD-1 is an 
immune-checkpoint receptor expressed by T cells. When bound to either PD-L1 or PD-L2, 
the PD-1 pathway negatively regulates T-cell effector functions. The PD-1 pathway 
functions to limit unwanted or excessive immune responses, including autoimmune 
reactions. PD-L1 is typically expressed at low levels on various non-hematopoietic tissues, 
and PD-L2 is only detectably expressed on antigen-presenting cells in the lymphoid tissue 
or chronic inflammatory environments.  
PD-L1 is also expressed in the tumor microenvironment of various cancers (Zou 2008). 
Activation of the PD-1 pathway may be a critical mechanism to evade T-cell mediated 
tumor rejection (Dong 2002, Pardoll 2012). High levels of PD-L1 expression are correlated 
with poor prognosis and survival in renal cell carcinoma (RCC) (Thompson 2007), 
pancreatic carcinoma (Nomi 2007), hepatocellular carcinoma (HCC) (Gao 2009), and 
ovarian carcinoma (Hamanishi 2007).  
Immune-checkpoint inhibition of another inhibitory T-cell receptor, CTLA-4, with the 
mAb ipilimumab, demonstrated significant prolongation of overall survival (OS) in patients 
with melanoma in two phase 3 trials (Hodi 2010, Robert 2011, Ribas 2012). As an 
immunotherapy target, PD-1 is distinct from CTLA-4 because it can be activated directly 


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by the cancer and it regulates the effector phase of T-cell response, whereas CTLA-4 
regulates the initial stage of T-cell activation (Pardoll 2012, Ribas 2012). Antibodies 
targeting the PD-1 pathway have demonstrated durable objective responses in phase 1 and 
2 trials. Nivolumab showed an overall response rate (ORR) of approximately 28% in 
subjects with advanced melanoma, 27% in subjects with RCC, and 18% in subjects with 
non-small cell lung cancer (NSCLC) who had failed prior therapy (Topalian 2012). MK-
3475 (pembrolizumab) has shown an ORR of approximately 38% in patients with 
melanoma (Hamid 2013) and ~20% in patients with NSCLC (Merck & Co. 2014). 
2.2.1.1 
Clinical Development of MK-3475 (pembrolizumab) 
Clinical data are derived from an ongoing, first-in human phase 1 study (PN001, 
NCT01295827) to evaluate the safety and clinical activity of MK-3475 
(pembrolizumab) as a monotherapy, sponsored by Merck Sharp & Dohme. There are 
five parts to this study (Parts A-D and F) (Merck & Co. 2014).  
Part A was a 3+3 dose-escalation study in subjects with solid tumors to evaluate safety, 
tolerability, pharmacokinetics (PK), and pharmacodynamics, and to determine a 
maximum tolerated dose (MTD) or preliminary recommended phase 2 doses (RP2Ds). 
Doses were 1, 3, and 10 mg/kg every 2 weeks (Q2W); doses of either 2 mg/kg or 10 
mg/kg were also administered every 3 weeks (Q3W). All 3 dose levels were well 
tolerated and no dose-limiting toxicities (DLTs) were observed; therefore, the MTD 
was not determined. The RP2D was determined by the sponsor based on safety, PK, 
and pharmacodynamic measurements, along with the strength of antitumor activity 
signals observed. 
The remaining four parts aim to characterize the safety profile and tolerability of MK-
3475 (pembrolizumab) and to evaluate the clinical activity of MK-3475 
(pembrolizumab) in the following patient populations:  
Part B: Advanced melanoma patients who have either received prior ipilimumab (IPI-
treated) or were naïve to prior ipilimumab (IPI-naïve). Patients in Part B receive MK-
3475 (pembrolizumab) three dose levels: 2 mg/kg Q3W, 10 mg/kg Q3W, and 10 mg/kg 
Q2W.  
Part C: NSCLC patients. Patients in Part C receive MK-3475 (pembrolizumab) at 10 
mg/kg Q3W.  
Part D: Advanced melanoma patients that are IPI-naïve. Patients in Part D receive MK-
3475 (pembrolizumab) at 2 mg/kg Q3W and 10 mg/kg Q3W.  
Part F: NSCLC patients with and without prior systemic therapy whose tumors express 
PD-L1 when exposed to MK-3475 (pembrolizumab). Patients in Part F receive MK-
3475 (pembrolizumab) at 2 mg/kg or 10 mg/kg Q3W, or 10 mg/kg Q2W.  
Pharmacokinetics  
The half-life (t1/2) of MK-3475 (pembrolizumab) is approximately 4 weeks and there 
was no indication of dose dependency of half-life in the three dose groups (1, 3, and 10 


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mg/kg) (Investigator’s Brochure, 2014). The long t1/2 supports a dosing interval of 
every 2 or 3 weeks. 
There was a dose-related increase in exposure from 1 to 10 mg/kg (Investigator’s 
Brochure, 2014). Serum concentrations of MK-3475 (pembrolizumab) were lower by a 
factor of approximately 5 in patients receiving 2 mg/kg Q3W than in those receiving 10 
mg/kg Q3W (Hamid 2013), (Merck & Co. 2014). Steady-state trough concentrations 
were 20% greater in the patients receiving 10 mg/kg Q2W than in those receiving the 
same dose Q3W. 
Anti-Drug Antibodies (ADA) Data 
The occurrence of ADA has been observed in less than 1% of the patients screened, 
indicating a low potential of MK-3475 (pembrolizumab) to elicit the formation of ADA 
(Merck & Co. 2014). No impact of ADA on MK-3475 (pembrolizumab) exposure has 
been observed. 
Efficacy 
When treated with MK-3475 (pembrolizumab) monotherapy, the ORR for IPI-treated 
patients with melanoma (Part B) was 25%/27% according to the Response Evaluation 
Criteria in Solid Tumors (RECIST)/investigator-assessed immune-related response 
criteria (irRC), respectively (Merck & Co. 2014). The ORR for IPI-naïve patients with 
melanoma (Parts B and D) was 39%/43% by RECIST/investigator-assessed irRC, 
respectively. The majority of responses were seen in patients with melanoma by 16 
weeks of therapy with MK-3475 (pembrolizumab); however, some responses have been 
reported after 24 weeks or more of therapy with MK-3475 (pembrolizumab). 
Responses can be delayed, and in some patients, a RECIST-defined progression 
followed by a response has been observed. 
The preliminary objective response rate for 38 patients with NSCLC (Part C) was 
21%/24% by RECIST/investigator-assessed irRC, respectively (Merck & Co. 2014).  
Pharmacodynamics/Biomarkers  
PD-L1 is being investigated as a predictive biomarker for MK-3475 (pembrolizumab) 
treatment. At the 15th World Conference on Lung Cancer, Garon, et al. presented 
preliminary data on a subset of patients suggesting that higher levels of tumor PD-L1 
expression are associated with increased clinical activity (Garon 2013). Objective 
responses by RECIST 1.1 occurred in 4 out of 7 patients with higher levels of PD-L1 
expression (57%, 95% confidence interval [CI] 18-90%) vs. 2 out of 22 patients with 
lower levels of PD-L1 expression (9%, 95% CI 1-29%). These data are extremely 
preliminary, and PD-L1 is not being used for patient selection.  
Biomarkers to evaluate immune modulation and markers in the tumor 
microenvironment, such as T-cell infiltration, the baseline expression of markers of T-
cell suppression FoxP3 or the immunoregulatory enzyme indoleamine 2,3-dioxygenase 
(IDO) in tumor biopsies, were associated with a high response rate (Berman 2009, 
Hamid 2009). 


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2.2.1.2 
Safety data  
The most frequent treatment-related adverse events (AEs) were fatigue, nausea, 
arthralgia, pruritus, diarrhea, and rash (Merck & Co. 2019). Most AEs were not 
considered serious. 
The important identified risks for MK-3475 (pembrolizumab) are mostly of an 
immune-mediated nature, and include the following: pneumonitis; colitis; hepatitis; 
nephritis; endocrinopathies that include hypophysitis (including hypopituitarism and 
secondary adrenal insufficiency), thyroid disorder (hypothyroidism, hyperthyroidism, 
and thyroiditis), and Type I diabetes mellitus; uveitis; myositis; Guillain-Barre 
syndrome; pancreatitis; myocarditis; myasthenic syndrome; encephalitis; sarcoidosis; 
severe skin reactions including SJS and TEN, some with fatal outcome; and “solid 
organ transplant rejection following pembrolizumab treatment in donor organ 
recipients.” 
Based upon additional information received from the clinical study and postmarketing 
environments, the following changes has been made to the safety information for 
pembrolizumab: 
• Information regarding exacerbation of myasthenia gravis was added to product 
labeling to further characterize the existing risk of myasthenic syndrome;  
• Information regarding primary adrenal insufficiency was added to product 
labeling to further characterize the existing risk of immune-mediated 
endocrinopathies; 
• A new adverse drug reaction (ADR) of Vogt-Koyanagi-Harada syndrome was 
identified based primarily on postmarketing experience and added to the 
Postmarketing Experience section of the Company Core Data Sheet (CCDS). 
Note: Vogt-Koyanagi-Harada syndrome may include a constellation of 
signs/symptoms which are already listed in product labeling, namely, the 
existing adverse event of special interest (AEOSI)/risk of ‘uveitis.’ However, 
considering the clinical significance of timely recognition and treatment of the 
condition, and that the term was identified primarily based on postmarketing 
experience, Merck decided to add the distinct term of Vogt-Koyanagi-Harada 
syndrome to the CCDS Postmarketing Experience section. 
• A new ADR of hemophagocytic lymphohistiocytosis was identified based 
primarily on postmarketing experience and will be added to the Postmarketing 
Experience section of the CCDS. 
 
Other Agent(s): Combination Antiretroviral therapy (cART) 
Patients must be on an effective cART regimen, generally a 3-drug regimen based on Department 
of Health and Human Services (DHHS) treatment guidelines: 
http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. For most current 
product information on antiretroviral agents, refer to manufacturers’ Prescribing Information. 


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Appendix D provides a table of common side effects observed with agents prescribed as part of 
DHHS-recommended and alternate cART regimens.  
Effective antiretroviral therapy in people with HIV leads to substantially decreased infectious 
morbidity and mortality, CD4+ T-cell immune reconstitution, and substantially increased 
longevity. Contemporary antiretroviral therapies are very well tolerated, and when taken regularly, 
lead to effective control of HIV viremia. Concurrent cART in this protocol is required for optimal 
patient outcomes. There are no predicted drug-drug interactions and minimal expected overlapping 
toxicities with addition of MK-3475 (pembrolizumab) to a cART regimen with established 
efficacy and tolerability.  
 
Rationale 
In addition to optimal care for patients with HIV, optimal management of HIV using cART is 
required to maximize T-cell immunity and for evaluation of the effect of MK-3475 
(pembrolizumab) on the HIV reservoir. We hypothesize that patients with HIV and cancer will 
tolerate and benefit clinically from anti-PD-1 therapy through antitumor responses and improved 
control of HIV and other concurrent viral infections when present. We propose to implement a 
multicenter phase 1 trial investigating the safety of the monoclonal anti-PD-1, MK-3475 
(pembrolizumab), in patients with HIV/AIDS and malignancy. Correlative studies will evaluate the 
effect of MK-3475 (pembrolizumab) on immune cell subsets in patients with HIV (virally 
suppressed on cART) and cancer, and evaluate the effect of MK-3475 (pembrolizumab) on the 
HIV reservoir. Anti-PD-1 therapy may be particularly useful in this patient population; however, 
specific safety data are required. Furthermore, patients with HIV/AIDS are often excluded from 
early phase clinical trials of cancer therapy, so the current proposal addresses an extremely 
important unmet clinical need. 
 
Correlative Studies Background 
2.5.1 Evaluation of Peripheral Blood CD4+ and CD8+ T-cell counts— Integral Correlative 
Study #1 
CD4+ and CD8+ T-cells are important biomarkers for the effect of HIV on T-cell 
immunity. In the setting of HIV in patients with cancer, the CD4+ and CD8+ T-cell counts 
may also be affected by the underlying malignancy (i.e. classical Hodgkin lymphoma) or 
else chemotherapy of radiation therapies used to treat malignancy. Commonly used 
thresholds that have been used historically for initiation of HIV therapy include CD4+ T-
cell <200 cells/uL and CD4+ T-cell < 350 cells/uL. The highest risk for infectious 
complications and poor outcomes occurs in patients with a CD4+ T-cell count <100. 
Historically, CD4+ T-cell count less than 100 has been associated with poor outcomes in 
therapeutic studies for AIDS-related lymphomas and KS. In addition to absolute CD4+ T-
cell count, the ratio of CD4+/CD8+ T-cells may provide additional prognostic information, 
and a ratio < 0.4 has been shown to be associated with poor outcomes in the cART 
era.(Serrano-Villar 2014)  
Importantly, in patients with HIV but not cancer, the degree of PD-1 upregulation on T-
cells is inversely proportional to the CD4+ T-cell count (Cockerham 2014), and this 
provides additional justification for the stratification employed in this study. 


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CD4+ and CD8+ T-cell counts are routinely evaluated in Clinical Laboratory Improvement 
Amendments (CLIA) certified laboratories at US institutions that care for patients with 
HIV, and this study will employ results from the CLIA certified laboratories at the treating 
institution for evaluation of protocol eligibility, stratification to cohort, and monitoring for 
potential decreases that would require changes in supportive care or alterations in therapy 
may all be affected by this Integral Correlative Study. CD4+ and CD8+ T-cell counts will 
be evaluated at baseline, Cycle 1 Day 8, prior to dosing at Cycles 2, 3, and 4, then prior to 
dosing at every third cycle, at end of therapy, and at the 30-Day Safety Follow-up Visit. 
2.5.2 Assessment of HIV Reservoir  
2.5.2.1 
Single copy HIV plasma HIV RNA (SCA) -- Correlative Study #2 
In patients with HIV well controlled on cART, the plasma HIV viral load, as measured 
by commercial RNA PCR assays, is generally suppressed to <20 copies/mL, although 
“blips” up to 400 copies/mL are sometimes noted, and not necessarily associated with 
virologic failure. Plasma measurements of HIV RNA by PCR are thought to largely 
represent reactivated virus from HIV infected reservoirs in this setting (Cillo 2014), and 
persistence of HIV-1 viremia can still be detected and quantified using a “single copy” 
quantitative real time PCR assay targeting the HIV-gag RNA that is sensitive down to 
0.3 copies/mL, using methods previously described (Cillo 2014).  
If residual plasma HIV viral load in patients on cART represents a combination of 
spontaneous and induced latency reversal, measurements over time would be expected 
to correlate with the size of the HIV reservoir. “Steady-state” HIV plasma HIV RNA 
viral load will be used as a correlate of the total HIV reservoir, and should a patient a 
patient obtain a persistently undetectable plasma HIV by the SCA, additional 
evaluation of the HIV reservoirs through cell based assays (Section 2.5.2.2) or 
evaluation of tissues may be warranted. 
Importantly, MK-3475 (pembrolizumab) may lead to reversal of HIV latency, which 
would be expected to lead to changes in CD4+ T-cell transcription leading to cell 
activation, increased expression of HIV RNA, with the effect of leading to release of 
HIV RNA into plasma despite optimal cART. 
The SCA will be employed to: 
• Evaluate the kinetics of HIV latency reversal during cycle 1 and cycle 2, 
looking at baseline, 2-hours, 24-hours, and 1 week after the dose of MK-3475 
(pembrolizumab) in cycle 1, and before dosing, 2-hours and 24-hours in cycle 2.  
• Compare the steady state HIV plasma RNA in patients on cART at baseline to 
that 3 weeks following each of the first 3 doses of MK-3475 (pembrolizumab), 
and then at time of tumor progression and/or off therapy 
2.5.2.2 
CD4+ T-cell associated HIV unspliced RNA and HIV DNA—Correlative Study #3 
In addition to measuring plasma HIV RNA, measures of basal and induced HIV 
transcription will be evaluated using an assay quantifying cell-associated unspliced 
HIV using a semi-nested real-time quantitative PCR for HIV-gag US RNA in sorted 
CD4+ T-cells as in previously described methods. This assay has previously been 


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employed in studies evaluating HIV latency reversal agents (Pasternak 2009, Elliott 
2014, Wightman 2015). As with the SCA assay, the cell associated unspliced HIV 
RNA assay will be employed to: 
• Evaluate the kinetics of HIV latency reversal during cycle 1, looking at 
baseline, 24-hours, and 1 week after the first dose of MK-3475 
(pembrolizumab)  
• Compare the cell associated unspliced HIV RNA in patients on cART at 
baseline to that 3 weeks following each of the first and third doses of MK-3475 
(pembrolizumab), and then at time of tumor progression and/or off therapy. 
Cell-associated total HIV DNA will also be quantified in the same samples using real 
time PCR using previously described methods (Lewin 2008). 
2.5.2.3 
Evaluation of HIV-1 molecular evolution —Correlative Study #4 
Inferences about clonality of residual HIV reservoirs can be evaluated, in part, by 
exploring changes in the phylogenetics of plasma HIV using molecular phylogenetic 
approaches. Evaluation of clonality of HIV sequences may be particularly useful when 
evaluating changes in total HIV vial load by single copy assay, and may provide further 
support that changes in plasma HIV RNA correlate with changes in clonal “wild-type” 
HIV infected cells. The effects of MK-3475 (pembrolizumab) on HIV-1 molecular 
evolution in patients on cART will be evaluated by evaluating single genome sequences 
of HIV at baseline, cycle 2, cycle 4, and time of tumor progression and/or off therapy. 
Intra-patient HIV populations will be evaluated overtime using phylogenetic analyses, 
as previously described (Kearney 2014). 
2.5.2.4 
TAT/REV Induced Limiting Dilution Assay: TILDA—Correlative Study #5 
In addition to measuring plasma HIV RNA and measuring cell-associated replication-
competent HIV, we will also measure the size of the HIV reservoir in latently infected 
CD4+ T-cells using the TAT/REV Induced Limiting Dilution Assay (TILDA). This 
quantitative assay measures the frequency of cells with multiply-spliced HIV RNA 
upon activation with PMA/ionomycin and does not require extraction of viral nucleic 
acids. It is rapid, precise and sensitive and can be performed on cryopreserved cells 
obtained from relatively small amounts of blood. TILDA will be employed to analyze 
the latent reservoir at baseline, Cycle 7, Cycle 13, at time of PR and/or CR and at End 
of Treatment (EOT). 
2.5.2.5 
HIV Transcriptome Analyses -- Correlative Study #6 
We will also use gene microarrays and bioinformatics to characterize host gene 
expression and nature of host gene expression in whole blood at baseline and following 
MK-3475 (pembrolizumab) administration and to determine whether there is a distinct 
transcriptional profile associated with changes in CA-US RNA resulting from 
treatment. Transcriptional profiling will be performed in the laboratory of Rafick-Pierre 
Sekaly, and will used to evaluate:  
• Baseline (pretreatment predictors) of clinical outcome  
• Baseline (pretreatment predictors) of HIV reservoir decay  
• Baseline (pretreatment predictors) of HIV specific immune reconstitution  
• Post-treatment correlates of clinical outcome  


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34 
• Post-treatment correlates of reservoir decay  
• Post-treatment correlates of immune reconstitution 
For these analyses, blood from several time points (pre-treatment; 24 hours post-first 
dose; prior to dosing on cycle 7; and EOT) will be collected directly into PAXgene 
tubes. PAXgene Blood RNA Tubes allow for the collection of whole blood and 
stabilization of cellular RNA for up to 3 days and protects RNA from degradation and 
minimizes induction of gene expression. Cells will be processed and lysed for RNA 
extraction which will be aliquoted and stored at –80C. Samples will be run in batches. 
cDNA will be obtained by reverse transcription and used for gene expression analyses 
using Illumina gene expression technology similar to described (Elliott 2014). 
Gene expression work will be analysed using functional genomics bioinformatics based 
on R, bioconductor and edgeR. Briefly, RNA Seq reads will be mapped onto the current 
version of the UCSC Human Genome (hg19). Transcript abundance will be estimated 
by counting the number of reads mapping to the exons that are unique to the transcripts 
of a gene. The transcript counts will be normalized by the Trimmed Mean of M-values 
method and corrected for the library size. 
Differential gene expression will be determined for each gene by fitting a generalized 
linear model (GLM; an extension to classic linear models to non-normally distributed 
data) to the expression data with the sample’s time point () as independent variable. To 
identify statistically significant differences between gene-expression pre-infusion of 
anti-PD-1 Ab (day 0) and post-infusion, a likelihood ratio test will be performed on the 
coefficients of regression in the GLM. To identify genes correlated with the different 
outcomes, a GLM will be fitted per sample pre (0) and post-infusion time points () for 
each gene, to study the association of gene expression with different quantitative 
parameters of outcome (clinical and laboratory) as continuous variables. A Likelihood 
ratio test will be conducted for the coefficient (measures of immune responses post-
infusion of anti-PD-1 antibody) in the linear model. 
GeneSet Enrichment Analysis will be performed on the selected genes to identify the 
canonical pathways and networks associated with measures of immune responses or 
clinical outcome based on objective measures and perturbed by infusion of the anti-PD-
1 antibody 
For the differential expression analysis (systems Biology component), 36 volunteers 
(pooling the three groups stratified as to their CD4 counts) will allow us to detect 
transcript with 1.5-fold difference in mean expression between anti-PD-1 infusion and 
post-infusion samples at a significance level of 0.05 and a power greater than 90%, 
assuming a 50% variation in expression between samples within pre-infusion or post-
infusion group. 
2.5.3 Evaluation of HIV-specific CD8+ T-cell cytotoxicity—Correlative Study #7 
A potential benefit of anti-PD-1 therapy may be improved autologous anti-HIV-specific 
CD8+ T-cell activity. We will evaluate virus specific CD8+ T-cell cytotoxicity using an 
assay developed in the laboratory of Dr. Connors. In this study, we will evaluate the effect 


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35 
of MK-3475 (pembrolizumab) on CD8+ T-cell cytotoxic activity against HIV infected 
autologous CD4+ T-cells, as measured by BD Pathways bioimaging platform of Infected 
CD4+ T-cell elimination (ICE). Samples will be collected at baseline, cycle 4, and at either 
EOT or cycle 13. 
Changes of CD8+ T-cell anti-HIV cytotoxic activity may be evaluated in relation to 
changes in other measures of the HIV reservoir (Migueles 2009). 
2.5.4 Evaluation of lymphocyte and monocyte phenotypes—Correlative Study #8 
The effect of MK-3475 (pembrolizumab) on lymphocyte number and phenotype will be 
assessed at baseline and at defined time points during the trial using flow cytometry. 
Assays will be performed under the direction of Dr. Steven Fling in the CITN Central 
Laboratory. 
We will assess the effect of the MK-3475 (pembrolizumab) regimen on the frequency and 
phenotypic character of PBMC subsets including dendritic cells (DCs), monocyte 
populations, T cells, natural killer (NK) cells, and B cells. The effect of MK-3475 
(pembrolizumab) on these immune cell subtypes is being investigated in other CITN trials 
and may provide important correlative information on the success or failure of anti-PD-1 
therapy. 
A validated immunophenotyping assay on cryopreserved PBMC using cell surface markers 
CD3, CD4, CD8, CD11c, CD14, CD16, CD19, CD45, CD56, CD122, CD123, and HLA-
DR will be used to quantify the number and proportion of T cells (both CD8+ and CD4+), 
NK cells (CD56+CD3-), NKT cells (CD56+CD3+), B cells (CD19+), and monocytes 
(CD16+). In addition, both myeloid (CD45+HLA-DR+CD11c+CD123-) and plasmacytoid 
(CD45+HLA-DR+CD11c-CD123+) (DC) frequencies can be measured in this precision-
validated multiparameter flow cytometric assay.  
Multiparameter flow cytometry will also be used to further define the phenotype of T and 
NK cells, to identify activated T cells, T cell subsets (including regulatory T cells) and NK 
cell subsets. The markers used to better define the expanded populations include (but are 
not limited to): CD3, CD4, CD8, CD25, CD28, CD45, CD45RA, CD127, CCR7 (CD197), 
ICOS (CD278), PD-1 (CD279) and HLA-DR. For these phenotypic analyses, the 
percentage of cells positive for the marker and/or mean fluorescence intensity (MFI) at 
baseline (before MK-3475 (pembrolizumab)), cycle 2 day 1; cycle 4 day 1; then on day 1 
of cycles 7 and 13, at time of PR and/or CR and EOT, will be compared and the change 
will be calculated.  
Myeloid-derived suppressor cell frequencies (MDSC) may also be assessed using in this 
study using an immunophenotyping panel developed and in process of validation. The 
MDSC panel contains FITC-labeled lineage markers: CD3-, CD16-, CD56-, CD19- and 
CD20-FITC. MDSC are further delineated with markers to HLA-DR, CD45, CD33, 
CD11b, CD15 and CD14. Sub-populations of MDSC can then be defined as monocytic 
MDSC (LIN-DR-/CD14+), granulocytic MDSC (LIN-DR-CD14-CD33+CD11b+), 
neutrophil MDSC (LIN-DR-CD14-CD15+). The minor granulocytic MDSC sub-


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36 
population will likely be lost during cryopreservation, though majority mMDSC sub-
population will be maintained and evaluated. The absolute change in each parameter as 
well as variance in change over time for each patient (mean, median, and standard 
error/standard deviation) will be evaluated.  
Assays will be performed in the specimens collected and shipped as described in Section 
9.2.7. 
2.5.5 Plasma multiplex cytokines—Correlative Study #9 
Several perturbations in cytokines, chemokines, and growth factors have been associated 
with cancers occurring in in the setting of HIV and cancer. Additionally, the immunologic 
effects of anti-PD-1 therapy has been associated with measurable changes in plasma 
sIL2Ra, IL-1a and CXCL10 (IP-10) (Das 2015). Cytokines implicated in HIV infection and 
/or IRIS include INF-g, TNFa, CXCL10, IL-2, IL-6, IL-8, IL-10, IL-12, IL-15, IL-18 and 
IL-21. IL-7 and IL-15 may contribute to the persistence of latently infected T-cells through 
upregulation of pro-survival pathways in CD4+ T-cells. Additionally, sIL2Ra is a marker 
of CD4+ T-cell activation in patients with IRIS. Comparison of baseline plasma cytokines, 
chemokines and growth factors to longitudinal measurements with therapy may improve 
understanding of the distinct immunologic effects of MK-3475 (pembrolizumab) in 
patients with HIV and cancer. Longitudinally collected plasma samples will be evaluated 
using a commercial V-PlexTM (Mesoscale Discovery, Gaithersburg, MD) multiplex 
sandwich immunoassay that is quantified by immunochemiluminescence detection 
technology. Plasma will be derived from samples collected at same time points as for 
Correlative Study 2.5.2.1 (Single copy HIV plasma HIV RNA). 
2.5.6 Assessment of PD-L1 expression at baseline—Correlative Study #10 
PD-L1 is a critical ligand for PD-1 and its expression has been identified as a potential 
important correlative biomarker for clinical response to anti-PD-1 therapy, including MK-
3475 (pembrolizumab). Therefore, PD-L1 expression will be quantitated by IHC in 
baseline formalin-fixed paraffin-embedded tumor specimens as an important part of the 
correlative studies. For this, formalin-fixed, paraffin-embedded tissue block(s) from tumor 
obtained before MK-3475 (pembrolizumab) therapy will be obtained by the clinical site 
either from archival samples obtained from the relevant pathology laboratories where they 
were processed and stored, or from baseline biopsy (core, punch or excisional) as part of 
this protocol. We will test the hypothesis that PD-L1 expression correlates with MK-3475 
(pembrolizumab) response. PD-L1 expression will be tested by IHC at Merck Research 
Laboratories in Palo Alto, CA, or their suggested designee. 
2.5.7 Assessment of tumor biopsy for actionable mechanisms of failure by IHC—Correlative 
Study #11 
We will evaluate tumor biopsies for immune cell infiltrate and other biomarkers by IHC 
using available archival tumor biopsy. Or if sufficient archival tumor tissue collected 
before MK-3475 (pembrolizumab) therapy is not available, a baseline biopsy will be 
obtained before enrolling in the study, assuming this can be carried out safely. Infiltrates 
derived from pre-therapy tumor tissue and from optional biopsies taken at time of 


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37 
confirmed progression (and at Cycle 3 Day 1 for cohort 4 participants) will be assessed by 
IHC to determine extent and the nature of the T-cell infiltration and the immune milieu of 
the tumor microenvironment. The following cellular markers will be analyzed by IHC 
analyses in this study: CD3, CD8, PD-1. The majority of the IHC studies will be performed 
at the FHCRC Core Laboratory, Seattle, WA. Pre- and post-treatment levels of CD8+ T-
cell tumor infiltrates will be assessed using criteria defined in Paulson, et al (Paulson 
2011). 
PD-1 and PD-L1 expression will be tested by multiparametric IHC at Merck Research 
Laboratories in Palo Alto, CA, or an equivalent vendor and PD-1 expression will also be 
tested with chromogenic IHC at a Merck-designated CRO or an equivalent vendor. The 
multiparametric studies performed by Merck Research Laboratories will allow 
simultaneous determination of subcellular localization and identity of tumor/inflammatory 
cell types expressing PD-L1.  
Additionally, with a view to further characterize the immune cell infiltrate (pending 
discussions between investigators and Merck in light of study results and current literature), 
tumors may also be assayed by IHC for a variety of other markers including MHC Class I, 
CD68 (monocytes/macrophages), CD4 (T cells), CD56 and CD16 (NK and NK T 
cellsCD45 (leukocytes), CD79a (B cells), glucocorticoid-induced tumor necrosis factor 
receptor family–related gene (GITR), TIM-3, forkhead box P3 (FOXP3), lymphocyte-
activation gene 3 (LAG3).  
2.5.8 Assessment of tumor biopsy for actionable mechanisms of failure by gene expression 
analysis—Correlative Study #12 
Tumor tissue may also be tested for gene expression using NanoString technology on 
unstained tissue FFPE slide material. Specifically, slides will be analyzed using a 770 gene 
panel (Nanostring nCounter PanCancer Immune Profiling Panel) which contains markers 
for 24 different immune cell types and populations, 30 common cancer antigens and genes 
that representing immune responses including checkpoint blockade genes. Analyses of 
Cancer gene Pathways (using nCounter PanCancer Pathways Panel) may also be performed 
pending agreements between investigators, Merck and the CITN. Assays will be performed 
either at Merck Research Laboratories in Palo Alto, CA, or performed at NanoString 
Technologies in Seattle, WA, pending mutual agreement on feasibility and logistics 
between NanoString Technologies & Investigators/CITN. Pre-therapy tumor tissue and 
tissue from optional biopsies taken at time of confirmed progression (and at Cycle 3 Day 1 
for cohort 4 participants) will be assessed. 
2.5.9 Assessment of KSHV viral load in patients in Cohort 4 – Correlative Study #13  
Longitudinal evaluation of PBMC-associated KSHV viral load will be performed to 
explore the effect of pembrolizumab on potential biomarkers of KSHV disease burden and 
KSHV lytic activation. PBMC associated KSHV viral load will be evaluated using primers 
for K6, normalized for human endogenous retrovirus-3 (ERV-3) as previously described [de 
Sanjose S 2002]. 


