Clinical and Genomic Factors for Prognosis of AIDS Primary Effusion Lymphoma
Conditions: AIDS-Related Primary Effusion Lymphoma
Sponsor: AIDS Malignancy Consortium

AMC #S004 (Version 3.0) 23AUG2019 
 
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SUMMARY OF CHANGES 
Clinical and Genomic Factors for Prognosis of AIDS Primary Effusion Lymphoma 
(Version 3.0) 
 
NCI Protocol #: AMC-S004 
Local Protocol #: AMC-S004 
 
NCI Version Date: DDJUL2019 
Protocol Date: DDJUL2019 
 
I. 
Administrative and Editiorial Changes by Principal Investigator: 
# 
Section 
Comments 
1. 
Global 
The protocol date and version have been updated to 23AUG2019 and version 3.0. 
2. 
Global 
The AMC operations page URL has been updated. 
3. 
Protocol 
Roster 
The protocol roster has been updated to reflect current contacts. 
4. 
3.0 
Template language has been added to indicate that an AMC rostered investigator must 
establish eligibility.  
5. 
4.2 
Appendix numbers have been updated for consistency with current protocol. 
6. 
7.5 
The AMC name has been updated. 
7. 
Appendix I 
The AMC Data and Safety Monitoring Plan has been updated to the current version, v6.0 

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AIDS MALIGNANCY CONSORTIUM 
 
AMC PROTOCOL # S004: 
CLINICAL AND GENOMIC FACTORS FOR PROGNOSIS OF AIDS 
PRIMARY EFFUSION LYMPHOMA 
A TRIAL OF THE AIDS MALIGNANCY CONSORTIUM (AMC) 
 
Sponsored by: 
National Cancer Institute 
Office of HIV and AIDS Malignancy (OHAM) 
 
NCT Registration 
Number: 
NCT02823327 
 
Protocol Chair: 
Erin Gourley Reid, MD 
 
Protocol Co-Chair: 
William Wachsman, MD, PhD 
 
Version 3.0, August 23, 2019 
NCI Version Date: August 23, 2019 

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AMC PROTOCOL SIGNATURE PAGE 
I, ____________, Principal Investigator at site ______________________, agree to conduct and 
follow this protocol: AMC Protocol # S004 – Clinical and Genomic Factors for Prognosis of 
Primary Effusion Lymphoma (Version 3.0, 23AUG2019), as written according to AMC, NCI, 
and FDA guidelines. I understand that no deviations from the protocol eligibility criteria or waivers 
for protocol deviations will be permitted. 
 
 
_________________________________ 
 
 
_____________________ 
 
Signature 
Date (mm/dd/yyyy) 
 
 

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TABLE OF CONTENTS 
SUMMARY OF CHANGES ................................................................................................................ i 
AMC PROTOCOL SIGNATURE PAGE ......................................................................................... 2 
TABLE OF CONTENTS .................................................................................................................... 3 
PROTOCOL ROSTER ....................................................................................................................... 5 
PROTOCOL SYNOPSIS .................................................................................................................... 6 
1.0 
OBJECTIVES .......................................................................................................................... 7 
1.1 
Hypothesis................................................................................................................7 
1.2 
Primary Objectives...................................................................................................7 
2.0 
BACKGROUND ...................................................................................................................... 8 
2.1 
Study Disease ...........................................................................................................8 
2.2 
Study Design and Rationale .....................................................................................9 
3.0 
PARTICIPANT SELECTION ............................................................................................. 10 
3.1 
Eligibility Criteria ..................................................................................................10 
3.2 
Exclusion Criteria ..................................................................................................10 
3.3 
Number of Participants to be Enrolled...................................................................10 
3.4 
Participant Enrollment Procedures ........................................................................11 
4.0 
RESEARCH METHODS ..................................................................................................... 12 
4.1 
Overview ................................................................................................................12 
4.2 
Study Plan ..............................................................................................................12 
4.3 
Genomics Methods ................................................................................................13 
5.0 
STATISTICAL CONSIDERATIONS ................................................................................. 16 
5.1 
Study Design/Endpoints.........................................................................................16 
5.2 
Sample Size/Accrual Rate ......................................................................................16 
6.0 
ROLE OF DATA MANAGEMENT .................................................................................... 17 
6.1 
Records to Be Kept ................................................................................................17 
6.2 
Source Documentation ...........................................................................................17 
6.3 
Role of Data Management .....................................................................................17 
6.4 
Clinical Site Monitoring and Record Availability .................................................17 
7.0 
ETHICAL AND REGULATORY CONSIDERATIONS .................................................. 18 
7.1 
Institutional Review Board (IRB) Review and Informed Consent ........................18 
7.2 
Changes to the Protocol .........................................................................................19 
7.3 
Participant Confidentiality .....................................................................................19 

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7.4 
Study Discontinuation ............................................................................................20 
7.5 
Women and Minorities ..........................................................................................20 
8.0 
PUBLICATION OF RESEARCH FINDINGS ................................................................... 21 
9.0 
REFERENCES ...................................................................................................................... 22 
APPENDIX I: AMC DATA AND SAFETY MONITORING PLAN ........................................... 23 
APPENDIX II: SPECIMEN PREPARATION AND SHIPPING INSTRUCTIONS .................. 27 
 
 

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PROTOCOL ROSTER 
AMC Protocol # S004 
Clinical and Genomic Factors for Prognosis of Primary Effusion Lymphoma 
Protocol Chair: 
Erin G. Reid, MD 
Moores UCSD Cancer Center 
Room 2238 
3855 Health Sciences Drive 
La Jolla, CA 92093-0987 
Tel: (858) 822-6271 
Fax: (858) 822-6288 
Email: egreid@ucsd.edu 
Protocol Statistician: 
Jeannette Y. Lee, PhD 
University of Arkansas for Medical Sciences 
4301 West Markham, #781 
Ed III, Room 3212 
Little Rock, Arkansas 72205 
Tel: (501) 526-6712 
Fax: (501) 526-6729 
Email: jylee@uams.edu 
Protocol Co-Chair: 
William Wachsman, MD, PhD 
VA San Diego Healthcare System 
Section of Hematology-Oncology (111E) 
3350 La Jolla Village Drive 
San Diego, CA 92161-0001 
Tel: 858-552-8585 
Fax: (858) 552-7416 
Email: wwachsman@ucsd.edu 
AMC Biorepository Director: 
Sylvia Silver, DA 
George Washington University Medical Center 
Ross Hall, Room 118 
2300 Eye Street, NW 
Washington, DC 20037 
Tel: (202) 994-2945 
Fax: (202) 994-5056 
Email: ssilver@gwu.edu 
AMC Lymphoma Working Group 
Chair: 
Richard F. Ambinder MD, PhD 
Johns Hopkins School of Medicine 
1650 Orleans Street 
CRB1, Room 389 
Baltimore, MD 21287 
Tel: 410-955-8839 
Fax 410-955-0960 
Email: ambinri@jhmi.edu  
 
