Clinical trial NCT05442554
Conditions: T-Cell Lymphoma
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2022-11-28; Completion date: 2024-08-09
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main aim is to check the long-term side effects of treatment with Brentuximab Vedotin and to see if that treatment improves symptoms of cluster of differentiation antigen 30 (CD30-Positive) Cutaneous T-Cell Lymphoma in Chinese adults.

Participants will receive brentuximab vedotin through the vein on day 1 of each 21 day cycle up to maximum 16 cycles.

Detailed description:
The drug being tested in this study is called brentuximab vedotin (SGN-35). Brentuximab vedotin is being tested to treat people who have CD30-positive cutaneous T-Cell lymphoma.

The study will enroll approximately 10 patients. Participants will receive a single treatment i.e., brentuximab vedotin monotherapy:

• Brentuximab vedotin 1.8 mg/kg

Participants will be administered with brentuximab vedotin by intravenous (IV) infusion given for approximately 30 minutes on Day 1 of each 21-day cycle up to 16 cycles followed by the end of treatment (EOT) visit 30 days after receiving the final dose of study drug. Participants with progressive disease (PD) at any time during the study will be discontinued from study drug.

This multi-center trial will be conducted in China. Participants will remain in this study for approximately 56 weeks.

Arms: arm 1: Participants received brentuximab vedotin 1.8 milligrams per kilogram (mg/kg), IV on Day 1 of each 21-day cycle for up to a total of 16 cycles.
Interventions: intervention 1: Brentuximab vedotin
Intervention descriptions: intervention 1: Brentuximab vedotin IV infusion.

Protocol documents:
Prot_000.pdf: 
For non-commercial use only


PROTOCOL
A Phase 4, Single Arm, Open Label, Multicenter Study of Brentuximab Vedotin Treatment 
of Chinese Patients With CD30-Positive Cutaneous T-Cell Lymphoma
Sponsor:
Takeda Development Center Americas, Inc.
Study Number:
C25029
EudraCT Number:
Not Applicable
Compound:
Brentuximab vedotin (SGN-35)
Date:
31 January 2022
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her 
staff, and applicable institutional review committee and regulatory agencies to enable conduct of the study.
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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts 
A separate contact information list will be provided to each site.
Serious adverse event (SAE) and pregnancy reporting information is presented in Section 10.0, 
as is information on reporting product complaints. 
The names and contact information for the medical monitor and responsible medical officer are 
in the study manual.
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1.2
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance with the 
following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH) E6 Good Clinical Practice (GCP): Consolidated
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, clinical
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer can be found on the signature page.
Electronic Signatures may be found on the last page of this document.
, MD
Project Clinician,
Clinical Science,
Date
, PhD
Project Statistician,
Biostatistics, 
Date
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 
prescribing information, and any other product information provided by the sponsor. I agree to 
conduct this study in accordance with the requirements of this protocol and also to protect the 
rights, safety, privacy, and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

ICH, E6 Good Clinical Practice: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting SAEs defined in Section 10.0 of this protocol.

Terms outlined in the clinical study site agreement.