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38 
2.5.10 Assessment of anti-KSHV immune response in patients in Cohort 4 – Correlative Studies 
#14 
KSHV specific immunity may be altered by pembrolizumab. We will compare baseline and 
on treatment specimens for alterations in humoral and T-cell immunity. KSHV serology 
will be evaluated to detect antibodies in plasma, using multiplex serology against a broad 
range of KSHV-encoded antigens using a novel Luminex based multiplex assay performed 
in the D. Whitby Lab (NCI). KSHV specific CD8+ T-cell cytotoxicity will be evaluated by 
proteome wide ELISPOT performed in the D. Whitby Lab (NCI).  
2.5.11 Assessment of the effect of pembrolizumab on peripheral blood immune cell phenotypes 
by mass cytometry -- Correlative Studies #15 
To assess immune responses to anti-PD-1 therapy in HIV-infected individuals with cancer, 
we will perform high-dimensional single cell analysis of longitudinal PBMCs isolated from 
CITN-12 participants using two separate 42-parameter mass cytometry (CyTOF) panels 
(requiring 1e6 cells each). With the first CyTOF panel, we will explore how CD4+, CD8+ 
and non-classical T cell subsets, phenotypes and differentiation states are altered after PD-1 
blockade. In particular, this panel will include staining for Ki-67 and PD-1 to identify 
“anti-PD-1-responsive” cells (i.e., the subset of cells that proliferates after blockade 
therapy). The panel will focus on understanding how treatment impacts T cell expression of 
PD-1 and other co-inhibitory molecules (e.g., CTLA-4, TIM-3, TIGIT), as well as co-
receptors (e.g., CD28). With a second, more exploratory CyTOF panel, we will determine 
how subsets of B cells and innate immune cells (e.g., monocytes, dendritic cells, NK cells) 
are impacted by anti-PD-1 therapy. 
3. 
PATIENT SELECTION 
 
Eligibility Criteria 
3.1.1 Histologically or cytologically proven metastatic or locally advanced tumors for which no 
standard therapy exists, or where standard therapy has failed, or in patients otherwise 
ineligible for standard therapy, or for an indication that anti-PD-1 therapy has been shown 
to be effective in studies in HIV-uninfected participants. Disease-specific criteria will be 
applied for certain common cancers and cancers strongly associated with HIV. However, 
enrollment will not be confined to these tumors. 
3.1.1.1 
NSCLC 
i. 
Metastatic or locally advanced disease that progressed after at least one prior 
therapy  
Note: Patients that have actionable molecular targets (e.g., epidermal growth factor 
receptor [EGFR], anaplastic lymphoma kinase [ALK], c-ros oncogene 1[ROS1] 
mutations) must have received (when indicated) prior appropriate targeted therapy 
using FDA-approved agents 


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39 
3.1.1.2 
AIDS-related non-Hodgkin lymphoma and other non-Hodgkin lymphoma 
i. 
Failed standard first-line therapy; and 
ii. 
Failed autologous stem cell transplant if indicated for histology (i.e diffuse large 
B-cell lymphoma) or autologous stem cell transplant is not feasible 
3.1.1.3 
Classical Hodgkin lymphoma 
i. 
Relapsed or refractory de novo classical Hodgkin lymphoma having failed 
standard first-line therapy; and 
ii. 
May have failed to achieve a response or progressed after treatment with 
brentuximab vedotin or may be brentuximab vedotin naïve but is ineligible or 
unable to receive brentuximab vedotin; and 
iii. 
May have failed to achieve a response to, progressed after, or is ineligible for 
autologous stem cell transplant (auto-SCT)  
3.1.1.4 
HCC 
i. 
Not eligible for curative attempt resection or liver transplant 
  
3.1.1.5 
Kaposi sarcoma impacting physical and/or psychological wellbeing and not amenable 
to local therapy. Patients who have received prior therapy and treatment naïve patients 
are both potentially eligible to participate.  
i. 
On ART with suppressed HIV viral load for >3 months (Note: an extended 
washout period is needed to avoid treatment during the period of risk for the 
highly toxic and often fatal “Immune Reconstitution Inflammatory Syndrome 
(IRIS)” 
ii. 
No KSHV-associated multicentric Castleman disease in past 5 years 
iii. 
No symptomatic pulmonary KS or chest X-rays positive for un-evaluated 
abnormalities  
iv. 
Disease evaluable by AIDS Clinical Trial Group (ACTG) KS response criteria 
v. 
CD4+ T-cell count ≥50 cells/μL  
vi. 
For KS patients, the following laboratory values supersede values in section 
3.1.6: 
- 
platelets 
> lower limit of normal 
- 
hemoglobin 
>10 g/dL 
3.1.1.6 
Melanoma 
i. 
Unresectable or metastatic disease progression following a BRAF inhibitor if 
BRAF V600 positive 
Note: Prior therapy with ipilimumab not required 


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3.1.2 Available pretreatment biopsy, either fresh (optimal) or archival (acceptable)  
3.1.3 Resolution of any AEs from prior treatments must be resolved to baseline or grade ≤1 at 
enrollment (with the exception of alopecia), neuropathy, and ototoxicity (i.e., AEs that are 
not expected to improve within the washout period). 
3.1.4 On an effective combination cART regimen, generally a 3-drug regimen based on 
Department of Health and Human Services (DHHS) treatment guidelines. 
i. 
Patients must be on cART ≥4 weeks; and 
ii. 
Evidence of viral suppression defined as HIV viral load <200 copies/mL; and  
iii. 
No symptomatic AEs > Grade 1 by CTCAE criteria probably or definitely 
attributed to cART; and 
iv. 
No laboratory AEs noted on protocol defined screening laboratories > Grade 1 
by CTCAE criteria probably or definitely attributed to cART, with exceptions 
noted below in section 3.1.6.  
Note: If cART is modified during the screening period, patients must be on an 
effective new regimen for ≥ 2 weeks and otherwise meet eligibility criteria. 
Most patients have viral loads that are suppressible to <50 copies/mL, but about 25% of 
patients will occasionally have blips up to 400–500 copies/mL, which do not appear to 
correlate with lack of viral suppression in most studies. Thus, an HIV viral load of ≤400 
copies/mL for an occasional “blip” will be allowed, if there is documentation of an HIV 
viral load <200 on the same regimen and no significant treatment interruption.  
3.1.5 CD4+ T-cell count ≥50 cells/μL 
3.1.6 Patients must have marrow function and organ function as defined below.  
Note: To remain on treatment, any abnormal lab values allowed by the PI must remain 
stable or improve during treatment. Similar off treatment rules will be applied to all 
patients, except the following: the grade of any abnormal lab value allowed by the Protocol 
PI at enrollment will be considered the patient’s baseline for potentially resuming therapy 
after modification/holding of therapy when off treatment criteria are applied. 
System 
Laboratory value 
• 
leukocytes 
no lower limit 
• 
absolute neutrophil count 
>500/mcL 
• 
platelets 
>50,000/mcL 
• 
hemoglobin 
>9 g/dL 
• 
total bilirubin 
<1.5 X upper limit of normal (ULN); or 
 
<3 x institutional ULN for Gilbert’s 
syndrome or HIV protease inhibitors; or <5 x 
ULN and direct bilirubin < 0.7 mg/dL for 
patients on atazanavir containing HIV 
regimen 


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41 
• 
AST(SGOT)/ALT(SGPT) 
<2.5 × institutional ULN  
 
• 
Creatine kinase 
<5 X institutional ULN 
• 
serum creatinine 
<2.5 X institutional ULN 
OR 
• 
Measured or calculateda creatinine clearance 
(CrCl) (Glomerular filtration rate [GFR] can 
also be used in place of creatinine or CrCl) 
≥30 mL/min for subject with creatinine 
levels >2.5 X institutional ULN 
 
• 
Thyroid Stimulating Hormone (TSH) 
 
 
Within Institutional Limits (ie: Normal). If 
TSH is greater or less than institutional limits 
patients may participate if their T4 is WNL. 
Patients may be on a stable dose of 
replacement thyroid medication. Dose 
adjustments are allowed if needed.  
aCreatinine clearance should be calculated per institutional standard. 
 
3.1.7 Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1 (Appendix A) 
3.1.8 At least 2 weeks from end of chemotherapy with resolution of neutropenia to above level 
3.1.9 At least 2 weeks from end of radiation therapy 
3.1.10 At least 4 weeks from end of monoclonal antibody therapy 
3.1.11 At least 2 weeks from end of targeted therapy 
3.1.12 Female patients of childbearing potential must have a negative urine or serum pregnancy 
within 72 hours before receiving the first dose of study medication. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
Note: The effects of MK-3475 on the developing human fetus are unknown. For this reason 
and because anti-PD-1 agents may be teratogenic, women of child-bearing potential must 
agree to use 2 methods of birth control, or be surgically sterile, or abstain from 
heterosexual activity beginning with the screening visit and for the duration of study 
participation, through 120 days beyond last dose of MK-3475 administration. Patients of 
childbearing potential are those who have not been surgically sterilized or have not been 
free from menses for >1 year. 
Should a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately.  
3.1.13 Men treated or enrolled on this protocol must agree to use 2 adequate methods of 
contraception starting with the screening visit, for the duration of study participation and 
through 120 days after the last dose of MK-3475 administration. 


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42 
3.1.14 No prior treatment with anti-PD-1 or anti-PD-L1 
3.1.15 Measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 or 
other tumor-specific criteria or disease assessable by physical exam or other methods if not 
measurable by RECIST 
3.1.16 Baseline tumor tissue, either fresh (preferred) or from paraffin block/unstained slides if 
contemporary biopsy is unsafe or not otherwise obtainable from the primary tumor site or 
metastatic site to be available for use on correlative studies 
3.1.17 Age ≥18 years.  
Because no dosing or adverse event data are currently available on the use of MK-3475 
(pembrolizumab) in combination with cART in patients <18 years of age, children are 
excluded from this study, but will be eligible for future pediatric trials. 
3.1.18 Ability to understand and willingness to sign a written informed consent document. 
 
Exclusion Criteria 
3.2.1 Active systemic immunosuppressive therapy 
3.2.2 Systemic steroid therapy or steroid therapy that cannot be discontinued with more than 7 
consecutive days of steroids within the prior 2 weeks 
Note: The use of prednisone or equivalent <0.125 mg/kg/day (absolute maximum of 15 
mg/day) as replacement therapy is permitted. Inhaled or topical corticosteroids are 
permitted. 
3.2.3 Current or history of systemic autoimmune disease requiring systemic therapy. 
Note: the following will NOT be exclusionary:  
i. 
The presence of laboratory evidence of autoimmune disease (e.g., positive 
antinuclear antibody (ANA) titer or lupus anticoagulant) without associated 
symptoms 
ii. 
Clinical evidence of vitiligo or other forms of depigmenting illness 
iii. 
Mild autoimmunity not impacting the function of major organs (e.g., limited 
psoriasis) 
3.2.4 Grade 3 or 4 immune related toxicity associated with prior ipilimumab therapy that has not 
resolved to grade 0 or 1.  
3.2.5 Cardiovascular disease that meets one of the following: congestive heart failure (New York 
Heart Association Class III or IV), active angina pectoris, or recent myocardial infarction 
(within the last 6 months) 
3.2.6 Active tuberculosis (TB) or atypical mycobacterial infection:  
i. 
Patients who are undergoing systemic antibiotics for active mycobacterial infection 
ii. 
Patients with TB immune reconstitution syndrome (IRIS) requiring corticosteroids 


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43 
Note: Patients who are receiving treatment for latent tuberculosis (INH or alternative) may 
be eligible after discussion with the Protocol P.I. 
3.2.7 Cirrhosis with Child-Pugh score of B or C 
3.2.8 Uncontrolled HBV infection, defined as acute liver failure or protracted, severe course, as 
indicated by total bilirubin >3 mg/dL (or direct bilirubin >1.5 mg/dL), international 
normalized ratio >1.5, encephalopathy, or ascites.  
Note: the following will NOT be exclusionary:  
i. 
A positive hepatitis B serology indicative of previous immunization (i.e., HBsAb 
positive and HBcAb negative), or a fully resolved acute HBV infection  
ii. 
Patients with chronic HBV infection suppressed by appropriate antiretroviral 
therapy with activity against HBV, as outlined in DHHS guidelines  
3.2.9 Uncontrolled HCV infection, defined as plasma HCV RNA detectable by PCR.  
Note: the following will NOT be exclusionary:  
i. 
Positive HCV serology but no detectable HCV RNA, indicative of spontaneously 
cleared HCV infection 
ii. 
Patients who have been successfully treated for HCV as long as therapy for HCV 
has been completed  
3.2.10 Patients who are receiving any other investigational agents for cancer 
3.2.11 Extensive active brain disease including symptomatic brain metastases or the presence of 
leptomeningeal disease, and all patients with infratentorial tumors 
Note: Patients with brain metastasis after definitive therapy with surgery or stereotactic 
radiation and stable off steroids for >4 weeks are eligible as are patients with asymptomatic 
brain metastasis as long as less than 1 cm and thus deemed as not requiring therapy by the 
primary physician and the lesions(s) are not infratentorial. 
3.2.12 Pregnancy or nursing or unwilling to take adequate birth control during therapy 
3.2.13 Prior organ allograft or allogeneic transplantation, if the transplanted tissue is still in place.  
3.2.14 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia  
3.2.15 Medical or psychiatric illness or social situations that would, in the opinion of the 
investigator, preclude participation in the study or the ability of patients to provide 
informed consent for themselves  
3.2.16 Clinically significant lung disease including known history or evidence of interstitial lung 
disease or chronic obstructive pulmonary disease (COPD) that requires oxygen therapy. 


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3.2.17 Active non-infectious pneumonitis ≥ Grade 2 or history of Grade 3 non-infectious 
pneumonitis requiring steroids within the past 12 months; or any history of Grade 4 non-
infectious pneumonitis. 
3.2.18 Grade 3-4 ascites or pleural effusion.  
Note: The following will NOT be exclusionary: A participant who is clinically stable 
following treatment for ascites or pleural effusion (including therapeutic thoracentesis or 
paracentesis). 
3.2.19 Receipt of live vaccines within 30 days before the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, seasonal flu, H1N1 flu, 
rabies, BCG, and typhoid vaccine. 
3.2.20 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to MK-3475 (pembrolizumab). 
 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
4. 
REGISTRATION PROCEDURES 
 
Investigator (IVR), Non-Physician Investigator (NPIVR), and Associate Plus (AP) 
Registration with CTEP 
4.1.1 CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all investigators contributing to any NCI-sponsored clinical trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of Investigator (IVR), 
Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
https://ctepcore.nci.nih.gov/rcr.  
RCR utilizes five person registration types. 
• IVR — MD, DO, or international equivalent; 
• NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD); 
• AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the Roster Update Management [RUMS], OPEN, Rave, acting as a primary site 
contact, or with consenting privileges;  


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45 
• Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
• Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
 
 
 
Financial Disclosure Form 
 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
 
GCP training  
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
CV (optional) 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU ) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
• Addition to a site roster; 
• Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• Act as the site-protocol Principal Investigator (PI) on the IRB approval 
 
In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug shipment, or as 
the CI on the DTL must be rostered at the enrolling site with a participating organization (i.e., 
Alliance).  
Additional information is located on the CTEP website at  
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR 
Help Desk by email at RCRHelpDesk@nih.gov. 


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4.1.2 CTEP-IAM Account 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) 
application is a web-based application required to be used by all registration types (IVR, 
NPIVR, AP, Associate (A) and Associate Basic (AB)). IAM provides a solution for CTEP 
Enterprise and CTSU applications with the primary goal of streamlining user provisioning.  
Additional information can be found on the CTEP website at 
https://ctepcore.nci.nih.gov/iam/index.jsp 
For questions, please contact the CTEP Registration Help Desk by email at 
CTEPRegHelp@nih.gov. 
 
Site Registration 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
4.2.1 IRB Approval 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept 
the NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB 
review will continue to be accepted for studies that are not reviewed by the CIRB, or if the 
study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory Office 
following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet (SSW) 
for Local Context to the CIRB using IRBManager to indicate their intent to open the study 
locally. The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU 
Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB 
approvals across their Signatory Network. Site preferences can be set at the network or 
protocol level. Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by emailing the email address above or calling 1-888-651-CTSU (2878). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website. Acceptable documentation of local IRB/REB approval includes: 
• Local IRB documentation; 
• IRB-signed CTSU IRB Certification Form; and/or 
• Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form. 


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47 
In addition, the Site-Protocol Principal Investigator (PI) (i.e., the investigator on the IRB/REB 
approval) must meet the following criteria to complete processing of the IRB/REB approval 
record: 
• Holds an Active CTEP status; 
•  Active status at the site(s) on the IRB/REB approval (applies to US and 
Canadian sites only) on at least one participating organization’s roster; 
• If using NCI CIRB, active on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s) record; 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 
in the RCR profile; and 
• Holds the appropriate CTEP registration type for the protocol. 
 
4.2.2 Additional Requirements 
Additional site requirements to obtain an approved site registration status include: 
• An active Federal Wide Assurance (FWA) number; 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO);  
• An active roster affiliation with the NCI CIRB roster under at least one CIRB Signatory 
Institution (US sites only); and 
• Compliance with all protocol-specific requirements (PSRs). 
 
4.2.3 Downloading Site Registration Documents 
Download the site registration forms from the CITN-12 protocol page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting 
documents is restricted to institutions and its associated investigators and staff on a 
participating roster. To view/download site registration forms:.  
• Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password; 
• Click on Protocols in the upper left of your screen.  
• Either enter the protocol number in the search field at the top of the protocol 
tree, or 
• Click on the By Lead Organization folder to expand, then select CITN, and 
protocol CITN-12.  
• Click on Documents, Protocol Related Documents, and use the Document Type filter 
and select Site Registration to download and complete the forms provided. (Note: For 
sites under the CIRB initiative, IRB data will load automatically to the CTSU as 
described above.) 


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4.2.4 Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU member’s website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-
CTSU (2878), or CTSURegHelp@coccg.org in order to receive further instruction and 
support. 
4.2.5 Checking Site’s Registration Status 
Site registration status may be verified on the CTSU members’ website.  
• Click on Regulatory at the top of the screen; 
• Click on Site Registration; and 
• Enter the sites 5-character CTEP Institution Code and click on Go: 
▪ Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks. 
 
Patient Registration 
The Oncology Patient Enrollment Network (OPEN)  is a web-based registration system available 
on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the Lead 
Protocol Organization (LPO) registration/randomization systems or Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. OPEN 
will populate the patient enrollment data in NCI’s clinical data management system, Medidata 
Rave. 
Requirements for OPEN access:   


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49 
• A valid CTEP-IAM account; 
• To perform enrollments or request slot reservations:  Be on a LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type; 
• If a Delegation of Tasks Log (DTL) is required for the study, the registrar(s) must hold the 
OPEN Registrar task on the DTL for the site; and 
• Have an approved site registration for a protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, crediting, 
consenting, drug shipment (IVR only), or receiving investigator for a transfer in OPEN, the IVR or 
NPIVR must list the IRB number used on the site’s IRB approval on their Form FDA 1572 in 
RCR. If a DTL is required for the study, the IVR or NPIVR must be assigned the appropriate 
OPEN-related tasks on the DTL. 
Enrollment will be facilitated using the Slot-Reservation System in conjunction with the 
Registration system in the Oncology Patient Enrollment Network (OPEN). Prior to discussing 
protocol entry with the patient, all site staff must use the CTSU OPEN Slot Reservation System to 
ensure that a slot on the protocol is available to the patient. Once a slot-reservation confirmation is 
obtained, site staff may then proceed to enroll patients to this study.  
Prior to accessing OPEN, CITN member site staff should verify the following: 
• Patient has met all eligibility criteria within the protocol stated timeframes; and  
• All patients have signed an appropriate consent form and Health Insurance Portability and 
Accountability Act (HIPAA) authorization form (if applicable).  
Note: The OPEN system will provide the site with a printable confirmation of registration 
information and treatment information. Please print this confirmation for your records. 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or at https://open.ctsu.org. For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
 
General Guidelines 
Following registration, patients should begin protocol treatment as soon as possible. Issues that 
would cause treatment delays should be discussed with the Principal Investigator. If a patient does 
not receive protocol therapy following registration, the patient’s registration on the study may be 
canceled. The Study Coordinator should be notified of cancellations as soon as possible. 
5. 
TREATMENT PLAN 
This is a phase I multi-institutional trial of MK-3475 (pembrolizumab) in patients with stable, 
treated HIV on cART with metastatic or refractory/advanced malignant neoplasm including AIDS-


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50 
defining or NADM. The primary aim is to assess safety and tolerability of MK-3475 
(pembrolizumab) in this patient category. The trial is open-labeled and nonrandomized.  
Patients will be stratified based on CD4+ T-cell counts at entry as some issues of safety and 
tolerability may vary according to CD4+ T-cell levels. Patients with HIV and malignancy that have 
been treated with multiple lympholytic therapies will present with a wide spectrum of CD4+ T-cell 
counts, even when on optimal HIV therapy and otherwise eligible to participate in a research 
protocol. For results of a safety study to be generalizable in this population, an adequate sample 
size is required to evaluate safety across a range of CD4+ T-cell counts, especially for a drug that 
modulates the immune system. For example, the safety of MK-3475 (pembrolizumab) may vary 
based on CD4+ T-cell count. As in some non-cancer settings, PD-1 upregulation on CD4+ and 
CD8+ T cells in patients with HIV correlates with CD4+ T-cell count. In order to better address 
the primary objective, the accrual will be stratified by CD4+ T-cell levels. The CD4+ T-cell levels 
indicated below for definition of the cohorts are standard for many HIV therapy trials.  
Cohort 1: 50-199 CD4+ T cells/mcL  
Cohort 2: 200-350 CD4+ T cells/mcL 
Cohort 3: >350 CD4+ T cells/mcL  
Cohort 4: >50 CD4+ T cells/mcL 
Accrual to each cohort (1-3) will be based on unacceptable AE during first treatment cycle of 21 
days. If 2 or more unacceptable AE occur in the first 6 patients, the cohort will not be expanded to 
12 patients until the AE are assessed by the Toxicity Evaluation Committee and the Committee 
approves the expansion.  
The treatment plan and study procedures are detailed in the Study Calendars and footnotes 
(Section 10). Study procedures described in the Study Calendars will be performed prior to drug 
administration for a given cycle, with the exception of certain blood draws. Disease assessments 
are performed prior to starting study drug regimen, then every 9 weeks thereafter during the first 
year of treatment, and every 12 weeks during the second year of treatment.  
 
Agent Administration 
5.1.1 MK-3475 (pembrolizumab) 
After a screening phase for eligibility, patients will receive the standard pembrolizumab 
regimen with a fixed dose of 200 mg every 3 weeks by IV infusion over 30 minutes in 
conjunction with effective cART therapy administered orally daily (Section 5.1.2).  
Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed. Trial treatment may be administered up to 7 
days before or after the scheduled Day 1 of each cycle due to administrative reasons. See 
also Sections 6.1 and 6.2 for guidelines related to modification of therapy and delayed 
visits for reasons other than toxicity. Treatment will generally be administered on an 
outpatient basis. Treatment cycle intervals may be increased due to toxicity as described in 
Section 6.1. Infusion timing should be as close to 30 minutes as possible; however, a 


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51 
window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 
min/+10 min). 
Reported adverse events and potential risks are described in Section 7. Appropriate dose 
modifications are described in Section 6. No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to treat the 
patient's malignancy. 
Agent 
Dose 
Route 
Schedule 
Cycle Length 
MK-3475 
(pembrolizumab) 
200 mg 
IV infusion over 30 
minutes 
Day 1 of each cycle 
21 days 
(3 weeks) 
5.1.2 Other Agent(s) 
Patients must be on an effective cART regimen, generally a 3-drug regimen based on 
Department of Health and Human Services (DHHS) treatment guidelines 
http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. Administration 
of cART will follow instructions and dosing in the manufacturers’ Prescribing Information 
for any given individual regimen. 
Patients with concurrent HBV require cART regimens based on DHHS Guidelines that are 
effective against concurrent HBV. Active agents include 3TC, TDF, and FTC. A cART 
regimen containing TDF and FTC is preferred for HBV co-infected patients if feasible. 
Antiretroviral therapy will generally be managed in conjunction with a primary care 
physician or infectious disease specialist. The following regimens are current DHHS 
recommended and alternative regimen for treatment naive patients with no caveats 
regarding HIV viral load or CD4 count at baseline, and are all acceptable regimens. This 
list will be updated periodically at the time of protocol amendments. 
Table 2: DHHS Recommended and Alternative cART regimens 
Recommended 
Brand Names  
 Integrase Strand Transfer Inhibitor (INSTI) Based Regimens 
 Dolutegravir/abacavir/lamivudine (DTG/ABC/3TC)  
Triumeq® 
 Dolutegravir plus tenofovir disoproxil fumarate (TDF) 
/emtricitabine (FTC) 
Tivicay® + Truvada® 
 Elvitegravir/cobicistat/TDF/FTC (EVG/c/TDF/FTC) 
Stribild® 
 Raltegravir (RAL) plus TDF/FTC 
Isentress® + Truvada® 
 Protease Inhibitor Based Regimens 
Darunavir/ritonavir (DRV/r) plus TDF/FTC 
Prezista® + Truvada® 
 
 
Alternative Regimens 
 
 Protease Inhibitor Based Regimen 
 


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52 
Atazanavir/ritonavir plus TDF/FTC 
Reyataz® + Norvir® + 
Truvada® 
 Non-nucleoside reverse transcriptase-based regimen 
 
Efavirenz/TDF/FTC 
Atripla® 
 
All patients on abacavir (ABC) based regimens must have documentation of being 
HLA B57*01 negative. Combination tablets are noted above, but in some instances, 
individual agents may be preferable for some cART regimens. cART regimens that are not 
on this list that are proven effective and tolerable in a given patient need not be modified.  
All regimens not on this list should be discussed with the Principal Investigator (PI). 
All patients with AEs attributed to cART noted during the screening process should be 
discussed with the PI.  
Modification of cART is allowed during the screening process, although patients must be 
on a modified regimen for at least 2 weeks, and otherwise meet eligibility criteria before 
enrolling.  
Modification of cART is allowed for patients while on study after completing the first 
cycle.  
There are no predicted drug-drug interactions between cART and MK-3475 
(pembrolizumab).  
5.1.3 Other Modality(ies) or Procedures: N/A 
 
Safety Monitoring and Definition of Unacceptable Adverse Events (AEs)  
5.2.1 Safety will be evaluated on all cycles. AEs will be evaluated using the Common 
Terminology Criteria for Adverse Events (CTCAE) v4 or current CTCAE version.  
Unacceptable AEs are used to determine whether to stop or hold therapy in individual 
patients. AEs requiring stopping or holding therapy in a particular patient, are defined in 
Section 5.2.3. Management of specific AEs, including criteria for holding and resuming 
MK-3475 (pembrolizumab), are outlined in Section 6.1. 
Unacceptable AEs are also used to determine whether to expand individual cohorts from 6 
to 12 patients (Section 5.2.2). Rules for expanding or not expanding the individual cohorts 
are based upon unacceptable AEs observed during the first 21 days of therapy and deemed 
at least possibly attributable to MK-3475 (pembrolizumab). (See Statistical Section 13.1). 
For the purpose of cohort expansion, unacceptable AEs are defined as any grade 4 AE or 
any grade 3 AE that requires holding therapy in an individual patient (see below). Any 
grade 3 or grade 4 AE that does not require holding therapy in an individual patient will not 
be considered an unacceptable AE for purposes of cohort expansion.  