Data Management/Operations: 
AMC Operations and Data Management Center 
The Emmes Company 
401 N. Washington Street, Suite 700 
Rockville, MD 20850 
Tel: (301) 251-1161 
Fax: (240) 238-2842 
Email: amcpm@emmes.com 

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PROTOCOL SYNOPSIS 
Title: 
Clinical and Genomic Factors for Prognosis of Primary Effusion 
Lymphoma 
Phase of Study: 
Retrospective case series 
Participating Institutions: 
This study will be open to participation at all AMC and member 
institutions 
Accrual Target: 
80 participants 
Population: 
Participants diagnosed with primary effusion lymphoma (HIV 
seropositive or negative) on or after January 1, 1998 and on 
whom survival status at 2 years post diagnosis is available. 
Duration: 
Record review and data collection will occur for up to 2 year after 
the protocol is activated for enrollment of eligible cases. 
Primary Objective: 
Objective 1 (Primary clinical objective): Identify baseline 
clinical characteristics and treatment strategies in patients with 
AIDS-associated primary effusion lymphoma (PEL) that 
correlate with long-term survival (≥ 2 years). 
Objective 2 (Primary genomic objective): Identify differentially 
expressed genes in PEL that are associated with long-term 
survival (≥ 2 years). 
 
 

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1.0 
OBJECTIVES 
1.1 
Hypothesis 
We hypothesize that there will be a sub-set of PEL clinical characteristics and differentially 
expressed genes in PEL cells that will be predictive of long-term survival (≥ 2 years), when 
data from long-term and short-term survivors of the disease are compared. 
1.2 
Primary Objectives 
1.1.1 Primary clinical objective: 
Identify baseline clinical characteristics and treatment strategies in patients with 
AIDS-associated primary effusion lymphoma (PEL) that correlate with long-term 
survival (≥ 2 years). 
1.1.2 Primary genomic objective: 
Identify differentially expressed genes in PEL that are associated with long-term 
survival (≥ 2 years). 

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2.0 
BACKGROUND 
2.1 
Study Disease 
Primary effusion lymphoma (PEL) is a rare type of non-Hodgkin lymphoma (NHL) that 
presents with predominately body cavity involvement and is nearly universally associated 
with Kaposi’s sarcoma herpesvirus (KSHV), with Epstein Barr virus (EBV) also present 
in a fraction of cases1. PEL is typically associated with a poor prognosis with a median 
survival of 6 months2. A solid variant has also been described and carries a similarly poor 
prognosis3. PEL typically arises in the context of HIV infection, where it accounts for 
approximately 2-3% of AIDS-NHL2. 
Data supporting optimal treatment strategies of PEL are limited given the rarity of the 
disease. There are rare reports of remissions in PEL occurring with the introduction of 
HAART therapy in HIV patients, who are not on highly active antiretroviral therapy 
(HAART) at the time of diagnosis. However, HAART is not sufficient for adequate 
treatment in the vast majority of AIDS-PEL cases. Therefore, combined chemotherapy 
regimens and other anti-viral treatments are now routinely used for AIDS-PEL treatment. 
In addition to classic CHOP-based chemotherapy, clinicians and investigators have 
employed one or more of the following: (a) infusional chemotherapy regimens (EPOCH); 
(b) methotrexate (after chemotherapeutic debulking or drainage of effusions); (c) VEGF 
inhibition, aggressive effusion drainage; (d) taken advantage of latent gamma herpes virus 
tumor infection using bortezomib as an inducer of lytic viral replication and an inhibitor of 
NF-kB4; and (e) cidofovir or valganciclovir as inhibitors of KSHV replication, with or 
without interferon5. Auto- and allo-geneic hematopoietic stem cell transplant is also 
reported in the salvage setting with variable success. Long-term AIDS-PEL survivors have 
been reported2, some of whom are being followed at UCSD as well as by collaborators at 
other institutions within the AMC. 
Most of the literature on AIDS-PEL is in the form of single or small case reports, with the 
largest series including 28 participants reported from a French cohort in 20052. This series 
explored baseline clinical factors associated with poor survival and identified ECOG 
performance status > 2 and lack of HAART use at time of diagnosis as independent 
predictors of shorter survival. A recent review of case in the literature identified the number 
of body cavity sites as predictive of survival6. 
An initial genomic evaluation of 9 PEL cases was published by Klein et al., in 2003 and 
reported PEL as having a distinct profile from other NHLs – including those from 
immunocompetent and HIV-seropositive hosts – with features of both immunoblasts and 
plasma cells7. Although distinct, AIDS-PEL had a profile most similar to EBV+ 
immunoblastic diffuse large B cell lymphoma. Despite the limited sample size, they were 
able to identify 51 genes differentially expressed between PEL cells and normal B cells as 
well as NHL, including AIDS-NHL. 
Past work on gene expression profiling of AIDS-PEL determined that it was quite different 
from other types of non-HIV and AIDS-related non-Hodgkin’s lymphoma7 and discerned 
sub-types of PEL that were primarily associated with the presence, or absence of either 
KSHV or EBV8. In the first study, 9 cases of fresh AIDS-PEL specimens, in the form of 
cell blocks prepared from cytospins of the PEL fluid, were expression profiled on the 
Affymetrix U95 GeneChip. Although distinct, AIDS-PEL had a profile most similar to 