Responsibilities of the investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix B of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
2.0
STUDY SUMMARY ....................................................................................................10
3.0
STUDY REFERENCE INFORMATION ......................................................................12
3.1
Study-Related Responsibilities.................................................................................12
3.2
Principal Investigator/Coordinating Investigator ......................................................12
3.3
List of Abbreviations ...............................................................................................13
3.4
Corporate Identification...........................................................................................14
4.0
INTRODUCTION.........................................................................................................15
4.1
Background .............................................................................................................15
4.1.1
Overview of Cutaneous T-cell lymphoma........................................................15
4.1.2
CD30+ CTCL Subtypes...................................................................................15
4.1.2.1
CTCL Subtypes .......................................................................................15
4.1.2.2
Other CD30+ CTCL Subtypes .................................................................16
4.1.2.3
Prognosis and Staging..............................................................................16
4.1.2.4
Symptom Burden.....................................................................................17
4.1.3
Standard of Care..............................................................................................17
4.1.4
Rationale for the Use of Brentuximab Vedotin to Treat CTCL.........................18
4.2
Rationale for the Proposed Study.............................................................................19
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................19
5.1
Objectives................................................................................................................19
5.1.1
Primary Objective............................................................................................19
5.1.2
Secondary Objectives ......................................................................................19
5.1.3
Safety Objective ..............................................................................................19
5.2
Endpoints.................................................................................................................19
5.2.1
Primary Endpoint.............................................................................................19
5.2.2
Secondary Endpoints .......................................................................................19
5.2.3
Safety Endpoints..............................................................................................20
6.0
STUDY DESIGN..........................................................................................................20
6.1
Overview of Study Design.......................................................................................20
6.2
Number of Patients ..................................................................................................20
6.3
Duration of Study ....................................................................................................21
6.3.1
Duration of an Individual Patient’s Study Participation....................................21
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6.3.2
End of Study/Study Completion Definition and Planned Reporting..................21
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures ......21
6.3.4
Total Study Duration .......................................................................................22
6.3.5
Posttrial Access ...............................................................................................22
7.0
STUDY POPULATION................................................................................................22
7.1
Inclusion Criteria .....................................................................................................22
7.2
Exclusion Criteria ....................................................................................................23
8.0
STUDY DRUG .............................................................................................................25
8.1
Study Drug Administration......................................................................................25
8.2
Dose Modification Guidelines..................................................................................25
8.2.1
Criteria for Beginning or Delaying a Subsequent Treatment Cycle, and 
Discontinuation of Study Drug.........................................................................25
8.2.2
Criteria for Dose Reduction .............................................................................26
8.3
Excluded Concomitant Medications and Procedures ................................................27
8.4
Permitted Concomitant Medications and Procedures................................................27
8.5
Precautions and Restrictions ....................................................................................27
8.6
Management of Clinical Events ...............................................................................28
8.6.1
Nausea and/or Vomiting ..................................................................................28
8.6.2
Diarrhea...........................................................................................................28
8.6.3
Management of Infusion-Related Reactions.....................................................28
8.6.4
Management of Peripheral Neuropathy............................................................29
8.6.5
Management of PML.......................................................................................29
8.7
Blinding and Unblinding..........................................................................................29
8.7.1
Electrocardiogram ...........................................................................................29
8.8
Description of Investigational Agents ......................................................................29
8.9
Preparation, Reconstitution, and Dispensation..........................................................30
8.10
Packaging and Labeling...........................................................................................30
8.11
Storage, Handling, and Accountability.....................................................................30
9.0
STUDY CONDUCT......................................................................................................31
9.1
Study Personnel and Organizations..........................................................................31
9.2
Arrangements for Recruitment of Patients................................................................31
9.3
Study Procedures.....................................................................................................31
9.3.1
Informed Consent ............................................................................................31
9.3.2
Patient Demographics......................................................................................31
9.3.3
Medical History...............................................................................................31
9.3.4
Physical Examination ......................................................................................31
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9.3.5
Patient Height..................................................................................................32
9.3.6
Patient Weight .................................................................................................32
9.3.7
Vital Signs.......................................................................................................32
9.3.8
Pregnancy Test ................................................................................................32
9.3.9
Concomitant Medications and Procedures........................................................32
9.3.10
Adverse Events................................................................................................32
9.3.11
Enrollment.......................................................................................................32
9.3.12
ECG ................................................................................................................33
9.3.13
Clinical Laboratory Evaluations.......................................................................33
9.3.13.1
Clinical Chemistry, Hematology, and Urinalysis......................................33
9.3.14
Disease Assessment.........................................................................................34
9.3.15
Response Assessment ......................................................................................34
9.3.15.1