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5.2.2 Safety will be monitored by the ad hoc Toxicity Evaluation Committee which will be 
composed of the trial principal investigator (PI), two site PIs (one with HIV expertise and 
one with cancer expertise), the CITN Director, a representative from CTEP and ad hoc 
members as warranted for specific toxicity issues. 
If the unacceptable AEs (defined below) observed are typical of known MK-3475 
(pembrolizumab) toxicities, the Toxicity Evaluation Committee will consider (1) revising 
the protocol eligibility requirements to decrease the likelihood of toxicities, (2) modifying 
the dose, or (3) allowing the trial to proceed as designed given that patients in this trial will 
have fatal diseases and few other treatment options. The Toxicity Evaluation Committee 
will need to evaluate the risk/benefit ratio in this situation.  
If unexpected, unacceptable AEs observed are considered to be related to concurrent 
administration of cART and MK-3475 (pembrolizumab), the Toxicity Evaluation 
Committee will consider revising the protocol eligibility requirements to decrease the 
likelihood of toxicities or may consider allowing the trial to proceed as designed given the 
risk/benefit ratio for this population. 
During prolonged dosing of MK-3475 (pembrolizumab) in patients who are benefiting 
from therapy, modification of the cART regimen will be allowed. 
5.2.3 Unacceptable AEs 
MK-3475 (pembrolizumab) will be withheld in individual patients for unacceptable AEs 
until or unless the toxicity resolves to an acceptable level. If an unexpected event occurs in 
a patient who was previously tolerating cART that is not probably or definitely attributable 
to another cause, then that event will be at least possibly attributable to MK-3475 
(pembrolizumab), and stopping rules will be applied as outlined for MK-3475 
(pembrolizumab)–related events. In that circumstance, cART will not be stopped, 
especially during the period in which unacceptable AEs are being evaluated. MK-3475 
(pembrolizumab) dose will not be modified or delayed for potential cART-related events. 
Unacceptable AEs requiring holding therapy and acceptable toxicity level for restarting 
therapy are listed below and in Sections 5.7 and 6.1. The list is not comprehensive for all 
potential happenstances. Any nondefined AE or exceptions will be presented to the 
Toxicity Evaluation Committee for assessment and decision.  
Grade 4 AEs 
• Grade 4 AE will require stopping trial therapy in the affected patient. The patient will 
not be rechallenged, except in exceptional circumstances, after review by the Toxicity 
Evaluation Committee. There are several exceptions to stopping therapy for Grade 4 
AE: 
– Given the possibility of transient effects of MK-3475 (pembrolizumab) on CD4 
counts, patients with Grade 4 lymphocytopenia or CD4 lymphocytopenia in the 
absence of infectious complication or other indications to come off therapy may 
be monitored on therapy and given appropriate prophylactic antibiotics for one 
cycle. If follow-up evaluation of CD4 count also reveals Grade 4 


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54 
lymphocytopenia or CD4 lymphocytopenia, MK-3475 (pembrolizumab) will be 
held for up to 12 weeks until CD4 lymphocytopenia resolves to Grade 2 or less, 
but resumed in patients otherwise tolerating therapy with stable disease or 
better. 
– MK-3475 (pembrolizumab) will be held in patients with Grade 4 neutropenia or 
thrombocytopenia, and can be restarted if resolves to ≤ Grade 1. 
Grade 3 AEs 
• Grade 3 AE will require holding trial therapy in the affected patient until or unless the 
AE resolves to a grade 2 AE within 12 weeks, and the trial PI and the CITN Director 
agree with reinstitution of therapy (exceptions noted below and in Section 5.7). 
• Grade 3 colitis and pneumonitis need to resolve to grade 1 before considering 
reinstituting therapy.  
• Any grade 3 AE lasting >12 weeks will require permanently stopping trial therapy in 
the affected patient, except in exceptional circumstances after review by the Toxicity 
Evaluation Committee. A most important exceptional circumstance potentially allowing 
continued therapy would be a patient responding to MK-3475 (pembrolizumab) in the 
face of a nonemergent life-threatening AE. 
• A drug-related autoimmune or inflammatory event including uveitis, pneumonitis, 
diarrhea, colitis, neurologic AEs, hypersensitivity reaction, infusion reaction, or 
immune reconstitution inflammatory syndrome (IRIS) or incident KSHV-associated 
multicentric Castleman disease of any duration requires discontinuation if the 
AE/symptoms do not resolve to baseline within 12 weeks with appropriate medical 
management. 
• An irAE requiring continued systemic steroid or other immunosuppressive treatment 
and patient cannot be tapered to a steroid dose ≤15 mg prednisone equivalent within 12 
weeks will require permanently stopping trial therapy. 
• Grade 3 AE that do not require holding therapy in the affected patient include: 
– Infusion-related reaction resolving within 6 hours and controlled with medical 
management 
– Transient (≤12 hours) flu-like symptoms or fever, which is controlled with 
medical management 
– Transient (≤24 hours) fatigue, local reactions, headache, nausea, or emesis that 
resolves to ≤grade 1 
– Single laboratory values out of normal range that are unlikely related to trial 
treatment according to the investigator, do not have any clinical correlate, and 
resolve to ≤grade 1 within 21 days with adequate medical management  
– Transient creatine phosphokinase (CPK) elevation due to exercise or trauma 


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55 
– Tumor-flare phenomenon defined as local pain, irritation, or rash localized at 
sites of known or suspected tumor that resolves to ≤grade 2 within 21 days with 
appropriate therapy 
– Lymphopenia, CD4+ T-cell lymphopenia, neutropenia 
– Anemia, unless hemoglobin less than 7 gm/dL 
– For patients on protease inhibitor–based cART regimens, a total bilirubin < 5x 
ULN will not be an unacceptable AE in patients with a grade 2-3 elevation in 
bilirubin at baseline due to Gilbert’s disease or protease inhibitors. 
– Asymptomatic hypophosphatemia 
– Dry skin, not limiting self-care activities of daily living (ADL)  
• Grade 2 AEs that require holding therapy in affected patients include: 
– 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 12 weeks 
• Any dosing interruption lasting >12 weeks requires stopping and not reinstituting 
therapy with the following exceptions: 
– Dosing interruptions >12 weeks that occur for non–drug-related reasons may be 
allowed if approved by the PI. Before reinitiating treatment in a participant with 
a dosing interruption lasting >12 weeks, the PI must be consulted.  
• The following conditions will not be considered unacceptable AEs: 
– Preexisting manifestations of HIV infection or therapy for HIV infection 
 
General Concomitant Medication and Supportive Care Guidelines 
5.3.1 Concomitant Medication 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other 
medications or vaccinations specifically prohibited during the trial, discontinuation from 
trial therapy or vaccination may be required. The investigator should discuss any questions 
regarding this with Protocol PI and CITN Director. The final decision on any supportive 
therapy or vaccination rests with the investigator and/or the subject's primary physician; 
however, the decision to continue the subject on trial therapy or vaccination schedule 
requires the mutual agreement of the Investigator, Protocol PI and CITN Director, and the 
patient. Non-urgent medications should not be introduced during the first cycle of MK-
3475 (pembrolizumab), as they may interfere with evaluation of AEs and DLTs during this 
time period. 
Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards 
of medical care. All concomitant medications will be recorded on the case report form 
(CRF) including all prescription, over-the-counter (OTC), herbal supplements, and IV 


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medications and fluids. If changes occur during the trial period, documentation of drug 
dosage, frequency, route, and date should also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded. Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs. 
Opportunistic Infection Prophylaxis: 
Patients with CD4+ T-cell counts less than 200 cells/uL should receive prophylaxis against 
Pneumocystis pneumonia with one of the following: 
• Trimethoprim/sulfamethoxazole 160/800 mg (Bactrim DS® tab) orally every Monday, 
Wednesday, Friday (Preferred) 
• Atovaquone 1500 mg orally daily 
• Pentamidine 300 mg via nebulizer every 4 weeks 
Prohibited Concomitant Medications 
Patients are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
• Anti-cancer systemic chemotherapy or biological therapy  
Note: Exception for patients with concurrent prostate cancer successfully controlled on 
hormonal therapy or history of breast cancer on adjuvant hormonal therapy.  
• Immunotherapy not specified in this protocol. 
• Investigational agents other than MK-3475 (pembrolizumab). 
• Radiation therapy  
Note: Generally, patients who have symptomatic progression requiring radiation 
therapy while on protocol should be taken off protocol-directed therapy and judged to 
have progressed. Exceptional cases should be discussed with the Protocol PI, CITN, 
and CTEP on an individual basis, after consultation with a local radiation oncologist. 
Any lesion treated with radiation cannot serve as a predefined target lesion for 
evaluating MK-3475 (pembrolizumab) efficacy. 
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. Flu-Mist®) 
are live attenuated vaccines, and are not allowed. 
• Glucocorticoids for any purpose other than to modulate symptoms from an event of 
suspected immunologic etiology. The use of physiologic doses of corticosteroids no 
greater than prednisone 15 mg (or equivalent) may be approved after consultation with 
CITN.  


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Patients who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
Patients may receive other medications that the investigator deems to be medically 
necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. There 
are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
Duration of Therapy 
MK-3475 (pembrolizumab) will be continued in each patient until confirmed progression or the 
development of an unacceptable AE that meets criteria defined in Section 5.2.3. Treatment for 
patients that achieve a stable disease (SD) or a partial response (PR) can continue for a maximum 
of 2 years (35 doses).  
In the absence of treatment delays due to adverse event(s), treatment may continue for up to 2 
years (35 doses) or until one of the following criteria for discontinuation of therapy applies: 
• Disease progression warranting alternative therapy. Progression will be confirmed by RECIST, 
Lugano criteria for malignant lymphoma or other methods for participants with non-
measurable disease, or other tumor specific criteria such as the modified ACTG criteria for 
participants with Kaposi sarcoma; or 
• Intercurrent illness that prevents further administration of treatment; or 
• Patient decides to withdraw from the study; or 
• General or specific changes in the patient's condition render the patient unacceptable for further 
treatment in the judgment of the investigator. 
• An individual participant will not receive any further investigational product if any of the 
following occur in the participant in question: 
- 
Withdrawal of consent from further participation in study-related assessments and follow-
up 
- 
Withdrawal of consent from further treatment with investigational product 
- 
Lost to follow-up 
- 
An AE that, in the opinion of the investigator or the sponsor, contraindicates further dosing 
- 
Any AE that meets criteria for discontinuation as defined above 
- 
Study participant is determined to have met one or more of the exclusion criteria for study 
participation following study entry and continuing investigational therapy might constitute 
a safety risk 
- 
Pregnancy or intent to become pregnant 
- 
Participant noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal (e.g., refusal to adhere to scheduled visits) 
- 
Initiation of alternative anticancer therapy, including another investigational agent 


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- 
Confirmed progressive disease (solid tumors) and continued treatment criteria (below) in 
setting of progressive disease are not fulfilled 
 
 
Duration of Follow Up 
Patients will be followed for 1 year after discontinuation of MK-3475 (pembrolizumab) or until 
death, whichever occurs first. Patients removed from treatment for unacceptable adverse event(s) 
will be followed until resolution or stabilization of the adverse event. 
After the end of treatment, (time of decision to discontinuation of therapy, based on above 
criteria), patients will undergo an end of therapy evaluation.  
• Subsequently, each patient will be followed for 30 days for AE monitoring and be 
scheduled for a post-treatment safety follow up visit at 30 days +/- 3 days. All AEs 
occurring within 30 days after the last dose of study treatment will be recorded. Serious 
AEs (SAEs) related and unrelated to study treatment will be collected for 90 days after the 
last dose of study treatment or the start of new anticancer treatment, whichever comes first. 
After 90 days only SAEs related to study treatment are to be reported. 
 
For patients who discontinue study therapy without documented disease progression:  
• Continue to be monitored for disease status by radiologic imaging according to the 
guidelines described in the Study Calendars for post-treatment follow-up. 
• Continue to come to the clinic for follow up visits every 12 weeks (+/- 2 weeks) for 1 year 
for review of medication, review of AEs, physical exam, and laboratory evaluations. 
• If the patient experiences disease progression or starts a new anticancer therapy during this 
time, they can move to survival follow up for the remainder of the follow up period. 
For patients who discontinue study therapy due to documented disease progression:  
• In-clinic follow up visits and/or monitoring for disease status by radiologic imaging is not 
required.  
• Conduct survival follow up every 12 weeks (+/- 2 weeks) for one year. 
For all patients, after one year of in person or survival follow up, the patient is considered off study 
and no follow up of any kind is required. 
 
Criteria for Removal from Study 
Patients will be removed from study when any of the applicable criteria including  completion of 
follow up (Section 5.5), or items listed in Section 5.4. The reason for study removal and the date 
the patient was removed must be documented in the Case Report Form. 


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Criteria to Resume Treatment 
For non-autoimmune or inflammatory events, patients may resume treatment with study drug when 
the drug-related AE(s) resolve to Grade ≤1 or baseline value, with the following exceptions: 
• Patients may resume treatment in the presence of Grade 2 fatigue.  
• Patients with baseline Grade 1 AST/ALT or total bilirubin, or elevated total bilirubin due to 
Gilbert disease or HIV protease inhibitor therapy who require dose delays for reasons other 
than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in the presence of 
Grade 2 AST/ALT OR total bilirubin, or <5X ULN in patients with Gilbert disease or on HIV 
Protease Inhibitor therapy (Section 5.1.2, Table 2). 
• Patients with combined Grade 2 AST/ALT AND total bilirubin values meeting study 
parameters outlined in Section 5.2.3 should have treatment permanently discontinued. 
• Non-drug-related toxicity including hepatic, pulmonary toxicity, diarrhea, or colitis, must have 
resolved to baseline or grade 1 AE before treatment is resumed. 
• Drug-related endocrinopathies (not including drug-related adrenal insufficiency or 
hypophysitis) adequately controlled with only physiologic hormone replacement may resume 
treatment after replacement correction and clinically stable regimen. 
If the criteria to resume treatment are met, the patient 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 12-week delay period.  
If treatment is delayed >12 weeks, the patient must be permanently discontinued from study 
therapy, except as specified in [Section 5.4 (Duration of Therapy)]. 
 
Treatment Beyond Progression 
Immunotherapeutic agents such as MK-3475 (pembrolizumab) may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses. The response patterns seen with such 
an approach may extend beyond the typical time course of responses seen with cytotoxic agents, 
and can manifest as a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions. 
Patients with documented progressive disease will have the option of continuing MK-3475 until 
confirmation approximately 4-6 weeks later, because of the possibility that the first follow up scan 
indicating PD may document pseudoprogression. A small subset of patients treated with MK-3475 
for melanoma experienced late responses with continued therapy. In the KEYNOTE-001 
melanoma trial using MK-3475 there was an additional 3.6% response rate with continued therapy. 
This category of response was defined as an “unconventional response” with “delayed 
pseudoprogression: ≥25% increase in tumor burden at any assessment after week 12 that was not 
confirmed as progressive disease per irRC at the next assessment”(Hodi 2014). 
If radiologic imaging or other ACTG KS response criteria shows progressive disease (PD), tumor 
assessment may be repeated by the site approximately 4 - 6 weeks later in order to confirm PD 
with the option of continuing treatment per below while awaiting radiologic confirmation of 
progression. If repeat imaging or ACTG KS criteria shows a reduction in the tumor burden 


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compared to the initial scan demonstrating PD, treatment may be continued as per treatment 
calendar. If repeat imaging confirms PD, patients will be generally discontinued from study 
therapy if alternative therapy is warranted. In determining whether or not the tumor burden has 
increased or decreased, investigators should consider all target lesions as well as non-target 
lesions. The decision to continue study treatment after the 1st evidence of disease progression 
determined by radiologic imaging is at the Investigator’s discretion based on the clinical status of 
the patient as described in the table below.  
Patients may receive study treatment while waiting for confirmation of PD if they are clinically 
stable as defined by the following criteria: 
• Absence of signs and symptoms (including worsening of laboratory values) indicating disease 
progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) requiring 
urgent alternative medical intervention 
 
Clinically Stable 
Clinically Unstable 
 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of PD 
Repeat imaging at 
approximately 4 to 
6 weeks to confirm 
PD 
May continue 
study treatment at 
the Investigator’s 
discretion while 
awaiting 
confirmatory scan 
Repeat imaging at 
approximately 4 to 
6 weeks to confirm 
PD if possible 
Discontinue 
treatment if 
alternative therapy 
is warranted  
Repeat scan 
confirms PD 
No additional 
imaging required 
Discontinue 
treatment 
(exception is 
possible upon 
consultation with 
CTEP) 
No additional 
imaging required 
N/A 
Repeat scan shows 
SD, PR, or CR 
Continue regularly 
scheduled imaging 
assessments every 
9 weeks* 
Continue study 
treatment at the 
Investigator’s 
discretion 
Continue regularly 
scheduled imaging 
assessments every 
9 weeks* 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable 
per Investigator’s 
discretion 
*Tumor imaging/assessment will be performed at baseline and every 9 weeks (63±7 days) during the first 
year of treatment. Subsequently, tumor imaging will be performed every 12 weeks (84 ±7 days). 
 
 
Criteria for Discontinuing MK-3475 (pembrolizumab) in Patients Achieving a CR  
Patients that achieve a complete response (CR) can discontinue treatment after 6 months of therapy 
provided that the patient has had at least 2 cycles of treatment after validation of CR. Patients will 
continue to be followed as outlined in Section 5.5.  


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Retreating with MK-3475 (pembrolizumab) in Patients with Recurrence 
Patients that have a CR for whom the disease subsequently recurs off of therapy may be retreated 
off protocol at patient and investigator discretion. Patients that discontinue due to progression will 
not be eligible for re-treatment. 
6. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
MK-3475 (pembrolizumab) Dose Modifications 
6.1.1 General MK-3475 (pembrolizumab) Dose Modifications 
Adverse events (both nonserious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These AEs may occur shortly after the first dose or 
several months after the last dose of treatment.  Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as described in Section 6.1.3. 
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays).  Patients should be placed back on study therapy within 3 weeks of the 
scheduled interruption.  The reason for interruption should be documented in the patient's 
study record. 
6.1.2 Supportive Care Guidelines  
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are also outlined in the table in Section 6.1.3.  Where 
appropriate, these guidelines include the use of oral or IV treatment with corticosteroids as 
well as additional anti-inflammatory agents if symptoms do not improve with administration 
of corticosteroids.  Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased.  For each disorder, attempts 
should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care.  The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to 
pembrolizumab. 
Note:  If after the evaluation the event is determined not to be related, the investigator does 
not need to follow the treatment guidance (as outlined below). 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, 
or skin photography as part of the evaluation of the event. 
6.1.3  Dose Modification and Toxicity Management for Immune-related Adverse Events 
Associated with Pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology.  


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These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously.  Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical study data, most irAEs were reversible and could 
be managed with interruptions of pembrolizumab, administration of corticosteroids and/or 
other supportive care.  For suspected irAEs, ensure adequate evaluation to confirm etiology 
or exclude other causes.  Additional procedures or tests such as bronchoscopy, endoscopy, 
skin biopsy may be included as part of the evaluation. Based on the severity of irAEs, 
withhold or permanently discontinue pembrolizumab and administer corticosteroids.  
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis.  Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of 
infusion.  Dose modification and toxicity management guidelines for irAEs and infusion 
reactions associated with pembrolizumab are provided in the table below. 
 
Note that non-irAEs will be managed as appropriate, following clinical practice 
recommendations.


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Dose Modification and Toxicity Management Guidelines for Immune-related AEs and Infusion Reactions Associated with 
Pembrolizumab  
General instructions: 
1. For non-endocrine-related severe and life-threatening irAEs, investigators should consider the use of IV corticosteroids followed by oral 
steroids.  Other immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids.  Some non-endocrine 
irAEs do not require steroids.  For example, celiac disease induced by pembrolizumab can be controlled by diet alone. 
2. For non-endocrine-related toxicities, pembrolizumab must be permanently discontinued if the irAE does not resolve or the 
corticosteroid dose is not ≤10 mg/day within 12 weeks of the last pembrolizumab treatment.  
3. Generally, when corticosteroids are used, investigators should begin a taper when the irAE is ≤Grade 1 and continue at least 4 weeks. 
4. If pembrolizumab has been withheld due to a non-endocrine irAE, pembrolizumab may generally resume after the irAE has decreased 
to ≤Grade 1 after a corticosteroid taper. 
irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab  
Corticosteroid and/or other 
therapies  
Monitoring and follow-up  
Pneumonitis  
Grade 2 
Withhold  
Administer corticosteroids 
(initial dose of 1 to 2 
mg/kg prednisone or 
equivalent) followed by 
taper 
Add prophylactic antibiotics 
for opportunistic infections 
 
Monitor participants for signs 
and symptoms of 
pneumonitis 
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and 
initiate corticosteroid 
treatment 
 
Recurrent Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
Administer corticosteroids 
(initial dose of 1 to 2 
mg/kg prednisone or 
Monitor participants for signs 
and symptoms of 
enterocolitis (i.e., diarrhea, 
abdominal pain, blood or 
mucus in stool with or 


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Recurrent Grade 3 or 
Grade 4 
Permanently 
discontinue 
equivalent) followed by 
taper 
Patients who do not respond to 
corticosteroids should be 
seen by a 
gastroenterologist for 
confirmation of the 
diagnosis and 
consideration of secondary 
immune suppression 
 
 
without fever) and of bowel 
perforation (i.e. peritoneal 
signs and ileus) 
Specifically assess for celiac 
disease serologically, and 
exclude Clostridium difficile 
infection 
Participants with ≥Grade 2 
diarrhea suspecting 
enterocolitis should consider 
GI consultation and 
performing endoscopy to 
rule out enterocolitis and 
assess mucosal severity 
Participants with diarrhea/colitis 
should be advised to drink 
liberal quantities of clear 
fluids. If sufficient oral fluid 
intake is not feasible, fluid 
and electrolytes should be 
substituted via IV infusion 
AST or ALT elevation 
or Increased Bilirubin 
Grade 2 a 
Withhold 
Administer corticosteroids 
(initial dose of 0.5 to 1 
mg/kg prednisone or 
equivalent) followed by 
taper 
Monitor with liver function tests 
(consider weekly or more 
frequently until liver 
enzyme value returned to 
baseline or is stable) 


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Grade 3 b or 4 c 
Permanently 
discontinue 
Administer corticosteroids 
(initial dose of 1 to 2 
mg/kg prednisone or 
equivalent) followed by 
taper 
Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia 
Grade 1 or 2 
Continue 
 
Investigate for diabetes.  In the 
absence of corticosteroids or 
diabetes medication non-
adherence, any grade 
hyperglycemia may be an 
indication of beta-cell 
destruction and 
pembrolizumab-induced 
diabetes akin to type 1 
diabetes.  This should be 
treated as a Grade 3 event.  
Given this risk, exercise 
caution in utilizing non-
insulin hypoglycemic agents 
in this setting.  After a 
thorough investigation of 
other potential causes, 
which may involve a referral 
to an endocrinologist, follow 
institutional guidelines.   
Monitor glucose control. 


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New onset T1DM 
(evidence of -cell 
failure) or  
Grade 3 or 4 
hyperglycemia 
Withhold d 
Resume 
pembrolizumab 
when symptoms 
resolve and glucose 
levels are stable 
Initiate treatment with insulin 
If patient is found to have 
diabetic ketoacidosis or 
hyperglycemic 
hyperosmolar syndrome, 
treat as per institutional 
guidelines with appropriate 
management and 
laboratory values (e.g. 
anion gap, ketones, blood 
pH, etc.) reported 
 
Monitor for glucose control 
Strongly consider referral to 
endocrinologist 
Obtain C-peptide level paired 
with glucose, autoantibody 
levels (e.g. GAD65, islet 
cell autoantibodies), and 
hemoglobin A1C level 
 
Hypophysitis 
Grade 2 
Withhold 
Administer corticosteroids and 
initiate hormonal 
replacements as clinically 
indicated 
Monitor for signs and symptoms 
of hypophysitis (including 
hypopituitarism and adrenal 
insufficiency) 
Provide adrenal insufficiency 
precautions including 
indications for stress dose 
steroids and medical alert 
jewelry 
Strongly consider referral to 
endocrinologist 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 


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Hyperthyroidism 
Grade 2 
Consider 
withholding. 
Resume 
pembrolizumab 
when symptoms are 
controlled, and 
thyroid function is 
improving 
Treat with nonselective beta-
blockers (e.g., propranolol) 
or thionamides as 
appropriate 
Initiate treatment with anti-
thyroid drug such as 
methimazole or 
carbimazole as needed 
Monitor for signs and symptoms 
of thyroid disorders 
Strongly consider referral to 
endocrinologist 
 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3 or 4 
Continue 
Initiate thyroid replacement 
hormones (e.g., 
levothyroxine or 
liothyronine) per standard 
of care 
Monitor for signs and symptoms 
of thyroid disorders 
Nephritis: 
grading according to 
increased creatinine or 
acute kidney injury 
Grade 2 
Withhold 
Administer corticosteroids 
(prednisone 1 to 2 mg/kg 
or equivalent) followed by 
taper 
Monitor changes of renal 
function 
Strongly consider referral to 
nephrologist 
Grade 3 or 4 
Permanently 
discontinue 


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Cardiac Events 
(including myocarditis, 
pericarditis, 
arrhythmias, impaired 
ventricular function, 
vasculitis) 
Asymptomatic cardiac 
enzyme elevation with 
clinical suspicion of 
myocarditis (previously 
CTCAE v4.0 Grade 1), 
or Grade 1 
Withhold 
Based on severity of AE 
administer corticosteroids 
 
Ensure adequate evaluation to 
confirm etiology and/or 
exclude other causes 
Strongly consider referral to 
cardiologist and cardiac 
MRI 
Consider endomyocardial 
biopsy 
If event resolves to Grade 1 or 
better, taper corticosteroids 
over ≥1 month 


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Grade 2, 3 or 4 
Permanently 
discontinue 
Initiate treatment with 
corticosteroids equivalent 
to 1-2 mg/kg/day IV 
methylprednisolone and 
convert to 1-2 mg/kg/day 
oral prednisone or 
equivalent upon 
improvement 
If event does not improve 
within 48 hours after 
initiating corticosteroids, 
consider adding an 
immunosuppressive agent 
Initiate treatment per 
institutional guidelines and 
consider antiarrhythmic 
drugs, temporary 
pacemaker, extracorporeal 
membrane oxygenation 
(ECMO), ventricular assist 
device (VAD), or 
pericardiocentesis as 
appropriate 
Ensure adequate evaluation to 
confirm etiology and/or 
exclude other causes 
Strongly consider referral to 
cardiologist and cardiac 
MRI 
Consider endomyocardial 
biopsy 
If event resolves to Grade 1 or 
better, taper corticosteroids 
over ≥1 month 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, TEN, or 
DRESS 
Withhold 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation to 
confirm etiology or exclude 
other causes 
Strongly consider referral to 
dermatologist 
Consider skin biopsy for 
evaluation of etiology 
Confirmed SJS, TEN, 
or DRESS 
Permanently 
discontinue 


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All Other irAEs 
Persistent Grade 2 
Withhold 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation to 
confirm etiology or exclude 
other causes 
Grade 3 
Withhold or 
discontinue based on 
the event e  
Recurrent Grade 3 or 
Grade 4  
Permanently 
discontinue 
 
 
Infusion-Related Reactions 
Infusion Reactions 
NCI CTCAE Grade 
Treatment  
Premedication at subsequent 
dosing 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
  
Grade 1 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
None 


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Infusion Reactions 
NCI CTCAE Grade 
Treatment  
Premedication at subsequent 
dosing 
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs. 
Grade 2 
• 
Stop Infusion. 
• 
Additional appropriate medical therapy may 
include but is not limited to: 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDs 
• 
Acetaminophen 
• 
Narcotics 
• 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator. 
• 
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g. from 100 
mL/hr. to 50 mL/hr.). Otherwise dosing will be 
held until symptoms resolve and the participant 
should be premedicated for the next scheduled 
dose. 
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment 
Participant may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of study intervention 
with: 
Diphenhydramine 50 mg PO (or 
equivalent 
dose 
of 
antihistamine). 
Acetaminophen 500-1000 mg 
PO (or equivalent dose of 
analgesic). 


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Infusion Reactions 
NCI CTCAE Grade 
Treatment  
Premedication at subsequent 
dosing 
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 3 
• 
Stop Infusion. 
• 
Additional appropriate medical therapy may 
include but is not limited to: 
• 
Epinephrine** 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDs 
• 
Acetaminophen 
• 
Narcotics 
• 
Oxygen 
• 
Pressors 
• 
Corticosteroids (e.g. methylprednisolone 2 
mg/kg/day or dexamethasone 10 mg every 6 
hours) 
• 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator. 
• 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used 
immediately. 
Participant is permanently discontinued from further 
study drug treatment. 
 
No subsequent dosing. 
 


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Infusion Reactions 
NCI CTCAE Grade 
Treatment  
Premedication at subsequent 
dosing 
Life-threatening; 
pressor or ventilator 
support indicated 
 
Grade 4 
Admit participant to intensive care unit (ICU) and 
initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as 
needed. Monitor other organ function closely. 
Manage constitutional symptoms and organ toxicities 
as per institutional practice. 
Follow Grade 3 recommendations as applicable. 
No subsequent dosing. 
 


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Infusion Reactions 
NCI CTCAE Grade 
Treatment  
Premedication at subsequent 
dosing 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; ECMO=extracorporeal membrane oxygenation; GI=gastrointestinal; ICU=intensive care unit; IO=immuno-oncology; 
ir=immune related; IV=intravenous; MRI=magnetic resonance imaging; PO=per os; SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic 
Epidermal Necrolysis; ULN=upper limit of normal; VAD=ventricular assist device. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to 5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline 
normal; >3.0 to 10.0 x baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control 
achieved or ≤Grade 2, pembrolizumab may be resumed. 
e Events that require discontinuation include but are not limited to: encephalitis and other clinically important irAEs (e.g. vasculitis and 
sclerosing cholangitis). 
 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug 
administration. For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov. 
 