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EBV+ immunoblastic diffuse large B cell lymphoma. Despite the limited sample size, they 
were able to identify 51 genes differentially expressed between PEL cells and normal B 
cells as well as NHL, including AIDS-NHL. In the second study, 3 cases of freshly obtained 
AIDS-PEL mononuclear cells were expression profiled on the Affymetrix U133 
GeneChip. In contrast, the intent of this project is to identify genes in PEL, whose 
expression is associated with long-term survival (≥ 2 years). 
Currently, little is known about factors of prognostic importance in PEL. We hypothesize 
that there will be a sub-set of PEL clinical characteristics and differentially expressed genes 
in PEL cells that will be of prognostic value for this disease, when data from long-term and 
short-term survivors of the disease are compared. 
2.2 
Study Design and Rationale 
This is a retrospective analysis to determine the baseline characteristics, treatment patterns 
and gene expression associated with of long-term survival in HIV-seropositive and 
negative patients with PEL diagnosed on or after January 1, 1998, a time period during 
which use of HAART has been widespread in the United States. Due to the rare nature of 
this disease, data supporting optimal treatment strategies are limited. The AMC is 
interested in studying this disease because of the disproportional prevalence among people 
with HIV infection. Information gathered from this retrospective study might serve to 
initiate future prospective studies in the AMC. 
In this study, patient, disease, and treatment information will be obtained from multiple 
centers within the AMC. Archived biopsy specimens of PEL will also be collected when 
available for genomics portion of the analysis. The AMC Operations and Data 
Management Center (AMC ODMC) will provide an electronic clinical research form 
(CRF) to all participating sites via the AMC AdvantageEDCSM Internet Data Entry System. 
Each participating AMC center will perform chart reviews after obtaining an Institutional 
Review Board (IRB) waiver or approval to conduct the study, as determined by the local 
IRB. All case data will be entered in AdvantageEDC in a de-identified manner, and 
protected health information (PHI) collected will be limited to information necessary to 
determine participant eligibility and to address the research questions. Data will be 
provided to Jeannette Lee, Ph.D., at the AMC Statistical Center at the University of 
Arkansas for Medical Sciences for statistical analysis via secure electronic transfer. The 
data set will only be accessible by the registered investigators, Dr. Reid and Dr. Wachsman, 
the statistician, Dr. Lee, and the AMC ODMC for the purposes of data monitoring and 
analysis. 

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3.0 
PARTICIPANT SELECTION 
Protocol participants must meet all stated eligibility criteria. A rostered AMC investigator 
must document that each protocol participant meets all stated eligibility criteria 
Participating sites must have documentation that each eligibility requirement is satisfied 
prior to participant enrollment. In compliance with CTEP policy, no exceptions to 
eligibility criteria will be granted in any circumstance. 
3.1 
Eligibility Criteria 
Patients diagnosed with primary effusion lymphoma (HIV seropositive or negative) on or 
after January 1, 1998 on whom survival status at 2 years post PEL diagnosis is available. 
Participants may be enrolled to either or both the clinical or genomic portions of the 
study. 
The minimum data required to be able to include a participant for analysis of clinical 
prognostic factors are: 
a. HIV status, and for HIV-positive participants, include CD4 count, HIV viral load 
within one year prior PEL diagnosis (or within 3 months after PEL diagnosis) 
b. Age at PEL diagnosis 
c. Gender 
d. Stage at PEL diagnosis 
e. Treatment of PEL 
f. Response to PEL treatment 
g. Survival status at 2 years post diagnosis 
h. Pathology slides (or paraffin block) for central review 
i. Year of PEL diagnosis 
The minimum data required to be able to include a participant for analysis of genomic 
prognostic factors are:  
a. Availability of a pathologic specimen of PEL that will be submitted for genomic 
analysis 
b. Survival status at 2 years post diagnosis 
3.2 
Exclusion Criteria 
Patients who do not fulfill the criteria as listed in Section 3.1 above are ineligible. 
3.3 
Number of Participants to be Enrolled 
A survey of investigators participating in the AMC consortium regarding the number of 
PEL patients seen at their site in the last 5 years reported 23 participants from 11 responding 
sites. By including the last 13 years (HAART era), it is reasonable to expect approximately 
80 participants especially considering new sites added to the AMC. 
3.3.1 Proposed Sample Size 

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The enrollment goal is 80 participants with a minimum of 20 participants in the 
genomics portion of the study. 
3.3.2 Accrual Rate 
An average of 4 participants per month anticipated. 
3.3.3 Replacement of Participants in the Genomics Portion of the Study 
A participant in the genomics portion of the study will be replaced if insufficient 
specimens are received (see Section 4.2.1.2 for required specimens), or if 
insufficient genetic material is retrieved (see Section 4.3.1). However, the 
participant may still participate in the clinical portion of the study if the eligibility 
criteria are met (see Section 3.1). 
3.4 
Participant Enrollment Procedures 
This is a retrospective review. Enrollment is expected to occur over a two-year period. The 
medical records of participants who meet the inclusion/exclusion criteria will be reviewed. 
For participants enrolled into the genomics portion of the study, archived pathologic 
specimens will be obtained. Sites must obtain approval from their Institutional Review 
Boards (IRB) to waive the requirement for informed consent for this study, or conduct 
informed consent if required by the local IRB,  and register with the AMC ODMC before 
enrolling participants. 
After the investigator at the site has determined that a patient case is eligible for inclusion 
in this retrospective analysis, the participant will be registered for the protocol on-line via 
the AMC AdvantageEDCSM Internet Data Entry System. After successful registration, the 
participant will be assigned a system-generated ten-digit participant ID. Once the eligibility 
checklist is submitted, a system-generated confirmation email will be sent to the enroller 
upon successful completion of participant enrollment. If the online system is inaccessible, 
the site should notify the AMC ODMC (via email at amcpm@emmes.com or via phone at 
301-251-1161) for further instructions. 
 
 

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4.0 
RESEARCH METHODS 
4.1 
Overview 
Once an eligible case is enrolled on the protocol, the Primary Effusion Lymphoma 
Retrospective Analysis Forms will be available for data entry in the disease-specific 
Participant Assessment Form will be available for entry. The case report form will collect 
information regarding the participant’s HIV/AIDS medical history, staging of AIDS 
related malignancy and type of treatment. Sites are to complete forms based on the 
participant’s cancer diagnosis. 
4.2 
Study Plan 
4.2.1 Data, Documents, Records, or Specimen Identification: 
4.2.1.1 The following data will be collected for participants enrolled into the 
clinical portion of the study: 
• HIV status, and for HIV-positive participants, include CD4 count, HIV 
viral load within one year prior PEL diagnosis (or within 3 months after 
PEL diagnosis) 
• Age at PEL diagnosis 
• Gender 
• Stage at PEL diagnosis 
• Treatment of PEL 
• Best response to PEL treatment 
• Survival status at 2 years post diagnosis 
• Pathology slides for central review (See Appendix II for specimen 
preparation and shipping)  
• Year of PEL diagnosis 
4.2.1.2 The following will be collected for participants enrolled into the genomics 
portion of the study: 
• Pathology slides for central review (if unavailable, paraffin block may 
be submitted) 
• Pathologic specimen that will be submitted for genomic analysis: 
o Frozen specimens, formalin-fixed and paraffin-embedded (FFPE) 
demonstrating PEL including cytospins as well as any mass/nodal 
biopsies are acceptable (See Appendix II for specimen preparation 
and shipping) 
• Survival status at 2 years post diagnosis 
4.2.1.3 The following is a list of additional data that is highly desirable for inclusion 
whenever available for participants enrolled in either the clinical and/or 
genomics portion of the study: 
• Race and ethnicity 
• For participants with HIV: HIV treatment history (which HAART drugs 
has participant received prior to PEL diagnosis, after PEL diagnosis), 
baseline HIV characteristics (i.e., CD4 count and HIV viral load closest 