Cutaneous Disease Response Assessment................................................34
9.3.16
Skin Biopsies...................................................................................................41
9.4
Completion of Study Treatment (for Individual Patients) .........................................41
9.5
Completion of Study (for Individual Patients)..........................................................42
9.6
Discontinuation of Treatment With Study Drug and Patient Replacement................42
9.7
Withdrawal of Patients From Study .........................................................................42
9.8
Study Compliance....................................................................................................43
10.0
ADVERSE EVENTS ....................................................................................................43
10.1
Definitions...............................................................................................................43
10.1.1
AE Definition ..................................................................................................43
10.1.2
SAE Definition................................................................................................43
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................44
10.3
Monitoring of AEs and Period of Observation .........................................................45
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........45
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................46
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........46
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................46
11.1
Independent Data Monitoring Committee ................................................................46
12.0
DATA HANDLING AND RECORDKEEPING............................................................47
12.1
eCRFs......................................................................................................................47
12.2
Record Retention .....................................................................................................47
13.0
STATISTICAL METHODS..........................................................................................47
13.1
Statistical and Analytical Plans ................................................................................47
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13.1.1
Analysis Sets ...................................................................................................48
13.1.2
Analysis of Demographics and Other Baseline Characteristics.........................48
13.1.3
Efficacy Analysis.............................................................................................48
13.1.3.1
Analysis of Primary Efficacy Endpoints ..................................................48
13.1.3.2
Analyses of Secondary Efficacy Endpoints..............................................48
13.1.4
Safety Analysis................................................................................................49
13.2
Interim Analysis and Criteria for Early Termination ................................................49
13.3
Determination of Sample Size..................................................................................50
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................50
14.1
Study-Site Monitoring Visits ...................................................................................50
14.2
Protocol Deviations..................................................................................................50
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................50
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................51
15.1
IRB and/or IEC Approval ........................................................................................51
15.2
Subject Information, Informed Consent, and Subject Authorization .........................52
15.3
Subject Confidentiality ............................................................................................53
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................53
15.4.1
Publication.......................................................................................................53
15.4.2
Clinical Trial Registration................................................................................54
15.4.3
Clinical Trial Results Disclosure......................................................................54
15.5
Insurance and Compensation for Injury....................................................................54
16.0
REFERENCES..............................................................................................................55
LIST OF IN-TEXT TABLES
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................21
Table 8.a
Recommended Brentuximab Vedotin Dose Modifications for 
Treatment-Associated Toxicity ..........................................................................26
Table 9.a
Clinical Chemistry and Hematology Tests..........................................................33
Table 9.b
Clinical Urinalysis Tests ....................................................................................34
Table 9.c
mSWAT............................................................................................................35
Table 9.d
Response in Skin................................................................................................37
Table 9.e
Response in Lymph Nodes a...............................................................................38
Table 9.f
Response in Viscera...........................................................................................39
Table 9.g
Response in Blood .............................................................................................40
Table 9.h
Global Response Score ......................................................................................41
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LIST OF IN-TEXT FIGURES
Figure 9.a
mSWAT Percentage of TBSA for 12 Main Body Areas .....................................36
LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................59
Appendix B
Responsibilities of the Investigator.....................................................................62
Appendix C
ECOG Scale for Performance Status ..................................................................64
Appendix D
NYHA Classification of Cardiac Disease ...........................................................65
Appendix E
TNMB Classification and Clinical Staging System for MF.................................66
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2.0
STUDY SUMMARY
Name of Sponsor: Takeda Development Center Americas, 
Inc.
Compound: Brentuximab vedotin (SGN-35)
Title of Protocol: A Phase 4, Single Arm, Open Label, 
Multicenter Study of Brentuximab Vedotin Treatment of 
Chinese Patients With CD30-Positive Cutaneous T-Cell 
Lymphoma
EudraCT No.:
Not Applicable
Study Number: C25029
Phase: 4
Study Design:
This is a phase 4, open-label, single-arm, multicenter, postapproval commitment study to be conducted in China. All 
patients must have histologically-confirmed CD30-positive (CD30+) mycosis fungoides (MF) or primary cutaneous 
anaplastic large cell lymphoma (pcALCL) by local pathology assessment. CD30+ is defined as ≥10% target 
lymphoid cells demonstrating membrane, cytoplasmic, and/or Golgi staining pattern for CD30 at any intensity above 
background staining as noted on the corresponding negative control. Patients will receive treatment with 
brentuximab vedotin monotherapy on Day 1 of each 21-day cycle for up to 16 cycles total. 
Patients will receive study drug for up to 16 cycles of treatment with brentuximab vedotin. Patients with progressive 
disease (PD) at any time during the study will be discontinued from study drug. Patients with increasing modified 
severity weighted assessment tool (mSWAT) before assessment at the end of Cycle 3 will be allowed to continue 
therapy until the Cycle 3 assessment if, in the investigator’s opinion, the findings are due to tumor flare rather than 
PD.
Objective response over the course of the study, per investigator assessment, will be assessed by global response 
score, which consists of skin evaluation (mSWAT), nodal and visceral radiographic assessment, and detection of 
circulating Sézary cells (MF only). Objective response will be evaluated at the end of Cycles 3, 6, 9, 12, and 15, and 
at the end of treatment (EOT) visit.
Safety will be evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE), Version 5.0, by the incidence of treatment-emergent adverse events (TEAEs), severity and 
type of adverse events (AEs), and by changes from baseline in the patient’s vital signs, Eastern Cooperative 
Oncology Group (ECOG) performance status, and clinical laboratory results in the safety population. The study will 
be closed when all patients complete the EOT visit. 
Primary Objective: 
To determine the objective response rate (ORR) lasting at least 4 months with brentuximab vedotin in patients with 
CD30+ MF or pcALCL.
Secondary Objectives:

To determine the complete response (CR) rate with brentuximab vedotin

To determine the ORR with brentuximab vedotin

To assess the duration of response (DOR) with brentuximab vedotin.
Safety Objective:

To assess the safety of brentuximab vedotin.
Subject Population: Male or female Chinese patients at least 18 years of age with a diagnosis of CD30+ pcALCL 
who have received at least 1 prior systemic therapy or prior radiation therapy, or CD30+ MF who have received at 
least 1 prior systemic therapy for their disease.
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Number of Subjects:
Approximately 10 evaluable patients
Number of Sites: 
Approximately 3 to 5 investigative sites in China
Dose Level:
Brentuximab vedotin 1.8 mg/kg of each 21 day treatment 
cycle
Route of Administration:
Intravenous (IV)
Duration of Treatment: Up to 16 cycles
Period of Evaluation: Patients will be screened up to 
28 days before first dose of the study drug, receive 
study drug for up to 16 cycles, and will have an EOT 
assessment visit 30±2 days after receiving the final 
dose of study drug. The study will be closed when all 
patients complete the EOT visit. 
Main Criteria for Inclusion:
Patients ≥18 years of age with diagnosis of MF or pcALCL.
Eligible histologies include:

Histologically-confirmed CD30+ disease for MF or pcALCL at screening, defined as ≥10% CD30 expression.

Patients with pcALCL who have received prior radiation therapy or at least 1 prior systemic therapy; patients 
with MF who have received at least 1 prior systemic therapy.
Other inclusion criteria include:

Adequate bone marrow reserve and renal and hepatic function based on the laboratory parameters.

Radiographically or clinically measurable or evaluable disease.
Main Criteria for Exclusion:

Concurrent diagnosis of systemic anaplastic large cell lymphoma, or other non-Hodgkin lymphoma (excluding 
lymphomatoid papulosis).