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Neurological Toxicities 
 
Event 
Management 
Immune-mediated 
neuropathy, Grade 1 
• Continue pembrolizumab. 
• Investigate etiology. 
• Any cranial nerve disorder (including facial paresis) should be 
managed as per Grade 2 management guidelines below. 
Immune-mediated 
neuropathy, 
including facial 
paresis, Grade 2 
• Withhold pembrolizumab for up to 12 weeks after event onset. a 
• Investigate etiology and refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• For general immune-mediated neuropathy: 
o If event resolves to Grade 1 or better, resume 
pembrolizumab. b 
o If event does not resolve to Grade 1 or better while 
withholding pembrolizumab, permanently discontinue 
pembrolizumab. c 
• For facial paresis: 
o If event resolves fully, resume pembrolizumab. b 
o If event does not resolve fully while withholding 
pembrolizumab, permanently discontinue 
pembrolizumab. c 
Immune-mediated 
neuropathy, 
including facial 
paresis, Grade 3 or 4 
• Permanently discontinue pembrolizumab. c  
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
Myasthenia gravis 
and Guillain-Barré 
syndrome (any 
grade) 
• Permanently discontinue pembrolizumab. c 
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• Consider initiation of corticosteroids equivalent to 1−2 
mg/kg/day oral or IV prednisone. 
a Pembrolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day 
oral prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefit−risk by the investigator and in alignment with the protocol requirements 
for the duration of treatment and documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before pembrolizumab can be resumed. 
c Resumption of pembrolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge patients 
with pembrolizumab should be based on investigator's assessment of benefit−risk and 
documented by the investigator (or an appropriate delegate). 
 
 


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76 
Event 
Management 
Immune-mediated myelitis, 
Grade 1 
• 
Continue pembrolizumab unless symptoms worsen or 
do not improve. 
• 
Investigate etiology and refer patient to a neurologist.  
Immune-mediated myelitis, 
Grade 2 
• 
Permanently discontinue pembrolizumab.  
• 
Investigate etiology and refer patient to a neurologist. 
• 
Rule out infection. 
• 
Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day oral prednisone. 
Immune-mediated myelitis, 
Grade 3 or 4 
• 
Permanently discontinue pembrolizumab. 
• 
Refer patient to a neurologist. 
• 
Initiate treatment as per institutional guidelines. 
 
Event 
Management 
Immune-mediated 
meningoencephalitis, 
all grades 
• Permanently discontinue pembrolizumab. a 
• Refer patient to neurologist. 
• Initiate treatment with corticosteroids equivalent to 1−2 
mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month. 
a Resumption of pembrolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge patients 
with pembrolizumab should be based on investigator's assessment of benefit−risk and 
documented by the investigator (or an appropriate delegate). 
 
 
 
 
 
Delayed Visits for Reasons Other Than Toxicity 
A schedule for return visits should be established at the first visit. If a participant misses a 
treatment, the missed treatment will be administered as soon as possible, so that the subsequent 
treatments are given in the appropriate intervals. Treatment may be continued for an additional 
time period, if needed. Participants who are treated outside of the established schedule should 
return to the original schedule as soon as possible. 


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7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting via the CTEP Adverse Event Reporting 
System (CTEP-AERS) in addition to routine reporting. 
 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) 
7.1.1 CAEPRs for CTEP IND Agent(s): MK-3475 (pembrolizumab) 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
MK-3475 (pembrolizumab, NSC 776864) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In 
addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of 
events that are protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. 
Frequency is provided based on 3793 patients. Below is the CAEPR for Pembrolizumab (MK-3475). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the 
SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
       Version 2.7, December 13, 20221 
 
 Adverse Events with Possible  
 Relationship to Pembrolizumab (MK-3475) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
 
Anemia2 
 
 
 
 
 
Blood and lymphatic system 
disorders - Other (immune 
thrombocytopenic purpura)2 
 
 
 
Lymph node pain2 
 
 
 
CARDIAC DISORDERS 
 
 
 
 
Myocarditis2 
 
 
 
 
Pericarditis2 
 
 
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency2 
 
  
 
 
Endocrine disorders - Other 
(hypoparathyroidism) 
  
 
Endocrine disorders - Other 
(thyroiditis)2 
 
  
 
Hyperthyroidism2 
 
  
 
Hypophysitis2 
 
  
 
Hypopituitarism2 
 
  
 
Hypothyroidism2 
 
  


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78 
 
 Adverse Events with Possible  
 Relationship to Pembrolizumab (MK-3475) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
EYE DISORDERS 
  
 
 
Uveitis2 
  
 
 
Eye disorders - Other (Vogt-
Koyanagi-Harada syndrome) 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Colitis2 
 
  
 
Diarrhea2 
 
 Diarrhea2 (Gr 2) 
 
Mucositis oral2 
 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Pancreatitis2 
 
  
 
Small intestinal mucositis2 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills2 
 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever2 
 
  
HEPATOBILIARY DISORDERS 
  
 
Hepatobiliary disorders - Other 
(autoimmune hepatitis)2 
 
  
 
 
Hepatobiliary disorders - Other 
(sclerosing cholangitis) 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Anaphylaxis2 
  
 
 
Cytokine release syndrome2 
  
 
 
Immune system disorders - Other 
(acute graft-versus-host-disease)2,3 
  
 
 
Immune system disorders - Other 
(hemophagocytic 
lymphohistiocytosis)2 
  
 
Immune system disorders - Other 
(sarcoidosis)2 
 
  
 
 
Serum sickness2 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
 Infusion related reaction 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase increased2 
 
  
 
Alkaline phosphatase increased 
 
  
 
Aspartate aminotransferase increased2  
  
 
Blood bilirubin increased 
 
  
 
 
GGT increased 
  
 
 
Serum amylase increased 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
Hyponatremia 
 
  
 
 
Metabolism and nutrition 
disorders - Other (diabetic 
ketoacidosis)2 
  


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79 
 
 Adverse Events with Possible  
 Relationship to Pembrolizumab (MK-3475) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
 
Metabolism and nutrition 
disorders - Other (type 1 diabetes 
mellitus)2 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia2 
 
 Arthralgia2 (Gr 2) 
 
Arthritis2 
 
  
 
Back pain 
 
  
 
Joint range of motion decreased 
 
  
 
Myalgia2 
 
  
 
Myositis2 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Guillain-Barre syndrome2 
  
 
 
Nervous system disorders - Other 
(myasthenic syndrome)2 
  
 
 
Nervous system disorders - Other 
(neuromyopathy)2 
  
 
 
Nervous system disorders - Other 
(non-infectious encephalitis)2 
  
 
 
Nervous system disorders - Other 
(non-infectious meningitis)2 
  
 
 
Nervous system disorders - Other 
(non-infectious myelitis) 
  
 
 
Nervous system disorders - Other 
(optic neuritis) 
  
 
 
Nervous system disorders - Other 
(polyneuropathy)2 
  
 
 
Paresthesia 
  
 
 
Peripheral motor neuropathy2 
  
RENAL AND URINARY DISORDERS 
  
 
 
Renal and urinary disorders - 
Other (autoimmune nephritis)2 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 Cough 
 
  
 
 Pneumonitis2 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Bullous dermatitis2 
 
  
 
 
 Erythema multiforme2 
  
 
Erythroderma 
 
  
 
 
Palmar-plantar erythrodysesthesia 
syndrome 
  
 
Pruritus2 
 
 Pruritus2 (Gr 2) 
 
Rash acneiform2 
 
  
 
Rash maculo-papular2 
 
 Rash maculo-papular2 (Gr 2) 
 
Skin and subcutaneous tissue disorders 
- Other (dermatitis)2 
 
  
 
Skin hypopigmentation2 
 
  
 
 
Stevens-Johnson syndrome2 
  
 
 
Toxic epidermal necrolysis 
  
 
Urticaria2 
 
  


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80 
 
 Adverse Events with Possible  
 Relationship to Pembrolizumab (MK-3475) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
VASCULAR DISORDERS 
  
 
 
Vasculitis2 
  
 
 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Immune-mediated adverse reactions have been reported in patients receiving Pembrolizumab (MK-3475).  Adverse 
events potentially related to Pembrolizumab (MK-3475) may be manifestations of immune-mediated adverse events. 
In clinical trials, most immune-mediated adverse reactions were reversible and managed with interruptions of 
Pembrolizumab (MK-3475), administration of corticosteroids and supportive care. 
 
3Acute graft-versus-host disease has been observed in patients treated with Pembrolizumab (MK-3475) who 
received hematopoeitic stem cell transplants. 
 
Adverse events reported on Pembrolizumab (MK-3475) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that Pembrolizumab (MK-3475) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Disseminated intravascular coagulation; Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Chest pain - cardiac; Heart failure; Myocardial 
infarction; Pericardial effusion; Pericardial tamponade; Ventricular arrhythmia 
EYE DISORDERS - Eye pain 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Constipation; Duodenal hemorrhage; 
Dysphagia; Gastritis; Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal disorders - Other (intestinal 
obstruction); Gastrointestinal disorders - Other (intussusception); Oral pain; Rectal hemorrhage; Small intestinal 
perforation; Upper gastrointestinal hemorrhage; Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Edema limbs; Facial 
pain; Gait disturbance; General disorders and administration site conditions - Other (general physical health 
deterioration); Generalized edema; Malaise; Non-cardiac chest pain; Pain 
INVESTIGATIONS - CPK increased; Cholesterol high; Creatinine increased; Fibrinogen decreased; Lymphocyte 
count decreased; Neutrophil count decreased; Platelet count decreased; Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; Hypokalemia; Hypophosphatemia; 
Metabolism and nutrition disorders - Other (failure to thrive); Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Generalized muscle 
weakness; Joint effusion2; Musculoskeletal and connective tissue disorder - Other (groin pain); Pain in extremity 
NERVOUS SYSTEM DISORDERS - Aphonia; Depressed level of consciousness; Dysarthria; Edema cerebral; 
Encephalopathy; Headache; Hydrocephalus; Lethargy; Meningismus; Nervous system disorders - Other (brainstem 
herniation); Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury; Nephrotic syndrome; Proteinuria; Renal and 
urinary disorders - Other (hydronephrosis); Urinary incontinence; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Dyspnea; Hypoxia; Laryngeal 


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inflammation; Pleural effusion; Pleuritic pain2; Pneumothorax; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Skin and subcutaneous tissue 
disorders - Other (drug eruption) 
VASCULAR DISORDERS - Hypertension; Peripheral ischemia; Thromboembolic event 
 
 
Note: Pembrolizumab (MK-3475) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 
 
 


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Adverse Event Characteristics  
• CTCAE term (AE description) and grade: The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
will be utilized until March 31, 2018 for AE reporting. CTCAE version 5.0 will be utilized 
for AE reporting beginning April 1, 2018. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded 
from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
• For expedited reporting purposes only:  
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the grade 
is above the grade provided in the SPEER. 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
Expedited Adverse Event Reporting 
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event Reporting 
System), accessed via the CTEP Web site (https://ctepcore.nci.nih.gov/ctepaers/security/login). 
The reporting procedures to be followed are presented in the “NCI Guidelines for Investigators: 
Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” 
which can be downloaded from the CTEP Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). These 
requirements are briefly outlined in the tables below. 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to 
CTEP by telephone at 301-897-7497. Once Internet connectivity is restored, the 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original submitter 
at the site. 
7.3.1 Distribution of Adverse Event Reports 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals: Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization or Lead Organization, the local treating 
physician, and the Reporter and Submitter. CTEP-AERS provides a copy feature for 
other e-mail recipients.  


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83 
The Coordinating Center of the Corresponding Organization is responsible for submitting 
to the CTSU documentation of AEs that they deem reportable for posting on the CTSU 
protocol web page and inclusion on the CTSU bi-monthly broadcast. 
7.3.2 Expedited Reporting Guidelines 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
Note: A death on study requires both routine and expedited reporting, regardless of 
causality. Attribution to treatment or other cause must be provided. 
Death due to progressive disease should be reported as Grade 5 “Disease Progression” 
in the system organ class (SOC) “General disorders and administration site conditions”. 
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.  
Pregnancy loss 
Pregnancy loss is defined in CTCAE as “Death in Utero”. 
Any pregnancy loss should be reported expeditiously, as Grade 4 “pregnancy loss” under 
the Pregnancy, puerperium and perinatal conditions SOC. 
A pregnancy loss should NOT be reported as a Grade 5 event under the Pregnancy, 
puerperium and perinatal conditions SOC, as currently CTEP AERS recognizes this event 
as a patient death. 
Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse 
Events 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 adverse event is considered serious if it results in ANY of the following outcomes:  
3. Death 
4. A life-threatening adverse event  
5. An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
6. A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
7. A congenital anomaly/birth defect.  
8. 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 patient or subject 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). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 


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Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
• 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
• 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above 
applies after this reporting period. 
Effective Date: May 5, 2011 
 
 
Routine Adverse Event Reporting 
All Adverse Events must be reported in routine study data submissions. AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave. For this trial the Adverse Event CRF is used for routine AE 
reporting in Rave. 
 
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 expeditiously 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)  


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• 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.  
 
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 unless otherwise specified. 
 
Reporting of Pregnancy and Lactation to the Sponsor 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them) that occurs during the trial or within 120 days of completing the trial, or 30 
days following cessation of treatment if the subject initiates new anticancer therapy, whichever is 
earlier. All subjects who become pregnant must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform 
mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported 
as serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported. 
8. 
PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1. 
 
CTEP IND Agent 
8.1.1 MK-3475 (pembrolizumab) (SCH 900475) (NSC 776864) 
Other Names: pembrolizumab, SCH 900475 
Classification: Anti-PD-1 MAb 
Molecular Weight: 148.9-149.5 KDa 
CAS Number: 1374853-91-4 
Mode of Action: The programmed cell death 1 (PD-1) receptor is an inhibitory receptor 
expressed by T cells. When bound to either of its ligands, PD-L1 or PD-L2, activated PD-
1 negatively regulates T-cell activation and effector function. The pathway may be 
engaged by tumor cells to suppress immune control. MK-3475 (pembrolizumab) blocks 
the negative immune regulatory signaling by binding to the PD-1 receptor, inhibiting the 
interaction between PD-1 and its ligands. 


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Description: MK-3475 (pembrolizumab) is a humanized MAb of the IgG4/kappa 
isotype. 
How Supplied: MK-3475 (pembrolizumab) is supplied by Merck & Co., Inc. and 
distributed by the Pharmaceutical Management Branch, CTEP/DCTD/NCI. 
Pembrolizumab (MK-3475) injection is a sterile, preservative-free, clear to slightly 
opalescent, colorless to slightly yellow solution for intravenous use. Each vial contains 
100 mg of pembrolizumab (MK-3475) in 4 mL of solution.  Each 1 mL of solution 
contains 25 mg of pembrolizumab (MK-3475) and is formulated in: L-histidine (1.55 
mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP. 
Preparation: MK-3475 (pembrolizumab) solution for infusion must be diluted prior to 
administration. Do not shake the vials. Do not use if opaque or extraneous particulate 
matter other than translucent to white proteinaceous particles is observed. Do not use if 
discolored. To prepare the infusion solution add the dose volume of MK-3475 
(pembrolizumab) to an infusion bag containing 0.9% Sodium Chloride Injection, USP or 
5% Dextrose Injection, USP. Gently invert the bag 10-15 times to mix the solution. The 
final concentration must be between 1 mg/mL to 10 mg/mL. 
Compatible IV bag materials: PVC plasticized with DEHP, non-PVC (polyolefin), EVA, 
or PE lined polyolefin 
Storage: Store intact vials between 2°C - 8°C (36°F - 46°F). Do not freeze. Protect from 
light by storing in the original box. If a storage temperature excursion is identified, 
promptly return MK-3475 vials to 2-8°C and quarantine the supplies. Provide a detailed 
report of the excursion (including documentation of temperature monitoring and duration 
of the excursion) to PMBAfterHours@mail.nih.gov for determination of stability. 
Stability: Refer to the package label for expiration.  
Administer prepared solutions immediately after preparation. If not administered 
immediately, prepared solutions may be stored refrigerated for up to 24 hours. 
Pembrolizumab (MK-3475) solutions may be stored at room temperature for a 
cumulative time of up to 6 hours. This includes room temperature storage of liquid drug 
product solution in vials, room temperature storage of infusion solution in the IV bag, and 
the duration of infusion. 
Route of Administration: IV infusion only. Do not administer as an IV push or bolus 
injection. 
Method of Administration: Infuse over approximately 30 minutes (range: 25 - 40 
minutes) using an infusion set containing a low-protein binding 0.2 to 5 µm in-line filter 
made of polyethersulfone or polysulfone. Infusion rate should not exceed 6.7 mL/min. A 
central line is not required; however if a subject has a central venous catheter in place, it 
is recommended that it be used for the infusion. Do not co-administer other drugs through 
the same infusion line. Following the infusion, flush the IV line with normal saline.  


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Compatible infusion set materials: PVC plasticized with DEHP or DEHT, PVC and tri-
(2-ethylhexyl) trimellitate, polyethylene lined PVC, polyurethane, or polybutadiene 
Patient Care Implications: Refer to the protocol for information on evaluation and 
management of potential immune-related adverse events. 
Availability: MK-3475 (pembrolizumab) is an investigational agent supplied to 
investigators by the Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
MK-3475 (pembrolizumab) is provided to the NCI under a Collaborative Agreement 
between the Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study. 
8.1.2 Agent Ordering and Agent Accountability 
8.1.2.1 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution. The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents. The 
eligible participating investigators at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), NCI Biosketch, Agent Shipment Form, 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 participating investigator at that institution. 
 
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-IAM account and the maintenance of an “active” account status and a 
“current” password. For questions about drug orders, transfers, returns, or 
accountability, call (240) 276-6575 Monday through Friday between 8:30 am and 
4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. Refer to the PMB’s 
website for specific policies and guidelines related to agent management. 
8.1.2.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the NCI Investigational Agent 
(Drug) Accountability Record (DARF) available on the CTEP forms page. Store and 
maintain separate NCI Investigational Agent Accountability Records for each agent, 
strength, formulation and ordering investigator on this protocol. 
 


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8.1.2.3 
Investigator Brochure Availability – The current version of the IB will be accessible 
to site investigators and research staff through the PMB Online Agent Order 
Processing (OAOP) application. Access to OAOP requires the establishment of a 
CTEP-IAM account and the maintenance of an “active” account status, a current 
password, and active person registration status. Questions about IB access may be 
directed to the PMB IB coordinator via email.  
 
8.1.2.4 
MK-3475 Useful links and Contacts: 
CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm 
PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx 
CTEP Identity and Access Management (IAM) account: https://eapps-
ctep.nci.nih.gov/iam/ 
CTEP 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)  
IB Coordinator: IBCoordinator@mail.nih.gov  
 
Other Investigational Agent(s): N/A 
 
Commercial Agent(s): N/A 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
The study calendars and lab manual describe blood draws for safety labs, research labs, and 
storage of leftover samples in the Biorepository. In the interest of patient safety, we are including 
a provision to draw less blood if patients are anemic. A CBC will be performed as part of the 
safety labs each time research labs and biorepository blood needs to be drawn (safety labs drawn 
for screening will used for this purpose prior to the first blood draws for research). The results of 
the CBC will be reviewed and the following blood volumes will be drawn based upon the 
patient’s hemoglobin level (Please refer to the CITN-12 Laboratory Manual for a detailed 
description on types and numbers blood tubes for correlative studies): 
• For a hemoglobin over 10.0 g/dL, draw the full volume of blood for safety labs and research 
labs. 
• For a hemoglobin between 9.0 and 10.0 g/dL, draw the full volume of blood for safety labs 
and CD4+ /CD8+ T-cell counts. Limit research blood draws to 30 mL for plasma HIV 
studies, and 62 mL for cell associated studies.  
• For a hemoglobin less than 9.0 g/dL, draw the full volume of blood for safety labs and CD4+ 
/CD8+ T-cell counts. Limit research blood draws to 20 mL for plasma HIV studies, and 36 
mL for cell associated studies. 


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Integral Laboratory Studies 
9.1.1 Evaluation of CD4+ and CD8+ T-cell counts – Integral Laboratory Correlative Study #1  
CD4+ and CD8+ T-cell total number and percent total lymphocytes will be performed at 
the treatment site in a CLIA compliant laboratory. Results will be used for determining 
eligibility, stratifying patients, and monitoring for possible toxicity in the form of falling 
CD4+ and/or CD8+ T-cells. 
9.1.1.1 
Collection of Specimen(s): Per local institutional procedures 
9.1.1.2 
Handling of Specimens(s): Per local institutional procedures 
9.1.1.3 
Shipping of Specimen(s): NA 
9.1.1.4 
Site(s) Performing Correlative Study: To be performed at local site 
 
Exploratory/Ancillary Correlative Studies 
Specimens will be collected for several planned correlative studies. Many samples will be 
processed and stored, to be run in batches. The CITN Central Laboratory will provide lab kits, 
which will include all required blood tubes for specimen collection for the correlative studies, 
pre-printed labels, and shipping supplies. Specific instructions on numbers and types of tubes 
required for each visit are provided in the CITN-12 Laboratory Manual.  
When blood volume is limiting, the correlative studies will be considered secondary to tests 
needed to make clinical decisions. Also, they may be delayed or omitted if collecting the 
specimens may pose a danger to the patient, or if they cannot be done or processed (because of 
Federal Holidays, inclement weather, US Government shutdown, etc.). 
For plasma based studies, assays will be prioritized in the following order: 
HIV single copy assay (Correlative Study #2) 
Plasma cytokines (Correlative Study #9) 
HIV RNA sequencing (Correlative Study #4) 
Cohort 4: KSHV-associated assays will be prioritized over HIV studies. 
For cell associated studies, assays will be prioritized in the following order: 
PMBC-associated HIV assays (Correlative Study #3) 
HIV transcriptome (Correlative Study #6) 
Flow cytometry (Correlative Study #8) 
HIV-specific immunity (Correlative Study #7) 
HIV TILDA (Correlative Study #5) 
Cohort 4: KSHV- associated assays will be prioritized over HIV studies as follows: 
o KSHV T cell Immunity 
o PBMC associated KSHV viral load 
For HIV specific immunity and TILDA, if a sample cannot be collected at a given time point, 
collection on a subsequent cycle will be permitted. 
Collection of pre-treatment tumor tissue (archival tumor sample or fresh biopsy) is mandatory, 
but subsequent biopsies are optional. Biopsy-based correlatives are considered exploratory. 


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Prioritization of biopsy specimens will be made based on technical considerations, total number 
of samples acquired, and feasibility of correlative study based on the above considerations.  
The anticipated priority of biopsy-based correlatives is: 
• Immune cell infiltration IHC (Correlative Study #11) 
1. PDL1 expression (Correlative Study #12) 
2. mRNA expression (Correlative Study #12) 
9.2.1 Assessment of Single copy HIV plasma RNA - Exploratory Laboratory Correlative Study 
#2 
9.2.1.1 
Collection of Specimen(s) 
Blood draws will be performed on study subjects immediately before, during, and at 
end of treatment using tubes provided by the CITN Central Lab. 
9.2.1.2 
Handling of Specimens(s) 
Plasma will be isolated by the local laboratory per the HIV Molecular Monitoring 
Core (HMMC) protocol (Jeff Lifson, Frank Maldarelli, personal communication) and 
frozen at -80°C. 
9.2.1.3 
Shipping of Specimen(s) 
Plasma samples will be batch shipped overnight on dry ice to the CITN Central 
Laboratory. Sites will utilize a web-based specimen system (BSI-Web) to 
communicate with the CITN Central Laboratory. The CITN Central Laboratory will 
coordinate batch shipments on dry ice of samples to the Lifson Laboratory. 
9.2.1.4 
Site(s) Performing Correlative Study:  
Lifson Laboratory, at the NCI AIDS and Cancer Virus Program, Frederick, MD. 
9.2.2 Assessment of cell associated unspliced HIV RNA and cell associated total HIV DNA - 
Exploratory Laboratory Correlative Study #3 
9.2.2.1 
Collection of Specimen(s) 
Blood draws will be performed on study subjects immediately before, during, and at 
end of treatment using tubes provided by the CITN Central Lab. 
9.2.2.2 
Handling of Specimens(s) 
Blood samples will be collected at room temperature and shipped ambient to the 
CITN Central Laboratory the same day as the blood draw, so that the sample is 
received at the Central Laboratory within 24 hours of blood draw. PBMC will be 
processed from blood within 24 hours of the blood draw and aliquoted into tubes with 
a goal of 5-10 million PBMC per tube and then stored cryopreserved as PBMC pellets 
in liquid nitrogen or -80°C for subsequent analyses. 
9.2.2.3 
Shipping of Specimen(s) 
Blood draw tubes will be shipped at ambient temperature to the CITN Central 
Laboratory. Clinical sites will utilize a web-based specimen system (BSI-Web) to 
communicate with the CITN Central Laboratory. The CITN Central Laboratory will 


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coordinate batch shipment on dry-ice of PBMC (goal of total 10 million PBMC) to 
the Lewin Laboratory.  
9.2.2.4 
Site(s) Performing Correlative Study 
Lewin Laboratory, University of Melbourne, Victoria, Australia. 
9.2.3 Evaluation of HIV molecular evolution—Exploratory Laboratory Correlative Study #4 
9.2.3.1 
Collection of Specimen(s) 
Blood draws will be performed on study subjects immediately before, during, and at 
end of treatment using tubes provided by the CITN Central Lab. 
9.2.3.2 
Handling of Specimens(s) 
Plasma will be isolated by the local laboratory per the HIV Molecular Monitoring 
Core (HMMC) protocol (Jeff Lifson, Frank Maldarelli, personal communication) and 
frozen at -80°C. 
9.2.3.3 
Shipping of Specimen(s) 
Plasma samples will be batch shipped overnight on dry ice to the CITN Central 
Laboratory. Sites will utilize a web-based specimen system (BSI-Web) to 
communicate with the CITN Central Laboratory. The CITN Central Laboratory will 
coordinate batch shipments on dry ice of samples to the Maldarelli Laboratory at the 
NCI. 
9.2.3.4 
Site(s) Performing Correlative Study 
Maldarelli Laboratory/NCI DRP, Bethesda, MD. 
9.2.4 TAT/REV Induced Limiting Dilution Assay: TILDA-- Exploratory Laboratory 
Correlative Study #5 
9.2.4.1 
Collection of Specimen(s) 
Blood draws will be performed on study subjects immediately before, during, and at 
end of treatment using tubes provided by the CITN Central Lab. 
9.2.4.2 
Handling of Specimens(s) 
Blood samples will be collected at room temperature and shipped ambient to the 
CITN Central Laboratory the same day as the blood draw, so that the sample is 
received at the Central Laboratory within 24 hours of blood draw. PBMC will be 
processed from blood within 24 hours and cryopreserved in liquid nitrogen for 
subsequent batch analyses. 
9.2.4.3 
Shipping of Specimen(s) 
Blood draw tubes will be shipped at ambient temperature to the CITN Central 
Laboratory. Clinical sites will utilize a web-based specimen system (BSI-Web) to 
communicate with the CITN Central Laboratory. A key Quality Control component 
provided in the CITN shipping kits is the LogTag temperature monitor that records 
the real-time temperature during all overnight shipments of ambient specimens 
(primarily blood) to the CITN Central Lab. Data from each incoming LogTag is 


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linked to the corresponding incoming sample(s), graphed, and is available for Quality 
Control purposes. The CITN Central Laboratory will coordinate batch shipment of 
PBMC samples to the Chomont Laboratory utilizing cryogenic shippers. 
9.2.4.4 
Site(s) Performing Correlative Study 
Dr. Chomont/ Delaney AIDS Research Enterprise (DARE), Université de Montréal, 
Montréal, QC, Canada. 
9.2.5 HIV Transcriptome Analysis – Exploratory Correlative Study #6 
9.2.5.1 
Collection of Specimen(s) 
Blood draws will be performed on study subjects immediately before, during, and at 
end of treatment using tubes provided by the CITN Central Lab. 
9.2.5.2 
Handling of Specimens(s) 
Blood Samples will be collected at room temperature and shipped ambient to the 
CITN Central Laboratory the same day as the blood draw, so that the sample is 
received at the Central Laboratory within 24 hours of blood draw. RNA will be 
processed within 24 hours and cryopreserved at -80°C for subsequent batch analyses.  
9.2.5.3 
Shipping of Specimen(s) 
Blood draw tubes will be shipped at ambient temperature to the CITN Central 
Laboratory. Clinical sites will utilize a web-based specimen system (BSI-Web) to 
communicate with the CITN Central Laboratory. The CITN Central Laboratory will 
coordinate batch shipments of samples to Dr. Rafik Sekaly. 
9.2.5.4 
Site(s) Performing Correlative Study 
Dr. Rafik Sekaly, Department of Pathology, Case Western Reserve University, 
Cleveland, OH. 
9.2.6 Evaluation of autologous HIV-specific CD8+ T-cell cytotoxicity—Exploratory 
Laboratory Correlative Study #7 
9.2.6.1 
Collection of Specimen(s) 
Blood draws will be performed on study subjects immediately before, during, and at 
end of treatment using tubes provided by the CITN Central Lab. 
9.2.6.2 
Handling of Specimens(s) 
Blood Samples will be collected at room temperature and shipped ambient to the 
CITN Central Laboratory the same day as the blood draw, so that the sample is 
received at the Central Laboratory within 24 hours of blood draw. PBMC will be 
processed from blood within 24 hours and cryopreserved in liquid nitrogen for 
subsequent batch analyses. 
9.2.6.3 
Shipping of Specimen(s) 
Blood draw tubes will be shipped at ambient temperature to the CITN Central 
Laboratory. Clinical sites will utilize a web-based specimen system (BSI-Web) to 
communicate with the CITN Central Laboratory. A key Quality Control component 


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provided in the CITN shipping kits is the LogTag temperature monitor that records 
the real-time temperature during all overnight shipments of ambient specimens 
(primarily blood) to the CITN Central Lab. Data from each incoming LogTag is 
linked to the corresponding incoming sample(s), graphed, and is available for Quality 
Control purposes. The CITN Central Laboratory will coordinate batch shipment of 
PBMC samples to the Connors Laboratory at the NIAID utilizing cryogenic shippers. 
9.2.6.4 
Site(s) Performing Correlative Study 
Dr. Mark Connors Laboratory/NIAID, Bethesda, MD.  
9.2.7 Evaluation of lymphocyte and monocyte phenotypes—Exploratory Laboratory 
Correlative Study #8 
9.2.7.1 
Collection of Specimen(s) 
Blood draws will be performed on study subjects immediately before, during, and at 
end of treatment using tubes provided by the CITN Central Lab.  
9.2.7.2 
Handling of Specimens(s) 
Blood Samples will be collected at room temperature and shipped ambient to the 
CITN Central Laboratory the same day as the blood draw, so that the sample is 
received at the Central Laboratory within 24 hours of blood draw. PBMC will be 
processed from blood within 24 hours and cryopreserved in liquid nitrogen for 
subsequent batch analyses. 
9.2.7.3 
Shipping of Specimen(s) 
Blood draw tubes will be shipped at ambient temperature to the CITN Central 
Laboratory. Clinical sites will utilize a web-based specimen system (BSI-Web) to 
communicate with the CITN Central Laboratory. A key Quality Control component 
provided in the CITN shipping kits is the LogTag temperature monitor that records 
the real-time temperature during all overnight shipments of ambient specimens 
(primarily blood) to the CITN Central Lab. Data from each incoming LogTag is 
linked to the corresponding incoming sample(s), graphed, and is available for Quality 
Control purposes. 
9.2.7.4 
Site(s) Performing Correlative Study  
Flow cytometric immunophenotyping for quantification of PBMC and T-cell subsets 
will be performed under the direction of Dr. Fling at the CITN Central Laboratory, 
Seattle, WA, in collaboration with Dr. Nora Disis. 
9.2.8 Plasma Multiplex Cytokines—Exploratory Laboratory Correlative Study #9 
9.2.8.1 
Collection of Specimen(s) 
Blood draws will be performed on study subjects immediately before, during, and at 
end of treatment using tubes provided by the CITN Central Lab. 