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to time of PEL diagnosis, history of opportunistic infections) 
• Presence or history of other human herpesvirus-8 (HHV-8)-related 
diseases (i.e., Kaposi’s sarcoma, Multicentric Castleman’s Disease), 
and other malignancies) 
• Lymphoma baseline disease characteristics (immunophenotype, 
Epstein-Barr virus (EBV) and Kaposi sarcoma herpes virus (KSHV) 
status, sites of extranodal involvement), and either IPI or data required 
for calculation of International Prognostic Index (IPI) 
• Lymphoma treatment: type, number of treatment regimens, use of 
therapeutic effusion drainage 
• Best response to PEL treatment, best response duration 
• Survival status at time of enrollment and duration of survival in months 
from PEL diagnosis 
4.3 
Genomics Methods 
4.3.1 RNA Extraction and Quality Assessment 
The vast majority of specimens are in the form of archived blocks of cells prepared 
from cytospin of PEL fluid that are formalin-fixed and paraffin-embedded (FFPE). 
Each specimen will be centrally reviewed for morphology and immunophenotype 
to confirm the diagnosis of PEL and to ascertain the percentage of tumor cells in 
the tissue block. Only samples containing > 95% PEL cells will be further profiled. 
It should be noted that PEL effusions are typically quite homogeneous, such that 
all 9 of the specimens assessed by Klein et al. met this criteria7. Thus, we expect 
that nearly all of the FFPE PEL specimens received for this study should be able to 
move forward for expression profiling. Based on our experience and feedback from 
outside AMC investigators, we expect that 25-40% of the PEL samples will be from 
patients who are long-term survivors (20-32 of the 80 total PEL specimens). 
Total RNA will be extracted from FFPE PEL sections using a method that enables 
preparation of RNA for use in both microarray and RNA-Seq assay protocols (i.e., 
Prelude FFPE Isolation Module (NuGen Inc.)). Some 5 x 20 micron sections of the 
trimmed FFPE blocks will be extracted by column purification following 
deparaffinization and lysate preparation. RNA quantity will be measured by OD 
260/280/320 assay on a NanoDrop spectrophotometer. Although we anticipate the 
RNA to be variably degraded, we will still assess its quality by determining a RIN 
score following Bioanalyzer assay. This will permit us to determine whether a very 
poor RIN metric (i.e., < 7) was instrumental in the outcome of an expression assay 
and enable better comparison of the results. We will use enough of each PEL 
specimen to prepare approximately 400 ng of total RNA. The RNA will be stored 
at -80oC. 
4.3.2 RNA-Seq and Microarray Analysis of RNA 
4.3.2.1 RNA-Seq Analysis 
For RNA-Seq assays we will use Illumina’s TruSeq RNA Access Library 
Prep Kit to generate RNA libraries. This reagent kit, which focuses on 
transcriptome coding regions, can be performed with as little as 20ng of 

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degraded total RNA isolated from FFPE specimens. RNA libraries will be 
multiplexed and, following cluster generation, sequenced with 100 basepair 
(bp) single end (SE) reads to a depth of approximately 45 million reads per 
sample on an Illumina HiSeq2000 instrument. To mitigate assay noise we 
will perform RNA-Seq on each PEL RNA sample in triplicate, using an 
independently generated library for each RNA-Seq assay. Each sample will 
be barcoded and sequenced as part of a single pool with up to 30 samples 
loaded onto an 8-lane flow cell. 
The general approach to RNA-Seq data analyses is as follows: Multiplexed 
RNA-Seq data will be deconvoluted to separate each of the samples, after 
which, sequencing adapters and poly-A/T tails will be trimmed using 
cutadapt software. Sequencing reads of length less than 20 base pairs will 
be removed. Reads will be aligned to the human genome using STAR 
software. Aligned reads will be realigned using GATK’s IndelRealigner. 
Gene Expression: STAR genomic alignments will be filtered to remove any 
reads that align outside of Gencode exons. Remaining reads will be 
realigned to the Gencode transcriptome using bowtie2 and transcriptome 
alignments passed to eXpress for expression estimation. Gene expression 
will be calculated by summing the FPKM estimates for each of the gene’s 
transcripts. Genes with expression greater than zero FPKM will be 
considered expressed. All of the RNA-Seq data that pass these quality 
metrics will then be normalized and then subjected to supervised analysis 
to identify genes differentially expressed between PEL treatment 
responders vs non-responders. This supervised analysis will be performed 
by means of t-test with multi-testing correction (Westfall & Young 
Permutation method)11 (p < 0.05, FDR < 0.05). Based on past experience10, 
we expect that fewer than 500 genes will be found to be differentially 
expressed between treatment responders and non-responders. Lastly, we 
will take advantage of bioinformatic approaches to examine genes that are 
found to be differentially expressed between the sample groups. 
Bioinformatic 
software, 
such 
as 
Ingenuity 
Pathways 
(http://www.ingenuity.com), focus on the analysis of genetic networks and 
pathways and help place such genes, which may have prognostic 
significance, into biologic context. 
Following quantification and quality assessment of the RNA, RNA-Seq 
analyses, as described above will be performed on 20 PEL specimens, 10 of 
which are from long-term survivors and 10 from non-long-term survivors. 
The resulting data will be assessed for quality and adequacy: the total 
number of reads compatible with a transcript on the RNA-Seq assay. 
4.3.2.2 Microarray Analysis 
For microarray-based assays, we will follow an approach that we have 
successfully used in our past work10 with modifications to incorporate 
updates to the Affymetrix GeneChip technology. Total RNA (50-100 ng) 
will be amplified using the SensationPlus FFPE Amplification kit 
(Affymetrix, Inc.) with QC to assess the quantity and quality of the final 

