Conditions: Hepatosplenic T-Cell Lymphoma
Keywords: Lymphoma, T-Cell, Peripheral, Infliximab, Golimumab, Remicade, Simponi, Ulcerative Colitis, Crohn's Disease, Inflammatory Bowel Disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
This study is designed to collect tissue samples from the biopsy specimen that was used to diagnose hepatosplenic T-cell lymphoma (HSTCL), additional patient information, and if possible, to obtain additional samples including a single blood sample, a buccal swab sample and/or a bowel tissue sample. Samples obtained will be stored by the sponsor for future testing. In addition, demographic and clinical patient information will be collected. The study will be conducted in North America. Patients eligible for enrollment include males or females with IBD of any age who have a confirmed diagnosis of HSTCL. Patients will be identified through the sponsor's adverse event reporting systems. Cases reported to the sponsor's Medical Information Center will be queried to ascertain if the reporter is interested in participating in the study. Where appropriate, cases may also be identified through the sponsor's new or on-going clinical trials and registries. Samples may be collected from living patients or from stored tissue of deceased patients. This study will not restrict or introduce any therapeutic interventions, including medications. All patients will continue to be managed by their personal physicians. No healthy subjects will be enrolled in this study.

Detailed description:

Arms:
arm 1: Subjects with Inflammatory Bowel Disease with a diagnosis of Hepatosplenic T-cell lymphoma

Interventions: intervention 1: Infliximab intervention 2: Golimumab
Intervention descriptions: intervention 1: This study will not restrict or introduce any therapeutic interventions, including medications. Participants may continue to receive infliximab as instructed by their personal physicians. intervention 2: This study will not restrict or introduce any therapeutic interventions, including medications. Participants may continue to receive golimumab as instructed by their personal physicians.

Protocol document:
Prot_000.pdf: 
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CONFIDENTIAL
Janssen Research & Development *
Clinical Protocol
A Research Study to Bank Samples for Future Evaluation to Identify Biomarkers that 
Predispose Patients with Crohn’s Disease and Ulcerative Colitis to Develop 
Hepatosplenic T-Cell Lymphoma (HSTCL)
Protocol REMICADELYM4001; Phase 4
Amendment 3
REMICADE® (infliximab)
SIMPONI® (golimumab)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Scientific Affairs, LLC.; Janssen Biotech, Inc.; 
Janssen Products, LP; Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc.; Janssen 
Infectious Diseases BVBA; Janssen R&D Ireland; or Janssen Research & Development, LLC. The term 
“sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is 
identified on the Contact Information page that accompanies the protocol.  
Issue/Report Date:
Current, Amendment 3:
11 Aug 2017
Amendment 2:
17 Feb 2014
Amendment 1:  
26 March 2013
Original Protocol:  
25 June 2012
Prepared by:  
Janssen Scientific Affairs, LLC.
Document No.:  
EDMS-ERI-45190952
Compliance: This study will be conducted in compliance with this protocol, Good Clinical Practice, and applicable regulatory 
requirements.
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged
or confidential.
NCT01804166


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES.......................................................................................................................... 3
SYNOPSIS.................................................................................................................................................... 4
ABBREVIATIONS ........................................................................................................................................ 7
1.
INTRODUCTION.................................................................................................................................. 8
1.1.
Purpose............................................................................................................................................ 8
1.2.
Hepatosplenic T-cell Lymphoma...................................................................................................... 8
1.3.
Overall Rationale for the Study........................................................................................................ 9
2.
OBJECTIVE, ENDPOINTS, AND HYPOTHESIS ............................................................................. 10
3.
STUDY DESIGN ................................................................................................................................ 10
4.
PATIENT SELECTION...................................................................................................................... 12
4.1.
Inclusion Criteria ............................................................................................................................ 12
4.2.
Exclusion Criteria ........................................................................................................................... 12
5.
STUDY EVALUATIONS/PROCEDURES ......................................................................................... 13
5.1.
Sample Collection .......................................................................................................................... 13
5.1.1.
Tumor Biopsy Tissue Sample..................................................................................................... 13
5.1.2.
Additional Samples..................................................................................................................... 13
5.1.2.1.
Blood and/or Buccal Swab Samples ....................................................................................... 13
5.1.2.2.
Bowel Tissue Sample.............................................................................................................. 14
5.1.3.
Sample Collection and Handling ................................................................................................ 14
5.2.
Additional Patient Information ........................................................................................................ 14
5.3.
Scientific Advisory Committee ....................................................................................................... 15
5.4.
Withdrawal from the Study............................................................................................................. 16
6.
TEST METHODS AND DATA ANALYSIS........................................................................................ 16
7.
ADVERSE EVENT REPORTING ...................................................................................................... 16
7.1.
Definitions ...................................................................................................................................... 17
7.2.
Reporting and Follow-up of Serious Adverse Events .................................................................... 18
7.3.
Contacting Sponsor Regarding Safety........................................................................................... 18
8.
ETHICAL ASPECTS ......................................................................................................................... 18
8.1.
Regulatory Ethics Compliance....................................................................................................... 18
8.1.1.
Independent Ethics Committee or Institutional Review Board ................................................... 18
8.1.2.
Informed Consent ....................................................................................................................... 20
8.1.3.
Privacy of Personal Data ............................................................................................................ 21
8.1.4.
Long-Term Storage of Samples for Future Research ................................................................ 21
9.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 22
9.1.
Protocol Amendments.................................................................................................................... 22
9.2.
Regulatory Documentation ............................................................................................................ 22
9.2.1.
Regulatory Approval/Notification ................................................................................................ 22
9.2.2.
Required Prestudy Documentation............................................................................................. 22
9.3.
Source Documentation................................................................................................................... 23
9.4.
Case Report Form Completion ...................................................................................................... 23
9.5.
Data Quality Assurance/Quality Control ........................................................................................ 24
9.6.
Record Retention ........................................................................................................................... 24
9.7.
Use of Information and Publication................................................................................................ 25


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REFERENCES............................................................................................................................................ 26
ATTACHMENT 1
PROTOCOL HISTORY .............................................................................................. 28
AMENDMENT 3 – 02 AUGUST 2017 ........................................................................................................ 29
AMENDMENT 2 – 17 FEBRUARY 2014.................................................................................................... 44
AMENDMENT 1 – 26 MARCH 2013 .......................................................................................................... 51
INVESTIGATOR AGREEMENT ................................................................................................................. 57
LIST OF IN-TEXT TABLES 
TABLES
Table 1:  
Blood sample and volume collected ......................................................................................... 14


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SYNOPSIS
TITLE
A Research Study to Bank Samples for Future Evaluation to Identify Biomarkers that Predispose Patients 
with Crohn’s Disease and Ulcerative Colitis to Develop Hepatosplenic T-Cell Lymphoma (HSTCL)
PURPOSE
This study is being conducted to address 2 postmarketing requirements by the United States (US) Food 
and Drug Administration (FDA) to bank HSTCL tumor tissue as well as blood, buccal swab, and/or other 
tissue samples for future evaluation to identify genetic mutations and other biomarkers that may 
predispose inflammatory bowel disease (IBD) patients to develop hepatosplenic T-cell lymphoma 
(HSTCL). No medical or scientific benefit will be provided to patients who participate in the study; 
however, future patients at risk for developing HSTCL may benefit from the results of this research. 
OBJECTIVE, ENDPOINTS, AND HYPOTHESIS
The objective of this study is to collect samples from IBD patients diagnosed with HSTCL to identify 
biomarkers that may allow earlier evaluation of a patient’s risk of developing HSTCL.
There are no formal endpoints or hypothesis for this study.
OVERVIEW OF STUDY DESIGN
This study is designed to collect tissue samples from the biopsy specimen used to diagnose HSTCL in 
patients with IBD. Additional patient information, and if possible, additional blood, buccal swab, and/or 
tissue samples will be collected as described below in Evaluations. This study will be conducted in North 
America and the planned duration is 8 years. This study will not restrict or introduce any therapeutic 
interventions, including medications. All patients will continue to be managed
by their 
personal physicians.
PATIENT SELECTION
Patients eligible for enrollment include males or females with IBD of any age who have a confirmed 
diagnosis of HSTCL. No healthy subjects will be enrolled in this study.
Patients will be identified through the sponsor’s adverse event reporting systems. Cases reported to the 
sponsor’s Medical Information Center will be queried to ascertain if the reporter is interested in 
participating in the study. Where appropriate, cases may also be identified through the sponsor’s new or 
on-going clinical trials and registries. Samples may be collected from living patients or from stored tissue 
of deceased patients. 
EVALUATIONS
After obtaining informed consent as described in Section 8.1.2 in the body of the protocol, physicians of 
participating patients will be asked to provide the following: 

Sample(s) of the biopsy specimen used to confirm the diagnosis of HSTCL (tumor tissue and 
adjacent healthy tissue if possible)


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
Additional samples, if possible, including the following:
-
A single blood and/or a buccal swab sample (for genomic DNA analysis), and/or
-
A bowel tissue sample previously collected as part of the patient’s IBD diagnosis or treatment
(if available, for mutation analysis between the tumor and T cells residing in the bowel to 
attempt to determine the origin of the tumor clone). 
In addition, the following information will be collected:

HSTCL diagnosis and related information

Demographic data

Diseases and medical/surgical conditions prior to or at the time of diagnosis

Medical history including family history of cancer, if available

Cytogenetic and flow cytometric data, if available
Samples collected will be banked for future testing by the sponsor or its delegate. Potential test methods 
include, but are not limited to, the following: 

Deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) sequencing

Messenger ribonucleic acid (mRNA) gene expression

Protein expression or functional tests on cells isolated from peripheral blood 
STATISTICAL METHODS
A Scientific Advisory Committee has been established for this study that includes an independent panel 
of experts who will review the emerging science related to HSTCL and latest available test methods and 
make recommendations to the sponsor. When the types of analyses to be performed on the tissue samples 
collected have been determined by the sponsor in consultation with the Scientific Advisory Committee,
the sample analysis plan will be developed.  
Descriptive statistics of demographic information, information on medical/surgical (including treatment) 
history, and baseline characteristics at the time of HSTCL diagnosis will be summarized for all patients
enrolled in this study. Protein assay data will be summarized when available, using descriptive statistics. 
Gene expression in tumor cells may be compared with expression levels observed in cells isolated from 
whole blood with moderated t-statistics or other appropriate statistical methods.
Full genome or targeted sequencing may also be used to reveal patterns of mutations responsible for 
development of HSTCL. Somatic mutations will be identified by comparing HSTCL tumor DNA with
DNA from the same patient from the following:


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
The normal adjacent tissue from the same biopsy specimen, or 

The bowel tissue sample, or

Cells isolated from the buccal swab, or 

Peripheral blood mononuclear cells.
Individual mutations will be tabulated within and between patients and cross-referenced with human 
variation databases (eg, COSMIC, dbSNP, etc.). To identify cancer driver genes or pathways, somatic 
mutation frequencies will be evaluated per gene or pathway across all patients with HSTCL and 
compared with empirical background mutation frequencies by mutation type (Wendl, 2011; Youn, 2011).


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ABBREVIATIONS
CRF
case report form (paper)
DCFs
Data Correction/Clarification Forms
DNA
deoxyribonucleic acid
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
HSTCL
hepatosplenic T-cell lymphoma
HPRT
hypoxanthine-guanine phosphoribosyltransferase
IBD
inflammatory bowel disease
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
mRNA
messenger ribonucleic acid
RNA
ribonucleic acid
US
United States
TNF
tumor necrosis factor
USP
United States Pharmacopeia


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1.
INTRODUCTION
1.1.
Purpose
The United States (US) Food and Drug Administration (FDA) has requested that the sponsor
conduct a postmarketing study to collect samples from inflammatory bowel disease patients 
(IBD) treated with Remicade® (infliximab) and/or Simponi® (golimumab) to learn more about 
hepatosplenic T-cell lymphoma (HSTCL). Specifically, samples will be collected to identify
genetic mutations and other biomarkers that may allow earlier evaluation of a patient’s risk of 
developing HSTCL. Samples to be requested from each patient include the biopsy used to 
diagnose HSTCL, and if possible, additional samples including a single blood sample, buccal 
swab sample, and/or a bowel tissue sample previously collected as part of the patient’s IBD 
diagnosis or treatment. In addition, patient information will be collected including, but not 
limited to, patient demographics and medical history. Samples will be stored by the sponsor or 
its delegate for future testing. The study will be conducted in North America and the planned 
duration of the study is 8 years. 
A Scientific Advisory Committee has been established for this study and includes an 
independent panel of experts who will review the emerging science related to HSTCL and latest 
available test methods and make recommendations to the sponsor (see Section 5.3, Scientific 
Advisory Committee). When the types of analyses to be performed on the tissue samples 
collected have been determined by the sponsor in consultation with the Scientific Advisory 
Committee, the sample analysis plan will be developed. The test methods that may be used 
include deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) sequencing, messenger 
ribonucleic acid (mRNA) gene expression, protein expression, or functional tests on cells 
isolated from peripheral blood. No medical or scientific benefit will be provided to patients who
participate in the study; however, future patients at risk for developing HSTCL may benefit from 
the results of this research.
1.2.
Hepatosplenic T-cell Lymphoma
Hepatosplenic T-cell lymphoma (HSTCL) is a rare and aggressive subtype of peripheral T-cell 
lymphoma with a poor prognosis (Herrinton, 2011; de Leval, 2011). HSTCL generally shows 
T-cell proliferation, particularly in the sinusoids of the liver or spleen, without lymph node 
enlargement. It is also occasionally diagnosed through bone marrow aspirate and, later in its 
course, malignant T-cells can be found in peripheral blood. In the US, the incidence is 
approximately 0.3 cases per million person-years in the general population. However, in patients 
with immune mediated conditions such as IBD or acquired immune deficiency syndrome, the 
incidence increases as much as 100-fold. HSTCL has also been reported in organ transplant 
patients (Tey, 2008). DNA, RNA, or protein biomarkers may provide a method to identify 
patients predisposed to develop HSTCL.