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9.2.8.2 
Handling of Specimens(s) 
Plasma will be isolated by the local laboratory per the HIV Molecular Monitoring 
Core (HMMC) protocol (Jeff Lifson, Frank Maldarelli, personal communication) and 
frozen at -80°C. 
9.2.8.3 
Shipping of Specimen(s) 
Plasma samples will be batch shipped overnight on dry ice to the CITN Central 
Laboratory. Sites will utilize a web-based specimen system (BSI-Web) to 
communicate with the CITN Central Laboratory. The CITN Central Laboratory will 
coordinate batch shipments on dry ice of plasma samples to the NCI. 
9.2.8.4 
Site(s) Performing Correlative Study 
Multiplex analyses will be done at the Fred Hutchinson Cancer Research Center 
Shared Resources or equivalent laboratory. Studies will be overseen by Dr. Uldrick. 
9.2.9 Assessment of PD-L1 expression at baseline—Correlative Study #10 
9.2.9.1 
Collection of Specimen(s) 
Formalin-fixed, paraffin-embedded archival tissue block(s) from tumor obtained 
before MK-3475 (pembrolizumab) will be identified by the clinical site at the relevant 
pathology laboratories where they were processed and stored. Alternatively, patients 
will undergo a baseline biopsy (core, punch or excisional) as part of this protocol. 
9.2.9.2 
Handling of Specimens(s) 
Formalin-fixed, paraffin-embedded archival tumor blocks will be requested by fax 
and phone by the clinical site from the relevant pathology laboratory by providing the 
patient’s name, consent form, and date of collection. If patients undergo biopsy as 
part of this protocol, tissue will be placed in formalin for overnight shipping to the 
CITN Central Laboratory. The CITN Central Lab will arrange for all formalin 
samples to be embedded in paraffin by the FHCRC IHC Core, Seattle, WA. 
9.2.9.3 
Shipping of Specimen(s) 
Clinical sites will arrange for the formalin-fixed, paraffin-embedded archival tumor 
blocks to be shipped at ambient temperature to the CITN Central Laboratory. For 
biopsies done as part of this protocol, tissue in formalin will be shipped overnight at 
ambient temperature to the CITN Central Laboratory. Clinical sites will utilize a web-
based specimen system (BSI-Web) to communicate with the CITN Central 
Laboratory. Following tissue sectioning, unstained slides will be shipped by CITN 
Central Laboratory to Merck Research Laboratories. 
9.2.9.4 
Site(s) Performing Correlative Study 
PD-1 and PD-L1 expression will be tested by multiparametric IHC at Merck Research 
Laboratories in Palo Alto, CA, or their suggested designee. 


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9.2.10 Assessment of tumor biopsy for actionable mechanisms of failure by IHC—Correlative 
Study #11 
9.2.10.1 
Collection of Specimen(s) 
Formalin-fixed, paraffin-embedded archival tissue block(s) from tumor obtained 
before MK-3475 (pembrolizumab) will be identified by the clinical site at the relevant 
pathology laboratories where they were processed and stored. Alternatively, patients 
will undergo a baseline biopsy (core, punch or excisional) as part of this protocol. In 
patients with confirmed progression, a biopsy sample of a tumor may ideally be 
obtained near the time of progression if feasible and safe (core, punch or excisional 
biopsy). This biopsy is highly preferred, but optional. 
9.2.10.2 
Handling of Specimens(s) 
Formalin-fixed, paraffin-embedded archival tumor blocks will be requested by fax 
and phone by the clinical site from the relevant pathology laboratory by providing the 
patient’s name, consent form, and date of collection. If patients undergo biopsy as 
part of this protocol, tissue will be placed in formalin for overnight shipping to the 
CITN Central Laboratory. The CITN Central Lab will arrange for all formalin 
samples to be embedded in paraffin by the FHCRC IHC Core. 
9.2.10.3 
Shipping of Specimen(s) 
Clinical sites will arrange for the formalin-fixed, paraffin-embedded archival tumor 
blocks to be shipped at ambient temperature to the CITN Central Laboratory. For 
biopsies done as part of this protocol, tissue in formalin will be shipped overnight at 
ambient temperature to the CITN Central Laboratory. Clinical sites will utilize a web-
based specimen system (BSI-Web) to communicate with the CITN Central 
Laboratory. Following tissue sectioning, unstained slides will be shipped by CITN 
Central Laboratory at the FHCRC IHC Core, Seattle, WA. 
9.2.10.4 
Site(s) Performing Correlative Study 
Shared Resources, FHCRC, Seattle, WA. 
9.2.11 Assessment of tumor biopsy for actionable mechanisms of failure by gene expression 
analysis—Correlative Study #12 
9.2.11.1 
Collection of Specimen(s) 
Formalin-fixed, paraffin-embedded archival tissue block(s) from tumor obtained 
before MK-3475 (pembrolizumab) will be identified by the clinical site at the relevant 
pathology laboratories where they were processed and stored. Alternatively, patients 
will undergo a baseline biopsy (core, punch or excisional) as part of this protocol. In 
patients with confirmed progression, a biopsy sample of a tumor may ideally be 
obtained near the time of progression if feasible and safe (core, punch or excisional 
biopsy). This biopsy is highly preferred, but optional. 
9.2.11.2 
Handling of Specimens(s) 
Formalin-fixed, paraffin-embedded archival tumor blocks will be requested by fax 
and phone by the clinical site from the relevant pathology laboratory by providing the 
patient’s name, consent form, and date of collection. If patients undergo biopsy as 


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part of this protocol, tissue will be placed in formalin for overnight shipping to the 
CITN Central Laboratory. The CITN Central Lab will arrange for all formalin 
samples to be embedded in paraffin by the FHCRC IHC Core. 
9.2.11.3 
Shipping of Specimen(s) 
Clinical sites will arrange for the formalin-fixed, paraffin-embedded archival tumor 
blocks to be shipped at ambient temperature to the CITN Central Laboratory. For 
biopsies done as part of this protocol, tissue in formalin will be shipped overnight at 
ambient temperature to the CITN Central Laboratory. Clinical sites will utilize a web-
based specimen system (BSI-Web) to communicate with the CITN Central 
Laboratory. Following tissue sectioning, unstained slides will be shipped by CITN 
Central Laboratory to Merck Research Laboratories, Palo Alto, CA or NanoString 
Technologies, Seattle, WA. 
9.2.11.4 
Site(s) Performing Correlative Study: 
Merck Research Laboratories, Palo Alto, CA or NanoString Technologies, Seattle, 
WA. 
9.2.12 Assessment of KSHV viral load in patients in Cohort 4- Correlative Study #13 
9.2.12.1 
Collection of Specimen (s) 
Blood draws will be performed on study subjects immediately before, during and at 
end of treatment using tubes provided by the CITN Central Lab. 
9.2.12.2 
Handling of Specimen (s) 
Blood samples for PBMC will be collected at room temperature and shipped ambient 
to the CITN Central Laboratory the same day as the blood draw, so that the sample is 
received at the Central Laboratory within 24 hours of blood draw. PBMC will be 
processed from blood within 24 hours and cryopreserved in liquid nitrogen. 
9.2.12.3 
Shipping of Specimens (s) 
Blood draw tubes for PBMC will be shipped overnight at ambient temperature to the 
CITN Central Laboratory. Clinical sites will utilize a web-based specimen system 
(BSI-Web) to communicate with the CITN Central Laboratory. The CITN Central 
Laboratory will coordinate batch shipments of cryopreserved PBMC samples the D. 
Whitby Lab (NCI) for the PBMC associated KSHV viral load assay utilizing 
cryogenic shippers. 
9.2.12.4 
Sites performing Correlative Study: 
D. Whitby Lab (NCI). 
9.2.13 Assessment of anti-KSHV immune response in patients in Cohort 4 – Correlative Studies 
#14 
9.2.13.1 
Collection of Specimen (s) 
Blood draws will be performed on study subjects immediately before, during, and at 
end of treatment using tubes provided by the CITN Central Lab. 


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9.2.13.2 
Handling of Specimens (s) 
For humoral evaluations, plasma will be isolated by the local laboratory per the HIV 
Molecular Monitoring Core (HMMC) protocol and frozen at -80°C. 
Blood Samples for PBMC studies will be collected at room temperature and shipped 
ambient to the CITN Central Laboratory the same day as the blood draw, so that the 
sample is received at the Central Laboratory within 24 hours of blood draw. PBMC 
will be processed from blood within 24 hours and cryopreserved in liquid nitrogen. 
9.2.13.3 
Shipping of Specimens (s) 
Plasma will be batch shipped overnight on dry ice to the CITN Central Laboratory. 
Sites will utilize a web-based specimen system (BSI-Web) to communicate with the 
CITN Central Laboratory. The CITN Central Laboratory will coordinate batch 
shipments on dry ice of plasma to the D. Whitby Lab (NCI) for luminex assays. 
Blood draw tubes for PBMC will be shipped overnight at ambient temperature to the 
CITN Central Laboratory. Clinical sites will utilize a web-based specimen system 
(BSI-Web) to communicate with the CITN Central Laboratory. The CITN Central 
Laboratory will coordinate batch shipment of cryopreserved PBMC samples to the 
Whitby Lab for the T cell assays utilizing cryogenic shippers. 
9.2.13.4 
Sites performing Correlative Study:  
D. Whitby Lab (NCI) 
9.2.14 Assessment of peripheral blood immune cell phenotype by mass cytometry – Correlative 
Studies #15 
9.2.14.1 
Collection of specimens 
Specimens will be collected as outlined in 9.2.2.  
9.2.14.2 
Handling of Specimens 
For specimens from Cohorts 1, 2 and 3 subjects: Aliquots of cells from PBMCs 
previously sent to the S. Lewin lab for HIV studies (See Section 9.2.2.) will be used. 
Briefly, at the time of thawing to enrich for CD4 cells and quantify DNA and RNA 
for the HIV studies, an aliquot of two million PBMC will be separated and saved in 
fixative and frozen and stored and then sent to UCSF for CytoF analysis. The sort for 
CD4 T-cells will be done by negative selection using magnetic beads, as previously 
described (Elliott 2014). The CD4 negative fraction will also be stored for potential 
future analysis using RNAseq. 
For specimens from Cohort 4 subjects: PBMC will be processed at CITN. Blood 
Samples will be collected at room temperature and shipped ambient to the CITN 
Central Laboratory the same day as the blood draw, so that the sample is received at 
the Central Laboratory within 24 hours of blood draw. PBMC will be processed from 
blood within 24 hours and cryopreserved in liquid nitrogen. 


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9.2.14.3 
Shipping of Specimens  
Blood draw tubes will be shipped at ambient temperature to the CITN Central 
Laboratory. Clinical sites will utilize a web-based specimen system (BSI-Web) to 
communicate with the CITN Central Laboratory. The CITN Central Laboratory will 
coordinate batch shipments of PBMC to the Lewin Laboratory (Cohorts 1-3) and to 
the Hunt Lab (Cohort 4).  
For the specimens from Cohorts 1-3, The Lewin Lab with coordinate batch shipping 
on dry ice of the aliquots of fixed cells to the Hunt Lab at UCSF. 
9.2.14.4 
Site performing correlative study 
Hunt Lab, UCSF (investigator Rachel Rutishauser)  
 
Special Studies 
9.3.1 HLA Class I and Class II typing 
DNA will be prepared at the CITN Central Lab by extraction of DNA from residual cells 
off the PBMC preparations described in section 9.2.2. DNA will be stored at -80°C at the 
CITN Central Lab. Specimens will be assayed at the laboratory of Dr. Dan Geraghty 
(FHCRC). The CITN Central Laboratory will coordinate batch sample shipping to 
Geraghty Lab.


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10. 
STUDY CALENDARS 
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy. Scans and other baseline disease 
assessments must be done <4 weeks prior to the start of therapy. In the event that the patient’s condition is deteriorating, laboratory 
evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy. 
Calendar 1: Screening and Cycles 1 through 4 
Trial Period 
Screening Phase 
Treatment Cycles a 
 
 
 
To be repeated up to 2 years 
Therapy Cycle/Title 
Pre-Therapy 
Cycle 1 
Day 1 
Cycle 1 Day 1,  
2 hrs post tx 
Cycle 1 
Day 2 
Cycle 1 
Day 8 
Cycle 2 
Day 1  
Cycle 2 Day 1, 
2 hrs post tx 
 
Cycle 2 
 Day 2 
Cycle 3  
Day 1 
Cycle 4 
 Day 1 
Scheduling Window 
(Days) 
Day -28 to Day 0 
 
± 15 minutes 
± 60 
minutes 
 
Day1±7 
± 15 minutes 
± 60 
minutes 
Day1±7 
Day1±7 
MK-3475 (pembrolizumab) 
administration b 
 
X 
 
 
 
X 
 
 
X 
X 
cART therapy x 
X 
Administrative procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Concomitant Meds n 
X 
X 
 
 
 
X 
 
 
X 
X 
Medical History, 
demographics, etc. 
X 
 
 
 
 
 
 
 
 
 
Clinical Procedures/Assessments a 
Review of AEs d, e 
 
X 
 
X 
X 
X 
 
X 
X 
X 
Physical Exam t 
X 
X 
 
 
 
X 
 
 
X 
X 
Vital Signs  
X 
X 
 
 
X 
X 
 
 
X 
X 
Height and Weight f 
X 
X 
 
 
 
X 
 
 
X 
X 
12-Lead EKG g 
X 
 
 
 
 
 
 
 
 
 
Pulmonary function u 
X 
 
 
 
 
 
 
 
 
 
ECOG PS 
X 
X 
 
 
X 
X 
 
 
X 
X 
Laboratory Assessments (Safety Labs)a,h,k 
Pregnancy Test  
(Urine or Serum HCG) h, i 
X 
 
 
 
 
X 
 
 
X 
X 
CBC with 
Diff/Reticulocytes 
X 
X 
 
 
X 
X 
 
 
X 
X 


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Trial Period 
Screening Phase 
Treatment Cycles a 
 
 
 
To be repeated up to 2 years 
Therapy Cycle/Title 
Pre-Therapy 
Cycle 1 
Day 1 
Cycle 1 Day 1,  
2 hrs post tx 
Cycle 1 
Day 2 
Cycle 1 
Day 8 
Cycle 2 
Day 1  
Cycle 2 Day 1, 
2 hrs post tx 
 
Cycle 2 
 Day 2 
Cycle 3  
Day 1 
Cycle 4 
 Day 1 
Scheduling Window 
(Days) 
Day -28 to Day 0 
 
± 15 minutes 
± 60 
minutes 
 
Day1±7 
± 15 minutes 
± 60 
minutes 
Day1±7 
Day1±7 
Comprehensive serum 
chemistry panel k 
X 
X 
 
 
X 
X 
 
 
X 
X 
Creatine kinase 
X 
X 
 
 
X 
X 
 
 
X 
X 
HBV/HCV serology 
X 
 
 
 
 
 
 
 
 
 
HBV DNA viral load 
X 
 
 
 
 
 
 
 
 
X 
HCV RNA viral load 
X 
 
 
 
 
 
 
 
 
X 
HIV viral load 
X 
 
 
 
 
X 
 
 
X 
X 
Urinalysisk, l 
X 
 
 
 
 
 
 
 
 
 
FT4, and TSH k, l 
X 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood Draws c 
CD4+, CD8+ T cells 
X y 
 
 
 
X 
X 
 
 
X 
X 
HIV SC plasma RNA 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PBMC HIV DNA and 
unspliced RNA 
 
X 
 
X 
X 
X 
 
 
 
X 
HIV RNA sequencing/ 
molecular evolution 
 
X 
 
 
 
X 
 
 
 
X 
Plasma cytokines 
 
X 
 
 
X 
X 
 
X 
X 
X 
HIV-specific T-cell 
immunity 
 
X 
 
 
 
 
 
 
 
X 
Flow Cytometry 
 
X 
 
 
 
X 
 
 
 
X 
PBMC TILDA 
 
X 
 
 
 
 
 
 
 
 
HIV transcriptome 
 
X 
 
X 
 
 
 
 
 
 
Cohort 4 Correlative Studies 
KSHV Viral Load 
 
X 
 
X 
X 
X 
 
 
 
X 
KSHV- T-cell response 
 
X 
 
 
 
 
 
 
 
X 
KSHV humoral response 
 
X 
 
 
 
 
 
 
 
X 
CyTOF 
 
X 
 
X 
X 
X 
 
 
 
X 
HLA-Typing 
 
X 
 
 
 
 
 
 
 
 
Efficacy Measurements 
Tumor Imaging o,p,q 
X 
 
 
 
 
 
 
 
 
X 
KS Measurements 
 
Xw 
 
 
 
 
 
 
Xw 
 


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Trial Period 
Screening Phase 
Treatment Cycles a 
 
 
 
To be repeated up to 2 years 
Therapy Cycle/Title 
Pre-Therapy 
Cycle 1 
Day 1 
Cycle 1 Day 1,  
2 hrs post tx 
Cycle 1 
Day 2 
Cycle 1 
Day 8 
Cycle 2 
Day 1  
Cycle 2 Day 1, 
2 hrs post tx 
 
Cycle 2 
 Day 2 
Cycle 3  
Day 1 
Cycle 4 
 Day 1 
Scheduling Window 
(Days) 
Day -28 to Day 0 
 
± 15 minutes 
± 60 
minutes 
 
Day1±7 
± 15 minutes 
± 60 
minutes 
Day1±7 
Day1±7 
KS Photographyv 
 
Xw 
X (at time of documentation of CR, PR or PD) 
Tumor Biopsies/Archival Tissue Collection 
Tumor Biopsies r 
X 
 
 
 
 
 
 
 
X 
 
 
 
 


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Calendar 2: Cycles 5 and Beyond, End of Treatment and Post-Treatment Follow Up 
Trial Period 
Treatment Cycles, Cycle 5 and beyond 
Time of PR 
and/or CR 
End of Tx 
Post-treatment follow-up 
 
 
Tx Cycle/Title 
Cycles without scans, 
q 3 weeks 
beginning with Cycle 5 
Cycles with scans, q 9 weeks 
(Cycles 7, 10, 13, etc., during 
year 1), q 12 weeks year 2 
PR and/or 
CR 
D/C 
therapy 
Post-Tx 
Safety FU 
Follow-up 
Visitsp 
Survival Follow-ups 
Scheduling Window 
(Days) 
Day 1±7 
Day 1 ±7 
 
At time 
of D/C 
± 3 weeks 
30 days ±3 
days post 
D/C 
Every 12 
weeks ± 2 
weeks post-
D/C 
Every 12 weeks ± 2 
weeks phone contact 
MK-3475 
(pembrolizumab) 
administration b 
X 
X 
 
 
 
 
 
cART therapyx 
X 
Administrative Procedures 
Concomitant Meds n 
X 
X 
X 
X 
X 
X 
X 
Clinical Procedures/Assessments 
Review of AEs d, e 
X 
X 
X 
X 
X 
X 
 
Physical Exam t 
X 
X 
X 
X 
X 
X 
 
Vital Signs, Height and 
Weight f 
X 
X 
 
X 
X 
X 
 
ECOG PS 
X 
X 
 
X 
X 
X 
 
Pregnancy Test (Urine 
or Serum HCG) h, i 
X 
X 
 
X 
 
 
 
CBC with 
Diff/Reticulocytes 
X 
X 
 
X 
Xm 
X 
 
Comprehensive Serum 
chemistry panel k 
X 
X 
 
X 
Xm 
X 
 
Creatine kinase 
X 
X 
 
X 
X 
 
 
HBV/HCV serology 
 
 
 
 
 
 
 
HBV DNA viral load 
 
X (if seropositive) 
 
X 
X 
(if seropositive) 
 
 
HCV RNA viral load 
 
X (if seropositive) 
 
X 
X 
(if seropositive) 
 
 
HIV viral load 
 
X 
 
X 
X 
 
 
Urinalysis k, l 
 
X (Cycle 7 and every 6th 
cycle) 
 
Xm 
 
 
 


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Trial Period 
Treatment Cycles, Cycle 5 and beyond 
Time of PR 
and/or CR 
End of Tx 
Post-treatment follow-up 
 
 
Tx Cycle/Title 
Cycles without scans, 
q 3 weeks 
beginning with Cycle 5 
Cycles with scans, q 9 weeks 
(Cycles 7, 10, 13, etc., during 
year 1), q 12 weeks year 2 
PR and/or 
CR 
D/C 
therapy 
Post-Tx 
Safety FU 
Follow-up 
Visitsp 
Survival Follow-ups 
Scheduling Window 
(Days) 
Day 1±7 
Day 1 ±7 
 
At time 
of D/C 
± 3 weeks 
30 days ±3 
days post 
D/C 
Every 12 
weeks ± 2 
weeks post-
D/C 
Every 12 weeks ± 2 
weeks phone contact 
FT4, and TSH k, l 
 
X (Cycle 7 and every 6th 
cycle) 
 
Xm 
 
 
 
Correlative Studies Blood Draws 
CD4+, CD8+ T cells 
 
X 
 
X 
X 
X 
 
HIV SC plasma RNA 
 
 
X 
X 
X (optional) 
 
 
HIV RNA sequencing/ 
molecular evolution 
 
 
X 
X 
X (optional) 
 
 
Plasma cytokines 
 
 
X 
X 
X (optional) 
 
 
HIV-specific T-cell 
immunity 
 
X (Cycle 13 or EOT) 
 
X (Cycle 
13 or 
EOT) 
 
 
 
PBMC HIV DNA and 
US-RNA 
 
 
X 
X 
X (optional) 
 
 
Flow Cytometry 
 
X (Cycles 7 and 13) 
X 
X 
(or at time 
of PD) 
 
 
 
PBMC TILDA 
 
X (Cycle 7 and 13) 
X 
X 
 
 
 
HIV Transcriptome 
 
X (Cycle 7) 
 
X 
 
 
 
Cohort 4 Correlative Studies* 
KSHV Viral Load* 
 
 
 
X* 
 
 
 
KSHV- T-cell 
response* 
 
 
 
X* 
(optional) 
 
 
 
KSHV humoral 
response* 
 
 
 
X* 
(optional) 
 
 
 
Efficacy Measurements 
Tumor Imaging o, p, q 
 
X 
X 
X 
 
X 
 
KS Photographyx 
X (at time of documentation of CR, PR or PD) 
X 
X 
 
 
 
KS Measurements 
Prior to odd numbered cycles and on days photography is performed 
 
 
 
 


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Trial Period 
Treatment Cycles, Cycle 5 and beyond 
Time of PR 
and/or CR 
End of Tx 
Post-treatment follow-up 
 
 
Tx Cycle/Title 
Cycles without scans, 
q 3 weeks 
beginning with Cycle 5 
Cycles with scans, q 9 weeks 
(Cycles 7, 10, 13, etc., during 
year 1), q 12 weeks year 2 
PR and/or 
CR 
D/C 
therapy 
Post-Tx 
Safety FU 
Follow-up 
Visitsp 
Survival Follow-ups 
Scheduling Window 
(Days) 
Day 1±7 
Day 1 ±7 
 
At time 
of D/C 
± 3 weeks 
30 days ±3 
days post 
D/C 
Every 12 
weeks ± 2 
weeks post-
D/C 
Every 12 weeks ± 2 
weeks phone contact 
Tumor Biopsies/Archival /Tissue Collection 
Tumor Biopsies r 
 
 
 
X 
(or at time 
of PD) 
 
 
 
Abbreviations: AE, adverse event(s); cART, combination antiretroviral therapy; CBC, complete blood count; CyTOF, mass cytometry; D/C, 
discontinuation/discontinue; ECG/EKG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EOC, end of cycle; FT4, free T4; FU, follow-up; 
HBV, hepatitis B virus; HCV, hepatitis C virus; HCG, human chorionic gonadotropin; HIV, human immunodeficiency virus; HLA, human leukocyte antigen; 
Kyn/Trp, kynurenine/tryptophan; KS, Kaposi sarcoma; PBMC, peripheral blood mononuclear cell; PS, performance status; RNA, ribonucleic acid; TILDA, 
TAT/REV induced limiting dilution assay; TSH, thyroid-stimulating hormone; tx, treatment; US, unspliced.  
a. 
In general, safety labs and assessments/procedures are to be performed on Day 1 and before the first dose of treatment for each cycle unless otherwise 
specified. Safety labs may be drawn on Day -1 or Day 1 prior to Cycle 1 and up to 72 hours before drug administration for subsequent cycles. In general, the 
window for each drug administration visit after Cycle 1 is ± 7 days unless otherwise noted. Treatment cycles are 3 weeks (21 days); however, the treatment 
cycle interval may be increased due to toxicity according to the dose-modification guidelines provided in Section 6. If the interval is increased, all 
procedures except imaging should be performed based on the new dosing schedule.  
b. MK-3475 (pembrolizumab) will be administered as an IV infusion over 30 minutes. The dose is 200 mg every 3 weeks (21 days). The infusion is given in an 
out-patient setting. Patients who restart treatment after relapse from CR should resume at the same dose and cycle interval which they were receiving before 
discontinuation. 
c. 
Blood for correlative studies will be drawn as indicated on Study Calendars. Study Calendar 1 includes the Screening Phase and Cycles 1 through 4. Study 
Calendar 2 includes Cycles 5 and beyond, End of Treatment, 30 Day Safety Visit and Follow Up visits. After Cycle 4, most correlative labs will be drawn 
every 3rd cycle during year 1 of treatment and every 4th cycle during year 2, If the correlative blood draw is not obtained at time of determination of CR, PR 
or disease progression, then this collection will be done at the End-of-Therapy visit. 
d. AEs and laboratory safety measurements will be graded per NCI CTCAE version 5.0. All AEs, whether gradable by CTCAE or not, will also be evaluated 
for seriousness. 
e. 
Record all AEs occurring within 30 days after the last dose of trial treatment. Report all SAEs (related and unrelated to trial treatment) and occurring up until 
90 days after the last dose of trial treatment or the start of new anticancer treatment, whichever comes first. Afterwards, report only SAEs and ECIs that are 
related to trial treatment. 
f. 
Vital signs to include temperature, pulse, respiratory rate, weight, and blood pressure. Height will be measured at baseline only. 
g. EKG will be performed at baseline.  
h. Laboratory tests for screening are to be performed within 14 days before the first dose of trial treatment.  HBV DNA and HCV RNA may be performed 
within 28 days of enrolling the patient on protocol. 