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amplified product. We will use the Affymetrix GeneChip Human 
Transcriptome Array 2.0 for performing gene expression profiling of the 
PEL RNA. Following amplification of the RNA specimen, the sample will 
be hybridized, labeled with the WT Labeling Kit (Affymetrix, Inc.), 
washed, and scanned as per the Affymetrix protocol. Spike-in hybridization 
controls 
will 
facilitate 
data 
normalization 
between 
specimens. 
Normalization of array CEL files will be carried out using the gcrma 
software from the Bioconductor suite (http://www.bioconductor.org). The 
percent present calls and 3’/5’ ratio of GAPDH will be determined for each 
sample. Samples with less than 25% presents calls will be considered 
technical failures. This methodology is specifically meant for GeneChip 
assay of small amounts of partially degraded RNA from clinical samples. 
4.3.2.3 Analytic Strategy 
RNA-Seq assay of PEL is the preferred approach because it has a better 
linear dynamic range than does a GeneChip assay and may provide insights 
about PEL genomics that are not possible to be discerned by GeneChip-
based expression profiling (i.e., novel splice junctions and transcripts, viral 
RNAs, etc.). However, because of the high likelihood of very substantial 
RNA degradation in these FFPE samples, we are concerned about the 
potential for poor quality RNA-Seq data. RNA-Seq will be the primary 
method for genomic analysis of the PEL specimens, if it satisfies QC 
metrics for read number and data quality (i.e., 30 million pair-end reads of 
length > 30 nucleotides, of which 20-25 million may be mapped to the 
genome or known transcriptome; R2 (Pearson) correlation between 
technical replicates of the same sample of > 0.9). If the QC metrics are not 
met, GeneChip assay will be performed instead, as these should yield higher 
quality data. In summary, GeneChip assay is planned as a backup in the 
event that RNA-Seq QC is inadequate. 
 
 

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5.0 
STATISTICAL CONSIDERATIONS 
5.1 
Study Design/Endpoints 
5.1.1 Analysis/Statistics 
Survival will be estimated using the Kaplan Meier method and Cox proportional 
hazards model will be used to assess differences between treatment groups and 
categorical baseline variables. Response rates will be reported with 95% confidence 
intervals (binomial distribution). Descriptive statistics will be used to summarize 
baseline clinical, histological, and viral characteristics. 
We will perform either RNA-Seq or GeneChip assays, as described in Section 4.3, 
expression profiling on a total of up to 80 AIDS-PEL specimens. We are already 
aware of at least 10 long -term AIDS-PEL survivors within the AMC. Resultant 
data will be assessed for quality, normalized, and then analyzed for differential gene 
expression. We will use standard algorithms in both GeneSpring and Bioconductor 
for this purpose, with which we have considerable experience (see Preliminary 
Studies above). In particular, the RNA-Seq data will be analyzed by the DESeq 
algorithm in Bioconductor1. Lastly, we will take advantage of bioinformatic 
analysis approaches to help make sense of possible biological links between the 
genes found to be differentially expressed between the sample groups that may be 
of prognostic significance. These bioinformatic approaches, such as Ingenuity 
Pathways (http://www.ingenuity.com), focus on the analysis of genetic networks 
and pathways and help place genes identified as differentially expressed into 
biologic context. 
5.2 
Sample Size/Accrual Rate 
We expect to obtain clinical data and pathology specimens on 80 participants from sites 
throughout the AIDS Malignancy Consortium. It is estimated that 15-25% of these 
participants will be long-term survivors. 
 
 

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6.0 
ROLE OF DATA MANAGEMENT 
6.1 
Records to Be Kept 
CRFs will be provided for each participant via the AMC AdvantageEDCSM Internet Data 
Entry System upon enrollment. Participants must be identified by participant ID number 
only on all study documents. Data will be recorded on the CRFs using the unique 
participant identification number assigned at registration. Sample CRFs will be available 
on the AMC Operations Center web site (www.AIDSCancer.org). 
6.2 
Source Documentation 
Source documents are defined as the first place where data are recorded. For purposes of 
this study, medical records, chart notes that are signed and dated, and reports received from 
a local or central laboratory (e.g., Western blot, HIV-1 RNA) are considered source 
materials for this study. 
6.3 
Role of Data Management 
Instructions concerning the recording of study data on CRFs will be provided by the AMC 
Operations Center. The AMC Internet Data Entry System User’s Guide can be found on 
the AMC Operations Center web site (www.AIDSCancer.org). Each site is responsible for 
keying the data in and submitting the forms according to the target submission dates set 
forth by the AdvantageEDCSM system. 
It is the responsibility of the AMC Operations Center to assure the quality of computerized 
data for each AMC study (See Appendix I, AMC Data and Safety Monitoring Plan). This 
role extends from protocol development to generation of the final study databases. 
6.4 
Clinical Site Monitoring and Record Availability 
This protocol will follow the AMC Data and Safety Monitoring Plan (see Appendix I). 
This study will be monitored in compliance with AMC policies and by the Clinical Data 
Update System (CDUS) Version 3.0. Cumulative protocol- and participant-specific CDUS 
data will be submitted electronically to CTEP on a quarterly basis. Reports are due January 
31, April 30, July 31, and October 31. Instructions for submitting data using the CDUS can 
be found on the CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html). 
The AMC ODMC is responsible for compiling and submitting CDUS data to CTEP for all 
participants and for providing the data to the Principal Investigator for review. 
 
 

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7.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
7.1 
Institutional Review Board (IRB) Review and Informed Consent 
The principles of Institutional Review Board (IRB) approval and informed consent 
described in the Department of Health and Human Services (DHHS) regulations for the 
Protection of Human Subjects regulations (45 CFR Part 46) must be followed. IRB 
approval of the protocol must be given in writing. 
The sponsor’s designee (AMC ODMC) must receive a copy of the letter of approval from 
the IRB, which specifically approves the protocol, before participant enrollment. The IRBC 
must also approve any significant changes to the protocol and documentation of this 
approval must be sent to the AMC ODMC. The IRB must review the research project at 
least once every 365 days during the duration of the project. Continuing approval of the 
project must also be given in writing and provided to the AMC ODMC. 
Records of all study review and approval documents must be kept on file by the 
Investigator and are subject to inspection during or after completion of the study. AEs must 
be reported to the IRB according to local procedures. The IRB should receive notification 
of completion of the study and final report within 3 months of study completion and 
termination. The Investigator will maintain an accurate and complete record of all 
submissions made to the IRB, including a list of all reports and documents submitted. 
A request to waive the requirement to obtain informed consent is being requested for this 
retrospective chart data collection and analysis. A model informed consent document is 
available if the IRB at a participating site denies waiver of consent. The investigator 
believes this study meets the following requirements for this request per 46 CFR 46.117(c): 
• The research involves no more than minimal risk to the participants. The only risk is 
the loss of patient confidentiality, which will be minimized as described in the 
confidentiality section (Section 7.3). 
• The waiver or alteration will not adversely affect the rights and welfare of the 
participants. There will be no contact with the participants and no documentation of 
this study in their medical records. 
• The research could not practicably be carried out without the waiver or alteration. As 
described above, this disease is very rare, and patients with retrospective cases of PEL 
may be deceased or unavailable to contact for consent; therefore, it would not be 
practical to recruit prospectively. 
• The project could not practicably be conducted without the use of PHI. PHI collected 
will be limited to dates, such as the year of diagnosis, treatment, response, and 
diagnosis. Collection of select dates is necessary to obtain data elements that are 
required to determine participant eligibility and are important to the question being 
studied. The AMC also requires collection of demographic data (participant initials, 
birth date, and zip code) in standard forms for the purpose of required demographic 
reporting to the NCI. 
• An adequate plan to protect identifiers from improper use and disclosure is included in 
the research proposal. Only authorized study personnel have access to this information 
in AdvantageEDC, which is secured from unauthorized access with login/password 
controls. Participant initials are encrypted in the AdvantageEDC data entry system 