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Specific risk factors that contribute to HSTCL in patients with IBD have been reviewed (Kotylar, 
2010; Kotylar, 2011), and include gender (> 90% male); age (90% under 35 years of age); 
treatment with thiopurines such as 6-mercaptopurine or azathioprine (100%); treatment with a 
tumor necrosis factor (TNF) inhibitor such as infliximab (REMICADE®; 56%, all with 
concomitant thiopurine treatment); and duration of thiopurine treatment (97% >2 years). HSTCL 
has also been reported in patients treated with other TNF inhibitors such as adalimumab 
(Ochenrider, 2010), and other monoclonal antibodies with other mechanisms of action such as 
natalizumab (Kotylar, 2010). Although most published cases of HSTCL have occurred in 
immunocompromised individuals, a recent study describes some patients with no history of 
immune-related comorbidities or immunosuppressive therapy (Voss, 2013). 
Literature describing the clinical and presenting features of patients with HSTCL has been 
reviewed (Tripido, 2009). Diagnosis is typically confirmed by bone marrow, liver, or spleen 
biopsy using histologic, flow cytometric, and cytogenetic analyses. The tumor cells are generally 
γ/δ T cells with a Vδ1 variable region, positive for CD3 and occasionally positive for CD8 or 
CD56 but negative for CD4. The chromosomal abnormality isochromosome 7q has been 
reported in many cases (Alonsozana, 1997; Kotylar, 2010).  Recently, in an analysis of HSTCL 
cases, some of which included paired germline DNA, mutations were commonly found in the 
genes SETD2, INO80, STAT5B, SMARCA2, TET3, and PIK3CD (McKinney, 2017).
1.3.
Overall Rationale for the Study
While there is no formal hypothesis to be tested in this study, the samples collected during this 
study will be used to explore several possible hypotheses for the development of HSTCL 
reported in IBD patients. Methods such as genome sequencing (Chapman, 2011; Ng, 2010), 
mRNA gene expression microarray profiles (Miyazaki, 2009), and multiplex analysis of serum 
proteins may be used to identify these biomarkers.
1. Genes that increase susceptibility for developing inflammatory bowel disease.  The 
incidence of HSTCL is approximately 100-fold greater in IBD patients compared with 
the general population (Herrington, 2011).  Therefore, IBD susceptibility genes identified 
through genome-wide association studies (Franke, 2010; McGovern, 2010) may also be 
susceptibility genes for HSTCL.
2. Genes that are part of the TNF signaling pathway.  Although HSTCL is generally
observed in infliximab-treated IBD patients who received infliximab in combination with 
a thiopurine, TNF blockade may also increase susceptibility for developing HSTCL
independent of thiopurine exposure. Therefore, genes that are part of the TNF signaling 
pathway may also influence susceptibility for HSTCL. 


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3. Genes whose expression is significantly different than other T-cell lymphomas.  The 
majority of HSTCL in infliximab-treated IBD patients are known to be γ/Vδ1 T-cell 
clones, although α/β T-cell clones have also been reported (Mackey, 2009). One group 
(Miyazaki, 2009) studied the gene expression profile of peripheral T-cell lymphomas and 
identified a distinctive profile for 5 cases of HSTCL, including 4 cases that were γ/δ 
lymphomas and 1 case that was α/β T-cell lymphoma. Others have found that mutations 
that occur frequently in other T cell lymphomas in genes such as RHOA, CD28 and 
CCR4 were either absent or occurred at a much lower frequency in HSTCLs (McKinney, 
2017). Recognizing HSTCL tumor cell genes with significantly different expression 
compared with other types of T-cell lymphomas suggests these genes might influence 
susceptibility for development of HSTCL. 
4. Genes that are part of the DNA mismatch repair pathway.  Thiopurines are mutagens that 
cause base pair mismatches when incorporated into replicating DNA; these are corrected 
by the DNA mismatch repair pathway (Hsieh, 2008). One group (Nyugen, 2009) 
investigated the frequency and spectra of somatic mutation events at the hypoxanthine-
guanine phosphoribosyltransferase (HPRT) locus in T-cells from IBD patients. 
Thiopurine treatment resulted in a total dose-dependent (p<0.001) and duration of 
treatment-dependent (p<0.001) increase in the frequency of somatic mutations. Mutations 
in genes from the DNA mismatch repair pathway might increase the mutation rate due to 
thiopurine treatment and thereby increase the risk of HSTCL. 
5. Cytogenetic abnormalities.  Chromosomal abnormalities often associated with HSTCL 
include isochromosome 7q and trisomy 8 (Jonveaux, 1996); these abnormalities were 
also reported in IBD patients who developed HSTCL (Kotylar, 2010). The copy number 
or expression level of genes influenced by these abnormalities might also be linked to 
susceptibility to the development or progression of HSTCL.
2.
OBJECTIVE, ENDPOINTS, AND HYPOTHESIS
The objective of this study is to collect samples from IBD patients diagnosed with HSTCL to
identify biomarkers that may allow earlier evaluation of a patient’s risk of developing HSTCL. 
There are no formal endpoints or hypothesis for this study.
3.
STUDY DESIGN 
This study is designed to collect tissue samples from the biopsy specimen used to diagnose 
HSTCL, additional patient information, and if possible, to obtain additional samples including a 
single blood sample, a buccal swab sample, and/or a bowel tissue sample as described in further 
detail below. Samples obtained will be stored by the sponsor or its delegate for future testing.
The study will be conducted in North America and the planned duration of the study is 8 years. 


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Patients eligible for enrollment include males or females with IBD of any age who have a 
confirmed diagnosis of HSTCL. Patients will be identified through the sponsor’s adverse event
reporting systems. Cases reported to the sponsor’s Medical Information Center will be queried to 
ascertain if the reporter is interested in participating in the study. Where appropriate, cases may 
also be identified through the sponsor’s new or on-going clinical trials and registries. Samples 
may be collected from living patients or from stored tissue of deceased patients.
This study will not restrict or introduce any therapeutic interventions, including medications. All 
patients will continue to be managed by their personal physicians. No healthy subjects will be 
enrolled in this study. 
After obtaining informed consent as described in Section 8.1.2, physicians of participating 
patients will be asked to provide the following: 

Sample(s) of the biopsy specimen used to confirm the diagnosis of HSTCL (tumor tissue 
and adjacent healthy tissue if possible)

Additional samples, if possible, including the following:
-
A single blood and/or a buccal swab sample (for genomic DNA analysis), and/or 
-
A bowel tissue sample previously collected as part of the patient’s IBD diagnosis or 
treatment (if available, for mutation analysis between the tumor and T cells residing 
in the bowel to attempt to determine the origin of the tumor clone). 
In addition, the following information will be collected:

HSTCL diagnosis and related information

Demographic data

Diseases and medical/surgical conditions prior to or at the time of diagnosis

Medical history including family history of cancer, if available

Cytogenetic and flow cytometric data if available
Samples collected will be banked for future testing by the sponsor or its delegate. Potential test 
methods include, but are not limited to, the following: 

Deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) sequencing

Messenger ribonucleic acid (mRNA) gene expression

Protein expression or functional tests on cells isolated from peripheral blood 


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A Scientific Advisory Committee has been established for this study as described in Section 5.3, 
Scientific Advisory Committee. When the types of analyses to be performed on the tissue 
samples collected have been determined by the sponsor in consultation with the Scientific 
Advisory Committee, the sample analysis plan will be developed. 
It is important to note that participation in this study provides no direct medical or scientific 
benefit to the patient; however, future patients at risk for developing HSTCL may benefit from 
the results of this research.
4.
PATIENT SELECTION
The inclusion and exclusion criteria for enrolling patients in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator should consult with the appropriate sponsor representative before enrolling a patient
in the study. 
4.1.
Inclusion Criteria
Each potential patient must satisfy all of the following criteria to be enrolled in the study. Each 
patient must:
1.
Be a male or female of any age
2.
Have a confirmed diagnosis of IBD
3.
Have a confirmed diagnosis of HSTCL
4.
Modified per Protocol Amendment 3
4.1
Provide written informed consent (either by the patient or his/her legal representative) 
as described in Section 8.1.2. Consent from a legally acceptable representative of a 
deceased patient will be obtained for enrollment into the study and sample collection.
5.
Be willing to provide a tumor biopsy sample for the study
4.2.
Exclusion Criteria
Any potential patient who meets one or both of the following criteria will be excluded from 
participating in the study. The patient will be excluded if he or she:
1.
Has any condition that, in the opinion of the investigator, would make participation not 
be in the best interest (eg, compromise the well-being) of the patient or that could 
prevent, limit, or confound the protocol-specified assessments
2. 
Is unable to provide critical clinical and/or demographic patient and/or sample 
information


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5.
STUDY EVALUATIONS/PROCEDURES
The sponsor (or delegate) will identify cases of HSTCL through the sponsor’s adverse event 
reporting system. Cases reported to the sponsor’s Medical Information Center will be queried to 
ascertain if the reporter is interested in participating in the study. Where appropriate, cases may 
also be identified through the sponsor’s new or ongoing clinical trials and registries. 
Once a patient with HSTCL has been identified, the treating physician will be contacted and 
invited to participate in the study. When the physician agrees to participate, study related 
information will be provided to the physician for submission to the affiliated Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC). Each patient (or their legal 
representative) must give written informed consent as described in Section 8.1.2. 
The collection and processing of personal data from patients enrolled in this study will be limited 
to data necessary to fulfill the objectives of the study. Sample data and corresponding relevant 
demographic and clinical data will be made non-identifiable by the removal of personal 
identifiers and are to be sent to the sponsor in coded form, in which the patient is identified by 
means of a study number. The code should be retained at the study site of the treating 
physician(s). Samples collected will be shipped under protocol-defined conditions as described 
in the laboratory reference manual to the sponsor’s (or delegate’s) bioanalytical facility for 
storage and future analysis. Samples will be shipped with a unique identifier to maintain 
confidentiality. Samples may be kept and used for up to 15 years after the study is completed; 
see also Section 8.1.2, Informed Consent, for sample handling if a patient withdraws consent.
Detailed instructions for sample collection/processing and shipments will be defined in a 
laboratory reference manual.
5.1.
Sample Collection
A tissue sample from the biopsy specimen used to diagnose HSTCL is required for this study. In 
addition, although not required for entry into the study, every effort is to be made to obtain a 
single blood sample, a buccal swab sample, and/or a bowel tissue sample as described in further 
detail in the following subsections.
5.1.1.
Tumor Biopsy Tissue Sample
A sample of the tumor biopsy tissue, including adjacent non-tumor tissue if available, originally 
used for the diagnosis of HSTCL must be provided to the sponsor (or delegate). Approximately 
ten,
6-micron sections of the formalin-fixed, paraffin-embedded tumor are required 
(approximately 50 milligrams of the tumor biopsy).
5.1.2.
Additional Samples
5.1.2.1.
Blood and/or Buccal Swab Samples
A single blood and/or buccal swab sample is requested (each optional) for genomic DNA 
analysis.
The estimated total blood volume to be collected from each patient will be based on patient 
weight as per the table below.  


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Table 1:  
Blood sample and volume collected
Blood Sample Type
Blood Volume
(total volume approximately 20 - 37 mL) *
Serum
5 mL (2 x 2.5 mL)
Whole blood for RNA
5 mL (2 x 2.5 mL)
Whole blood for DNA
10 mL (2 x 5 mL) 
Whole blood for cellular analysis
17 mL (2 x 8.5 mL) *
* Obtain whole blood sample for cellular analysis only if patient weight is ≥45 kg
Buccal swabs will be used to collect cells from the cheek area inside the mouth of the patient.  
5.1.2.2.
Bowel Tissue Sample
If possible, a sample of bowel tissue previously collected as part of the patient’s IBD diagnosis 
or treatment is requested (optional) if a specimen is already available. The sample will be used 
for mutation analysis of IBD to tumor.  Approximately ten, 6-micron sections of the formalin-
fixed, paraffin-embedded tissue are required (approximately 50 milligrams of the bowel tissue 
biopsy). 
5.1.3.
Sample Collection and Handling
Collection tubes for the blood samples, the buccal swab collection kit, and the slides for tumor 
biopsy tissue and bowel tissue samples will be provided to the patient’s physician with specific 
instructions for collection, labeling, storing, and shipping to the sponsor or delegate.
The actual dates and times of sample collection must be recorded in the case report form (CRF)
or laboratory requisition form. If blood samples are collected via an indwelling cannula, an 
appropriate amount (1 mL) of serosanguineous fluid slightly greater than the dead space volume 
of the lock will be removed from the cannula and discarded before each blood sample is taken.
After blood sample collection, the cannula will be flushed with 0.9% sodium chloride, United 
States Pharmacopeia (USP) (or equivalent) and charged with a volume equal to the dead space 
volume of the lock. If a mandarin (obturator) is used, blood loss due to discard is not expected.
Please refer to the laboratory reference manual for detailed instructions for the collection, 
handling, and shipment of blood, tissue, and buccal swab samples. 
5.2.
Additional Patient Information
For each identified case of HSTCL for which the treating physician(s) agreed to participate, the 
investigator or an authorized member of the investigational staff will collect data from the 


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patient’s medical records and transfer this information to the CRF at a data collection visit at the 
treating physician(s) site. 
The data elements to be collected from patient’s medical records include:
1.
HSTCL diagnosis
a. Diagnosis confirmation and date. Tumor stage and findings that support staging 
including system used.
b. Clinical course
c. Type, dose, and duration of treatment with corticosteroids and any immunomodulator 
therapies (including biologics) prior to and at time of diagnosis of lymphoma
2.
Demographic data including age at diagnosis of HSTCL, gender, race, and nationality 
3.
Diseases and medical/surgical conditions prior to or at the time of diagnosis (including 
date of diagnosis, treatment and medications, and outcome) including but not limited to 
the following:
a. Autoimmune disease 
b. Cancer
c. Organ transplant
d. Infection with human immunodeficiency virus (HIV)
4.
Medical history including family history of cancer, if available
5.
Cytogenetic and flow cytometric data, if available
Care must be taken to safeguard the privacy of patients and ensure that all applicable privacy 
guidelines are met. Collected data entered on the CRF are to be sent to the sponsor in coded 
form, in which the patient was identified by means of numbers. The code should be retained at 
the study site of the treating physician(s).
5.3.
Scientific Advisory Committee
A Scientific Advisory Committee has been established and includes representatives from the 
sponsor and global medical experts in the disease under study. Meetings will be held as needed
to review the emerging science related to HSTCL, the latest available test methods, and to 
determine the types of analyses to be performed on the tissue samples collected. Details will be 
provided in a separate Scientific Advisory Committee Charter.