Patients with a history of progressive multifocal leukoencephalopathy or known active cerebral/meningeal 
disease related to the underlying malignancy.
Main Criteria for Evaluation and Analyses:
Efficacy:
The primary efficacy endpoint for this study is the ORR lasting at least 4 months with brentuximab vedotin in 
Chinese patients with CD30+ MF or pcALCL.
The secondary efficacy endpoints for this study are: CR rate with brentuximab vedotin, ORR with brentuximab 
vedotin, DOR with brentuximab vedotin. 
Safety:
The secondary safety endpoints for this study are: incidence of TEAEs, SAEs, changes from baseline in the, 
patient’s vital signs, ECOG performance status, clinical laboratory results. 
Statistical Considerations:
For all efficacy and safety assessments, descriptive summaries and analyses will be performed. 
Sample Size Justification: Per China Health Authority requirement, approximately 10 evaluable patients with 
CD30+ MF or pcALCL are needed for this postapproval commitment study. All efficacy analyses will be based on 
the full analysis set (FAS), which is defined as all enrolled patients identified as CD30+ and received at least 1 dose 
of the study drug. The response-evaluable population will include a subset of the FAS patients with measurable 
disease at baseline and with at least 1 post-baseline response assessment. The safety analysis set will consist of all 
enrolled patients who receive at least 1 dose of study drug. 
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the 
clinical supplier list in the study manual. The identified vendors will perform specific 
study-related activities either in full or in partnership with the sponsor.
3.2
Principal Investigator/Coordinating Investigator
Takeda will select a signatory coordinating investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research, and study participation. The signatory coordinating investigator will be required to 
review and sign the clinical study report (CSR) and by doing so agrees that it accurately 
describes the results of the study.
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3.3
List of Abbreviations
AE(s)
adverse event(s)
ALT
alanine aminotransferase
AST
aspartate aminotransferase
CD30+
CD30-positive
CR
complete response
CSR
clinical study report
CT
computed tomography
CTCL
cutaneous T-cell lymphoma
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EORTC
European Organisation for Research and Treatment of Cancer
EOT
end of treatment
FAS
full analysis set
FDG
fluorodeoxglucose
GCP
Good Clinical Practice
GRS
Global Response Score
HRQoL
health-related quality of life
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IEC
independent ethics committee
IRB
institutional review board
IV
intravenous
IxRS
Interactive Response System
JCV
John Cunningham virus
LPD
lymphoproliferative disorders
LyP
lymphomatoid papulosis
MF
mycosis fungoides
MRI
magnetic resonance imaging
mSWAT
modified severity weighted assessment tool
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NYHA
New York Heart Association
ORR
objective response rate
OS
overall survival
pcALCL
primary cutaneous anaplastic large cell lymphoma 
PD
progressive disease/disease progression
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PET
positron emission tomography
PML
progressive multifocal leukoencephalopathy
PR
partial response
QOL
quality of life
SAE(s)
serious adverse event(s)
sALCL
systematic anaplastic large cell lymphoma
SAP
statistical analysis plan
SD
stable disease
SDTs
skin-directed therapies
SS
Sézary syndrome 
SUSAR
suspected unexpected serious adverse reactions
TBSA
total body surface
TEAE(s)
treatment-emergent adverse event(s)
TNMB
tumor-node-metastasis-blood (classification)
TSEBT
total skin electron beam therapy 
ULN
upper limit of the normal range
US
United States
USP
United States Pharmacopeia
WHO
World Health Organization
3.4
Corporate Identification 
TDC Americas Takeda Development Center Americas, Inc.
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4.0
INTRODUCTION
4.1
Background
4.1.1
Overview of Cutaneous T-cell lymphoma
Cutaneous T-cell lymphoma (CTCL) is a subset of extranodal non-Hodgkin lymphoma arising 
from malignant transformation of mature skin-resident or skin-infiltrating T cells (Girardi et al. 
2004). Clinical manifestations in the skin are variable, but the burden of the skin disease is 
considerable. Patches and plaques may persist for years and eventually spread and progress to 