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and in the study database, and can only be viewed in AdvantageEDC by the clinical 
site staff. 
• An adequate plan to destroy the identifiers at the earliest opportunity, or justification 
for retaining identifiers, is included in the research proposal. The PHI collected is a 
component of standard AMC data entry forms for compliance with NCI demographic 
reporting requirements, and is also required for data analysis. Protections for this 
information will be applied as stated above. 
• The project plan includes written assurances that PHI will not be reused or disclosed 
for other purposes. Data access will be restricted to the parties listed in Section 7.3, 
and will not be reused or disclosed for any other purpose. No PHI, including dates, 
will be included in any study publications. 
• The AMC routinely provides study summaries for participants on its website. 
A waiver of HIPAA Authorization is being requested for this study. As described above, 
the use or disclosure of PHI involves no more than minimal risk; granting of the waiver 
will not adversely affect privacy rights or the welfare of the individuals whose records will 
be used; the project could not practicably be conducted without a waiver; and the project 
could not practicably be conducted without use of PHI. Further, the privacy risks are 
reasonable relative to the anticipated benefits of research, as the importance of the 
knowledge that may reasonably be expected to result outweighs the minimal risk posed to 
participants. PHI will not be re-used or disclosed for other purposes and, whenever 
appropriate, the participants will be provided with additional pertinent information after 
participation. In accordance with Good Clinical Practice and the retention of records under 
45 CFR 46.115, study records will not be destroyed until at least three years after the 
completion of the research. Only de-identified data will be retained. 
In addition, any institution(s) conducting research according to the guidelines of this 
protocol is required to adhere to local and state laws and regulations governing the 
confidentiality and disclosure of health information. 
7.2 
Changes to the Protocol 
Any change or addition to this protocol requires a written protocol amendment that must 
be approved by the Protocol Chair before implementation. All protocol amendments 
require approval by the IRB of each participating institution. A copy of the written approval 
of the IRB must be provided to the AMC ODMC. 
7.3 
Participant Confidentiality 
Confidentiality of a participant’s protected health information will be maintained by the 
following methods. Each participant will be assigned a separate study number that will be 
used as the main form of identification. The participant identification number will be linked 
to the medical record number in the participating site’s study records, but this information 
will be known only to the primary investigators at each site. Thus, there will be no direct 
link between confidential medical information, the medical record number, or the 
participant identification number in AdvantageEDC. Data submitted by AMC sites will be 
identified only by the study number and not by the participant’s name or medical record 
number. The information will be stored in a password-protected database for data analysis. 
The data set will provided to the AMC Statistical Center at UAMS for data analysis via 
secure electronic transfer and will only be accessible by the registered investigator, Dr. 

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Erin Reid, the AMC Biostatistician, Dr. Jeannette Lee, and the AMC ODMC, as necessary 
for data monitoring and analysis. 
Furthermore, study-specific records containing PHI, and copies of study-related medical 
records, will be maintained in compliance with existing local standards for data security 
and confidentiality to prevent unauthorized access to confidential patient information. In 
accordance with the AMC’s Certificate of Confidentiality, clinical information will not be 
released without the written permission of the participant, except as necessary for 
monitoring by the AMC ODMC, the IRB, the NCI, the OHRP, or designee. 
7.4 
Study Discontinuation 
The study may be discontinued at any time by the IRB, the NCI, the OHRP, or other 
government agencies as part of their duties to ensure that research participants are 
protected. 
7.5 
Women and Minorities 
This study is being conducted by the NCI-sponsored AIDS Malignancy Consortium 
(AMC). As part of their contractual obligations, each participating site within the AMC 
and the AMC as a whole is required to assure that the participation of women and minority 
participants reflects the percentage representation of these populations in their geographic 
region and, for the AMC, the United States as a whole. As such, it is expected that the 
representation of participants on this trial will reflect the constitution of the respective 
populations. 
Accrual Targets 
 
 
 
 
 
 
 
 
 
 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
2 
+ 
4 
= 
6 
Not Hispanic or Latino 
4 
+ 
70 
= 
74 
Ethnic Category: Total of all participants 
6 
+ 
74 
= 
80 
Racial Category 
 
American Indian or Alaskan Native 
1 
+ 
1 
= 
2 
Asian 
1 
+ 
2 
= 
3 
Black or African American 
1 
+ 
34 
= 
35 
Native Hawaiian or other Pacific 
Islander 
1 
+ 
1 
= 
2 
White 
2 
+ 
36 
= 
38 
Racial Category: Total of all participants 
6 
+ 
74 
= 
80 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 

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8.0 
PUBLICATION OF RESEARCH FINDINGS 
Publication of the results of this trial will be governed by the AMC’s Standard Operating 
Procedures for Publication Policy. 
 