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5.4.
Withdrawal from the Study
If a patient withdraws from the study or withdraws consent, refer to Section 8.1.2, Informed 
Consent, for further details on handling of samples.
6.
TEST METHODS AND DATA ANALYSIS
In consultation with the Scientific Advisory Committee (see Section 5.3), a detailed analysis plan 
will be written and statistical analysis will be done by the sponsor or under the authority of the 
sponsor. A general description of the statistical methods to be used is outlined below. Specific 
details will be provided in the Statistical Analysis Plan.
Descriptive statistics of demographic information, information on medical/surgical (including 
treatment) history, and baseline characteristics at the time of HSTCL diagnosis will be 
summarized for all patients enrolled in this study.  Protein assay data will be summarized using 
descriptive statistics. Gene expression in tumor cells may be compared with expression levels 
observed in normal tissue surrounding the tumor or in bowel tissue sample, or with cells isolated 
from whole blood or from buccal swabs with moderated t-statistics or other appropriate 
statistical methods.
Full genome or targeted sequencing may also be used to reveal patterns of mutations responsible 
for development of HSTCL. Somatic mutations will be identified by comparing HSTCL tumor 
DNA from the same patient from the following: 

The normal adjacent tissue from the same biopsy specimen, or 

The bowel tissue sample, or

Cells isolated from the buccal swab, or 

Peripheral blood mononuclear cells. 
Individual mutations will be tabulated within and between patients and cross-referenced with 
human variation databases (eg, COSMIC, dbSNP, etc.). To identify cancer driver genes or 
pathways, somatic mutation frequencies will be evaluated per gene or pathway across all patients 
with HSTCL and compared with empirical background mutation frequencies by mutation type 
(Wendl, 2011; Youn, 2011).  
7.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of patients, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
During the conduct of this study, adverse events may be reported that are related to venipuncture 
for blood sample collection or buccal swab collection as described in Section 7.2. 


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7.1.
Definitions
For the purposes of this study, and in accordance with ICH and the sponsor’s safety reporting 
guidelines, the following definitions will apply.
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study patient administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 
related to that medicinal (investigational or non-investigational) product. (Definition per ICH)
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the informed consent form.
Serious Adverse Event
A serious adverse event based on ICH and European Union (EU)
Guidance
on 
Pharmacovigilance for Medicinal Products for Human Use is any untoward medical occurrence 
that at any dose:

Results in death

Is life-threatening
(The patient was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is medically important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the patient 
or might require intervention to prevent one of the other outcomes listed above. These should 
usually be considered serious.
For reports of hospitalization, it is the sign, symptom, or diagnosis which led to hospitalization 
that is the serious event for which details must be provided.


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7.2.
Reporting and Follow-up of Serious Adverse Events
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The investigator (or sponsor where required) must report these events to the 
appropriate IRB/IEC that approved the protocol unless otherwise required and documented by 
the IRB/IEC.
Adverse events that are associated with study interventions (eg, bruising or infection at 
venipuncture site, fainting, irritation, and bleeding at the inside of the cheek from the buccal 
swab) will be captured within the study database. All other adverse events/serious adverse events
that are identified through the study data collection processes and not associated with study 
interventions (eg, blood draw, buccal swabbing) will be reported as solicited reports.  
All serious adverse events that are considered as related to study intervention (eg, venipuncture)
will be followed until resolution, stabilization, or follow-up is no longer possible.
7.3.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document.
8.
ETHICAL ASPECTS
This study is being conducted to address 2 postmarketing requirements by the US FDA to bank 
blood, buccal cells, and/or tissue samples for future evaluation to identify genetic mutations and 
other biomarkers that may predispose IBD patients to develop HSTCL. No medical or scientific 
benefit will be provided to patients who participate in the study; however, future patients at risk 
for developing HSTCL may benefit from the results of this research.
8.1.
Regulatory Ethics Compliance
This research study is to be performed in accordance with the protocol, current ICH guidelines 
on GCP, and applicable regulatory and country-specific requirements.  
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human patients. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study patients are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the clinical study data are credible.
8.1.1.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IRB/IEC with current and complete copies of the following documents:

Final protocol and, if applicable, amendments

Sponsor-approved informed consent form (and any other written materials to be provided 
to the patients)


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
Information on compensation for study-related injuries or payment to patients for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IRB/IEC)

Information regarding funding, name of the sponsor, institutional affiliations, other 
potential conflicts of interest, and incentives for patients

Any other documents that the IRB/IEC requests to fulfill its obligation
This study will be undertaken only after the IRB/IEC has given full approval of the final 
protocol, amendments (if any), the informed consent form, applicable recruiting materials, and 
patient compensation programs, and the sponsor has received a copy of this approval. This 
approval letter must be dated and must clearly identify the IRB/IEC and the documents being 
approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IRB/IEC for their review and approval, where appropriate:

Protocol amendments

Revision(s) to informed consent form and any other written materials to be provided to 
patients

Revisions to compensation for study-related injuries or payment to patients for 
participation in the study, if applicable  

Summaries of the status of the study at intervals stipulated in guidelines of the IRB/IEC (at 
least annually)

New information that may adversely affect the safety of the patients or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the patients

Report of deaths of patients under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IRB/IEC
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for patients, data or trial conduct), the amendment and applicable informed 
consent form revisions must be submitted promptly to the IRB/IEC for review and approval 
before implementation of the change(s). If applicable, at least once a year, the IEC/IRB will be 
asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IRB/IEC
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8.1.2.
Informed Consent
Each patient (or a legally acceptable representative) must give written consent according to local 
requirements after the nature of the study has been fully explained. The consent form must be 
signed before performance of any study-related activity. The consent form and assent form that 
is used must be approved by both the sponsor and by the reviewing IRB/IEC and be in a 
language that the patient can read and understand. The informed consent should be in accordance 
with principles that originated in the Declaration of Helsinki, current ICH and GCP guidelines, 
applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the investigational 
staff must explain to potential patients or their legally acceptable representatives the aims, 
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail. Patients will be told that the investigator will maintain a 
patient identification register for the purposes of long-term follow up if needed and that their 
records may be accessed by health authorities and authorized sponsor staff without violating the 
confidentiality of the patient, to the extent permitted by the applicable law(s) or regulations. By 
signing the informed consent form the patient or legally acceptable representative is authorizing 
such access, and agrees to allow his or her study physician to recontact the patient for the 
purpose of obtaining consent for additional safety evaluations, if needed, and subsequent disease-
related treatments, or to obtain information about his or her health status.
The patient or legally acceptable representative will be given sufficient time to read the informed 
consent form and the opportunity to ask questions. After this explanation and before entry into 
the study, consent should be appropriately recorded by means of either the patient's or his or her 
legally acceptable representative's personally dated signature. After having obtained the consent, 
a copy of the informed consent form must be given to the patient.
If the patient or legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 
all written information) and should personally date and sign the informed consent form after the 
oral consent of the patient or legally acceptable representative is obtained.
Children (minors) or patients who are unable to comprehend the information provided can be 
enrolled only after obtaining consent of a legally acceptable representative. Assent must be 
obtained from children (minors) capable of understanding the nature of the study, typically 
patients 6 years of age and older, depending on the institutional policies. Written assent should be 
obtained from patients who are able to write. A separate assent form written in language the 
patient can understand should be developed for adolescents. After having obtained the assent, a 
copy of the assent form must be given to the patient, and to the patient's parent and/or legally 
acceptable representative.


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Patients will be informed that their participation is voluntary and that they may withdraw consent 
to participate at any time by contacting the sponsor through the contact information given on the 
ICF. They will be informed that choosing not to participate will not affect the care he/she will 
receive for the treatment of his/her disease. The sponsor will destroy any remaining samples 
upon receipt of such a request. However, sample testing that has already taken place will be 
retained by the sponsor to avoid compromising data analysis. 
Consent from a legally acceptable representative of a deceased patient will be obtained for 
enrollment into the study and sample collection.      
8.1.3.
Privacy of Personal Data
The collection and processing of personal data from patients enrolled in this study will be limited 
to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of study patients confidential.
The informed consent obtained from the patient (or his or her legally acceptable representative)
includes explicit consent for the processing of personal data and for the investigator to allow 
direct access to his or her original medical records for study-related monitoring, audit, IRB/IEC
review, and regulatory inspection. This consent also addresses the transfer of the data to other 
entities and to other countries.
The patient has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory DNA, pharmacodynamic, biomarker, pharmacokinetic, and immunogenicity
research is not conducted under standards appropriate for the return of data to patients. In 
addition, the sponsor cannot make decisions as to the significance of any findings resulting from 
exploratory research. Therefore, exploratory research data will not be returned to patients or 
investigators, unless required by law. Privacy and confidentiality of data generated in the future 
on stored samples will be protected by the same standards applicable to all other clinical data.
8.1.4.
Long-Term Storage of Samples for Future Research 
Samples may be kept and used for up to 15 years after the study is completed; see also 
Section 8.1.2, Informed Consent, for sample handling if a patient withdraws consent.


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9.
ADMINISTRATIVE REQUIREMENTS
9.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment.
All protocol amendments must be issued by the sponsor, and signed and dated by the 
investigator. Protocol amendments must not be implemented without prior IRB/IEC approval, or 
when the relevant competent authority has raised any grounds for non-acceptance, except when 
necessary to eliminate immediate hazards to the patients, in which case the amendment must be 
promptly submitted to the IRB/IEC and relevant competent authority. Documentation of 
amendment approval by the investigator and IRB/IEC must be provided to the sponsor or its 
delegate. When the change(s) involves only logistic or administrative aspects of the study, the 
IRB (and IEC where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative (see Contact Information page(s) provided separately). Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and 
agree on an appropriate course of action. The data recorded in the CRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
9.2.
Regulatory Documentation
9.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities. 
A study may not be initiated until all local regulatory requirements are met.
9.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study-related
materials (eg, sample collection kit) to the investigational site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed, written IRB/IEC approval of the protocol, amendments, 
informed consent form, any recruiting materials, and if applicable, patient compensation 
programs. This approval must clearly identify the specific protocol by title and number 
and must be signed by the chairman or authorized designee.

Name and address of the IRB/IEC, including a current list of the IRB/IEC members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IRB/IEC, a general statement may be substituted for this list. If an investigator or 
a member of the investigational staff is a member of the IRB/IEC, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.


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
Regulatory authority approval or notification, if applicable

Any other documentation required by local regulations
9.3.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the CRF: patient identification, eligibility, and study identification; study discussion 
and date of informed consent; results of safety parameters as required by the protocol; record of 
all adverse events and follow-up of adverse events, if applicable.
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a study patient should be 
consistent with that commonly recorded at the site as a basis for standard medical care and 
recorded in the CRF (see Section 5.2).
9.4.
Case Report Form Completion
Case report forms are provided for each patient in printed format.
All printed forms must be filled out legibly in black ballpoint pen or typed. The appropriate 
pages of the CRF must be signed and dated by the investigator.  
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the patient's source documentation. All data relating to the
study must be recorded in CRFs prepared by the sponsor. Data must be entered into CRFs in 
English. Designated site personnel must complete the CRF as soon as possible. 
All CRF entries, corrections, and alterations must be made by the investigator or other authorized 
study-site personnel. The investigator or an authorized member of the investigational staff must 
adjust the CRF (if applicable) and complete the query.
Corrections to paper CRFs must be made in such a way that the original entry is not obscured. 
Correction fluid or tape must NOT be used. The correct data must be inserted, dated, and 
initialed by the investigator or an authorized member of the investigational staff. If multi-part 
pressure-sensitive CRFs are used, the investigational staff must not write on separated parts of 
the CRFs left at the investigational site once the original has been sent to the sponsor. Completed 
CRFs will be continuously submitted according to the sponsor's instructions and reviewed by the 
sponsor to determine their acceptability. If necessary, Data Correction/Clarification Forms 
(DCFs) will be generated and transmitted to the study site. The investigator or an authorized 
member of the investigational staff must complete, sign, and date the DCFs.
If corrections to a CRF are needed after removal of the original CRF copy from the 
investigational site, a DCF will be used.


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9.5.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the review of protocol 
procedures with the investigator and associated personnel before the study. Written instructions 
will be provided for collection, preparation, and shipment of samples.
Guidelines for CRF completion will be provided and reviewed with study personnel before the 
start of the study. The sponsor or delegate will review CRFs for accuracy and completeness; any 
discrepancies will be resolved with the investigator or designee, as appropriate. The data will be 
entered into the study database and verified for accuracy and consistency with the data sources.
9.6.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRFs 
and all source documents that support the data collected from each patient, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
For CRFs completed on pressure-sensitive paper, a copy is to be retained in the archives of the 
sponsor. A second copy must be archived by the investigator.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator must permit access to such reports.
The study will be considered complete upon submission of the final clinical study reports to the 
FDA for the two postmarketing requirements for which this study is being conducted.


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9.7.
Use of Information and Publication
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Study subject 
identifiers will not be used in publication of results. Any work created in connection with 
performance of the study and contained in the data that can benefit from copyright protection 
(except any publication by the investigator as provided for below) shall be the property of the 
sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as 
required by law.


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Ng S, Buckingham KJ, Lee C, et al. Exome sequencing identifies the cause of a mendelian disorder. Nat Genet.
2010;42:30-6.
Nguyen T, Vacek PM, O’Neill PO, Colletti RB, Finette BA.  Mutagenicity and potential carcinogenicity of 
thiopurine treatment in patients with inflammatory bowel disease.  Cancer Res. 2009;69:7004-12.  
Ochenrider MG, Patterson DJ, Aboulafia DM. Hepatosplenic T-cell lymphoma in a young man with Crohn's 
disease: case report and literature review. Clin Lymphoma Myeloma Leuk. 2010;10:144-8.  
Tey SK, Marlton PV, Hawley CM, Norris D, Gill DS. Post-transplant hepatosplenic T-cell lymphoma successfully 
treated with HyperCVAD regimen. Am J Hematol. 2008;83:330-3.
Tripido C, Iannitto E, Florena AM, et al. Gamma-delta T-cell lymphomas. Nat Rev Clin Oncol. 2009;6:707-17.