tumors; dissemination to lymph nodes and visceral organs is a late manifestation associated with 
poor prognosis (Agar et al. 2010). In Europe, CTCL represents 75% to 80% of cutaneous 
lymphomas, but this distribution is known to vary worldwide (Willemze et al. 2005).
4.1.2
CD30+ CTCL Subtypes
CTCL is classified into several major subtypes according to clinical, histological, and 
cytogenetic features (Swerdlow et al. 2008; Swerdlow et al. 2016). Subtypes that are commonly 
associated with CD30 expression include mycosis fungoides (MF), Sézary syndrome (SS), and 
the primary cutaneous CD30+ T-cell lymphoproliferative disorders (LPDs), primary cutaneous 
anaplastic large cell lymphoma (pcALCL) and lymphomatoid papulosis (LyP).
4.1.2.1
CTCL Subtypes
The common subtypes MF and CD30+ T-cell LPDs constitute more than 70% of CTCL cases. 
MF accounts for 44% of all cutaneous lymphomas and approximately 55% of all CTCL cases 
(Bradford et al. 2009; Imam et al. 2013). A chronic, relapsing disease with a protracted course, it 
occurs most often in middle-aged to elderly adults, with a higher incidence in men than in 
women; this difference increases with age. Classic MF typically presents with well-defined, 
often pruritic and/or erythematous patches and plaques that may eventually evolve to tumors; all 
of these lesion types can be present concomitantly (Jawed et al. 2014). Individuals with MF can 
develop a morphologic transformation from small-and intermediate-sized cerebriform tumor 
cells to a large cell variant (transformed MF) that is also associated with a more aggressive 
disease course and reduced overall survival (OS) (Arulogun et al. 2008). CD30 expression in MF 
is variable and heterogeneous, but the available data suggest that it may be present in most cases 
(Edinger et al. 2009). 
Primary cutaneous CD30+ T-cell LPDs are the second most common CTCL subtype, accounting 
for approximately 15% of all CTCL cases (Bradford et al. 2009; Imam et al. 2013). pcALCL 
presents in adults as solitary or localized nodules that may undergo partial necrosis and 
resolution but do not spontaneously regress. The tumor cells involve the dermis extensively and 
may infiltrate subcutaneous tissue but show little infiltration of the epidermis (Kempf et al. 
2011). A diffuse infiltrate of anaplastic, strongly CD30+ tumor cells is typical of pcALCL 
lesions (Willemze et al. 2005), and diagnostic criteria for pcALCL require CD30 expression by 
≥75% of tumor cells (Kempf et al. 2011; Willemze et al. 2005).
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4.1.2.2
Other CD30+ CTCL Subtypes
LyP is a rare primary cutaneous CD30+ T-cell LPD with a waxing and waning clinical course 
defined by CD30+ lesions that may spontaneously regress (Wieser et al. 2016). Although LyP is 
considered by the World Health Organization (WHO) to be an indolent lymphoma, various 
reports have described a cumulative risk for progression of LyP to lymphoma between 2% and 
14% after 5 years, and between 30% and 80% after 20 years (Bekkenk et al. 2000; Cabanillas et 
al. 1995; el-Azhary et al. 1994; Sanchez et al. 1983). CD30+ T-cell LPD subtypes pcALCL and 
LyP are histologically similar, and the differential diagnosis is often dependent upon clinical 
presentation and disease course; cases in which a definite distinction between pcALCL and LyP 
cannot be made are designated “borderline” (Kempf et al. 2011; Swerdlow et al. 2008). 
SS is a rare, aggressive, leukemic form of CTCL that is distinguished from MF primarily on the 
basis of the presence of high levels of circulating atypical T cells (Sézary cells), extensive skin 
erythema (erythroderma), and severe pruritus (Jawed et al. 2014; Whittaker et al. 2016). While 
SS is generally considered separate from MF, progression from MF to SS is occasionally 
observed (Arulogun et al. 2008). 
Primary cutaneous gamma-delta T-cell lymphoma is a form of CTCL that accounts for less than 
1% of all primary cutaneous lymphomas, though this may be because of limitations in diagnostic 
capabilities. Primary cutaneous gamma-delta T-cell lymphoma is associated with a more 
aggressive clinical course, and CD30 expression is variable (Guitart et al. 2012).
4.1.2.3
Prognosis and Staging
CTCL is a disfiguring, incurable, and frequently debilitating disease characterized by a relapsing 
and progressive clinical course. CD30+ CTCL generally follows an indolent course in the early 