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i. 
For women of reproductive potential, pregnancy testing will be performed prior to each cycle. A urine pregnancy test should be performed within 72 hours 
before first dose of trial treatment. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test performed by the local study site 
laboratory will be required. Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.  
k. Serum chemistry to include albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, 
potassium, total protein, SGOT [AST], SGPT [ALT], and sodium. After Cycle 1, lab samples can be collected up to 72 hours before the scheduled time 
point. 
l. 
Urinalysis and thyroid function testing to be repeated every 6 cycles after baseline beginning with Cycle 7 (cycles 7, 13, 19, etc) and at the Post-Treatment 
Follow Up visit. 
m. Unresolved abnormal labs that are drug related AEs should be followed until resolution. Labs do not need to be repeated after the end of treatment if labs are 
within normal range. 
n. Concomitant medications – Enter new medications started during the trial through the safety follow-up visit. Record all medications taken for SAE reporting 
as defined in Section 5.3.1. 
o. The initial tumor imaging/disease assessment will be performed within 28 days before the first dose of trial treatment. Scans performed as part of routine 
clinical management are acceptable for use as the screening scan if they are of diagnostic quality and performed within 28 days before the first dose of trial 
treatment. On-study imaging will be performed prior to Cycle 4 and reviewed before drug administration. Patients who show progression at Cycle 4 will 
continue on therapy and have a conformational scan 4 to 6 weeks later. Patients with no evidence of disease progression will have scans every 3 cycles 
(every 9 weeks) during the first year of treatment. Scan frequency will be decreased to every 4 cycles (every 12 weeks) during second year of treatment. For 
cycles with scans scheduled, scans should occur within 7 days before scheduled drug administration so that the investigator may evaluate the patient for 
possible progression before administering the next dose of study medication. The same imaging technique should be used in a patient throughout the trial. 
Local reading (investigator assessment with site radiology reading) will be used to determine eligibility and for patient management; Sponsor may collect 
radiological assessments for retrospective analysis by a central vendor. (See Patient Visit Timeline). Imaging is not required in patients with Kaposi sarcoma. 
If performed to evaluate lymph node or non-cutaneous disease, imaging should be performed every 4 cycles and timed with KS cutaneous disease 
assessments. 
p. In patients who discontinue study therapy without confirmed disease progression, a radiological evaluation should be performed at the time of treatment 
discontinuation (i.e., date of discontinuation ± 4 week window). If a previous scan was obtained within 4 weeks before the date of discontinuation, then a 
scan at treatment discontinuation is not mandatory. Patients will attend follow up visits every 12 weeks for 1 year. Patients will continue to have tumor 
assessments during post-treatment follow-up performed based on the standard of care for a given malignancy. For patients with measurable disease, this will 
include, at minimum, imaging at the final 12 month follow up visit. Patients who discontinue study therapy due to progression will be followed for survival 
via phone contacts every 12 weeks. 
q. A scan/disease assessment must be performed within 28 days before restarting treatment with MK-3475 (pembrolizumab) after relapse from CR. Imaging 
should continue to be performed at frequencies described in footnote “o” above from the first dose of trial treatment or more frequently if clinically 
indicated. The Sponsor may collect radiological assessments for retrospective analysis by a central vendor. 
r. 
Tumor biopsy tissue is required per screening requirements. When feasible, when therapy is discontinued, optional post-treatment biopsy samples will be 
obtained when tumors do not fully respond. For cohort 4, optional C3D1 biopsy sample is requested.  
s. 
After the start of new anticancer treatment or documented disease progression, the patient should be contacted by telephone every 12 weeks to assess for 
survival status.  
t. 
After cycle 1, limited physical exam performed on visits not correlated with scans. 
u. PFTs required for patients with clinically significant lung disease, including chronic obstructive pulmonary disease (COPD), which requires oxygen therapy. 
v.  For KS patients, photography is to be performed at baseline, at PD or CR, and at the End of Treatment visit.  


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w.  May be performed any time after enrollment, but before the first dose of study drug. KS measurements may be performed up to 3 days prior to drug 
administration in subsequent cycles.  
x. cART is required, and will generally include agents recommended by the DHHS guidelines: 
http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. 
y.  The collection window for screening CD4/CD8 cells is 14 days prior to start of protocol therapy. 
* 
No additional blood volumes are required for this laboratory test. Testing will be performed on blood drawn for research labs.


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11. 
MEASUREMENT OF EFFECT 
Although the clinical benefit of MK-3475 (pembrolizumab) in patients with HIV and cancer has 
not yet been established, the intent of offering this treatment is to provide a possible therapeutic 
benefit, and thus the patient will be carefully monitored for tumor response and symptom relief 
in addition to safety and tolerability. Patients with measurable disease will be assessed by 
standard criteria.  
 
Antitumor Effect – Solid Tumors 
For the purposes of this study, patients should be evaluated for response by spiral CT scan in 
accordance with standard practice at 9-week intervals during the first year of treatment, with the 
initial scan at week 9 of the trial, before drug administration. During the second year of 
treatment, scans will be performed every 12 weeks. Throughout the trial, for cycles with scans 
scheduled, scans shall occur before scheduled drug administration so that the investigator may 
evaluate the patient for possible progression before administering the next dose of study 
medication. Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised RECIST guideline (Version 1.1) (Eisenhauer 2009).  
Immunotherapeutic agents such as MK-3475 (pembrolizumab) may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses that may be functionally anergic. 
The response patterns seen with such an approach may extend beyond the typical time course of 
responses seen with cytotoxic agents and can manifest a clinical response after an initial increase 
in tumor burden or even the appearance of new lesions. Standard RECIST guidelines may not 
provide a CR assessment of immunotherapeutic agents such as MK-3475 (pembrolizumab), 
especially at early therapeutic time points. Because of the possibility that the initial scan at 9 
weeks may misclassify MK-3475 (pembrolizumab) responders as progressing on therapy, those 
MK-3475 (pembrolizumab)–treated patients who appear to be progressing at week 9 can 
continue therapy until progression is confirmed 4 to 6 weeks later, providing they meet the 
guidelines stated inSection 5.8. If progression is confirmed, then MK-3475 (pembrolizumab) 
therapy will be discontinued and the patient will attend the end-of-treatment and 30-day follow-
up visits. The time of progression will be reported as the first time that progression was noted. If 
patients regress or have SD as determined by the confirmatory imaging study, the time of 
eventual progression will be separately reported. 
If progression is noted on subsequent routine disease monitoring scans, which will continue 
throughout the trial at 9-week to 12-week intervals, a confirmatory scan will be obtained 4 to 6 
weeks later. If this confirmatory scan identifies a MK-3475 (pembrolizumab)-treated patient as 
progressing on therapy, the patient will discontinue treatment and be followed as indicated 
above. (See Patient Visit Timeline). 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) (Eisenhauer 2009). 
11.1.1 Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their 
first treatment with MK-3475 (pembrolizumab). 


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108 
Evaluable for objective response. Only those patients 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. Patients who received at least one 
cycle of treatment but did not have a response assessment will be counted as not 
evaluable and included in the estimates of response. Patients will have their response 
classified according to the definitions stated below. (Note: Patients who exhibit objective 
disease progression prior to the end of cycle 1 will also be considered evaluable.) 
Evaluable Non-Target Disease Response. Patients 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.  
11.1.2 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 (≥2 cm) 
by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or 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.  
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]). 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 [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] 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 patient, these are preferred for selection as target 
lesions. 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 


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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 5 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.  
11.1.3 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 (≥1 cm) 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 (0.5 cm) or less. If CT 
scans have slice thickness greater than 5 mm (0.5 cm), 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 


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110 
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.  
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 complete response (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 patient 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 
(Bubley 1999, Rustin 2004); 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 
(Vergote 2000). 
Cytology, Histology: These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 


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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 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
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:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. 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 
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. 
c. 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. 
11.1.4 Response Criteria 
11.1.4.1 
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 (<1 cm). 
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 (0.5 cm). 
(Note: the appearance of one or more new lesions is also considered progression). 


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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. 
11.1.4.2 
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 
[<1 cm] short axis). 
Note: If tumor markers are initially above the upper normal limit, they must 
normalize for a patient 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. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
11.1.4.3 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
Documented at least once >4 wks. 
from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


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See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** Only for non-randomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.” Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used 
as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can 
be measured is not advised 
 
11.1.5 Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
Duration of stable disease: Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
11.1.6 Progression-Free Survival 
Progression-free survival is defined as the time from the first dose of study drug to 
progressive disease or death, whichever occurs earlier, based upon investigator 
assessment using RECIST 1.1, “Lugano Criteria” for Malignant Lymphoma or other 
tumor-specific criteria. Patients without documented progressive disease or death will be 
censored at the last disease assessment date.  


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11.1.7 Response Review 
Imaging studies will be collected for a possible expert review of responses. Investigator 
determined responses will be chronicled and reported unless or until a central expert 
review takes place.  
 
Antitumor Effect – Hodgkin Lymphoma and non-Hodgkin Lymphoma 
The response categories being used to assess efficacy are based on the Response Assessment of 
Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification (Cheson 2014). 
These criteria strongly recommend PET-CT for staging of routinely FDG-avid, nodal-
lymphomas (essentially all histologies except chronic lymphocytic leukemia/small lymphocytic 
lymphoma, lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia, mycosis 
fungoides, and marginal zone NHLs, unless there is a suspicion of aggressive transformation) 
especially in clinical trials. A contrast enhanced CT scan should be included for a more accurate 
measurement of nodal size if required for trials; if necessary, to more accurately distinguish 
bowel from lymphadenopathy; and in the setting of compression/thrombosis of 
central/mediastinal vessels. Contrast enhanced CT is also preferred for radiation planning. 
Variably FDG avid and low FDG avid histologies should be staged with a CT scan. 
11.2.1 Disease Parameters 
11.2.1.1 
For patients assessed with PET-CT: 
Focal uptake in nodal and extranodal sites that is in keeping with lymphoma, 
according to the distribution and/or CT characteristics, is considered involvement 
with lymphoma, including spleen, liver, bone, thyroid, and so on.  
11.2.1.2 
For patients staged with CT: 
Measured dominant lesions: up to six of the largest target nodes, nodal masses, or 
other lymphomatous lesions that are measurable in two diameters (longest diameter 
[LDi] and shortest diameter) should be identified from different body regions 
representative of the patient’s overall disease burden and include mediastinal and 
retroperitoneal disease, if involved. A measurable node must have an LDi greater than 
1.5 cm. Measurable extranodal disease (e.g., hepatic nodules) may be included in the 
six representative, measured lesions. A measurable extranodal lesion should have an 
LDi greater than 1.0 cm. 
Non-measured lesions: Any disease not selected as measured, dominant disease and 
truly assessable disease should be considered not measured. These sites include any 
nodes, nodal masses, and extranodal sites not selected as dominant or measurable or 
that do not meet the requirements for measurability but are still considered abnormal, 
as well as truly assessable disease, which is any site of suspected disease that would 
be difficult to follow quantitatively with measurement, including pleural effusions, 
ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions 
that cannot be confirmed and followed by imaging. 


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11.2.1.3 
Cytology confirmation of DLBCL is required when there is an appearance on CT of a 
new lesion ≥1.5 cm in its long axis and is PET-negative. 
 
11.2.1.4 
For fluid collection (ascites, pleural, or pericardial effusions), cytology confirmation 
for presence of lymphoma is required. 
 
 


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11.2.2 Response Criteria 
 
PET-CT Based Response 
CT-Based Response 
Complete Response 
Complete Metabolic Response 
Complete Radiologic Response 
(all of the following) 
Lymph nodes and 
extralymphatic sites 
Score 1, 2, or 3* with or without a 
residual mass on 5PS† 
It is recognized that in Waldeyer’s 
ring or extra-nodal sites with high 
physiologic uptake or with activation 
within spleen or marrow (e.g., with 
chemotherapy or myeloid colony-
stimulating factors), uptake may be 
greater than normal mediastinum 
and/or liver. In this circumstance, 
complete metabolic response may be 
inferred if uptake at sites of initial 
involvement is no greater than 
surrounding normal tissue even if the 
tissue has high physiologic uptake 
Target nodes/nodal masses must 
regress to ≤ 1.5 cm in longest 
transverse diameter of a lesion 
No extralymphatic sites of disease 
Non-measured lesion 
Not applicable 
Absent 
Organ enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in 
marrow 
Normal by morphology; if 
indeterminate, IHC negative 
Abbreviations: CT, computed tomography; FDG, fluorodeoxyglucose; IHC, immunohistochemistry; 
PET, positron emission tomography 
† PET 5point scale: 1, no uptake above background; 2, uptake _ mediastinum; 3, uptake _ mediastinum 
but _ liver; 4, uptake moderately _ liver; 5, uptake markedly higher than liver and/or new lesions; X, new 
areas of uptake unlikely to be related to lymphoma. 
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the 
time of an interim scan. However, in trials involving PET where de-escalation is investigated, it may be 
preferable to consider a score of 3 as inadequate response (to avoid undertreatment).  


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PET-CT Based Response 
CT-Based Response 
Partial Response 
Partial Metabolic Response 
Partial Remission 
(all of the following) 
Lymph nodes and 
extralymphatic sites 
Score 4 or 5† with reduced uptake 
compared with baseline and residual 
mass(es) of any size 
At interim, these findings suggest 
responding disease. At end of 
treatment, these findings indicate 
residual disease. 
≥ 50% decrease in SPD of up to 6 
target measurable nodes and 
extranodal sites 
When a lesion is too small to 
measure on CT, assign 5 mm x 5 
mm as the default value; when no 
longer visible, 0 x 0 mm 
For a node > 5 mm x 5 mm, but 
smaller than normal, use actual 
measurement for calculation 
Non-measured lesion 
Not applicable 
Absent/normal, regressed, but no 
increase 
Organ enlargement 
Not applicable 
Spleen must have regressed by > 
50% in length beyond normal 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake in 
normal marrow but reduced compared 
with baseline (diffuse uptake 
compatible with reactive changes 
from chemotherapy allowed). If there 
are persistent focal changes in the 
marrow in the context of a nodal 
response, consideration should be 
given to further evaluation with MRI 
or biopsy or an interval scan 
Not applicable 
Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission 
tomography; SPD, sum of the product of the perpendicular diameters for multiple lesions. 
† PET 5point scale: 1, no uptake above background; 2, uptake _ mediastinum; 3, uptake _ mediastinum 
but _ liver; 4, uptake moderately _ liver; 5, uptake markedly higher than liver and/or new lesions; X, new 
areas of uptake unlikely to be related to lymphoma. 


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PET-CT Based Response 
CT-Based Response 
No Response or Stable 
Disease 
No metabolic response 
Stable disease 
Lymph nodes and 
extralymphatic sites 
Score 4 or 5† with no significant 
change in FDG uptake from 
baseline at interim or end of 
treatment 
< 50% decrease from baseline in SPD of 
up to 6 dominant, measurable nodes and 
extranodal sites; no criteria for 
progressive disease are met 
Non-measured lesion 
Not applicable 
No increase consistent with progression 
Organ enlargement 
Not applicable 
No increase consistent with progression 
New lesions 
None 
None 
Bone marrow 
No changes from baseline 
Not applicable 
Progressive Disease 
Progressive Metabolic Disease 
Progressive Disease 
(at least 1 of the following) 
Individual target 
nodes/nodal masses 
Extranodal lesions 
Score 4 or 5† with an increase in 
intensity of uptake from baseline 
and/or 
New FDG-avid foci consistent 
with lymphoma at interim or end-
of-treatment assessment 
An individual node/lesion must be 
abnormal with: 
LDi _ 1.5 cm and 
Increase by _ 50% from PPD nadir and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions ≤ 2 cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, the 
splenic length must increase by _ 50% of 
the extent of its prior increase beyond 
baseline (e.g., a 15-cm spleen must 
increase to > 16 cm). If no prior 
splenomegaly, must increase by at least 
2 cm from baseline 
New or recurrent splenomegaly 
Non-measured lesion 
None 
New or clear progression of preexisting 
nonmeasured lesions 
New lesions 
New FDG-avid foci consistent 
with lymphoma rather than 
another etiology (eg, infection, 
inflammation). If uncertain 
regarding etiology of new lesions, 
biopsy or interval scan may be 
considered 
Regrowth of previously resolved lesions 
A new node > 1.5 cm in any axis 
A new extranodal site >1.0 cm in any 
axis; if < 1.0 cm in any axis, its presence 
must be unequivocal and must be 
attributable to lymphoma 
Assessable disease of any size 
unequivocally attributable to lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 


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Abbreviations: CT, computed tomography; FDG, fluorodeoxyglucose; LDi, longest transverse diameter 
of a lesion; PET, positron emission tomography; PPD, cross product of the LDi and perpendicular 
diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the product of the perpendicular 
diameters for multiple lesions. 
† PET 5point scale: 1, no uptake above background; 2, uptake _ mediastinum; 3, uptake _ mediastinum 
but _ liver; 4, uptake moderately _ liver; 5, uptake markedly higher than liver and/or new lesions; X, new 
areas of uptake unlikely to be related to lymphoma. 
 
 
Antitumor Effect - Kaposi Sarcoma  
Subjects will be assessed according to the response schedule established in the study calendar 
(Section 10). Kaposi sarcoma will be evaluated using a modified version (consistent with other 
HAM Branch studies) of the AIDS Clinical Trial Group Oncology Committee staging and 
response definitions for Kaposi sarcoma (Krown 1989). (Assessment guidelines are provided in 
Appendix E). It should be noted that there is some observer variability in the evaluation of the 
number, size, nodularity, and color of lesions, and this must be taken into account when 
measurements are interpreted. 
- 
For evaluation of less than complete responses in subjects with more than 50 lesions at 
entry, only the previously selected 1 - 3 representative areas that contain at least 20 
lesions will be considered. However, complete responses still require the absence of any 
detectable disease over the entire body (i.e. not confined to the representative areas). 
11.3.1 Methods of Evaluation for Measurable Disease 
11.3.1.1 
KS Tumor Photography 
Scheduled as per study calendar (Section 10) 
Whole body photographs will be obtained upon entry into the study and at time of 
change in response (i.e. determination of partial or complete response or time of 
progressive disease) as well as at the end of the study. At these time points, 5 lesions 
(hereafter called marker lesions), representative of the patient’s disease and, if 
possible, located on separate areas of the body will be selected. These marker lesions 
should be lesions that have never been treated with local therapies such as radiation 
therapy or intralesional injections. An attempt will be made to distribute the “marker” 
lesions between the representative areas (described below in Section 11.3.1.3.1) and 
the rest of the body. Detailed photographs of these lesions will be obtained with a 
metric rule beside them.  
11.3.1.2 
Documentation of Marker Lesions 
Scheduled as per study calendar (Section 10) 
The size, color and nodularity of the marker lesions will be recorded. Documentation 
will depend on the number of lesions. 
11.3.1.3 
Documentation of Extent of Disease 
Scheduled as per study calendar (Section 10) 


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11.3.1.3.1. 
Subjects with 50 or more KS lesions: for subjects with 50 or more lesions at entry, 
between 1 and 3 representative areas will be selected at baseline and these will be 
used for each subsequent evaluation. Representative areas are sections of the body 
(e.g. the back, a leg, an arm, etc.), which contain at least 20 KS lesions. The total 
number of lesions in these representative areas will be counted and a record made 
of whether they are flat or raised. If, in the course of treatment, a single lesion 
breaks up into 2 or more smaller lesions whose area does not extend beyond the 
boundary of the initial lesion, these lesions will still be counted as single lesions 
for the purpose of assessing total numbers in defining a response to therapy.  
11.3.1.3.2. 
Subjects with fewer than 50 KS lesions: for subjects with less than 50 lesions at 
entry, the total number of lesions will be counted and a record made of whether 
they are flat or raised. 
11.3.1.3.3. 
Additional studies for visceral KS involvement: additional studies, including but 
not limited to, gastrointestinal endoscopy and bronchoscopy will be performed at 
baseline where clinically indicated, based on clinical evaluation of the patient. 
Abnormal studies will be repeated at the end of treatment. 
11.3.2 KS Response Criteria 
11.3.2.1 
Complete Response  
• The absence of any detectable residual disease, including tumor associated 
edema, persisting for at least 4 weeks. 
• For subjects with pigmented macular skin lesions persisting after apparent 
complete response, a biopsy of at least one representative lesion is required to 
document the absence of malignant cells. If a lesion has not been biopsied, the 
patient may be classified as having a clinical CR. 
• For subjects with visceral disease, the diagnostic radiologic or endoscopic 
study should be repeated if not medically contraindicated and found to be 
negative for evidence of disease. If such procedures are medically 
contraindicated but the patient has no clinical evidence of visceral disease, the 
patient may be classified as having a clinical CR. 
11.3.2.2 
Clinical Complete Response 
The absence of any detectable residual disease, including tumor associated edema, 
persisting for at least 4 weeks. 
• For subjects with pigmented macular skin lesions persisting after apparent 
complete response, if a representative lesion has not been biopsied. 
• For subjects with visceral disease, the diagnostic radiologic or endoscopic 
study should be repeated if not medically contraindicated and found to be 
negative for evidence of disease. If such procedures are medically 
contraindicated but the patient has no clinical evidence of visceral disease, the 
patient may be classified as having a clinical CR. 
11.3.2.3 
Partial Response 
No progressive disease (see below and noting, that single lesions which split up into 2 
or more smaller lesions during the course of treatment will still be counted as one); no 
new lesions occurring in previously uninvolved areas of the body; no new visceral 
sites of involvement or the appearance or worsening of tumor-associated edema or 


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effusions and: 
• A 50% or greater decrease in the number and/or size of 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 lesions become macular) lasting for at 
least 4 weeks or 
• A 50% decrease in radiologically measurable visceral lesions sustained 
without evidence of re-growth for at least 4 weeks or 
• A 50% decrease in radiologically measurable visceral lesions sustained 
without evidence of re-growth for at least 4 weeks or 
• Subjects who otherwise meet the criteria for a CR but still have residual 
tumor-associated edema or effusions will be classified as having a PR. 
11.3.2.4 
Progressive Disease 
For those criteria that involve measurement of lesions in the clinic, the designation of 
progression should be made, when feasible, only when the criteria below have been 
met in two measurements spaced at least 1 week apart. For participants who are 
stable, repeat evaluation may be 4-6 weeks later, following guidelines outlined in 
section 5.8. Treatment Beyond Progression.  For the assignment of progressive 
disease for the primary outcome analysis, progression will be defined in comparison 
to baseline measurements. 
• An increase of 25% or more over baseline in the number of lesions and/or the 
size (sum of the products of the largest perpendicular diameters) of the marker 
lesions or 
• A change in character from macular to plaque-like or nodular of at least 25% 
of the lesions or 
• New visceral sites of involvement or progression of visceral disease or 
• The development of new or increasing tumor-associated edema or effusion 
that lasts at least 1 week and interferes with the patient’s normal activities. 
11.3.2.5 
Stable Disease 
Any tumor measurement not meeting the criteria for Complete Response, Partial 
Response, or Progressive Disease. 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
Data Reporting 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  


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• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, 
Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
• 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
• 
Rave Investigator role must be registered as an Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
• 
Rave Read Only role must have at a minimum an Associates (A) registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), 
all persons with Rave roles assigned on the appropriate roster will be sent a study 
invitation email from iMedidata. To accept the invitation, site staff must either click on 
the link in the email or log in to iMedidata via the CTSU members’ website  under Data 
Management > Rave Home and click to accept the invitation in the Tasks pane located in 
the upper right corner of the iMedidata screen. Site staff will not be able to access the 
study in Rave until all required Medidata and study specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings) and can be 
accessed by clicking on the eLearning link in the Tasks pane located in the upper right 
corner of the iMedidata screen. If an eLearning is required for a study and has not yet 
been taken, the link to the eLearning will appear under the study name in the Studies pane 
located in the center of the iMedidata screen; once the successful completion of the 
eLearning has been recorded, access to the study in Rave will be granted, and a Rave 
EDC link will replace the eLearning link under the study name.  
Site staff that have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in RSS will receive a separate invitation 
from iMedidata to activate their account. Account activation instructions are located on 
the CTSU website in the Data Management section under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional information 
on iMedidata/Rave is available on the CTSU members’ website in the Data Management 
> Rave section at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-
823-5923 or by email at ctsucontact@westat.com.   
12.1.1 Method 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS). Data 
will be submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP). Information on CTMS reporting is available at: 
http://www.theradex.com/CTMS. On-site audits will be conducted on an 18-36 month 
basis as part of routine cancer center site visits. More frequent audits may be conducted if 
warranted by accrual or due to concerns regarding data quality or timely submission. For 
CTMS monitored studies, after users have activated their accounts, please contact the 
Theradex Help Desk at (609) 799-7580 or by email at ctms@theradex.com for additional 
support with Rave and completion of CRFs. 


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12.1.2 Responsibility for Data Submission 
It is the responsibility of the PI(s) at the site to ensure that all investigators at the site 
understand the procedures for data submission and that protocol specified data are 
submitted accurately and in a timely manner to the CTMS via the electronic data capture 
system, Medidata Rave.  
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 
than once every 2 weeks. The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS. Metrics for timeliness will be followed and 
assessed on a quarterly basis. For the purpose of Institutional Performance Monitoring, 
data will be considered delinquent if it is greater than 4 weeks past due. 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing 
basis as data is received. Queries will be issued by CTMS directly within Rave. The 
queries will appear on the Task Summary Tab within Rave for the CRA to resolve. 
Monthly web-based reports are posted for review by the Drug Monitors in the IDB, 
CTEP. Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching 
goal of ensuring the integrity of data generated from NCI-sponsored clinical trials 
An End of Study CRF is to be completed by the PI, and is to include the recommended 
phase 2 dose (RP2D), and a description of any dose-limiting toxicities (DLTs). CTMS 
will utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository 
(caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models). Customized eCRFs will 
be included when appropriate to meet unique study requirements. The PI is encouraged to 
review the eCRFs, working closely with CTMS to ensure prospectively that all required 
items are appropriately captured in the eCRFs prior to study activation. CTMS will 
prepare the eCRFs with built-in edit checks to the extent possible to promote data 
integrity. 
CDUS data submissions for will be carried out by the CTMS contractor, Theradex. 
CDUS submissions are performed by Theradex on a monthly basis. The trial’s lead 
institution is responsible for timely submission to CTMS via Rave, as above. 
 
CTEP Multicenter Guidelines 
This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines. 
The specific responsibilities of the Principal Investigator and the Coordinating Center (Study 
Coordinator) and the procedures for auditing are presented in Appendix B. 
• The Principal Investigator/Coordinating Center is responsible for distributing all IND Action 
Letters or Safety Reports received from CTEP to all participating institutions for submission 
to their individual IRBs for action as required. Submit documentation of reportable adverse 
events to CTSUprotocol@westat.com and state in the subject line “Safety Report for NCI 
protocol #” or “Action Letter for NCI protocol #”, as appropriate. A brief summary cover 
page on Coordinating Center letterhead is encouraged. These documents will be posted to the 
CTSU protocol web page and included in the next CTSU bi-monthly broadcast. 


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• Except in very unusual circumstances, each participating institution will order DCTD-
supplied agents directly from CTEP. Agents may be ordered by a participating site only after 
the initial IRB approval for the site has been forwarded by the Coordinating Center to the 
CTEP PIO (PIO@ctep.nci.nih.gov) except for Group studies. 
 
 
Collaborative Agreements Language 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (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: 
1. 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 
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 patient or patient’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. 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject 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 NCI, 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 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 
Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available 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 


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125 
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. 
4. 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. 
5. 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. 
6. 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. 
13. 
STATISTICAL CONSIDERATIONS 
 
Study Design/Endpoints 
13.1.1 Phase 1 
The primary objective is to assess the safety and tolerability of MK-3475 
(pembrolizumab) in HIV-infected patients on effective antiretroviral therapy and with 
metastatic or locally advanced AIDS-defining malignancies or NADMs for which no 
standard therapy exists or where standard therapy has failed.  
This is a phase I multi-institution trial of MK-3475 (pembrolizumab) to assess the safety 
and tolerability of MK-3475 (pembrolizumab) in HIV-infected patients on effective 
antiretroviral therapy with metastatic or locally advanced AIDS-defining or non-AIDS 
defining malignancies. The trial is open-labeled and nonrandomized. As the primary aim 
is to assess the safety and tolerability of MK-3475 (pembrolizumab) in this patient 
category, formal statistical sample size calculations do not apply.  