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Voss MH, Lunning MA, Maragulia JC, et al. Intensive induction chemotherapy followed by early high-dose therapy 
and hematopoietic stem cell transplantation results in improved outcome for patients with hepatosplenic T-cell 
lymphoma: a single institution experience. Clin Lymphoma Myeloma Leuk. 2013;13:8-14.
Wendl MC, Wallis JW, Lin L, et al. PathScan: a tool for discerning mutational significance in groups of putative 
cancer genes. Bioinformatics. 2011;27:1595-1602. 
Youn A, Simon R. Identifying cancer driver genes in tumor genome sequencing studies. Bioinformatics.
2011;27:175-81.


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Attachment 1 Protocol History
Original Protocol:  25 June 2012
Amendment 1:  
26 March 2013
Amendment 2: 
17 February 2014
Amendment 3: 
02 August 2017


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Amendment 3 – 02 August 2017
The protocol has been revised to incorporate this amendment, which applies to all study centers. The rationale and description of the 
changes to the protocol are provided below. Minor formatting and typographical errors have also been corrected to improve the clarity 
and accuracy of the protocol text; these changes do not affect the overall conduct of the study and therefore have not been included in 
the following table. Note that in the following table, unless otherwise noted, the new text is shown in a bold, black font with italicized 
text, and deleted text is shown in a black font with strikethrough.
1.
Description/Rationale:  The protocol has been updated to:
-
Provide more details on how patients will be identified for participation in the study,
-
Provide clarification on potential sample collection from deceased patients, 
-
Update information on HSTCL,
-
Update information on the Scientific Advisory Committee,
-
Update the protocol text to be consistent with the most recent version of the sponsor’s protocol template, and
-
Revise text for clarity and to correct inadvertent errors or omissions.
Sections Affected
Original Content
Amended/New Content
Synopsis, Purpose
… to bank blood and/or tissue samples for future…
… to bank HSTCL tumor tissue as well as blood, buccal swab, 
and/or other tissue samples for future…
Synopsis and Section 2, Objective, 
Endpoints, and Hypothesis 
(previously Objective)
OBJECTIVE
The objective of this study is to collect samples from 
IBD patients diagnosed with HSTCL for the purpose of 
identifying biomarkers that may allow earlier evaluation 
of a patient’s risk of developing HSTCL.
OBJECTIVE, ENDPOINTS, AND HYPOTHESIS
The objective of this study is to collect samples from IBD 
patients diagnosed with HSTCL for the purpose of identifying 
to identify biomarkers that may allow earlier evaluation of a 
patient’s risk of developing HSTCL.
There are no formal endpoints or hypothesis for this study.
Synopsis, Overview of Study 
Design
(Note that the entire section 
was revised; however, most 
changes entailed deleting text 
and moving it as appropriate to 
other sections in the synopsis.)
This study is designed to collect tissue samples from the 
biopsy specimen used to diagnose HSTCL, and if 
possible, to obtain a single blood sample, a buccal swab 
sample (to determine the patient tissue type and 
establish non-mutated deoxyribonucleic acid [DNA] 
baseline), and a bowel tissue sample (if available, for 
mutation analysis between the tumor and T cells 
residing in the bowel to attempt to determine the origin 
of the tumor clone). Samples obtained will be stored by 
the sponsor or its delegate for future testing. In addition, 
demographic and clinical patient information will be 
collected. The study will be conducted in North 
America.
This study is designed to collect tissue samples from the biopsy 
specimen used to diagnose HSTCL in patients with IBD. 
Additional patient information, and if possible, additional 
blood, buccal swab, and/or tissue samples will be collected as 
described below in Evaluations. This study will be conducted in 
North America and the planned duration is 8 years. This study 
will not restrict or introduce any therapeutic interventions, 
including medications. All patients will continue to be managed 
by their personal physicians. 


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The study population will include IBD patients with 
HSTCL who are identified through the sponsor’s 
adverse event reporting systems. Cases of HSTCL will 
be identified through the sponsor’s postmarketing 
adverse event reporting system (eg, spontaneous 
reports, reports from late phase clinical trials, reports 
from patient registries), from parties seeking 
participation in the study through reporting of cases 
directly to the sponsor’s Medical Information Center, or 
from the sponsor’s new or ongoing clinical trials. 
Eligible for enrollment are male or female patients of 
any age who have a confirmed diagnosis of HSTCL. 
There is no study-related therapeutic intervention and 
this protocol will not restrict or introduce any 
therapeutic interventions, including medications. All 
patients will continue to be managed by their personal 
physicians. No healthy subjects will be enrolled in this 
study.  
Informed consent/assent will be obtained by the 
investigator (ie, patient’s physician or designee), from 
all adult patients or parents/legally acceptable 
representative(s), and pediatric patients prior to 
collection of any information or samples.  
Synopsis, Patient Selection 
(Note that the section was 
revised to include information 
from the overview section of 
the synopsis and to add new 
information.)
Eligible are male or female patients of any age with 
IBD who also have a confirmed diagnosis of HSTCL.
Patients eligible for enrollment include males or females with 
IBD of any age with IBD who have a confirmed diagnosis of 
HSTCL. No healthy subjects will be enrolled in this study.
Patients will be identified through the sponsor’s adverse event 
reporting systems. Cases reported to the sponsor’s Medical 
Information Center will be queried to ascertain if the reporter 
is interested in participating in the study. Where appropriate, 
cases may also be identified through the sponsor’s new or on-
going clinical trials and registries. Samples may be collected 
from living patients or from stored tissue of deceased patients.
Synopsis, Evaluations 
(Note that this section was 
primarily revised for clarity 
and consistency with the body 
of the protocol.)
Physicians of participating patients will be asked to 
provide information on the following: 
demographics
medical and surgical history 
treatment history and medications 
After obtaining informed consent as described in Section 
8.1.2 in the body of the protocol, physicians of participating 
patients will be asked to provide the following: 
- Sample(s) of the biopsy specimen used to confirm the 
diagnosis of HSTCL (tumor tissue and adjacent healthy 


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samples of the biopsy specimen that was used to 
confirm the diagnosis of HSTCL (tumor tissue and 
adjacent healthy tissue if possible) 
In addition, if possible, every effort is to be made to 
obtain other specimens including a single blood sample, 
a buccal swab sample (to determine the patient tissue 
type and establish non-mutated DNA baseline), and a 
bowel tissue sample (if available, for mutation analysis 
between the tumor and T cells residing in the bowel to 
attempt to determine the origin of the tumor clone). 
Samples collected will be banked for future testing. 
Potential test methods include the following: …
tissue if possible)
- Additional samples, if possible, including the following:
- A single blood and/or a buccal swab sample (for 
genomic DNA analysis), and/or 
- A bowel tissue sample previously collected as part of 
the patient’s IBD diagnosis or treatment (if available, 
for mutation analysis between the tumor and T cells 
residing in the bowel to attempt to determine the origin 
of the tumor clone). 
In addition, the following information will be collected:
- HSTCL diagnosis and related information
- Demographic data
- Diseases and medical/surgical conditions prior to or at the 
time of diagnosis
- Medical history including family history of cancer, if 
available
- Cytogenetic and flow cytometric data, if available
Samples collected will be banked for future testing by the 
sponsor or its delegate. Potential test methods include, but are 
not limited to, the following: …
Synopsis, Statistical Methods
1st paragraph, 1st sentence. 
Similar changes were made 
throughout the protocol as 
appropriate.
A Scientific Advisory Committee will be established for 
this study that will include an independent panel of 
experts who will … 
A Scientific Advisory Committee will behas been established 
for this study that will include anincludes an independent panel 
of experts who will…
3rd paragraph, 1st through 3rd
sentences
Full genome or targeted sequencing may also be used to 
reveal patterns of mutations responsible for 
development of HSTCL. Somatic mutations will be 
identified by comparing HSTCL tumor DNA with 
normal lining tissue DNA from the same biopsy 
specimen, or DNA from a bowel tissue sample, or DNA 
from cells isolated from the buccal swabs, or DNA 
isolated from peripheral blood mononuclear cells 
obtained from the same patient. Buccal swab sample 
analysis will help to determine the patient’s genetic 
makeup and the bowel tissue sample analysis will help 
Full genome or targeted sequencing may also be used to reveal 
patterns of mutations responsible for development of HSTCL. 
Somatic mutations will be identified by comparing HSTCL 
tumor DNA with normal lining tissue DNA from the same 
patient from the following:
The normal adjacent tissue from the same biopsy specimen, 
or DNA from a
The bowel tissue sample, or DNA from
Cells isolated from the buccal swabsswab, or DNA isolated 
from 


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to perform mutation analysis of IBD to the tumor.
Peripheral blood mononuclear cells obtained from the same 
patient. Buccal swab sample analysis will help to determine 
the patient’s genetic makeup and the bowel tissue sample 
analysis will help to perform mutation analysis of IBD to the 
tumor. . 
Section 1.1. Purpose, 1st paragraph 
revised
The United States (US) Food and Drug Administration 
(FDA) has requested that the sponsor collect samples 
for the purpose of identifying biomarkers that may 
allow earlier evaluation of a patient’s risk of developing 
hepatosplenic T-cell lymphoma (HSTCL). Medical and 
surgical information, samples from the biopsy used to 
diagnose HSTCL, and if possible, additional samples (a 
single blood sample, a buccal swab sample, and a bowel 
tissue sample), will be requested from each patient and 
stored by the sponsor or its delegate for future testing. 
The planned duration for sample collection is 6 years. 
The United States (US) Food and Drug Administration (FDA) 
has requested that the sponsor conduct a postmarketing study 
to collect samples for the purpose of identifying from 
inflammatory bowel disease patients (IBD) treated with 
Remicade® (infliximab) and/or Simponi® (golimumab) to 
learn more about hepatosplenic T-cell lymphoma (HSTCL). 
Specifically, samples will be collected to identify genetic 
mutations and other biomarkers that may allow earlier 
evaluation of a patient’s risk of developing hepatosplenic T-cell 
lymphoma (HSTCL). Medical and surgical information, 
samples from HSTCL. Samples to be requested from each 
patient include the biopsy used to diagnose HSTCL, and if 
possible, additional samples including a single blood sample, a 
buccal swab sample, and/or a bowel tissue sample), will be 
requested from each patient andpreviously collected as part of 
the patient’s IBD diagnosis or treatment. In addition, patient 
information will be collected including, but not limited to, 
patient demographics and medical history. Samples will be
stored by the sponsor or its delegate for future testing. The 
study will be conducted in North America and the planned 
duration for sample collectionof the study is 68 years. 
Section 1.3. Overall Rationale for 
the Study, No. 3 under first 
paragraph (new 4th sentence 
and corresponding new 
reference)
3. …T-cell lymphoma. Recognizing HSTCL tumor… 
3. …T-cell lymphoma. Others have found that mutations that 
occur frequently in other T cell lymphomas in genes such 
as RHOA, CD28 and CCR4 were either absent or 
occurred at a much lower frequency in HSTCLs 
(McKinney, 2017). Recognizing HSTCL tumor …
Corresponding New Reference:  
McKinney M, Moffitt AB, Gaulard P. The Genetic Basis of 
Hepatosplenic T Cell Lymphoma. Cancer Discovery. 
2017;7:369-79.
Section 3. Study Design 
(Note that the entire section 
This study is designed to collect tissue samples from the 
biopsy specimen used to diagnose HSTCL, and if 
This study is designed to collect tissue samples from the biopsy 
specimen used to diagnose HSTCL, additional patient 


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Amended/New Content
was revised for clarity and to 
add new information.)
possible, to obtain a single blood sample, a buccal swab 
sample (to determine the patient tissue type and 
establish non-mutated DNA baseline), and a bowel 
tissue sample (if available, for mutation analysis 
between the tumor and T cells residing in the bowel to 
attempt to determine the origin of the tumor clone). In 
addition, demographic and clinical patient information 
will be collected and samples obtained will be stored by 
the sponsor or its delegate for future testing. The study 
will be conducted in North America.
The study population will include IBD patients with 
HSTCL who are identified through the sponsor’s 
adverse event reporting systems. Cases of HSTCL will 
be identified through the sponsor’s postmarketing 
adverse event reporting system (eg, spontaneous 
reports, reports from late phase clinical trials, reports 
from patient registries), from parties seeking 
participation in the study through reporting of cases 
directly to the sponsor’s Medical Information Center, or 
from the sponsor’s new or ongoing clinical trials. 
Eligible for enrollment are male or female patients of 
any age who have a confirmed diagnosis of HSTCL.   
There is no study-related therapeutic intervention and 
this protocol will not restrict or introduce any 
therapeutic interventions, including medications. All 
patients will continue to be managed by their personal 
physicians. No healthy subjects will be enrolled in this 
study.  
Informed consent/assent will be obtained by the 
investigator (ie, patient’s physician or designee), from 
all adult patients or parents/legal guardians, and 
pediatric patients prior to collection of any information 
or samples.  
When referring to the signing of the informed consent 
form, the terms legal guardian and legally acceptable 
representative refer to the legally appointed guardian of 
the child.
For each pediatric patient, his or her parent(s) 
(preferably both parents, if available) or a legally 
information, and if possible, to obtain additional samples 
including a single blood sample, a buccal swab sample, and/or a 
bowel tissue sample as described in further detail below. 
Samples obtained will be stored by the sponsor or its delegate 
for future testing. The study will be conducted in North 
America and the planned duration of the study is 8 years. 
Patients eligible for enrollment include males or females with 
IBD of any age who have a confirmed diagnosis of HSTCL. 
Patients will be identified through the sponsor’s adverse event
reporting systems. Cases reported to the sponsor’s Medical 
Information Center will be queried to ascertain if the reporter 
is interested in participating in the study. Where appropriate, 
cases may also be identified through the sponsor’s new or on-
going clinical trials and registries. Samples may be collected 
from living patients or from stored tissue of deceased patients.
This study will not restrict or introduce any therapeutic 
interventions, including medications. All patients will continue 
to be managed by their personal physicians. No healthy 
subjects will be enrolled in this study.  
After obtaining informed consent as described in Section 
8.1.2., physicians of participating patients will be asked to 
provide the following:
• Sample(s) of the biopsy specimen used to confirm the 
diagnosis of HSTCL (tumor tissue and adjacent healthy 
tissue if possible)
• Additional samples, if possible, including the following:
- A single blood and/or a buccal swab sample (for genomic 
DNA analysis), and/or 
- A bowel tissue sample previously collected as part of the 
patient’s IBD diagnosis or treatment (if available, for 
mutation analysis between the tumor and T cells residing 
in the bowel to attempt to determine the origin of the 
tumor clone).
In addition, the following information will be collected:
• HSTCL diagnosis and related information
• Demographic data
• Diseases and medical/surgical conditions prior to or at the 