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9.0 
REFERENCES 
1. Nador RG, Cesarman E, Chadburn A, Dawson DB, Ansari MQ, Sald J, Knowles DM. Primary 
effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's 
sarcoma-associated herpes virus. Blood. 1996 Jul 15; 88 (2): 645-56. 
2. Boulanger, Emmanuelle, Gerard, Laurence, Gabarre, Jean, Molina, Jean-Michel, Rapp, 
Christophe, Abino, Jean-Francois, Cadranel, Jacques, Chevret, Sylvie, Oksenhendler, Eric. 
Prognostic Factors and Outcome of Human Herpesvirus 8 Associated Primary Effusion 
Lymphoma in Patients With AIDS. J Clin Oncol 2005 23: 4372-4380. 
3. Carbone A, Gloghini A, Vaccher E, Cerri M, Gaidano G, Dalla-Favera R, Tirelli U. Kaposi's 
sarcoma-associated herpesvirus/human herpesvirus type 8-positive solid lymphomas: a 
tissue-based variant of primary effusion lymphoma. J Mol Diagn. 2005 Feb; 7 (1): 17-27. 
4. Reid EG. Bortezomib-induced Epstein-Barr virus and Kaposi sarcoma herpes virus lytic gene 
expression: oncolytic strategies. Curr Opin Oncol. 2011 Sep; 23 (5): 482-7. 
5. Sunil M, Reid E, Lechowicz M. Update on HHV-8 associated malignancies. Curr Infect Dis 
Rep. 2010 March; 12 (2): 147–154. 
6. Castillo JJ, Shum H, Lahijani M, Winer ES, Butera JN. Prognosis in primary effusion 
lymphoma is associated with the number of body cavities involved. Leuk Lymphoma. 2012 
Jun 13. 
7. Klein U, Gloghini A, Gaidano G, Chadburn A, Cesarman E, Dalla-Favera R, Carbone A. Gene 
expression profile analysis of AIDS-related primary effusion lymphoma (PEL) suggests a 
plasmablastic derivation and identifies PEL-specific transcripts. Blood. 2003 May 15; 101 
(10): 4115-21. 
8. Fan W, Budman D, Chadburn A, Harrington W J, Cesarman E, Knowles D. Distinct Subsets 
of Primary Effusion Lymphoma Can Be Identified Based on Their Cellular Gene 
Expression Profile and Viral Association. J Virol. 2005 Jan; 79 (2): 1244-1251. 
9. Jenner RG, Maillard K, Cattini N, Weiss RA, Boshoff C, Wooster R, Kellam P. Kaposi's 
sarcoma-associated herpesvirus-infected primary effusion lymphoma has a plasma cell 
gene expression profile. Proc Natl Acad Sci U S A. 2003 Sep 2; 100 (18):10399-404. Epub 
2003 Aug 18. 
10. Wachsman W, Morhenn V, Palmer T, Walls L, Hata T, Zalla J, Scheinberg R, Sofen H, Mraz 
S, Gross K, Rabinovitz H, Polsky D, Chang S. Noninvasive genomic detection of 
melanoma. Br J Dermatol. 2011 Apr; 164 (4): 797-806. 
11. Westfall PH, Young SS. Resampling-Based Multiple Testing: Examples and Methods for P-
value Adjustment. New York: Wiley 1993. 
 

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APPENDIX I: AMC DATA AND SAFETY MONITORING PLAN 
Version 6.0  March 17, 2017 
 
Monitoring the Progress of Trials and the Safety of Participants 
All AMC protocols that collect safety data follow the National Cancer Institute (NCI), Cancer 
Therapy Evaluation Program (CTEP) Guidelines: Adverse Event Reporting Requirements 
(http://ctep.cancer.gov/guidelines/index.html). All adverse events that meet the NCI’s expedited 
reporting requirements are reported to the Investigational Drug Branch (IDB) of the NCI via the 
CTEP Adverse Event Reporting System (CTEP-AERS) web application. All expedited adverse 
event reports are also required to be submitted to the local Institutional Review Board (IRB) of the 
reporting institution. If NCI holds the IND or no IND is required for a study, the AMC site reports 
serious adverse events directly to the AMC Operations and Data Management Center (ODMC) via 
CTEP-AERS; expedited reporting via AdvantageEDC/Advantage eClinical may be permitted for 
select commercial agent studies per protocol requirements. In some instances, the AMC sites may 
report serious adverse events directly to a commercial sponsor holding the IND, who will then 
report the event to the AMC ODMC. Most AMC protocols require sites to report all serious 
adverse events via CTEP-AERS and the AMC ODMC to forward a copy of the report to the 
sponsor. The AMC ODMC also distributes all IND safety reports to all investigators upon receipt, 
and makes these reports available on the password-protected section of the AMC Operations web 
site. Unless an AMC protocol specifies an alternate plan for the review and submission of serious 
adverse events, all serious adverse events received by the AMC ODMC will be reviewed by the 
AMC Medical Monitor at the AMC ODMC. For protocols for which the IDB does not have an 
assigned drug monitor to review serious adverse event reports, in the event of disagreement 
between the reporting physician and the AMC Medical Monitor regarding the attribution of the 
event to the investigational agent(s) (i.e., determination of whether the relationship is unrelated, 
unlikely, possible, probable, or definite), the AMC Medical Monitor will provide the final 
determination of the relationship. 
The AMC ODMC provides listings of all reported adverse events and serious adverse events to 
the Protocol Chair and Co-chair(s) for review on a regular basis. The AMC ODMC compiles these 
events in a tabular format and posts them on the password-protected section of the AMC web site 
where these reports are updated nightly. The AMC web site is accessible to all AMC investigators, 
co-investigators, and their staff. Email notification that this information is available on the web 
site will be sent to all site PIs. It is the responsibility of each site to provide this information to 
their respective IRBs, if required by their IRB. For blinded studies, the serious adverse events are 
reviewed and tabulated without treatment assignment. The AMC Medical Monitor will review 
listings of all reported adverse events on a quarterly basis for safety concerns. 
Accrual summaries for each AMC trial are updated nightly on the password-protected section of 
the AMC web site. The progress of each AMC trial is reviewed regularly by the Protocol Chair 
and also by the appropriate disease-oriented Working Group during scheduled conference calls. 
For pilot or phase I dose escalation trials, dose escalation (or dose de-escalation) is based on the 
rules in the protocol and the Protocol Chair, AMC Medical Monitor, and Group Statistician 
determine whether these criteria have been met. For phase II trials, stopping the trial for toxicity 
or efficacy, or suspending enrollment pending observation of responses in a multi-stage phase II 