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Safety and tolerability of MK-3475 (pembrolizumab) is well defined for patients without 
concurrent HIV, but might be different in patients with HIV and confounded in 
unexpected ways by prior and concurrent administration of cART. Furthermore, safety 
and tolerability might be associated with initial CD4+ T-cell level. Patients will be 
stratified based on CD4+ T-cell counts at entry as some issues of safety and tolerability 
may vary according to CD4+ T-cell levels. Patients with HIV and malignancy that have 
been treated with multiple lympholytic therapies will present with a wide spectrum of 
CD4+ counts, even when on optimal HIV therapy and otherwise eligible to participate in 
a research protocol. For results of a safety study to be generalizable in this population, an 
adequate sample size is required to evaluate safety across a range of CD4+ counts, 
especially for a drug that modulates the immune system. For example, the safety of MK-
3475 (pembrolizumab) may vary based on CD4+ count. As in some non-cancer settings, 
PD-1 upregulation on CD4+ and CD8+ T cells in patients with HIV correlates with 
CD4+ count. In order to better address the primary objective, the accrual will be stratified 
by CD4+ T-cell levels. The CD4+ T-cell levels indicated below for definition of the 
cohorts are standard for many HIV therapy trials.  
Cohort 1: 50-199 CD4+ T cells/mcL  
Cohort 2: 200-350 CD4+ T cells/mcL 
Cohort 3: >350 CD4+ T cells/mcL  
Cohort 4: >50 CD4+ T cells/mcL 
Accrual to each cohort will be based on unacceptable AEs reported during first treatment 
cycle of 21 days. If 2 or more unacceptable AEs occur in the first 6 patients, the cohort 
will not be expanded to 12 patients until the AEs are assessed by the Toxicity Evaluation 
Committee and the Committee approves the expansion.  
The definition of an unacceptable AE for expansion of a cohort from 6 to 12 patients for 
the trial is detailed in Section 5.2.1.  
• If 2 or more of the first 6 patients in any individual cohort, and/or ≥1/3 of participants 
in any individual cohort in at any time experience unacceptable drug-related AE 
during the first 21 days of therapy, the entry into that cohort will be suspended and 
toxicities assessed by the Toxicity Evaluation Committee. The Toxicity Evaluation 
Committee will decide whether accrual should be stopped in that cohort or for the 
entire trial. The Toxicity Assessment Committee will need to assess the risk/benefit 
ratio given that all participants will have an otherwise fatal disease where 
conventional therapy has failed.  
• If greater than 1/3 of total patients, across all cohorts, develop an unacceptable AE in 
the first 21 days of therapy, the Toxicity Evaluation Committee will evaluate the 
totality of the data to determine whether accrual will be suspended in the trial. 
With an initial sample size of 6 participants in a specific cohort and a true unacceptable 
AE rate of 30%, there is a 58% chance of observing at least 2 unacceptable AEs. In the 


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enrollment expansion, in a given cohort of 12 patients there is a 75% chance of observing 
at least 3 unacceptable AEs. 
13.1.2 Safety Endpoints 
The primary safety endpoint is based on frequency of observed AEs graded using 
CTCAE (Version 5.0) criteria. Safety will be assessed based on the toxicities and grades 
experienced by treated participants, including SAEs and events of clinical interest (ECIs). 
Safety will be monitored by cumulative data reviews throughout the trial.  
Immune-related ECIs (irECIs), which include the occurrence of grade 2 or higher AEs 
with an immune etiology will be monitored.  
cART-related ECIs of grade 2 or higher AEs will be collected and summarized. Any AE 
of unknown etiology associated with study therapy will be evaluated to determine if it is 
possibly an ECI of a potentially immunologic etiology (i.e., irECI) or related to cART.  
Other safety endpoints include laboratory safety assessments, ECOG performance status, 
vital signs, and physical examinations.  
13.1.2.1 
Safety Analysis Population 
The safety population will include all patients who receive at least 1 dose of the study 
drug. The safety population will be used for the analysis of safety data in this study.  
13.1.2.2 
Statistical Methods for Safety Analyses  
Safety and tolerability will be assessed by summarizing all relevant parameters 
including AEs, SAEs, laboratory tests, vital signs, and electrocardiogram 
measurements. All summaries will be presented for each cohort and overall. 
Additional summaries of AEs will be presented by CTCAE grade. If the numbers are 
sufficient, the results may additionally be stratified by tumor type. No statistical 
hypothesis tests will be performed on safety parameters. 
13.1.3 Efficacy Endpoints 
Cohorts 1-3: The primary and secondary efficacy endpoints are described below. Given 
that there will be many different histologic types of tumors in enrolled participants, no 
overall analysis will be performed. The efficacy endpoints may be summarized for each 
relevant cancer type if the numbers are sufficient (at least five in a given type) by the use 
of tables or graphs. No statistical hypothesis tests will be performed.  
Objective response rate (ORR) is defined as the proportion of patients who have 
achieved CR or PR according to RECIST 1.1, “Lugano Criteria” for Malignant 
Lymphoma, ACTG criteria for KS, or other tumor-specific criteria. Patients with missing 
outcomes will be considered non-responders.  
Progression-Free Survival (PFS) is defined as the time from the first dose of study drug 
to progressive disease or death, whichever occurs earlier, based upon investigator 
assessment using RECIST 1.1, “Lugano Criteria” for Malignant Lymphoma or other 


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tumor-specific criteria. Patients without documented progressive disease or death will be 
censored at the last disease assessment date.  
Duration of response (DOR) is defined in participants experiencing CR or PR as the 
interval between the date of first response (CR/PR) and the date of progression, based 
upon investigator assessment using RECIST 1.1, “Lugano Criteria” for Malignant 
Lymphoma or other tumor-specific criteria. Patients without documented progression will 
be censored at the last disease assessment date. 
Overall survival (OS) is defined as the time from the first dose of study drug to death 
due to any cause. Patients without documented death at the time of analysis will be 
censored at the date last known to be alive. 
13.1.3.1 
Populations Chronicled 
The safety population will be used for the analysis of efficacy data in this study. The 
safety population consists of all patients who received at least 1 dose of study drug.  
13.1.3.2 
Exploratory Analyses by Pre-Therapy Biomarkers  
The analysis strategy for key efficacy variables is provided in the table below. 
Analysis Strategy for Key Efficacy Variables 
Endpoint/Variable 
(Description, Time point) 
Statistical Method 
Analysis Population Missing Data Approach 
Exploratory Objectives 
PFS 
Summary statistics using 
Kaplan-Meier method  
All patients who 
receive ≥1 dose of 
study drug 
Censored at last 
assessment of response 
ORR  
Clopper-Pearson 95% 
Confidence Intervals 
All patients who 
receive ≥1 dose of 
study drug 
Missing value considered 
nonresponder 
DOR 
Summary statistics using 
Kaplan-Meier method 
All responders who 
receive ≥1 dose of 
study drug 
Nonresponders are 
excluded in analysis 
OS 
Summary statistics using 
Kaplan-Meier method  
All patients who 
receive ≥1 dose of 
study drug 
Model based 
(censored at last date) 
PFS and OS by the following 
biomarker categories: 
• 
pre-therapy CD8+ T-cells 
• 
pre-therapy CD3+ T-cell 
infiltration in tumor 
• 
pre-therapy PD-1 and PD-
L1 expression in tumor 
Descriptive statistics 
All patients who 
receive ≥1 dose of 
study drug 
Censored at last 
assessment of response 


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Endpoint/Variable 
(Description, Time point) 
Statistical Method 
Analysis Population Missing Data Approach 
ORR by the following 
biomarker categories: 
• 
pre-therapy CD8+ T-cells 
• 
pre-therapy CD3+ T-cell 
infiltration in tumor 
• 
pre-therapy PD-1 and PD-
L1 expression in tumor 
Descriptive statistics 
All patients who 
receive ≥1 dose of 
study drug 
Missing value considered 
nonresponder 
 
13.1.4 Phase 1b, Efficacy Endpoints for KS Cohort (Cohort 4) 
The best objective response rate (partial response + complete response) as determined by 
modified ACTG criteria will be the primary efficacy endpoint in Cohort 4. Treatment of 
naïve patients and patients receiving pembrolizumab after one or more lines of prior 
therapy will be evaluated together. KS participants receiving therapy in cohorts 1-3 will 
be included in the efficacy analysis. A subset analysis evaluating KS treatment-naïve and 
previously treated KS participants separately will also be performed. Additional efficacy 
endpoints, outlined in 13.1.3, will also be evaluated in this cohort. 
 
Summaries of Baseline Characteristics, Demographics, and Other Analyses 
Demographic variables (e.g., age) and baseline characteristics will be summarized either by 
descriptive statistics (mean, standard deviation, median, range) or frequency tables.  
13.2.1 Extent of Exposure 
The extent of exposure will be summarized as duration of treatment in cycles. Dose 
intensity will also be summarized as appropriate. 
13.2.2 Reporting and Exclusions 
13.2.2.1 
Evaluation of Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment. AEs 
will be collected for 30 days after the last dose of study drug. 
13.2.2.2 
Evaluation of Response 
All patients enrolled in the study will be assessed for response to treatment, even if 
major deviations from protocol treatment occur or if they are ineligible. Response for 
each patient will be assigned one of the following categories as each response 
assessment: (1) CR, (2) PR, (3) SD (duration of SD will be noted, SD lasting ≥24 
weeks will be categorized separately), (4) progressive disease, (5) early death from 
malignant disease, (6) early death from toxicity, (7) early death because of other 
cause, or (9) unknown (not assessable, insufficient data). The best response observed 
during the study will be used in analysis.  


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All of the patients who met the eligibility criteria (with the possible exception of 
those who received no study medication) will be included in the main analysis of the 
response rate. Response in categories 4–9 will be considered to be a treatment failure 
(i.e., disease progression).  
 
Sample Size/Accrual Rate - Cohorts 1-3 
This study will initially evaluate up to 6 patients in each of three cohorts. If a safe dose (no more 
than 1 unacceptable AE out of 6 patients) is established in a specific cohort, an additional 6 
participants will be evaluated for safety and toxicities in that cohort. Thus, a minimum of 6 (2 
per cohort) and a maximum of 36 (12 per cohort) participants may be treated. Allowing for up to 
1 patient, one per cohort, to be replaced for patients consented and assigned but not receiving 
MK-3475 (pembrolizumab), a maximum of 39 participants will be enrolled.  
This protocol is designed to meet clinical needs of women and members of minority groups. The 
planned enrollment report (below) is based on US HIV demographics, and previous studies 
conducted in the HIV and AIDS Malignancy Branch.  
PLANNED ENROLLMENT REPORT (Cohorts 1-3) 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ 
Alaska Native 
 
 
 
 
 
Asian 
 
1 
 
 
1 
Native Hawaiian or 
Other Pacific Islander 
 
 
 
 
 
Black or African 
American 
3 
9 
1 
2 
15 
White 
2 
9 
1 
2 
14 
More Than One Race 
1 
2 
1 
2 
6 
Total 
6 
21 
3 
6 
36 
 
Cohort 4 Sample Size 
The protocol has an optimal Simon two stage design using type I error rate of <0.05 and power 
of > 0.90. The null hypothesis that the true response rate is <25% will be tested against a one-
sided alternative that the response with pembrolizumab is ≥55%. In the first stage, 9 patients will 
be accrued. If there are fewer than 3 responses in these first 9 patients in cohort 4, accrual to this 
cohort will be stopped. Otherwise, 15 additional patients will be accrued for a total of 24. The 
null hypothesis will be rejected if 10 or more responses are observed in 24 patients. As 3 of the 
first 5 participants have obtained a PR, we plan to enroll the full 24 patients. 


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PLANNED ENROLLMENT REPORT (COHORT 4) 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ 
Alaska Native 
 
 
 
 
 
Asian 
 
 
 
 
 
Native Hawaiian or 
Other Pacific Islander 
 
 
 
 
 
Black or African 
American 
 
11 
 
1 
23 
White 
 
11 
 
 
 
More Than One Race 
 
 
 
1 
1 
Total 
 
22 
0 
2 
24 
 
 
Stratification Factors 
Patients will be stratified based on CD4+ T-cell counts at entry as some issues of safety and 
tolerability may vary according to CD4+ T-cell levels. Patients with HIV and malignancy that 
have been treated with multiple lympholytic therapies will present with a wide spectrum of 
CD4+ T-cell counts, even when on optimal HIV therapy and otherwise eligible to participate in a 
research protocol. For results of a safety study to be generalizable in this population, an adequate 
sample size is required to evaluate safety across a range of CD4+ T-cell counts, especially for a 
drug that modulates the immune system. For example, the safety of MK-3475 (pembrolizumab) 
may vary based on CD4+ T-cell count. As in some non-cancer settings, PD-1 upregulation on 
CD4+ and CD8+ T cells in patients with HIV correlates with CD4+ T-cell count. In order to 
better address the primary objective, the accrual will be stratified by CD4+ T-cell levels. The 
CD4+ T-cell levels indicated below for definition of the cohorts are standard for many HIV 
therapy trials.  
Cohort 1: 50-199 CD4+ T cells/mcL  
Cohort 2: 200-350 CD4+ T cells/mcL 
Cohort 3: >350 CD4+ T cells/mcL  
Accrual to each cohort will be based on unacceptable AE during first treatment cycle of 21 days. 
If 2 or more unacceptable AEs occur in the first 6 patients, the cohort will not be expanded to 12 
patients until the AEs are assessed by the Toxicity Evaluation Committee and the Committee 
approves the expansion.  


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Analysis of Secondary Endpoints 
Analysis of secondary endpoints is discussed in Section 13.1.3.  
 
 


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Sznol, M. and L. Chen (2013). Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the 
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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time. Ambulatory 
and capable of all self-care, but 
unable to carry out any work 
activities. Up and about more than 
50% of waking hours. 
60 
Requires occasional assistance but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 


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APPENDIX B 
CTEP MULTICENTER GUIDELINES 
If an institution wishes to collaborate with other participating institutions in performing a CTEP-
sponsored research protocol, then the guidelines below must be followed. 
Responsibility of the Protocol Chair  
• 
The Protocol Chair will be the single liaison with the CTEP Protocol and Information Office 
(PIO). The Protocol Chair is responsible for the coordination, development, submission, and 
approval of the protocol as well as its subsequent amendments. The protocol must not be 
rewritten or modified by anyone other than the Protocol Chair. There will be only one version of 
the protocol, and each participating institution will use that document. The Protocol Chair is 
responsible for assuring that all participating institutions are using the correct version of the 
protocol. 
• 
The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress. All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
• 
The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure safety 
of the patients. 
• 
The Protocol Chair will be responsible for the review of and timely submission of data for study 
analysis. 
Responsibilities of the Coordinating Center 
• 
Each participating institution will have an appropriate assurance on file with the Office for 
Human Research Protection (OHRP), NIH. The Coordinating Center is responsible for assuring 
that each participating institution has an OHRP assurance and must maintain copies of IRB 
approvals from each participating site.  
• 
Prior to the activation of the protocol at each participating institution, an OHRP form 310 
(documentation of IRB approval) must be submitted to the CTEP PIO. 
• 
The Coordinating Center is responsible for central patient registration. The Coordinating Center 
is responsible for assuring that IRB approval has been obtained at each participating site prior to 
the first patient registration from that site. 
• 
The Coordinating Center is responsible for the preparation of all submitted data for review by the 
Protocol Chair. 
• 
The Coordinating Center will maintain documentation of AE reports. There are two options for 
AE reporting: (1) participating institutions may report directly to CTEP with a copy to the 
Coordinating Center, or (2) participating institutions report to the Coordinating Center who in 
turn report to CTEP. The Coordinating Center will submit AE reports to the Protocol Chair for 
timely review. 
• 
Audits may be accomplished in one of two ways: (1) source documents and research records for 
selected patients are brought from participating sites to the Coordinating Center for audit, or (2) 
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an audit at the Coordinating Center, then the Coordinating Center is responsible for having all 
source documents, research records, all IRB approval documents, NCI Drug Accountability 
Record forms, patient registration lists, response assessments scans, x-rays, etc. available for the 
audit. 
Inclusion of Multicenter Guidelines in the Protocol 
• 
The protocol must include the following minimum information:  
➢ The title page must include the name and address of each participating institution and the 
name, telephone number and e-mail address of the responsible investigator at each 
participating institution. 
➢ The Coordinating Center must be designated on the title page. 
➢ Central registration of patients is required. The procedures for registration must be stated in 
the protocol. 
➢ Data collection forms should be of a common format. Sample forms should be submitted with 
the protocol. The frequency and timing of data submission forms to the Coordinating Center 
should be stated. 
➢ Describe how AEs will be reported from the participating institutions, either directly to CTEP 
or through the Coordinating Center. 
➢ Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions. 
Agent Ordering 
• 
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
investigational agents directly from CTEP. Investigational agents may be ordered by a 
participating site only after the initial IRB approval for the site has been forwarded by the 
Coordinating Center to the CTEP PIO.  
 


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APPENDIX C 
BIOASSAY TEMPLATES 
Biomarker Namea 
AND Lead PI and Site 
Assay 
(CLIA: Y/N) 
Use (Integral, Integrated, or 
Exploratory) AND Purpose b 
Tissue/Body Fluid 
Tested 
and Timing of Assay 
M/O  
Funding 
Source(s) c 
CD4+ T and CD8+ T-cell 
counts 
To performed at 
each site by at a 
CLIA compliant 
laboratory. The 
technique is not 
specified by the 
protocol. 
CLIA: Yes 
Integral 
To be used as eligibility 
criterion for clinical 
monitoring for possible 
toxicity in the form of falling 
T-cell levels.  
Peripheral Blood 
Prior to first 3 doses of 
MK-3475 
(pembrolizumab) then 
before every third dose 
M 
CITN 
Single copy HIV plasma 
RNA; PMB HIV proviral 
DNA and unspliced RNA 
Frank Maldarelli MD PhD 
NCI HIV Drug Resistance 
Program 
 RT-PCR 
 
CLIA: No 
Exploratory 
To be used to evaluate the 
effect of MK-3475 
(pembrolizumab) on the HIV 
reservoir. 
 Plasma, PMC 
Screening, prior to first 3 
doses of MK-3475 
(pembrolizumab), at time 
of partial response and/or 
complete response, at off 
therapy visit. 
 M 
NCI HIV 
Drug 
Resistance 
Program 
PMB HIV unspliced RNA 
and HIV DNA 
Sharon Lewin, PhD 
University of Melbourne 
 
Quantitative 
PCR  
CLIA: No 
 
Exploratory 
To be used to evaluate the 
effect of MK-3475 
(pembrolizumab) on 
replication-competent HIV, 
quantifying latency reversal. 
Blood , PBMC 
M 
Investigator 
HIV-1 molecular 
evolution 
Frank Maldarelli MD PhD 
NCI HIV Drug Resistance 
Program 
RT-PCR and 
HIV viral 
sequencing 
CLIA: No 
Exploratory 
To be used to assess whether 
MK-3475 (pembrolizumab) 
mediated effects at increasing 
T-cell responses are reflected 
in changes in HIV virus level 
or genotype. 
 
Plasma, PMB 
Samples selected from 
reservoir studies. 
Potential time points 
include: Prior first 3 
doses of MK-3475 
(pembrolizumab), at time 
of partial or complete 
response, and at off 
therapy visit 
M 
NCI HIV 
Drug 
Resistance 
Program 
Quantify HIV reservoir in 
latently infected CD4+ T 
cells. 
Nicholas Chomont, PhD/ 
DARE 
TAT/ /REV 
Induced 
Limiting 
Dilution Assay 
(TILDA) 
CLIA: No 
Exploratory 
Peripheral Blood 
M 
Investigator 


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Biomarker Namea 
AND Lead PI and Site 
Assay 
(CLIA: Y/N) 
Use (Integral, Integrated, or 
Exploratory) AND Purpose b 
Tissue/Body Fluid 
Tested 
and Timing of Assay 
M/O  
Funding 
Source(s) c 
HIV Transcriptome  
Rafik Sekaly Lab, Case 
Western Reserve 
University 
Gene 
microarrays and 
bioinformatics—
Illumnina Gene 
Expression 
technology 
CLIA: No 
Exploratory 
To be used to characterize the 
kinetics and nature of host 
gene expression changes 
Whole blood 
Prior to first dose, 24 
hours after first dose, 
Cycle 7, and End of 
Treatment 
M 
Investigator 
HIV specific CD8+ T-cell 
cytotoxicity 
Mark Connors MD 
HIV-Specific Immunity 
Section at NIH/NIAID 
Autologous 
CD8+ T-cell 
cytotoxicity 
assays 
CLIA: No 
Exploratory 
To be used to assess whether 
MK-3475 (pembrolizumab) 
mediated effects at increasing 
tumor specific T-cell 
responses are also reflected in 
changes in autologous HIV-
specific T-cell responses 
 
Blood (PMB) 
Prior to first dose and 
fourth dose of MK-3475 
(pembrolizumab), and at 
one year or off-therapy 
visit (whichever is first) 
M 
HIV-Specific 
Immunity 
Section at 
NIH/NIAID 
Lymphocyte and 
Monocyte Phenotype 
Nora Disis, MD 
CITN Immune Monitoring 
Laboratory 
Flow Cytometry 
CLIA: No 
Exploratory 
To be used to assess the effect 
of MK-3475 (pembrolizumab) 
on circulating lymphocyte and 
monocyte numbers and 
phenotype 
Blood (PMB) 
Prior to first dose, Cycle 
4, Cycle 7, Cycle 13 
MK-3475 
(pembrolizumab) and at 
time of documented 
failure or End of Therapy 
M 
CITN 
Multiplex Cytokines 
(Mesoscale Discovery  V-
plex) 
Fred Hutchinson Cancer 
Research Center Shared 
Resources.,  
 
Multiplex 
ELISA 
CLIA: No 
Exploratory 
To be used to explore whether 
reactive changes in cytokine 
levels correlates with toxicity 
of efficacy of MK-3475 
(pembrolizumab).  
 
Plasma 
Prior to first, second and 
third doses of MK-3475 
(pembrolizumab) and at 
off therapy visit 
M 
CITN 


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Biomarker Namea 
AND Lead PI and Site 
Assay 
(CLIA: Y/N) 
Use (Integral, Integrated, or 
Exploratory) AND Purpose b 
Tissue/Body Fluid 
Tested 
and Timing of Assay 
M/O  
Funding 
Source(s) c 
Assessment of tumor 
biopsy for actionable 
mechanisms of failure by 
IHC  
Immunohistochemistry for 
CD80, arginase, IFN-
gamma CD3, CD5, CD4, 
CD8, TIA-1, CD20, PD-1, 
CD68, FOXP3, PDL1, 
CD11b, CD137, CD45RO, 
HLA-DR, CD301 
 
FHCRC Core Laboratory 
or PhenoPath Corp. 
IHC  
CLIA: No 
Exploratory 
To be used to explore whether 
biopsied tumors that are 
progressing in the face of MK-
3475 (pembrolizumab) offer 
clues as to potential 
mechanisms of failure 
 
Tumor biopsy 
Prior to first dose and at 
time of documented 
relapse or progression 
M/O 
CITN  
PD-L1 baseline 
Merck Research 
Laboratory or their 
suggested designee. 
IHC 
CLIA: No 
Exploratory 
To be used to explore whether 
this marker that correlates 
with response in other 
circumstances also correlates 
with response in this protocol 
population, especially given 
that the function of MK-3475 
(pembrolizumab) is to block 
binding of PD-1 to PD-L1.  
 
Tumor 
Pre-therapy biopsy 
M 
Merck 
Assessment of tumor 
biopsy for actionable 
mechanisms of failure by 
gene expression analysis  
NanoString Technologies 
or Merck Research 
Laboratory 
NanoString 
nCounter® 
PanCancer 
Immune 
Profiling Panel 
or nCounter® 
PanCancer 
Pathways Panel 
CLIA: No 
Exploratory 
To be used to explore whether 
biopsied tumors that are 
progressing in the face of MK-
3475 (pembrolizumab) offer 
clues as to potential 
mechanisms of failure 
 
Tumor biopsy 
Prior to first dose and at 
time of documented 
relapse or progression 
M/O 
CITN 
Assessment of KSHV 
Viral Load 
Whitby Lab (NCI) 
PCR 
CLIA: PBMC 
(Yes); Plasma 
(No) 
Exploratory 
Blood, longitudinal 
samples cycles 1-4. 
Cohort 4 only 
M/O 
NCI 
Anti-KSHV T-cell 
responses 
Whitby Lab (NCI) 
Whole viral 
proteome 
ELISPOT 
CLIA: No 
Exploratory 
Blood. Baseline, Cycle 4 
Cohort 4 only 
M/O 
NCI 


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Biomarker Namea 
AND Lead PI and Site 
Assay 
(CLIA: Y/N) 
Use (Integral, Integrated, or 
Exploratory) AND Purpose b 
Tissue/Body Fluid 
Tested 
and Timing of Assay 
M/O  
Funding 
Source(s) c 
Anti-KSHV humoral 
response 
Whitby Lab (NCI) 
Luminex 
multiplex 
serologic assay 
CLIA: No? 
Exploratory 
Blood. Baseline, Cycle 4 
Cohort 4 only 
M/O 
NCI 
Immune cell phenotype 
Hunt (UCSF) 
42- channel 
mass cytometry 
CLIA: No 
Exploratory 
Blood, longitudinal 
samples cycles 1-4. 
 
M/O 
NCI 
HLA-Typing 
Geraghty (FHCRC) 
High Res HLA 
Class I and II 
sequencing 
CLIA: Yes 
Exploratory 
Blood. Baseline only 
M 
CITN 
 
 


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APPENDIX D  
COMMON SIDE EFFECTS OBSERVED WITH AGENTS 
PRESCRIBED AS PART OF DHHS- RECOMMENDED AND 
ALTERNATE CART REGIMENS 
cART  
Common Side Effects (Observed in >5% of subjects on clinical studies) 
Atripla® 
Diarrhea, nausea, vomiting, fatigue, upper respiratory infections, headache, drowsiness, 
dizziness, anxiety, depression, insomnia, abnormal dreams, rash, elevated 
cholesterol, elevated CK, elevated amylase, increased creatinine 
Isentress® 
Insomnia, headache, dizziness, nausea, fatigue, neutropenia, elevated AST/ALT, 
elevated bilirubin, elevated CK, elevated fasting glucose, elevated amylase, elevated 
lipase, 
Norvir® 
Abdominal pain, dyspepsia, nausea, vomiting, fatigue blurred vision, cough, dizziness, 
dysguesia, flushing, pruritis, , rash, back pain, myalgia, neuropathy, edema, elevated 
AST/ALT, elevated triglycerides, elevated cholesterol, elevated CK,  
Prezista® 
Abdominal pain, nausea, diarrhea, headache, rash, elevated AST/ALT, elevated total 
cholesterol, elevated triglycerides, elevated glucose, elevated amylase 
Reyataz® 
Jaundice, elevated direct bilirubin, nausea, elevated CK, elevated total cholesterol, 
elevated triglycerides 
Stribild® 
Diarrhea, nausea, headache, abnormal dreams, elevated CK, increased creatinine 
Tivicay® 
Elevated AST/ALT, elevated CK, elevated glucose, elevated lipase 
Triumeq® 
Elevated AST/ALT, elevated CK, elevated glucose, elevated lipase 
Truvada® 
Diarrhea, nausea, fatigue, sinusitis, elevated CK, elevated cholesterol, elevated amylase, 
hypophosphatemia, decreased bone mineral density, neutropenia, increased 
creatinine 
See Section 5.1.2, Table 2, for Generic names and DHHS recommendations. 
Most AEs listed above are grade 1-2. For full list of adverse events, please see manufacturers’ 
Prescribing Information for individual agents. More common side effects attributed to medications are 
bold. Many symptomatic side effects decrease with continued use. Renal function should be monitored 
in patients on tenofovir containing regimens. 
Norvir® and Stibild® have significant CYP3A4 inhibitory effects, drug-drug interactions should be 
considered. 
 
 


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APPENDIX E  KS CUTANEOUS AND ORAL EXAM AND EVALUATION KS 
RESPONSE 
1. Kaposi’s Sarcoma Examination 
 
1.1. Kaposi’s Sarcoma Entry Examination 
Timing - The KS entry examination should be performed prior to receiving study 
medication but no earlier than 2 weeks before initiating treatment. Tumor measurements 
should include the following: 
A. Identify and Measure Cutaneous Marker Lesions  
Select Marker Lesions 
Select bi-dimensionally measurable marker lesions for assessing changes in lesion 
dimensions. Select the largest lesions with clearly defined margins. When available, a 
minimum of five bi-dimensionally measurable KS cutaneous marker lesions should be 
selected. If fewer than five bi-dimensionally measurable marker lesions are available, the 
total surface area of the marker lesion(s) should be ≥700mm². To facilitate repeated 
lesion measurements, the location of each marker lesion should be described in the 
Marker Lesion Table, recorded on the standard body diagram (Page 3 of Response Sheet, 
Appendix F) in relation to body landmarks and other nearby lesions and photographed as 
described in Section 3.  
Note: Lesions used as marker lesions for measuring response to treatment should 
NOT be the lesions chosen for biopsies for Tumor Marker Assessments. 
Measure Marker Lesions 
Each marker lesion should be measured in millimeters, indicating the longest linear 
dimension and the longest dimension perpendicular to it. For this protocol, the product of 
the largest perpendicular diameters of the marker lesion will be considered the AREA of 
the marker lesion. Please refer to the diagrams below: 
Next, calculate the sum of the products of the areas of the indicator lesion(s).  
The sum calculated at entry or at the best response will be used to determine the response 
status at follow-up visits.  
Calculate and Record Thresholds from Baseline for Partial Response and Progressive 
Disease 


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Next, calculate the sum of the products of the areas of the indicator lesion(s).  
To calculate the sum of the areas of the 5 example indicator lesions above, simply add the 
areas of each lesion: 
560 mm² + 625 mm² + 2223 mm² + 704 mm² + 752 mm² = 4864 mm² 
Using the five marker lesions above, the sum of the areas is 4864 mm². 
 
The sum calculated at entry or at the best response will be used to determine the response 
status at follow-up visits.  
Calculate and Record Thresholds from Baseline for Partial Response and Progressive 
Disease 
Partial Response threshold = Total product x 0.5 
Progressive Disease threshold = Total Product x 1.25 
Record Product thresholds on Page 1 of the Response Sheet. 
B. Evaluate Lesion Number (Total and Nodular/Raised) 
Select Representative Areas 
For participants with ≤50 total skin lesions, all lesions should be evaluated for changes in 
number and characteristics. For participants with >50 total skin lesions, choose three 
representative areas, if possible, for evaluating change in lesion numbers and 
characteristics (preferably each selected representative area should have at least 5 lesions, 
and the total number of lesions counted should be at least 20). If it is not practical to 
choose three representative areas, the number of areas selected is left to the 
investigator’s clinical judgment. On Measurement worksheet, note if greater than 50 
lesions. 
Note: A representative area is a single extremity, the back, chest, or face that has 
lesions similar in characteristics, i.e., nodularity, size, color, and number, to those 
found on other parts of the body. A representative area does not need to be the area 
with the largest number of lesions but should contain lesions that are truly 
representative of those throughout the remainder of the body. Confluent lesions 
should be avoided when possible. 
Lesion Count (Nodular/raised and Flat) 
The total number of nodular/raised and flat lesions (either total body or in the 
representative area(s)) must be counted. Use the Lesion Count tally sheet on Page 1 of the 
Response Sheet. Label body area counted, and use separate columns for Nodular and Flat 
lesions. Consider using a pen to mark lesions on skin as they are counted to aid. Mark the 
area counts and totals on Page 1 on the Response Sheet. 