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acceptable
representative(s), as required by local regulations, must 
give written consent (permission) according to local 
requirements after the nature of the study has been fully 
explained and before the performance of any study-
related assessments. Assent must be obtained from 
children (minors) capable of understanding the nature of 
the study, typically patients 7 years of age and older, 
depending on the institutional policies. For the purpose 
of this study, all references to patients who have 
provided consent/assent refer to the patient (assent as 
applicable) and his or her parent(s) or legally acceptable 
representative(s) who have provided consent according 
to this process. Minors who assent to a study and later 
withdraw that assent should not be maintained in the 
study against their will, even if their parents still want 
them to participate. If applicable, consent/assent will 
include permission to obtain a copy of the patient’s 
autopsy report or death certificate if available.
Physicians of participating patients will be asked to 
provide information on the following: 
•
demographics
•
medical and surgical history 
•
treatment history and medications 
•
samples of the biopsy specimen that was used to 
confirm the diagnosis of HSTCL (tumor tissue and 
adjacent healthy tissue if possible)
In addition, if possible, every effort is to be made to 
obtain additional samples including a single blood 
sample, a buccal swab sample, and a bowel tissue 
sample if available (discretionary) to be used for the test 
procedures that are part of this study. 
The planned duration for sample collection is 6 years. 
A Scientific Advisory Committee will be established for 
this study that will include an independent panel of 
experts who will review the emerging science related to 
HSTCL and latest available test methods and make 
recommendations to the sponsor (see Section 5.4, 
time of diagnosis
• Medical history including family history of cancer, if 
available
• Cytogenetic and flow cytometric data if available
Samples collected will be banked for future testing by the 
sponsor or its delegate. Potential test methods include, but are 
not limited to, the following: 
• Deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) 
sequencing
• Messenger ribonucleic acid (mRNA) gene expression
• Protein expression or functional tests on cells isolated from 
peripheral blood 
A Scientific Advisory Committee has been established for this 
study as described in Section 5.3, Scientific Advisory 
Committee. When the types of analyses to be performed on the 
tissue samples collected have been determined by the sponsor 
in consultation with the Scientific Advisory Committee, the 
sample analysis plan will be developed. 
It is important to note that participation in this study provides 
no direct medical or scientific benefit to the patient; however, 
future patients at risk for developing HSTCL may benefit from 
the results of this research.


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Scientific Advisory Committee). When the types of 
analyses to be performed on the tissue samples collected 
have been determined by the sponsor in consultation 
with the Scientific Advisory Committee, the sample 
analysis plan will be developed. 
Samples collected will be banked for future testing. The 
test methods that may be used include the following: 
•
DNA or RNA sequencing
•
mRNA gene expression
•
protein expression or functional tests on cells 
isolated from peripheral blood 
It is important to note that participation in this study 
provides no direct medical or scientific benefit to the 
patient; however, future patients at risk for developing 
HSTCL may benefit from the results of this research.
Section 4.1. Inclusion Criterion #4
4. Sign (or their legally-acceptable representatives 
must sign) an informed consent document 
indicating that they understand the purpose of and 
procedures required for the study and are willing to 
participate in the study. Assent is also required of 
children capable of understanding the nature of the 
study (typically 7 years of age and older) as 
described in Section 8.1.2, Informed Consent.
4. Modified per Protocol Amendment 3
4.1Sign (Provide written informed consent (either by the 
patient or his/her legal representative) as described in 
Section 8.1.2. Consent from a legally acceptable 
representative of a deceased patient will be obtained for 
enrollment into the study and sample collection.
Section 5. Study 
Evaluations/Procedures 
(This section was previously 
titled Study Evaluations. Note 
that the entire section was 
revised for clarity and to add 
new information. ) 
STUDY EVALUATIONS
The sponsor (or delegate) will identify cases of HSTCL 
through the postmarketing adverse event reporting 
system (eg, spontaneous reports, reports from late phase 
clinical trials, reports from patient registries), from 
parties seeking participation in the trial through 
reporting of cases directly to the sponsor’s Medical 
Information Center, or from the sponsor’s new or 
ongoing clinical trials. Once a patient with HSTCL has 
been identified, the treating physician will be contacted 
and invited to participate in the study. When the 
physician agrees to participate, study related 
information will be provided to the physician for 
submission to the affiliated Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC).  Each 
STUDY EVALUATIONS/PROCEDURES
The sponsor (or delegate) will identify cases of HSTCL through 
the sponsor’s adverse event reporting system. Cases reported 
to the sponsor’s Medical Information Center will be queried 
to ascertain if the reporter is interested in participating in the 
study. Where appropriate, cases may also be identified 
through the sponsor’s new or ongoing clinical trials and 
registries.
Once a patient with HSTCL has been identified, the treating 
physician will be contacted and invited to participate in the 
study. When the physician agrees to participate, study related 
information will be provided to the physician for submission to 
the affiliated Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC). Each patient (or their legal 
representative) must give written informed consent as 


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patient must give written consent according to local 
requirements after the nature of this research study has 
been fully explained. The informed consent form (ICF) 
must be signed before any study-related activity is 
performed. The ICF used must be approved by both the 
sponsor and the reviewing IRB/IEC and acceptable to 
the investigator. The ICF should be in accordance with 
principles that originated in the Declaration of Helsinki, 
current International Conference on Harmonisation 
(ICH) and Good Clinical Practice (GCP) guidelines, 
applicable regulatory requirements, and the sponsor’s 
policy.  
The collection and processing of personal data from 
patients enrolled in this study will be limited to data 
necessary to fulfill the objectives of the study. Sample 
data and corresponding relevant demographic and 
clinical data will be made non-identifiable by the 
removal of personal identifiers and are to be sent to the 
sponsor in coded form, in which the patient is identified 
by means of a study number. The code should be 
retained at the study site of the treating physician(s). 
Samples collected will be shipped under protocol-
defined conditions as described in the laboratory 
reference manual to the sponsor’s (or delegate’s) 
bioanalytical facility for storage and future analysis. 
Samples will be shipped with a unique identifier to 
maintain confidentiality. 
A patient may withdraw their consent for this research 
study at any time by contacting the sponsor through the 
contact information given on the ICF. The sponsor will 
destroy any remaining samples upon receipt of such a 
request. However, sample testing that has already taken 
place will be retained by the sponsor to avoid 
compromising data analysis. Detailed instructions for 
sample collection/processing and shipments will be 
defined in a laboratory reference manual.
described in Section 8.1.2.
The collection and processing of personal data from patients 
enrolled in this study will be limited to data necessary to fulfill 
the objectives of the study. Sample data and corresponding 
relevant demographic and clinical data will be made non-
identifiable by the removal of personal identifiers and are to be 
sent to the sponsor in coded form, in which the patient is 
identified by means of a study number. The code should be 
retained at the study site of the treating physician(s). Samples 
collected will be shipped under protocol-defined conditions as 
described in the laboratory reference manual to the sponsor’s 
(or delegate’s) bioanalytical facility for storage and future 
analysis. Samples will be shipped with a unique identifier to 
maintain confidentiality. Samples may be kept and used for up 
to 15 years after the study is completed; see also Section 8.1.2, 
Informed Consent, for sample handling if a patient withdraws 
consent. Detailed instructions for sample collection/processing 
and shipments will be defined in a laboratory reference manual.
Section 5.1. Sample Collection, 
entire section revised 
beginning with 2nd sentence in 
5.1.
Study Procedures
… every effort is to be made to obtain a single blood 
sample, a buccal swab sample, and a bowel tissue 
5.1.
Sample Collection
… every effort is to be made to obtain a single blood sample, a 
buccal swab sample, and/or a bowel tissue sample as described 


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Section 5.1
(This section was previously 
titled Study Procedures. Note 
that the section was revised for 
clarity.)
sample as described in further detail in the following 
subsections.
5.1.1.
Tumor Biopsy Tissue Sample
A sample of the tumor biopsy tissue, including lining 
tissue if available, originally used for the diagnosis of 
HSTCL …
5.1.2.
Blood Sample
A single blood sample is requested. The estimated total 
blood volume to be collected from each patient will be 
based on patient weight as per the table below.  
Table 1:  
Blood sample and volume collected
Blood Sample Type
Blood Volume
(total volume 
approximately 
37 mL)
Serum
5 mL (2 x 2.5 mL)
Whole blood for RNA
5 mL (2 x 2.5 mL)
Whole blood for DNA
‘10 mL (2 x 5 
mL) 
Whole blood for cellular analysis*
17 mL (2 x 8.5 
mL)*
*obtain sample only if patient weight is ≥ 45 kg
in further detail in the following subsections.
5.1.1 Tumor Biopsy Tissue Sample
A sample of the tumor biopsy tissue, including adjacent non-
tumor tissue if available, originally used for the diagnosis of 
HSTCL … 
5.1.2
Additional Samples
5.1.2.1
Blood and/or Buccal Swab Samples
A single blood and/or buccal swab sample is requested (each 
optional) for genomic DNA analysis. 
The estimated total blood volume to be collected from each 
patient will be based on patient weight as per the table below. 
Table 1:  Blood sample and volume collected
Blood Sample Type
Blood Volume
(total volume 
approximately 20 - 37 
mL) *
Serum
5 mL (2 x 2.5 mL)
Whole blood for RNA
5 mL (2 x 2.5 mL)
Whole blood for DNA
10 mL (2 x 5 mL) 
Whole blood for cellular 
analysis
17 mL (2 x 8.5 mL)*
* Obtain whole blood sample for cellular analysis only if 
patient weight is ≥ 45 kg


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5.1.3.
Buccal Swab Sample
A buccal swab sample is requested to determine the 
patient tissue type, and a sample collection kit will be 
provided. Buccal swabs will be used to collect cells 
from the cheek area inside the mouth of the patient.  
5.1.4.
Bowel Tissue Sample 
If possible, a sample of bowel tissue is requested …
5.2 Sample Collection and Handling
Buccal swabs will be used to collect cells from the cheek area 
inside the mouth of the patient.  
5.1.2.2
Bowel Tissue Sample
If possible, a sample of bowel tissue previously collected as 
part of the patient’s IBD diagnosis or treatment is requested 
… 
5.1.3. Sample Collection and Handling
(Note that the only change to this section was heading 
numbering)
Section 5.2. Additional Patient 
Information (Previously 
Section 5.3. Data Collection
2nd paragraph, order of 
information in numbers 1 
through 5 changed and “if 
available” was added to new 
number 4
5.3. Data Collection
The data elements that are collected from patient’s 
medical records include:
1. HSTCL diagnosis
2. Medical history including family history of cancer.
3. Diseases and medical/surgical conditions prior to or 
at the time of diagnosis (including date of diagnosis, 
treatment and medications, and outcome) including 
but not limited to the following:
4. Cytogenetic and flow cytometric data if available
5. Demographic data including age at diagnosis of 
HSTCL, gender, race, and nationality 
5.2. Data CollectionAdditional Patient Information
The data elements that are to be collected from patient’s 
medical records include:
1. HSTCL diagnosis 
2. Demographic data including age at diagnosis of HSTCL, 
gender, race, and nationality
3. Diseases and medical/surgical conditions prior to or at the 
time of diagnosis (including date of diagnosis, treatment and 
medications, and outcome) including but not limited to the 
following:
4. Medical history including family history of cancer, if 
available
5. Cytogenetic and flow cytometric data, if available
Section 5.3. Scientific Advisory 
Committee, 1st paragraph
A Scientific Advisory Committee will be established 
and will include representatives from the sponsor and 
global medical experts in the disease under study. 
Meetings will be held at regular intervals (eg, yearly) to 
review the emerging science related to HSTCL and 
latest available test methods and determine the types of 
analyses to be performed on the tissue samples 
collected. Details will be provided in a separate 
Scientific Advisory Committee Charter.
A Scientific Advisory Committee will behas been established 
and will includeincludes representatives from the sponsor and 
global medical experts in the disease under study. Meetings 
will be held at regular intervals (eg, yearly) as needed to review 
the emerging science related to HSTC and, the latest available 
test methods, and to determine the types of analyses to be 
performed on the tissue samples collected. Details will be 
provided in a separate Scientific Advisory Committee Charter.