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trial, is based on meeting criteria stated in the protocol, and the Protocol Chair, AMC Medical 
Monitor, and Group Statistician determine whether these criteria have been met. 
For phase III trials and other select studies requiring additional oversight, the AMC has formed an 
independent Data and Safety Monitoring Board (DSMB). Voting members of the DSMB are 
physicians, a statistician, and a patient advocate. All voting members are from outside the AMC. 
Nonvoting members are the AMC Group Statistician, the protocol statistician, an AMC Operations 
Center staff member, two representatives (normally a clinician or statistician) from the Office of 
HIV AIDS Malignancy (OHAM) or from the Cancer Therapy Evaluation Program, Division of 
Cancer Treatment and Diagnosis, of the National Cancer Institute (NCI). The DSMB reviews 
AMC phase III studies in accordance with the National Cancer Institute’s Policy for Data and 
Safety Monitoring. Confidential reports of all phase III trials are prepared by the AMC Group 
Statistician with support from the AMC ODMC. A written report containing the current status of 
each trial monitored, and when appropriate, any toxicity and outcome data, are sent to DSMB 
members by the AMC ODMC within the timelines specified by the DSMB Charter. This report 
addresses specific toxicity concerns as well as concerns about the conduct of the trial. The report 
may contain recommendations for consideration by the DSMB concerning whether to close the 
trial, report the results, or continue accrual or follow-up. 
The results of each DSMB meeting are summarized in a formal report sent by the DSMB Chair to 
the Group Chair and AMC ODMC. The DSMB report contains recommendations on whether to 
close each study reviewed, whether to report the results, and whether to continue accrual or follow-
up. A primary recommendation (e.g., continue with no change; recommended or required 
modification; stop) must be included in the document. The Group Chair is then responsible for 
notifying the Protocol Chair and relevant Disease-oriented Working Group Chair before the 
recommendations of the DSMB are carried out. In the unlikely event that the Protocol Chair does 
not concur with the DSMB, then the NCI Division Director or designee must be informed of the 
reason for the disagreement. The Study Chair, relevant Disease-oriented Working Group Chair, 
Group Chair, DSMB Chair, and NCI Division Director or designee will be responsible for reaching 
a mutually acceptable decision about the study. CTEP approval of a formal amendment will be 
required prior to any implementation of a change to the study. 
Following a DSMB meeting, a summary of the serious adverse events reported to the DSMB is 
posted to the AMC web site. It is each site’s responsibility for conveying this information to its 
IRB. 
Plans for Assuring Compliance with Requirements Regarding the Reporting of Adverse 
Events (AE) 
For trials monitored by the NCI’s Clinical Data Update System (CDUS), adverse event 
information is transmitted electronically to NCI on a quarterly basis. For trials monitored by NCI’s 
Clinical Trials Monitoring Service (CTMS), adverse event information is transmitted 
electronically to NCI every two weeks. 
The Protocol Chair, AMC Group Chair, and the AMC ODMC share responsibility in assuring that 
participating investigators comply with the protocol requirements for adverse event reporting. All 
AMC investigators certify compliance with NCI and FDA requirements for adverse event 
reporting by signing the AMC Adherence Statement for site membership, the protocol signature 
page for each protocol active at the site, and Form FDA-1572 for CTEP investigator registration 
and IND studies sponsored by AMC investigators. Investigators are responsible for identifying 

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and reporting all adverse events to the AMC ODMC, CTEP-AERS, and/or sponsors according to 
the protocol requirements, and assuring compliance with reporting to the local IRB. Protocol 
compliance with adverse event reporting requirements is assessed by the AMC ODMC during 
routine site audits by reviewing the site’s source documentation.  
The data entry system used for AMC studies, AdvantageEDC/Advantage eClinical (a web-based 
data entry and enrollment system), is programmed to notify the site investigator, protocol chair, 
AMC Medical Monitor, and AMC ODMC via email in the event that a site reports an adverse 
event that meets expedited reporting criteria to NCI and/or FDA. If the site does not follow with 
an expedited report, the AMC ODMC contacts sites to request compliance with reporting 
requirements. Additionally, the protocol chair, AMC ODMC, and the AMC Medical Monitor 
review reported adverse events on a routine basis to identify adverse events reported by sites that 
require expedited reporting. The Protocol Chair, AMC Group Chair, and IND sponsors have 
general oversight for assuring that routine and expedited adverse reporting requirements are met 
by the responsible parties. 
Plans for Assuring that any Action Resulting in a Temporary or Permanent Suspension of 
an NCI-Funded Clinical Trial is Reported to the NCI Grant Program Director Responsible 
for the Grant 
In the event that termination of the trial or major modification to the protocol is under 
consideration, the Protocol Chair will convene the AMC Data Coordinator and Disease-oriented 
Working Group Chair by conference call to discuss the options. For phase I and II trials, the 
Protocol Chair also has the option of asking the DSMB to review the study. The AMC ODMC will 
inform the CTEP Protocol Information Office (PIO) when studies are temporarily or permanently 
closed. The Cancer Treatment and Evaluation Program (CTEP) of the National Cancer Institute 
(NCI) must approve all protocol amendments prior to distributing to the AMC sites. 
Plans for Assuring Data Accuracy and Protocol Compliance 
All study data for AMC clinical trials are entered directly by AMC clinical site staff into 
AdvantageEDC/Advantage eClinical. During data entry, the system performs validation checks on 
many fields and performs consistency checks between select fields. Range checks are placed on 
each field to eliminate entry of out-of-range values. Edit check programs are run on the database 
on a set schedule to identify and resolve inconsistencies between forms or data collected at 
different points in time. AMC ODMC staff routinely interacts with site staff to resolve any data 
problems. 
In accordance with NCI guidelines, the AMC ODMC conducts audits at the AMC sites to evaluate 
compliance with regulatory issues, and to review data for specific cases by checking source 
documents. These reports are sent to the site Principal Investigator and to the NCI. In the event 
that major violations are identified, sites are asked to provide a written corrective and preventive 
action plan to correct deficiencies. If needed, a repeat site audit is conducted. In the event that a 
site does not correct deficiencies in a pre-determined time frame, the AMC Executive Committee 
has the option of taking action against the site. Possible actions include, but are not limited to, 
suspending enrollment of new patients to AMC trials until deficiencies are corrected; 
recommending a decrease in funding to the site; and requiring specific training for site 
investigators or staff members. 
 

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APPENDIX II: SPECIMEN PREPARATION AND SHIPPING INSTRUCTIONS 
BACKGROUND AND PROCEDURES 
The following specimens are required for participation in the genomics portion of the study: 
• Paraffin embedded tissue or cytology block or frozen tissue specimen (latter preferred if 
available). 
• Pathology slides and a pathology report for central pathology review. If slides are not available, 
the site must provide a paraffin block for review, which if adequate, will also be used for 
genomic studies. The participant can be included in the clinical portion of the trial if the 
material submitted is only sufficient for pathology review. 
• If neither slides nor adequate paraffin block is available, the participant will be considered 
ineligible. 
For participants in the clinical portion, pathology slides and a pathology report are required for 
central pathology review. 
Slides and/or tissue blocks will be returned to the site once all studies are complete. 
Details regarding specimen shipment are provided in the protocol Manual of Procedures. 
Technical questions regarding tissue specimens should be directed to Dr. Wachsman (see 
Protocol Roster). 
The AMC Biorepository will ship pathology slides and tissue specimens to UCSD and Cornell 
for central pathology review. Specimens for genomic analysis will be sent to UCSD.