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C. Evaluate Edema 
On page 2 of the Response Sheet, record the presence or absence of tumor-associated the 
severity of edema, and the location of tumor-associated edema, if present. 
In addition, lower extremity edema should be measured. Measure the circumference, in 
centimeters, of the ankle at the level of the malleoli and of the calf at a point 10 cm below 
the lower border of the patella. This must be done at entry in all participants whether 
there is edema or not. For patients with lower extremity edema, consider also 
documenting edema at the level of the thigh and pelvis. For each measurement, note the 
distance from an anatomical landmark. 
D. Perform Oral Examination 
An oral mucosal tissue examination will be conducted on all study participants to detect 
the presence of oral cavity KS lesions. 
The recommended standardized oral mucosal tissue examination should be conducted 
wearing gloves and 2x2 inch gauze and light. The oral examination should be conducted 
in the following sequence:  
Lips  
Begin examination by observing the lips, with the mouth both closed and opened. Note 
the color, texture, and any surface abnormalities of the upper and lower lip. 
Labial Mucosa 
With the mouth partially open, visually examine the lower labial mucosa by pulling the 
lower lip and stretching it over the chin, holding it between your thumb and index finger 
and using both hands. Repeat the same steps for the examination of the upper labial 
mucosa by pulling the upper lip and stretching it over the nose. 
Buccal Mucosa and Vestibules 
With the mouth open wide, examine first the right buccal mucosa (inside of cheek) 
extending from the labial commissures (corner of the lips) and back to the anterior 
tonsilar pillar. Examine both the upper and lower vestibule using the mirror to stretch the 
buccal mucosa and to help visualize the posterior vestibules. Examine the left buccal 
mucosa, following the same guidelines. 
Hard and Soft Palate  
With the mouth wide open and the participant’s head tilted backwards, inspect the hard 
palate (note the ridges or rugae) located in the anterior part, and then the soft palate and 
uvula (ask the participant to say “ahhh” to better visualize the soft palate). 
Tongue 
With the participant’s tongue at rest and mouth partially open, inspect the dorsum of the 
tongue for any swelling, ulceration, coating or variation in size, color, or texture. Also 
note any change in the pattern of the papillae covering the surface of the tongue and 
examine the top and the tip of the tongue. The participant should then protrude the 


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tongue, and the examiner should gasp the tip of the tongue with a piece of gauze to assist 
with full protrusion and allow examination of the margins or lateral borders. Note the 
small “lumps” located on each side of the posterior lateral tongue in the base of tongue 
area; these are the foliate papillae (considered to be an extension of the lingual tonsils). 
Then observe the ventral surface.  
Floor of Mouth 
With the tongue still elevated, inspect the floor of the mouth for swellings or other 
abnormalities. 
Gingiva 
First, examine the buccal and labial aspects of the gingiva and alveolar ridge. Start with 
the right maxillary posterior gingiva and alveolar ridge and move around the arch to the 
left posterior gingiva. Continue with the left mandibular posterior gingiva and alveolar 
ridge and move around the arch to the right posterior gingiva. 
Second, examine the palatal and lingual aspects as has been done on the facial side, from 
right to left on the palatal (maxilla) and left to right on the lingual (mandible). Use the 
mouth mirror to retract the posterior part of the tongue and focus the light to better 
visualize the lingual gingiva. 
Record the presence or absence of oral cavity KS lesions and their location on Page 1 of 
the Worksheet. Note whether lesions are raised or flat. 
E. Evaluating Disease that cannot be Measured by Physical Exam (Evaluable Disease, 
Visceral KS) 
Screening and Follow up for Visceral Disease 
A chest X-ray (CXR) will be performed at screening. If the CXR findings are abnormal, 
additional evaluations are required in consultation with a pulmonologist. Bronchoscopy 
with visualization of lesions consistent with Kaposi sarcoma or lung biopsy are required 
for documentation of pulmonary KS. Appropriate microbiologic evaluation to exclude 
infectious etiologies is required. If pulmonary KS is noted, a CT scan should be 
performed to document disease. 
At screening, potential study participants must be asked about the presence of 
gastrointestinal (GI) symptoms (odynophagia, nausea, vomiting, rectal bleeding, and/or 
abdominal pain). If GI symptoms are present or microcytic anemia are noted at 
baseline, further evaluations should include stool tests for occult blood and 
infectious etiologies if infection is suspected. Consultation with a gastroenterologist for 
upper and/or lower GI endoscopy is recommended in cases of occult blood loss or 
unexplained gastrointestinal symptoms. Documentation of gastrointestinal KS requires 
direct visualization of pigmented lesion(s) consistent with KS on endoscopy (with or 
without biopsy confirmation).  


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Other Sites of Disease 
CT scanning is not required at baseline in patients without other indications for a CT 
scan. If performed, KS involving other visceral organs or lymph nodes may be detected 
by advanced imaging techniques (e.g., CT or MRI scan, ultrasound) and confirmed by 
biopsy. If KS is confirmed by biopsy in visceral organs, this information should be 
recorded. If there is an unconfirmed abnormality on a scan or ultrasound, and KS cannot 
be confirmed by biopsy, that information should be recorded and the abnormality 
followed during study treatment to determine if it changes. 
Note presence of visceral lesions on page 1 of the Worksheet.  
Evaluable Disease 
Evaluable disease (also known as non-measurable disease) is disease that cannot be 
measured directly by the size of the tumor but can be evaluated by other methods. For 
purposes of this study, lesions considered truly non-measurable include: ascites, pleural 
or pericardial effusions, lymphangitic lung disease, abdominal masses/abdominal 
organomegaly identified by physical examination that is not measurable by reproducible 
imaging techniques, bone lesions without an identifiable soft tissue component that can 
be evaluated by cross-sectional imaging techniques, and lesions that can be identified 
only by endoscopic, bronchoscopic, or laparoscopic techniques. Changes in the size of 
other types of disease may not be accurately quantifiable, for example discrete lung 
lesions on chest x-ray. 
Effusions, when noted, should be evaluated to exclude primary effusion lymphoma 
whenever feasible before starting therapy. 
For purposes of response assessment, the evaluation of non-measurable disease is used 
primarily to determine whether an individual has shown tumor progression when 
evaluation of measurable disease (i.e., cutaneous marker lesions, lesion counts, numbers 
of raised and flat lesions, edema, visceral disease that is measurable in two dimensions on 
CT scan) indicates response or stable disease. We will use the standard of “unequivocal 
progression”, i.e., an overall level of substantial worsening of disease that is of a 
magnitude that, even in the presence of stable disease or partial response in measurable 
disease, the treating physician would feel it important to change therapy. This requires 
clinical judgment on the part of the investigator. For further guidance on the evaluation of 
non-measurable disease, please refer to the following: 
Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to 
treatment in solid tumors. European Organization for Research and Treatment of Cancer, 
National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl 
Cancer Inst 2000; 92(3):205-216. 
The KS follow-up examination will be performed according to the schedule of events. 
Tumor evaluation should follow the guidelines noted in Section 1.1 above, and include: 
• Record measurements of the longest linear dimension in millimeters and the 
longest dimension perpendicular to it of the same marker lesion(s) selected at 
entry; 


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• Record the total number of raised and flat lesions (in the same areas that were 
evaluated at entry, either total body or the representative area(s) selected at 
entry); 
• Record the location, size, or characteristics of oral cavity lesions, after the oral 
mucosal tissue examination is conducted in the same sequence as the oral 
examination at entry; 
• Record the severity of edema and the location of tumor-associated edema. If 
no edema was present at entry and no edema is present on the follow-up visit, 
repeat measurements are not required. If there was no edema at entry and 
edema develops at a follow-up visit, a re-measure at each KS follow-up 
evaluation is required. If edema was noted at entry, a re-measure at each KS 
follow-up evaluation is required. 
• Record changes of visceral KS at the intervals required by the protocol if 
visceral disease was present at entry, or if symptoms suggesting visceral 
disease develop. 
2. Calculating Response Status  
Response status will be classified as complete response (CR), partial response (PR), stable 
disease, or progressive disease (PD). For a detailed definition of the KS response status, please 
refer Section 11.3 of the protocol, as well as reference article provided. 
Response should be calculated from Baseline. For patients with decreasing tumor area or lesion 
counts, new thresholds should also be calculated for values at best response and used as a 
reference for comparison to subsequent values. Document Response for Baseline and 
Response from additional time points (by Date or cycle number) on Page 2 of the Response 
Sheet. 
2.1. Calculate Response Status Based on Area of Marker Lesion(s) 
To calculate the KS response status based on area of marker lesions you will need the 
area of the indicator lesions from entry. Next, calculate the area of the same indicator 
lesion(s) for the current visit. Subtract the area at the current visit from the area at entry, 
then divide this difference by the area at entry. Multiplying by 100% will give you the 
percentage change from entry. After a participant has had a confirmed CR or PR, 
subsequent measurements for PD should also be compared with the “best response” seen 
at a previous visit. 
An initial confirmed PR is a ≥50% decrease in the area of the indicator lesion(s) 
compared to entry lasting for at least 4 weeks. For example, if a participant had an area of 
the indicator lesions of 4000mm² at entry and an area of the indicator lesions of 2000mm² 
at week 3, and this decrease was maintained for at least 4 weeks, the participant would 
have a confirmed PR.  
PD is considered a ≥ 25% increase in the area of the indicator lesion(s) compared to entry 
or best response. For example, if the same participant as in the example above had an 
area of the indicator lesions of 5000mm² at week 3, the participant would have PD. 
Similarly, if a participant had an area of the indicator lesions of 4000mm² at entry and an 


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area of the indicator lesions of 2000mm² at week 9 that lasted for four weeks (a 
confirmed PR) but at a subsequent visit was found have an area of 3000mm2 (a greater 
than 25% increase over the best response), the participant would have PD. PD after a 
confirmed CR is defined by the presence of any KS following that confirmed CR. 
Note: If a confirmed CR has been achieved and subsequent evaluations do not 
meet criteria for CR, this would be reported as PD. 
Please note that "best response" may improve after the initial confirmed PR is 
documented. For example, if the entry area of the indicator lesions was 5000mm² and the 
area decreased to 2400mm² at weeks 9 and 15, this would be the initial confirmed PR. 
If, at week 18, the area of the indicator lesions decreased further to 2000mm², then 
2000mm2 is the new “best response”. In this example, subsequent assessments of PD 
for the area of indicator lesions would be with respect to the number 2000mm², not 
to 2400mm². Thus, if the area of the indicator lesions at week 24 increased from 
2000 to 2500mm2, this increase would constitute PD, despite the fact that 2500mm2 
is 50% smaller than the entry lesion area.  
Note: If a confirmed PR has been achieved and subsequent evaluations do not 
meet criteria for PD or CR, this would continue to be reported as PR. In the 
example above, if the entry area of the indicator lesions was 5000mm² and the 
area decreased to 2400mm² at weeks 9 and 15, and remained at 2400mm² at 
week 18, 2400mm² is the “best response” to date. If, at week 24, the area of the 
indicator lesions increased to 2800mm² this would continue to be reported as a 
PR because 2800 is less than a 25% increase from 2400. Similarly, if at week 24, 
the area of the indicator lesions decreased by an additional 10% to 2160mm², 
this would also continue to be reported as a PR.  
2.2. Calculate Response Status Based on the Total Number of Lesions 
To calculate the response status based on the total number of lesions, you will need the 
total number of lesions (either whole body or, in the case of participants with over 50 
lesions at entry, in the combined representative areas) from the entry KS exam. After an 
initial confirmed CR or PR, the percentage change for PD should be calculated from the 
“best response” seen at a previous visit. 
An initial confirmed PR is a 50% or greater decrease in the number of lesions present at 
entry (either whole body or, in the case of participants with over 50 lesions at entry, in 
the combined representative areas) lasting for at least 4 weeks. For example, if a 
participant had 40 lesions at entry and had only 20 lesions at follow-up and this decrease 
was maintained for at least 4 weeks, that participant would have a confirmed PR. 
For participants with ≤50 cutaneous lesions at entry, PD is defined as ≥25% increase in 
the total lesion count or a minimum of five new lesions, whichever is greater, compared 
to entry or best response. For example, if a participant had 35 lesions at entry and has 44 
at follow-up, that would be classified as PD. PD after a confirmed CR is defined by the 
presence of any KS following that confirmed CR. 


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Note: If a confirmed CR has been achieved and subsequent evaluations do not 
meet criteria for CR, this would be reported as PD. 
For participants with >50 cutaneous lesions at entry, PD is defined as ≥25% increase in 
the total number of lesions or a minimum of five new lesions, whichever is greater, in 
the combined prospectively-defined anatomic sites containing representative lesions 
compared to entry or best response, or a total of five new lesions in anatomic sites 
which were previously documented as having no evidence of cutaneous disease. For 
example, if a participant had a total of 40 lesions at entry on the back and the right leg 
and had a total of 50 lesions at follow-up on the back and the right leg that would be 
classified as PD. Also, if a participant had no lesions at entry on the right arm and had 
five lesions on the right arm at follow-up that would be classified as PD. Similarly, if a 
participant had 40 lesions at entry and 20 lesions at weeks 9 and 15 (a confirmed PR) 
but at a subsequent visit was found to have 30 lesions (a greater than 25% increase over 
the best response), the participant would have PD. PD after a confirmed CR is defined 
by the presence of any KS following that confirmed CR. 
Please note that "best response" may improve after the initial confirmed PR is 
documented. For example, if the entry number of lesions was 30 and the number of 
lesions decreased to 15 at weeks 9 and 15, this would be the initial confirmed PR. If, at 
the week 18 evaluation the number of lesions decreased further, e.g., to 10, then 10 is the 
new “best response” and subsequent assessments of PD for lesion counts would be with 
respect to the number 10, not to 15. Furthermore, if the number of lesions at week 24 
increased from 10 to 15, this increase would constitute PD, despite the fact that 15 is 
50% smaller than the entry lesion count. 
Note: If a confirmed PR has been achieved and subsequent evaluations do not 
meet criteria for PD or CR, this would continue to be evaluated as PR. In the 
example above, if the entry lesion count was 30 and the number of lesions 
decreased to 15 at weeks 9 and 15, then 15 is the “best response” to date. If, at 
week 24, the number of lesions increased to 18, this would continue to be 
reported as a PR because 18 is less than a 25% increase from 15. Similarly, if at 
week 24, the number of lesions decreased by an additional 20% to 12, this would 
also continue to be reported as a PR.  
2.3. Calculate Response Status Based on the Number of Raised Lesions 
To calculate the response status based on the number of raised lesions, you will need the 
total number of raised lesions (either whole body or, in the case of participants with >50 
lesions at entry, in the combined representative areas) from the entry KS exam. If, after 
an initial confirmed response, the disease appears to be getting worse, the percentage 
change for PD should be calculated from the “best response” seen at a previous visit. 
An initial confirmed PR is a complete flattening of at least 50% of all previously raised 
lesions (i.e., 50% of all nodular or plaque-like lesion become macules) present at entry 
(either whole body or, in the case of participants with >50 lesions at entry, in the 
combined representative areas) lasting for at least 4 weeks. For example, if a participant 


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had 30 raised lesions at entry and had only 15 raised lesions at follow-up and this 
decrease was maintained for at least 4 weeks that would be classified as a confirmed PR. 
For participants with ≤50 cutaneous lesions at entry, PD is defined as ≥25% increase in 
the number of raised lesions (minimum of 5 new raised lesions if there are very few 
raised lesions, for example <8), compared to entry or best response. For example, if a 
participant had 20 raised lesions at entry and had 25 raised lesions at follow-up that 
would be classified as PD. Also, if a participant had 7 raised lesions at entry and had 12 
at follow-up that would be classified as PD. PD after a confirmed CR is defined by the 
presence of any KS following that confirmed CR. 
Note: If a confirmed CR has been achieved and subsequent evaluations do not meet 
criteria for CR, this would be reported as PD. 
For participants with >50 cutaneous lesions at entry, PD is defined as ≥25% increase in 
the total number of raised lesions or a minimum of five new raised lesions, whichever 
is greater, in the combined prospectively-defined anatomic sites containing 
representative lesions (minimum of 5 raised lesions if there are very few raised lesions, 
for example <8). For example, if a participant had a total of 28 raised lesions on the back 
and right arm at entry and had a total of 35 raised lesions on the back and right arm at 
follow-up that would be classified as PD. Also, if a participant had a total of 7 raised 
lesions on the back and right arm at entry and had 12 raised lesions on the back and right 
arm at follow-up that would be classified as PD. Similarly, if a participant had 40 raised 
lesions at entry and 20 raised lesions at weeks 9 and 15 (a confirmed PR) but at a 
subsequent visit was found have 30 raised lesions (a greater than 25% increase over the 
best response), the participant would have PD. PD after a confirmed CR is defined by 
the presence of any KS following that confirmed CR. 
Please note that "best response" may improve after the initial confirmed PR is 
documented. For example, if the entry number of raised lesions was 30 and the number 
of raised lesions decreased to 15 at weeks 9 and 15, this would be the initial confirmed 
PR. If, at the week 18 evaluation, the number of raised lesions decreased further, e.g., to 
10, then 10 is the new “best response” and subsequent assessments of PD for raised 
lesions would be with respect to the number 10, not to 15. Furthermore, if the number 
of raised lesions at week 24 increased from 10 to 15, this increase would constitute 
PD, despite the fact that 15 is 50% smaller than the entry raised lesion count. 
Note: If a confirmed PR has been achieved and subsequent evaluations do not 
meet criteria for PD or CR, this would continue to be evaluated as PR. In the 
example above, it the entry raised lesion count was 30 and the number of raised 
lesions decreased to 15 at weeks 9 and 15, then 15 is the “best response” to date. 
If, at week 24, the number of raised lesions increased to 18, this would continue 
to be reported as a PR because 18 is less than a 25% increase from 15. Similarly, 
if at week 24, the number of raised lesions decreased by an additional 20% to 12, 
this would also continue to be reported as a PR. 


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2.4. Determining Response Status Combining Measurements of Lesion Size, Character, 
and Number and Visceral Disease and Edema 
Participants who show the absence of any detectable residual disease, including tumor-
associated edema, persisting for at least 4 weeks, will be classified as having CR. In some 
individuals, residual skin color changes may remain visible at one or more sites of lesions 
that were previously raised and/or red or violaceous. Suspected CR in those lesions refers 
only to residual macules (flat, non-palpable lesions) that are slightly darker than the 
surrounding normal skin. In the event such lesions are present in a participant otherwise 
believed to have a CR, biopsy of at least one such lesion is required to document the 
absence of malignant cells and to confirm CR. In the event that such a confirmatory 
biopsy is not performed and residual pigment persists, the response will be considered 
PR. In participants in whom all detectable cutaneous disease has resolved and in whom 
there are no visible pigmented macules as described above, a confirmatory skin biopsy is 
not required. In participants known to have had visceral disease, an attempt at restaging 
with appropriate endoscopic or radiographic procedures should be made. 
Participants who do not meet the criteria for CR, PR, or PD will be classified as Stable. 
The criteria for classifying participants as showing either PR or PD are shown in the 
tables below.  
Partial Response 
PR requires at least one of the highlighted criteria in the table below AND all of the 
categories shown on the same row, when compared to entry. 
Note: If any of the criteria for PD have been met, even in the presence of a criterion 
for PR, it is considered PD.  
Note: PR is always a comparison to entry even if there has been a prior PR. 
Criteria for Classifying PR 
Total body or representative areas 
PR 
Category 
Marker 
lesion area 
Number of 
lesions 
Number of 
raised lesions 
Visceral or  
Oral KS* 
Edema 
1 
Decrease 
≥50% 
<25% 
Increase 
<25% Increase 
<25% Increase of 
measurable lesions 
without unequivocal 
worsening of non-
measurable disease 
No significant 
increase or new 
sites 
2 
<25% 
Increase 
Decrease 
≥50% 
<25% Increase 
<25% Increase 
of measurable lesions 
without unequivocal 
worsening of non-
measurable disease 
No significant 
increase or new 
sites 


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Criteria for Classifying PR 
Total body or representative areas 
PR 
Category 
Marker 
lesion area 
Number of 
lesions 
Number of 
raised lesions 
Visceral or  
Oral KS* 
Edema 
3 
<25% 
Increase 
<25% 
Increase 
Decrease ≥50% 
<25% Increase 
of measurable lesions 
without unequivocal 
worsening of non-
measurable disease 
No significant 
increase or new 
sites 
4 
<25% 
Increase 
<25% 
Increase 
<25% Increase 
Decrease 
≥50% 
of measurable 
lesions without 
unequivocal 
worsening of non-
measurable disease 
or complete 
disappearance of 
non-measurable 
disease 
No significant 
increase or new 
sites 
*Please note that there is no need to physically measure the visceral or oral KS. 
 
Progressive Disease 
Any of the following (increase refers to a change over entry visit or when compared to 
the best response). If there has been a previous confirmed CR or PR, subsequent 
assessments of PD should be made with comparison to the best response for the category 
(or categories) that previously led to the assessment of CR or PR; for the other categories, 
the comparison should be made to entry. 
Note: PD is a comparison to entry unless there has been a confirmed PR or CR in 
which case it is then a comparison to best response. Only PD is compared to best 
response (see Section 3.4 below). 
Total body or representative areas 
Marker lesion 
area 
Number of 
lesions 
Number of raised 
lesions 
Visceral or Oral 
KS 
Edema 
≥25% Increase 
≥25% Increase 
≥25% Increase 
≥25% Increase or 
new sites 
or unequivocal 
worsening of non-
measurable 
disease 
Significant 
increase or new 
sites* 
 
*Significant increase in edema or new sites compared to entry or best response** are defined as:  


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• an increase in non-pitting/woody edema in an upper or lower extremity associated 
with an increase in limb circumference of at least 3 cm from entry or best response, 
sustained for at least two consecutive evaluations, and measured at a fixed point on 
the extremity with respect to a bony landmark (e.g., 10 cm below the lower border of 
the patella); AND/OR, 
• new appearance of non-pitting/woody edema in an extremity when none was 
previously present, sustained for at least two consecutive evaluations;  
AND/OR, 
• new or worsening edema in a non-extremity site (e.g., periorbital, genital) that 
interferes with function and is sustained for at least two consecutive evaluations. 
** If edema is present at entry and resolves completely (and this lasts for at least 
4 weeks), this is considered a “best response” of edema. Otherwise, all 
evaluations of edema in a given step are with respect to the status at entry to that 
step.  
2.5. Assessment of Response Status During Steps 2, 3 and 4 
At the time of Step 2, 3, or 4 entry, a different representative area, if preferable, may be 
chosen for determination of response status during Step 2, 3, or 4. Response status during 
Step 2, 3 or 4 will be determined by comparing Step 2, 3 or 4 visits to Step 2, 3, or 4 
entry, respectively. If possible, the same marker lesion(s) should be followed and 
measured throughout Steps 1, 2, 3, and 4.  
3. Photographic Record 
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 marker lesion(s), defined at study 
enrollment and used for clinical assessment of response. The marker lesion(s) must be labeled in 
the photographs #1–#5, as applicable. The same lesion(s) 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 photo that will show the lesion’s location on 
the body. 
In all participants, photos will also be needed 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 entry (e.g., the face). 
In participants with >50 cutaneous lesions, photographs will be taken of the representative areas 
(each should have at least 5 lesions), defined at study enrollment and used for clinical 
assessment of response.  


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Photographic documentation will be completed at entry and then at each visit when the KS 
response status changes. For example, if a participant’s KS response status 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 status, no photos are required. 
Note: The same markers lesions should be used throughout the study. In the event that 
the marker lesions coalescence or become immeasurable during follow-up, a new marker 
lesion may be selected at the entry of a new step for follow-up evaluations during that 
step. 
Photographs will be stored electronically under the participant ID number and back-up electronic 
storage will be kept. Only dedicated study staff and the sponsor should have access to the 
photographs. 
Appropriate measures must be taken to protect participant confidentiality. Photographs of 
participants’ faces should be avoided unless the area is being monitored for KS response. In 
cases where a participant’s face is photographed, no participant photos should be used in 
publication prior to removal of identifying characteristics, for example, the blacking out of a 
participant’s eyes. Site should take necessary measures to black out eyes and/or tattoos prior 
to uploading photos. 
Absolutely no identifying information should be included with the digital picture file. 
Photography Tips 
1. We recommend a 5 megapixel camera minimum. 
2. Include the participants PID in all of the photos. 
3. Always try to take the photos in the same setting with respect to participant 
positioning, lighting, background, and camera setting. 
4. Use auto-focus. The team does not recommend the use of manual controls. 
5. Use the “macro” mode for close-ups. The universal symbol for “macro” mode is a 
flower. 
6. Use the flash mode as often as possible when the lighting is poor, but avoid getting 
too close to the lesions as overexposure may wipe out the details. 
7. For very close shots, oblique views may be preferred 
8. Eliminate all distractions from the background. Try to take all photographs with a 
plain blue or green background. 
Framing Tips 
1. For different body areas certain standard framing patterns are followed 
2. For all lesions, make it a point to take at least 2 shots from each point of focus. 
Minimal blurring may not be obvious on the LCD screen and may be noticeable only 
after the image is viewed on the monitor. It is always better to have an extra copy 
from every focus point so that the best image can be selected. 


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3. Always try to capture distinctive elements like typical representative lesions, 
particular configurations, or distribution patterns. 
For generalized lesions take shots from at least three ranges: 
• A complete vertical view of the participant showing the extent and distribution of the 
rash;  
• A medium distance shot showing the arrangement and configuration of the rash; 
• A close-up view highlighting a representative lesion. 
For localized lesions take shots from at least two points: 
• A medium view showing the rash /lesion with respect to location and configuration  
Always include a recognizable body landmark so that the location is obvious. For 
example, lesions on the abdomen include the umbilicus in the medium distance shot) 
• A close-up view of the representative lesion  
For isolated lesions it is also advisable to include a discernible landmark in one of the 
shots. For the close-up shots use a measuring tape/ruler in the frame to demonstrate the 
size of the lesion. It would be advisable to take the close-up shots from more than one 
angle and include oblique shots. Shots with and without flash may be taken and the best 
shot selected for storage. 
Recommended Saving, Storing, and Uploading Files 
1.  SAVE as a JPG file. The major advantage of the JPG format is that the image size can 
be compressed considerably without significant visible loss of resolution. The back-
up copies can also be saved in the compressed JPG format so that the space taken up 
can be minimized. It always makes sense to delete images that are blurred as they are 
unlikely to be used by you and will unnecessarily clutter up the hard disk space. 
2. Make it a point to catalog all saved images (or containing folders) tagging them with 
the participant’s identification number, date and even the provisional diagnosis, if 
possible. Meticulous cataloging may seem cumbersome at the beginning but make 
future retrieval of images very convenient. 
 
 


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APPENDIX F  
KAPOSI SARCOMA RESPONSE SHEET 
 CITN-12 KAPOSI SARCOMA MEASUREMENT AND RESPONSE SUMMARY  
Initials 
 
Date 
 
Study  
 
Cycle  
 
Photos 
 
Baseline TIS T:     I:    S:  
REASON T1: 
MARKER LESIONS 
LESION 
COLOR, LOCATION 
FLAT OR NODULAR 
DIMENSIONS 
PRODUCT 
ONE 
 
 
 
 
TWO 
 
 
 
 
THREE 
 
 
 
 
FOUR 
 
 
 
 
FIVE 
 
 
 
 
 
LESION COUNT 
TOTAL LESIONS 
OVER 50 _______________ 
UNDER 50* _________________ 
*FOR PATIENTS WITH UNDER 50 LESIONS, WRITE 
‘TOTAL BODY’ FOR AREA AND USE LEFT COLUMN 
 
BODY AREA 
1 
2 
3 
TOTAL 
NUMBER FLAT 
 
 
 
 
NUMBER 
NODULAR 
 
 
 
 
TOTALS 
 
 
 
 
 
ORAL 
LESIONS 
PRESENT 
 
NONE 
 
NO 
EVAL 
 
DESCRIPTION 
IF PRESENT 
 
VISCERAL 
LESIONS 
PRESENT 
 
NONE 
 
NO 
EVAL 
 
DESCRIPTION 
IF PRESENT 
 
RESPONSE THRESHOLDS FROM:_______________ 
RESPONSE FROM 
BASELINE 
 


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PARTIAL RESPONSE 
PROGRESSIVE 
DISEASE 
RESPONSE  
BASED ON 
 
TOTAL 
 
TOTAL 
 
RESPONSE FROM 
BEST RESPONSE 
 
NODULAR 
 
NODULAR 
 
RESPONSE  
BASED ON 
 
PRODUCT 
 
PRODUCT 
 
RESPONSE  
CONFIRMED BY 
 
RECORDER 
SIGNATURE 
 
 
TUMOR EDEMA 
NO [ ] 
 
YES [ ]  
 
LOCATION 
LEFT 
RIGHT 
LEVEL 
DIST. 
DIAM. 
LEVEL 
DIST. 
DIAM. 
ANKLE  0cm 
 
ANKLE 
0cm 
 
CALF 
 
 
CALF 
 
 
THIGH 
 
 
THIGH 
 
 
PELVIS 
 
 
PELVIS