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Section 5.4. Withdrawal from the 
Study (New Section)
(No prior text)
5.4 Withdrawal from the Study
If a patient withdraws from the study or withdraws consent, 
refer to Section 8.1.2, Informed Consent, for further details 
on handling of samples.
Section 6. Test Methods and Data 
Analysis, 
1st paragraph
In consultation with the Scientific Advisory Committee, 
a detailed analysis plan will be written (see Section 5.4).  
In consultation with the Scientific Advisory Committee (see 
Section 5.3), a detailed analysis plan will be written (see 
Section ). and statistical analysis will be done by the sponsor 
or under the authority of the sponsor. A general description of 
the statistical methods to be used is outlined below. Specific
details will be provided in the Statistical Analysis Plan.
2nd paragraph, 3rd sentence
Protein assay data will be summarized using descriptive 
statistics. Gene expression in tumor cells may be 
compared with expression levels observed in normal 
tissue lining or in bowel tissue sample…
Protein assay data will be summarized using descriptive 
statistics. Gene expression in tumor cells may be compared 
with expression levels observed in normal tissue 
liningsurrounding the tumor or in bowel tissue sample…
3nd paragraph revised
Full genome or targeted sequencing may also be used to 
reveal patterns of mutations responsible for 
development of HSTCL. Somatic mutations will be 
identified by comparing HSTCL tumor DNA with 
normal lining tissue DNA from the same biopsy 
specimen, or DNA from a bowel tissue sample, or DNA 
from Cells isolated from the buccal swabs, or DNA 
isolated from Peripheral blood mononuclear cells 
obtained from the same patient.  Buccal swab sample 
analysis will help to determine the patient’s genetic 
makeup and the bowel tissue sample analysis will help 
to perform mutation analysis of IBD to the tumor.  
Full genome or targeted sequencing may also be used to reveal 
patterns of mutations responsible for development of HSTCL. 
Somatic mutations will be identified by comparing HSTCL 
tumor DNA withfrom the same patient from the following: 

The normal liningadjacent tissue DNAfrom the same 
biopsy specimen, or DNA from a

The bowel tissue sample, or DNA from

Cells isolated from the buccal swab, or DNA isolated from 

Peripheral blood mononuclear cells. obtained from the same 
patient.  Buccal swab sample analysis will help to 
determine the patient’s genetic makeup and the bowel tissue 
sample analysis will help to perform mutation analysis of 
IBD to the tumor.  
Section 7. Adverse Event 
Reporting, new last paragraph
(No prior text)
During the conduct of this study, adverse events may be 
reported that are related to venipuncture for blood sample 
collection or buccal swab collection as described in Section 
7.2.
7.1.1. Adverse Event Definitions 
and Classifications
7.1.1. Adverse Event Definitions and Classifications
(Section heading and text deleted, no new text)
Section 7.1, 2nd paragraph under 
*Medical and scientific judgment should be exercised in 
*Medical and scientific judgment should be exercised in 


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Serious Adverse Event
deciding whether other situations should be considered 
serious, such as important medical events that might not 
be immediately life threatening or result in death or 
hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other 
outcomes listed above.
deciding whether expedited reporting is also appropriate in
other situationsshould be considered serious, such as important 
medical events that might not be immediately life threatening 
or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other 
outcomes listed above. These should usually be considered 
serious.
Section 7.2. Reporting and Follow-
up of Serious Adverse Events, 
1st paragraph
There is no administration of study drug. This study is 
designed to collect a tissue sample from the biopsy 
specimen that was used to diagnose HSTCL, and if 
possible, to obtain a single blood sample, a buccal swab 
sample, and a bowel tissue sample. Samples obtained 
will be stored by the sponsor or delegate for future 
testing.
(Text deleted)
Section 7.2. Reporting and Follow-
up of Serious Adverse Events 
2nd paragraph, 1st sentence
The only potential adverse event related to this study 
would be secondary to the venipuncture that is 
performed to obtain a blood sample. This may cause 
bruising at the venipuncture site. Fainting, and in rare 
cases infection, may occur.  Adverse events that are 
associated with these study interventions will be 
captured within the study database.
The only potential adverse events related to this study would be 
secondary to the venipuncture that is performed to obtain a 
blood sample. This or buccal swab. Venipuncture may cause 
bruising at the venipuncture site. Fainting, and in rare cases 
infection, may occur. The buccal swab, which will be done 
against the inside of a patient’s cheek, may cause irritation and 
bleeding. Adverse events that are associated with these study 
interventions (eg, bruising or infection at venipuncture site, 
fainting, irritation, and bleeding at the inside of the cheek 
from the buccal swab) will be captured within the study 
database.
3rd paragraph
All serious adverse events that are considered as related 
to study intervention (ie, venipuncture) will be followed 
until resolution, stabilization, or follow-up is no longer 
possible.
All serious adverse events that are considered as related to 
study intervention (ieeg, venipuncture) will be followed until 
resolution, stabilization, or follow-up is no longer possible.
Section 8.1.1. IEC/IRB, 4th
paragraph
… for review and approval before implementation of 
the change(s). 
… for review and approval before implementation of the 
change(s). If applicable, at least once a year, the IEC/IRB will 
be asked to review and reapprove this study, where required.
Section 8.1.2. Informed Consent, 
1st paragraph 2nd sentence 
deleted
Patients will be informed that their participation is 
voluntary and that they may withdraw consent to 
participate at any time. They will be informed that 
Patients will be informed that their participation is voluntary
and that they may withdraw consent to participate at any time. 
They will be informed that choosing not to participate will not 


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Amended/New Content
choosing not to participate will not affect the care the 
patient will receive for the treatment of his or her 
disease. Finally, they will ….
affect the care the patient will receive for the treatment of his or 
her disease. Finally, they will ….
5th paragraph, 2nd sentence 
revised
…typically patients 7 years of age and older… 
… typically patients 7 6 years of age and older…   
6th paragraph revised and 7th
paragraph added
A patient may withdraw their consent for this research 
study at any time by contacting the sponsor through the 
contact information given on the ICF. The sponsor will 
destroy any remaining samples upon receipt of such a 
request. However, sample testing that has already taken 
place will be retained by the sponsor to avoid 
compromising data analysis. Detailed instructions for 
sample collection/processing and shipments will be 
defined in a laboratory reference manual.
Patients will be informed that their participation is voluntary 
and that they may withdraw consent to participate at any time 
by contacting the sponsor through the contact information 
given on the ICF. They will be informed that choosing not to 
participate will not affect the care he/she will receive for the 
treatment of his/her disease. The sponsor will destroy any 
remaining samples upon receipt of such a request. However, 
sample testing that has already taken place will be retained by 
the sponsor to avoid compromising data analysis.
Consent from a legally acceptable representative of a 
deceased patient will be obtained for enrollment into the study 
and sample collection.
Section 8.1.4. Long-Term Storage 
of Samples for Future 
Research 
Samples will be stored for an indefinite period of time 
by sponsor or delegate, until an expert panel (ie, 
Scientific Advisory Committee) decides on the 
appropriate analyses of the samples (see Section 5.4)
Samples may be kept and used for up to 15 years after the 
study is completed; see also Section 8.1.2, Informed Consent, 
for sample handling if a patient withdraws consent.
Section 9.2.2. Required Prestudy 
Documentation, 1st paragraph, 
new last bullet
(no prior text)

Any other documentation required by local regulations
Section 9.3. Source 
Documentation, last paragraph
At a minimum, the type and level of detail of source 
data available for a study patient should be consistent 
with that commonly recorded at the site as a basis for 
standard medical care.
At a minimum, the type and level of detail of source data 
available for a study patient should be consistent with that 
commonly recorded at the site as a basis for standard medical 
care and recorded in the CRF (see Section 5.2).
Section 9.6. Record Retention, 
2nd paragraph
Essential documents must be retained until at least 
formal discontinuation of the study. These documents
…
Essential documents must be retained until at least formal 
discontinuation of the study2 years after the last approval of a 
marketing application in an ICH region and until there are 
no pending or contemplated marketing applications in an 
ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the 
investigational product. These documents …


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Amended/New Content
New last paragraph
(No prior text)
The study will be considered complete upon submission of the 
final clinical study reports to the FDA for the two 
postmarketing requirements for which this study is being 
conducted.
Section 9.7. Use of Information and 
Publication (Note that the entire 
section was revised; only the 
revised text is shown in the 
Amended/New Content column.)
Results of this study will be presented in a final study 
report. The sponsor shall have the right to publish such 
data and information without approval from any 
participating investigator. Study patient identifiers will 
not be used in publication of results. For any 
publications or presentations that may contain 
patentable patient matter which, at the sponsor’s 
discretion, warrants intellectual property protection, the 
sponsor may delay any publication or presentation for 
up to 60 days for the purpose of pursuing such 
protection. Contributions to the study by investigators 
will be recognized by an acknowledgment or authorship 
based on guidelines described in the Uniform 
Requirements for Manuscripts Submitted to Biomedical 
Journals.
The results of the study will be reported in a Clinical Study 
Report generated by the sponsor and will contain data from 
all study sites that participated in the study as per protocol. 
Study subject identifiers will not be used in publication of 
results. Any work created in connection with performance of 
the study and contained in the data that can benefit from 
copyright protection (except any publication by the 
investigator as provided for below) shall be the property of the 
sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International 
Committee of Medical Journal Editors guidelines, the sponsor 
shall have the right to publish such primary (multicenter) 
data and information without approval from the investigator. 
The investigator has the right to publish study site-specific 
data after the primary data are published. If an investigator 
wishes to publish information from the study, a copy of the 
manuscript must be provided to the sponsor for review at least 
60 days before submission for publication or presentation. 
Expedited reviews will be arranged for abstracts, poster 
presentations, or other materials. If requested by the sponsor 
in writing, the investigator will withhold such publication for 
up to an additional 60 days to allow for filing of a patent 
application. In the event that issues arise regarding scientific 
integrity or regulatory compliance, the sponsor will review 
these issues with the investigator. The sponsor will not 
mandate modifications to scientific content and does not have 
the right to suppress information. For multicenter study 
designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a 
study have been published. Similarly, investigators will 
recognize the integrity of a multicenter study by not 
submitting for publication data derived from the individual 
study site until the combined results from the completed study
have been submitted for publication, within 12 months of the 
availability of the final data (tables, listings, graphs), or the 


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Amended/New Content
sponsor confirms there will be no multicenter study 
publication. Authorship of publications resulting from this 
study will be based on the guidelines on authorship, such as 
those described in the Uniform Requirements for Manuscripts 
Submitted to Biomedical Journals, which state that the named 
authors must have made a significant contribution to the 
design of the study or analysis and interpretation of the data, 
provided critical review of the paper, and given final approval 
of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the 
results of clinical studies as required by law.


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Amendment 2 – 17 February 2014
The protocol has been revised to incorporate this amendment, which applies to all study centers. The rationale and description of the 
changes to the protocol are provided below. Minor formatting and typographical errors have also been corrected to improve the clarity 
and accuracy of the protocol text; these changes do not affect the overall conduct of the study.
1. Description/Rationale:  Janssen Research & Development is a global organization that operates through different legal entities; therefore, references 
to specific legal entities have been updated as appropriate on the Title Page and, within the body of the protocol, references to specific legal entities 
have been removed and replaced with the term “sponsor.”
Sections Affected
Original Content
Amended/New Content
Title Page
No original content or Janssen Biotech Inc.
Janssen Scientific Affairs, LLC 
Throughout the protocol as 
appropriate
Reference to specific legal entities, eg, Janssen Biotech, 
Inc.; JBI
Sponsor
2. Description/Rationale:  The protocol has been expanded to include SIMPONI® (golimumab) in order to fulfill a postmarketing commitment to the 
Food and Drug Administration (FDA).
Sections Affected
Original Content
Amended/New Content
Title Page
REMICADE® (infliximab)
REMICADE® (infliximab)
SIMPONI® (golimumab)
Synopsis, Purpose (sentence 1)
8. Ethical Aspects (sentence 1)
This study is being conducted to address a postmarketing 
requirement…..
This study is being conducted to address a 2 postmarketing 
requirements…..
3. Description/Rationale:  The protocol has been expanded to include Canada in addition to the United States.
Sections Affected
Original Content
Amended/New Content
Throughout the document as 
appropriate
US
US North America
3. Study Design (paragraph 6)
For each pediatric patient, his or her parent(s) (preferably 
both parents, if available) or a legally acceptable 
representative(s), as required by US regulations, must 
give written consent (permission) according to US 
requirements after the nature of the study has been fully 
explained and before the performance of any study-
related assessments.
For each pediatric patient, his or her parent(s) (preferably both 
parents, if available) or a legally acceptable representative(s), 
as required by US local regulations, must give written consent 
(permission) according to US local requirements after the 
nature of the study has been fully explained and before the 
performance of any study-related assessments.
Throughout the document as 
appropriate
Institutional Review Board (IRB)
Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC)


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4. Description/Rationale:  The objective and protocol content were modified to clarify that the objective of the study is to identify markers that may 
predispose patients to HSTCL, not to identify biomarkers that may allow for an earlier diagnosis.
Sections Affected
Original Content
Amended/New Content
Synopsis, Objective
2. Objective
The objective of this study is to collect samples from 
IBD patients diagnosed with HSTCL for the purpose of 
identifying biomarkers that may allow either earlier 
evaluation of a patient’s risk of developing HSTCL or 
possibly earlier diagnosis.
The objective of this study is to collect samples from IBD 
patients diagnosed with HSTCL for the purpose of identifying 
biomarkers that may allow either earlier evaluation of a 
patient’s risk of developing HSTCL or possibly earlier 
diagnosis.
1.1. Purpose (sentence 1)
The United States (US) Food and Drug Administration 
(FDA) has requested that Janssen Biotech, Inc. (referred 
to hereafter as JBI or the sponsor) collect samples for the 
purpose of identifying biomarkers that may allow either 
earlier evaluation of a patient’s risk of developing 
hepatosplenic T-cell lymphoma (HSTCL) or possibly 
earlier diagnosis.
The United States (US) Food and Drug Administration (FDA) 
has requested that the sponsor collect samples for the purpose 
of identifying biomarkers that may allow either earlier 
evaluation of a patient’s risk of developing hepatosplenic T-
cell lymphoma (HSTCL) or possibly earlier diagnosis.
1.2. Hepatosplenic T-cell 
Lymphoma (paragraph 1, last 
sentence)
DNA, RNA, or protein biomarkers may provide a 
method to identify patients predisposed to develop 
HSTCL or may allow earlier diagnosis of HSTCL in 
these patient populations.
DNA, RNA, or protein biomarkers may provide a method to 
identify patients predisposed to develop HSTCL or may allow 
earlier diagnosis of HSTCL in these patient populations.
5. Description/Rationale:  The content of the protocol was modified to clarify that a sample of the biopsy specimen used to confirm the diagnosis of 
HSTCL is required; moreover, while not required, every effort is to be made to obtain additional samples including a single blood sample, a buccal 
swab sample, and if already available, a bowel tissue sample.
Sections Affected
Original Content
Amended/New Content
Synopsis, Overview of Study 
Design (paragraph 1, sentence 1)
3. Study Design (paragraph 1, 
sentence 1)
This study is designed to collect a single blood sample, if 
possible, and obtain tissue samples from the biopsy 
specimen that was used to diagnose HSTCL. Other 
specimens requested may include a buccal swab sample 
(to determine the patient tissue type and establish non-
mutated DNA baseline) and a bowel tissue sample (if 
available for mutation analysis between the tumor and T 
cells residing in the bowel to attempt to determine the 
origin of the tumor clone). 
This study is designed to collect a single blood sample, if 
possible, and obtain tissue samples from the biopsy specimen 
that was used to diagnose HSTCL, and if possible, to obtain a 
single blood sample, . Other specimens requested may include 
a buccal swab sample (to determine the patient tissue type and 
establish non-mutated deoxyribonucleic acid [DNA] baseline),
and a bowel tissue sample (if available for mutation analysis 
between the tumor and T cells residing in the bowel to attempt 
to determine the origin of the tumor clone). 


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Synopsis, Evaluations (original 
paragraph 2 removed, new 
paragraph 2 revised)
Patients will be asked to provide a single blood sample 
that will be used for the test procedures that are part of 
this study. 
Other specimens requested may include a buccal swab 
sample (to determine the patient tissue type and establish 
non-mutated DNA baseline) and a bowel tissue sample 
(if available for mutation analysis between the tumor and 
T cells residing in the bowel to attempt to determine the 
origin of the tumor clone). 
Patients will be asked to provide a single blood sample that 
will be used for the test procedures that are part of this study. 
In addition, if possible, every effort is to be made to obtain 
other specimens requested may including a single blood 
sample, a buccal swab sample (to determine the patient tissue 
type and establish non-mutated DNA baseline) and a bowel 
tissue sample (if available for mutation analysis between the 
tumor and T cells residing in the bowel to attempt to 
determine the origin of the tumor clone). 
1.1. Purpose (sentence 2)
Medical and surgical information, samples from the 
biopsy used to diagnose HSTCL, and a blood sample 
will be requested from each patient and stored by the 
sponsor for future testing.
Medical and surgical information, samples from the biopsy 
used to diagnose HSTCL, and if possible, additional samples 
(a single blood sample, a buccal swab sample, and a bowel 
tissue sample) will be requested from each patient and stored 
by the sponsor or its delegate for future testing.
3. Study Design (paragraph 8)
Patients will be asked to provide a single blood sample, a 
buccal swab sample, and a bowel tissue sample if 
available (discretionary) to be used for the test 
procedures that are part of this study.
In addition, if possible, every effort is to be made to obtain 
additional samples including, Patients will be asked to 
provide a single blood sample, a buccal swab sample, and a 
bowel tissue sample if available (discretionary) to be used for 
the test procedures that are part of this study.
5.1. Study Procedures (new 
paragraph 1)
No previous content
A tissue sample from the biopsy specimen used to diagnose 
HSTCL is required for this study. In addition, although not 
required for entry into the study, every effort is to be made to 
obtain a single blood sample, a buccal swab sample, and a 
bowel tissue sample as described in further detail in the 
following subsections.
7.2. Reporting and Follow-up of 
Serious Adverse Events 
(paragraph 1, sentence 2)
This study is designed to collect a single blood sample, if 
possible, and obtain tissue samples from the biopsy 
specimen that was used to diagnose HSTCL. Samples 
obtained will be stored by the sponsor for future testing. 
This study is designed to collect a single blood sample, if 
possible, and obtain tissue sample from the biopsy specimen 
that was used to diagnose HSTCL, and if possible, to obtain 
a single blood sample, a buccal swab sample, and a bowel 
tissue sample. 


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6. Description/Rationale:  The content of the protocol was modified to clarify that the planned duration of sample collection for this study is 6 years.
Sections Affected
Original Content
Amended/New Content
1.1. Purpose (sentence 3)
Because HSTCL is rare, it is expected that samples will
be collected over approximately 6 years.
The planned duration for sample collection is 6 years.
3. Study Design (paragraph 9)
It is anticipated that it will take approximately 6 years to 
collect samples for analyses because of the rare 
occurrence of HSTCL.
The planned duration for sample collection is 6 years.
7. Description/Rationale:  Text was reorganized in Section 1.2 Hepatosplenic T-cell Lymphoma for clarity. No substantive changes were made with the 
exception of additional information that provides context for the addition of golimumab to the protocol, and to remove the statement that no cases of 
HSTCL have been reported in rheumatoid arthritis patients as one such case has been identified in the sponsor database. Note that references were 
updated accordingly.
Sections Affected
Original Content
Amended/New Content
1.2. Hepatosplenic T-cell 
Lymphoma (revised paragraphs 1 
through 3) 
Hepatosplenic T-cell lymphoma (HSTCL) is a rare and 
aggressive subtype of peripheral T-cell lymphoma with a 
poor prognosis (Herrinton, 2011; de Leval, 2011). 
HSTCL generally shows T cell proliferation, particularly 
in the sinusoids of the liver or spleen, without lymph 
node enlargement. It is also occasionally diagnosed 
through bone marrow aspirate and, later in its course, 
malignant T-cells can be found in peripheral blood. In 
the US, the incidence is approximately 0.3 cases per 
million person-years in the general population. However, 
in patients with immune mediated conditions such as 
inflammatory bowel disease (IBD) or acquired immune 
deficiency syndrome, the incidence increases as much as 
100-fold. HSTCL has also been reported in organ 
transplant patients (Tey, 2008). DNA, RNA, or protein 
biomarkers may provide a method to identify patients 
predisposed to develop HSTCL or may allow earlier 
diagnosis of HSTCL in these patient populations.
Literature describing the clinical and presenting features 
of patients with HSTCL has recently been reviewed 
(Tripido, 2009). Diagnosis is typically confirmed by 
bone marrow, liver, or spleen biopsy using histologic, 
flow cytometric and cytogenetic analyses. The tumor 
cells are generally γ/δ T cells with a Vδ1 variable region, 
positive for CD3 and occasionally positive for CD8 or 
Hepatosplenic T-cell lymphoma (HSTCL) is a rare and 
aggressive subtype of peripheral T-cell lymphoma with a poor 
prognosis (Herrinton, 2011; de Leval, 2011). HSTCL 
generally shows T cell proliferation, particularly in the 
sinusoids of the liver or spleen, without lymph node 
enlargement. It is also occasionally diagnosed through bone 
marrow aspirate and, later in its course, malignant T-cells can 
be found in peripheral blood. In the US, the incidence is 
approximately 0.3 cases per million person-years in the 
general population. However, in patients with immune 
mediated conditions such as inflammatory bowel disease 
(IBD) or acquired immune deficiency syndrome, the incidence 
increases as much as 100-fold. HSTCL has also been reported 
in organ transplant patients (Tey, 2008). DNA, RNA, or 
protein biomarkers may provide a method to identify patients 
predisposed to develop HSTCL.
or may allow earlier 
diagnosis of HSTCL in these patient population..
Specific risk factors that contribute to HSTCL in patients 
with IBD have been reviewed (Kotylar, 2010; Kotylar, 2011), 
and include gender (> 90% male); age (90% under 35 years 
of 
age); 
treatment 
with 
thiopurines 
such 
as 
6-
mercaptopurine or azathioprine (100%); treatment with a 
tumor necrosis factor (TNF) inhibitor such as infliximab 
(REMICADE®; 56%, all with concomitant thiopurine 
treatment); and duration of thiopurine treatment (97% >2 


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CD56 but negative for CD4. The chromosomal 
abnormality isochromosome 7q has been reported in 
many cases (Alonsozana, 1997; Kotlyar, 2010).   
Specific risk factors that contribute to HSTCL in patients 
with IBD have been reviewed (Koltyar, 2010; Koltyar, 
2011). These specific risk factors in IBD include gender 
(>90% male); age (90% under 35 years of age); 
treatment with thiopurines such as 6-mercaptopurine or 
azathioprine (100%); and treatment with a tumor 
necrosis factor (TNF) inhibitor such as infliximab 
(REMICADE®; 56%, all with concomitant thiopurine 
treatment); and duration of thiopurine treatment (97% >2 
years). Of note, no cases of HSTCL have been reported 
in rheumatoid arthritis patients treated with infliximab 
(Koltyar, 2010; Herrinton, 2011).
years). HSTCL has also been reported in patients treated 
with other TNF inhibitors such as adalimumab (Ochenrider, 
2010), and other monoclonal antibodies with other 
mechanisms of action such as natalizumab (Kotylar, 2010). 
Although most published cases of HSTCL have occurred in 
immunocompromised individuals, a recent study describes 
some 
patients 
with 
no 
history 
of 
immune-related 
comorbidities or immunosuppressive therapy (Voss, 2013). 
Literature describing the clinical and presenting features of 
patients with HSTCL has recently been reviewed (Tripido, 
2009). Diagnosis is typically confirmed by bone marrow, 
liver, or spleen biopsy using histologic, flow cytometric, and 
cytogenetic analyses. The tumor cells are generally γ/δ T 
cells with a Vδ1 variable region, positive for CD3 and 
occasionally positive for CD8 or CD56 but negative for CD4. 
The chromosomal abnormality isochromosome 7q has been 
reported in many cases (Alonsozana, 1997; Kotylar, 2010).
1.3. Overall Rationale for the Study 
(Number 2) 
Although HSTCL is only observed in infliximab-treated 
IBD patients who received infliximab in combination 
with a thiopurine, TNF blockade may also increase 
susceptibility for developing HSTCL. Therefore, genes 
that are part of the TNF signaling pathway may also 
influence susceptibility for HSTCL.
Although HSTCL is generally observed in infliximab-treated 
IBD patients who received infliximab in combination with a 
thiopurine, TNF blockade may also increase susceptibility for 
developing HSTCL independent of thiopurine exposure. 
Therefore, genes that are part of the TNF signaling pathway 
may also influence susceptibility for HSTCL.
8. Description/Rationale:  Instructions were modified such that the sponsor may use a delegate during the study. 
Sections Affected
Original Content
Amended/New Content
Throughout the document as 
appropriate 
sponsor
sponsor or its delegate
sponsor (or delegate)
9. Description/Rationale:  Content was corrected in Section 5.1.4 to clarify that a bowel tissue sample is to be collected.
Sections Affected
Original Content
Amended/New Content
5.1.4. Bowel Tissue Sample 
(paragraph 1)
A sample of bowel tissue is requested (optional) if a 
specimen is already available. The sample will be used 
for mutation analysis of IBD to tumor.  Approximately 
ten 6-micron sections of the formalin-fixed, paraffin-
embedded tumor are required (approximately 50 
milligrams of the tumor biopsy).
If possible, a sample of bowel tissue is requested (optional) if 
a specimen is already available. The sample will be used for 
mutation analysis of IBD to tumor.  Approximately ten, 6-
micron sections of the formalin-fixed, paraffin-embedded 
tumor tissue are required (approximately 50 milligrams of the 
tumor bowel tissue biopsy).


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10.
Description/Rationale:  Content in Section 5.1.4 Bowel Tissue Sample was moved to Section 5.2 Sample Collection and Handling for clarity.
Sections Affected
Original Content
Amended/New Content
5.2 Sample Collection and 
Handling (previously last 
paragraph in Section 5.1.4; now 
first paragraph in Section 5.2)
Tubes for the blood samples, the buccal swab collection 
kit, and the slides for tumor biopsy tissue and bowel 
tissue samples will be provided to the patient’s physician 
with specific instructions for collection, labeling, storing, 
and shipping to the sponsor or delegate.
Collection tubes for the blood samples, the buccal swab 
collection kit, and the slides for tumor biopsy tissue and bowel 
tissue samples will be provided to the patient’s physician with 
specific instructions for collection, labeling, storing, and 
shipping to the sponsor or delegate.
11. Description/Rationale:  Content in Section 5.3 Data Collection instructions were modified for clarity.
5.3 Data Collection (paragraph 1)
For each identified case of HSTCL for which the treating 
physician(s) agreed to participate, the investigator or an 
authorized member of the investigational staff will 
collect data from the patient’s medical records to a CRF 
at a data collection visit at the treating physician(s) site.
For each identified case of HSTCL for which the treating 
physician(s) agreed to participate, the investigator or an 
authorized member of the investigational staff will collect data 
from the patient’s medical records
and transfer this 
information to the to a CRF at a data collection visit at the 
treating physician(s) site.
12.
Description/Rationale:  The Steering Committee was relabeled as the Scientific Advisory Committee for consistency across sponsor 
documents. In addition, the description of the members of the Scientific Advisory Committee was modified for accuracy in Section 5.4.
Sections Affected
Original Content
Amended/New Content
Throughout the document as 
appropriate
Steering Committee
Steering Scientific Advisory Committee
5.4 Scientific Advisory Committee 
(paragraph 1, sentence 1)
A Scientific Advisory Committee will be established and 
include representatives from the sponsor, appropriate 
expert health authority representatives, and global 
medical experts in the disease under study.
A Scientific Advisory Committee will be established and will 
include representatives from the sponsor, appropriate expert 
health authority representatives, and global medical experts in 
the disease under study.


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13.
Description/Rationale:  Section 7.1.1 Adverse Event Definitions and Classifications were updated to reflect the most recent guidance 
recommendations.
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Original Content
Amended/New Content
7.1.1. Adverse Event Definitions 
and Classifications, Serious 
Adverse Event (paragraphs 1, 2, 
and 3)
A serious adverse event based on ICH is any untoward 
medical occurrence that at any dose:
•
Results in death 
•
Is life-threatening
(The patient was at risk of death at the time of the 
event. It does not refer to an event that hypothetically 
might have caused death if it were more severe.)
•
Requires inpatient hospitalization or prolongation of 
existing hospitalization
•
Results in persistent or significant 
disability/incapacity
•
Is a congenital anomaly/birth defect
•
Is a suspected transmission of any infectious agent via 
a medicinal product
•
Is medically important*
A serious adverse event based on ICH and European Union 
(EU) Guidance on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence 
that at any dose:
•
Results in death 
•
Is life-threatening
(The patient was at risk of death at the time of the event. It 
does not refer to an event that hypothetically might have 
caused death if it were more severe.)
•
Requires inpatient hospitalization or prolongation of 
existing hospitalization
•
Results in persistent or significant disability/incapacity
•
Is a congenital anomaly/birth defect
•
Is a suspected transmission of any infectious agent via a 
medicinal product
•
Is medically important*
*Medical and scientific judgment should be exercised in 
deciding whether expedited reporting is also appropriate 
in other situations, such as important medical events that 
may not be immediately life threatening or result in 
death or hospitalization but may jeopardize the patient or 
may require intervention to prevent one of the other 
outcomes listed in the definition above. These should 
usually be considered serious.
*Medical and scientific judgment should be exercised in 
deciding whether other situations should be considered 
serious, such as important medical events that might not be 
immediately life threatening or result in death or 
hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes 
listed above.
For reports of hospitalization, it is the sign, symptom, or 
diagnosis which led to hospitalization that is the serious 
event for which details must be provided.
14.
Description/Rationale:  Content was clarified that while adverse events will be reported as solicited reports, these reports will not necessarily 
be reported via postmarketing routes only.
Sections Affected
Original Content
Amended/New Content
7.2. Reporting and Follow-up of 
Serious Adverse Events 
(paragraph 3, last sentence)
All other adverse events/serious adverse events that are 
identified through the study data collection processes and 
not associated with study interventions (ie, blood draw, 
buccal swabbing) will be reported as solicited reports via 
the postmarketing routes. 
All other adverse events/serious adverse events that are 
identified through the study data collection processes and not 
associated with study interventions (ieeg, blood draw, buccal 
swabbing) will be reported as solicited reports via the 
postmarketing routes. 


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Amendment 1 – 26 March 2013
The protocol has been revised to incorporate this amendment, which applies to all study centers. The rationale and description of the 
changes to the protocol are provided below. Minor formatting and typographical errors have also been corrected to improve the clarity 
and accuracy of the protocol text; these changes do not affect the overall conduct of the study.
1. Description/Rationale:  Revisions were made to allow for the collection of additional specimens (ie, buccal swab sample, and bowel tissue sample, if 
available).  In additional to a single blood sample (if possible) and tissue samples from the biopsy specimen used to diagnose HSTCL, other specimens requested 
may now include a buccal swab sample (to determine the patient tissue type and establish non-mutated DNA baseline) and a bowel tissue sample (if available for 
mutation analysis between the tumor and T cells residing in the bowel to attempt to determine the origin of the tumor clone).
Sections Affected
Original Content
Amended/New Content
Synopsis (Overview of Study 
Design, paragraph 1; Evaluations, 
new paragraph 3 added; 
3 Study Design (paragraph 1)
3 Study Design (paragraph 8)
Synopsis (Statistical Methods, 
paragraph 3)
This study is designed to collect a single blood sample, if 
possible, and obtain tissue samples from the biopsy 
specimen that was used to diagnose HSTCL. Samples 
obtained will be stored by the sponsor for future testing. In 
addition, demographic and clinical patient information will 
be collected. The study will be conducted in the US only.
Patients will be asked to provide a single blood sample that 
will be used for the test procedures that are part of this 
study.
Full genome or targeted sequencing may also be used to 
reveal patterns of mutations responsible for development of 
HSTCL. Somatic mutations will be identified by 
comparing HSTCL tumor DNA with normal tissue lining 
DNA from the same biopsy specimen or DNA isolated 
from peripheral blood mononuclear cells obtained from the 
This study is designed to collect a single blood sample, if 
possible, and obtain tissue samples from the biopsy 
specimen that was used to diagnose HSTCL. Other 
specimens requested may include a buccal swab sample 
(to determine the patient tissue type and establish non-
mutated DNA baseline) and a bowel tissue sample (if 
available for mutation analysis between the tumor and 
T cells residing in the bowel to attempt to determine the 
origin of the tumor clone). Samples obtained will be 
stored by the sponsor for future testing. In addition, 
demographic and clinical patient information will be 
collected. The study will be conducted in the US only.
Patients will be asked to provide a single blood sample, a 
buccal swab sample, and a bowel tissue sample if 
available (discretionary) to be used for the test 
procedures that are part of this study.
Full genome or targeted sequencing may also be used to 
reveal patterns of mutations responsible for development of 
HSTCL. Somatic mutations will be identified by 
comparing HSTCL tumor DNA with normal lining tissue 
DNA from the same biopsy specimen , or DNA from a 


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5.1  Study Procedures
(new subsection headings added; 
table header added, table row 1 
edited title, table row 5 deleted)
same patient. Individual mutations will be tabulated within 
and between patients and cross-referenced with human 
variation databases (eg, COSMIC, dbSNP, etc.). To 
identify cancer driver genes or pathways, somatic mutation 
frequencies will be evaluated per gene or pathway across 
all patients with HSTCL and compared with empirical 
background mutation rates by mutation type (Wendl, 2011; 
Youn, 2011).
5.1  Study Procedures
A sample of the tumor biopsy tissue, including lining tissue 
if available, originally used for the diagnosis of HSTCL 
must be provided to JBI. Approximately ten 6-micron 
sections of the formalin-fixed, paraffin-embedded tumor 
are required (approximately 50 milligrams of the tumor 
biopsy). 
A single blood sample is required. The estimated total 
blood volume to be collected from each patient will be 
based on patient weight as per the table below.  
Tubes for the blood samples and the slides for tumor 
samples will be provided to the patient’s physician with 
specific instructions for collection, labeling, storing, and 
shipping to the sponsor.
bowel tissue sample, or DNA from cells isolated from 
the buccal swabs, or DNA isolated from peripheral blood 
mononuclear cells obtained from the same patient. Buccal 
swab sample analysis will help to determine the 
patient’s genetic makeup and the bowel tissue sample 
analysis will help to perform mutation analysis of IBD 
to the tumor. Individual mutations will be tabulated within 
and between patients and cross-referenced with human 
variation databases (eg, COSMIC, dbSNP, etc.). To 
identify cancer driver genes or pathways, somatic mutation 
frequencies will be evaluated per gene or pathway across 
all patients with HSTCL and compared with empirical 
background mutation frequencies by mutation type 
(Wendl, 2011; Youn, 2011).
5.1.1  Tumor Biopsy Tissue Sample
A sample of the tumor biopsy tissue, including lining tissue 
if available, originally used for the diagnosis of HSTCL 
must be provided to JBI or designee. Approximately ten 6-
micron sections of the formalin-fixed, paraffin-embedded 
tumor are required (approximately 50 milligrams of the 
tumor biopsy).
5.1.2  Blood Sample
A single blood sample is requested. The estimated total 
blood volume to be collected from each patient will be 
based on patient weight as per the table below.
Table:  Blood sample and volume collected
Blood Sample Type
Blood Volume (total 
volume approximately 37 
mL)
5.1.3  Buccal Swab Sample
A buccal swab sample is requested to determine the
patient tissue type, and a sample collection kit will be 
provided.  Buccal swabs will be used to collect cells 
from the cheek area inside the mouth of the patient.  


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5.2  Sample Collection and Handling
(paragraph 2)
6  Test Methods and Data Analysis
(paragraph 2 and paragraph 3)
Instructions for the collection, handling, and shipment of 
samples are found in the laboratory reference manual.
Descriptive statistics of demographic information, 
information on medical/surgical (including treatment) 
history, and baseline characteristics at the time of HSTCL 
diagnosis will be summarized for all patients enrolled in 
this study.  Protein assay data will be summarized using 
descriptive statistics. Gene expression in tumor cells may 
be compared with expression levels observed in normal 
tissue lining or with cells isolated from whole blood with 
moderated t-statistics or other appropriate statistical 
methods.
Full genome or targeted sequencing may also be used to 
reveal patterns of mutations responsible for development of 
HSTCL. Somatic mutations will be identified by 
comparing HSTCL tumor DNA with normal tissue lining 
DNA from the same biopsy specimen or DNA isolated 
from peripheral blood mononuclear cells obtained from the 
same patient. Individual mutations will be tabulated within 
and between patients and cross-referenced with human 
variation databases (eg, COSMIC, dbSNP, etc.). To 
5.1.4  Bowel Tissue Sample
A sample of bowel tissue is requested (optional) if a 
specimen is already available.  The sample will be used 
for mutation analysis of IBD to tumor.  Approximately 
ten 6-micron sections of the formalin-fixed, paraffin-
embedded tumor are required (approximately 50 
milligrams of the tumor biopsy). 
Tubes for the blood samples, the buccal swab collection 
kit, and the slides for tumor biopsy tissue and bowel 
tissue samples will be provided to the patient’s physician 
with specific instructions for collection, labeling, storing, 
and shipping to the sponsor.
Please refer to the laboratory reference manual for 
detailed instructions for the collection, handling, and 
shipment of blood, tissue, and buccal swab samples. 
Descriptive statistics of demographic information, 
information on medical/surgical (including treatment) 
history, and baseline characteristics at the time of HSTCL 
diagnosis will be summarized for all patients enrolled in 
this study.  Protein assay data will be summarized using 
descriptive statistics. Gene expression in tumor cells may 
be compared with expression levels observed in normal 
tissue lining or in bowel tissue sample, or with cells 
isolated from whole blood or from buccal swabs with 
moderated t-statistics or other appropriate statistical 
methods.
Full genome or targeted sequencing may also be used to 
reveal patterns of mutations responsible for development of 
HSTCL. Somatic mutations will be identified by 
comparing HSTCL tumor DNA with normal lining tissue 
DNA from the same biopsy specimen, or DNA from a 
bowel tissue sample, or DNA from cells isolated from 
the buccal swabs, or DNA isolated from peripheral blood 


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7.2  Reporting and Follow-up of 
Serious Adverse Events (paragraph 
3, last sentence)
8.  Ethical Aspects
identify cancer driver genes or pathways, somatic mutation 
frequencies will be evaluated per gene or pathway across 
all patients with HSTCL and compared with empirical 
background mutation rates by mutation type (Wendl, 2011; 
Youn, 2011).  
All other adverse events/serious adverse events that are 
identified through the study data collection processes and 
not associated with study interventions (ie, blood draw) 
will be reported as solicited reports via the postmarketing 
routes.  
This study is being conducted to address a postmarketing 
requirement by the US FDA to bank blood and/or tissue 
samples for future evaluation aiming at identifying genetic 
mutations and other biomarkers that predispose IBD 
patients to develop HSTCL. No medical or scientific 
benefit will be provided to patients who participate in the 
study; however, future patients at risk for developing 
HSTCL may benefit from the results of this research. 
mononuclear cells obtained from the same patient. Buccal 
swab sample analysis will help to determine the 
patient’s genetic makeup and the bowel tissue sample 
analysis will help to perform mutation analysis of IBD 
to the tumor. Individual mutations will be tabulated 
within and between patients and cross-referenced with 
human variation databases (eg, COSMIC, dbSNP, etc.). To 
identify cancer driver genes or pathways, somatic mutation 
frequencies will be evaluated per gene or pathway across 
all patients with HSTCL and compared with empirical 
background mutation frequencies by mutation type 
(Wendl, 2011; Youn, 2011).
All other adverse events/serious adverse events that are 
identified through the study data collection processes and 
not associated with study interventions (ie, blood draw, 
buccal swabbing) will be reported as solicited reports via 
the postmarketing routes.  
This study is being conducted to address a postmarketing 
requirement by the US FDA to bank blood, buccal cells, 
and/or tissue samples for future evaluation to identify 
genetic mutations and other biomarkers that may 
predispose IBD patients to develop HSTCL. No medical or 
scientific benefit will be provided to patients who 
participate in the study; however, future patients at risk for 
developing HSTCL may benefit from the results of this 
research. 


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2. Description/Rationale: Revisions were made to include identification of HSTCL cases that may have been reported directly through the sponsor’s 
Medical Information Center.  This change may provide an increase in sample size. 
Sections Affected
Original Content
Amended/New Content
Synopsis (Overview of Study 
Design, paragraph 2)
3  Study Design (paragraph 2)
5  Study Evaluations (paragraph 1)
The study population will include IBD patients in the US 
with HSTCL who are identified through the sponsor’s 
adverse event reporting systems. Cases of HSTCL will be 
identified through postmarketing adverse event reporting 
(eg, spontaneous reports, reports from late phase clinical 
trials, reports from patient registries) or from the sponsor’s 
new or ongoing clinical trials. Eligible for enrollment are 
male or female patients of any age who have a confirmed 
diagnosis of HSTCL.
The study population will include IBD patients in the US 
with HSTCL who are identified through the sponsor’s 
adverse event reporting systems. Cases of HSTCL will be 
identified through the sponsor’s postmarketing adverse 
event reporting system (eg, spontaneous reports, reports 
from late phase clinical trials, reports from patient 
registries), from parties seeking participation in the trial 
through reporting of cases directly to the sponsor’s 
Medical Information Center, or from the sponsor’s new 
or ongoing clinical trials. Eligible for enrollment are male 
or female patients of any age who have a confirmed 
diagnosis of HSTCL.   
3. Description/Rationale: An exclusion criterion was added for any who are unable to provide critical clinical and/or demographic patient and/or 
sample information. 
Sections Affected
Original Content
Amended/New Content
4.2  Exclusion Criteria (criterion 2 
added)
2.  Unable to provide critical clinical and/or 
demographic patient and/or sample information.
4. Description/Rationale: Data collected were revised with clarifications and to include collection of information on medical history including family 
history of cancer. 
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Original Content
Amended/New Content
5.3 Data Collection (paragraph 2 
numbered items)
The data elements that are collected from patient’s medical 
records include:
1.
HSCTL diagnosis
a. Diagnosis confirmation
b. Clinical course
c. 
Type 
and 
duration 
of 
treatment 
with 
corticosteroids 
and 
any 
immunomodulator 
therapies (including biologics) prior to and at time 
of diagnosis of lymphoma
The data elements that are collected from patient’s medical 
records include:
1.
HSCTL diagnosis
a. Diagnosis confirmation and date. Tumor stage 
and findings that support staging including 
system used.
b. Clinical course
c. Type, dose, and duration of treatment with 
corticosteroids and any immunomodulator 
therapies (including biologics) prior to and at time 


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2.
Diseases and medical/surgical conditions prior to 
or at the time of diagnosis (including date of 
diagnosis, 
treatment 
and 
medications, 
and 
outcome) including but not limited to the 
following:
a. Autoimmune disease 
b. Cancer
c. Organ transplant
d. Infection with human immunodeficiency virus 
(HIV)
3.
Cytogenetic and flow cytometric data if available
4.
Demographic data including age at diagnosis, 
gender, race, and nationality 
of diagnosis of lymphoma
2.
Medical history including family history of 
cancer.
3.
Diseases and medical/surgical conditions prior to 
or at the time of diagnosis (including date of 
diagnosis, treatment and medications, and 
outcome) including but not limited to the 
following:
a. Autoimmune disease 
b. Cancer
c. Organ transplant
d. Infection with human immunodeficiency virus 
(HIV)
4.
Cytogenetic and flow cytometric data if available
5.
Demographic data including age at diagnosis of 
HSTCL, gender, race, and nationality 


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INVESTIGATOR AGREEMENT
PPD