stages, but it commonly becomes refractory after repeated exposure to treatment and more 
aggressive with progression to advanced-stage systemic disease. Certain histologic findings and 
clinical presentations can distinguish patients who are at higher risk for aggressive disease and 
inferior outcomes.
Classification and staging of MF is most commonly based on the tumor-node-metastasis-blood 
(TNMB) classification criteria proposed by the International Society for Cutaneous Lymphomas 
(ISCL)/the United States Cutaneous Lymphoma Consortium (USCLC)/European Organisation 
for Research and Treatment of Cancer (EORTC) (Kim et al. 2007; Olsen et al. 2011b). For MF, 
disease stage at diagnosis dictates both prognosis and choice of treatment. Early-stage MF is 
generally associated with excellent prognosis; estimates of 5-year disease-specific survival range 
from 89% to 98% in patients with Stage IA through IIA disease (Agar et al. 2010). However, 
more advanced-stage MF is associated with substantially increased risk of mortality, with 5-year 
disease-specific survival falling to 18% to 39% in patients with Stage IVB disease (Agar et al. 
2010; Scarisbrick et al. 2015). Poor prognostic features in MF include the presence of large-cell 
transformation, folliculotropism, cutaneous tumors, extensive skin erythema (erythroderma), and 
extracutaneous disease in the blood, lymph nodes, or visceral organs (Agar et al. 2010; Arulogun 
et al. 2008; Horwitz et al. 2008; Kempf et al. 2011; Kim et al. 2003; Scarisbrick et al. 2015; 
Trautinger et al. 2006).
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The ISCL/USCLC/EORTC staging proposal for non-MF CTCL, including pcALCL, uses the 
tumor-node-metastasis (TNM) nomenclature for classification; however, because the prognostic 
and therapeutic value of this system remains to be validated in this setting, TNM classification is 
generally used descriptively for patients with primary cutaneous CD30+ T-cell LPDs (Kim et al. 
2007). Because of the chemosensitive and radiosensitive nature of the disease, OS in patients 
with primary cutaneous CD30+ T-cell LPDs is generally very good: 5-year disease-specific 
survival estimates range from 95% to 96% for pcALCL and from 73% to 100% for LyP 
(Bekkenk et al. 2000; Bradford et al. 2009; Willemze et al. 2005). However, survival prognosis 
does not reflect the disease burden that these patients suffer, which can be extremely disfiguring 
and debilitating, greatly affecting patients’ quality of life (QOL). Indications of advanced-stage 
disease at diagnosis, which portends a worse clinical course in pcALCL, include the presence of 
multifocal or extensive lesions, extensive limb involvement, and extracutaneous disease (Kempf 
et al. 2011; Trautinger et al. 2006; Woo et al. 2009). For patients with advanced/disseminated 
pcALCL, clinical features, prognosis, and treatment paradigms are similar to those with 
systematic anaplastic large cell lymphoma (sALCL). 
4.1.2.4
Symptom Burden
CTCL symptoms can be severely debilitating, and the overall burden of disease is substantial 
across disease stage and subtype. Skin involvement is frequently accompanied by cutaneous 
tumor formation, ulceration, exfoliation, pruritus, and pain (Rosen and Querfeld 2006). 
Furthermore, skin lesions are often complicated by infections, cause cosmetic disfigurement, and 
result in a loss of function in regular daily activities (Demierre et al. 2006; Horwitz et al. 2008; 
Rosen and Querfeld 2006). 
Results from a 2005 survey of 630 patients in the United States (US) with CTCL indicated that 
striking health distress was prevalent in almost all respondents, with more than half reporting 
depression, frustration, anger, or lost sleep (Demierre et al. 2006). Most respondents were 
bothered by itching (88%), scaling (83%), skin redness (94%), or pain (53%); 82% reported that 
their disease interfered with work or school, 80% reported that it prevented them from meeting 
family needs, and 80% worried about dying from their disease. Demierre et al (2006) note that 
CTCL, being both a dermatologic disease and a cancer, may have a more profound effect on 
patients’ QOL than a purely dermatologic disease (Demierre et al. 2006). 
In a study of 95 patients in Italy with CTCL, both aspects of the disease were evaluated with 
different QOL instruments. The most frequent items reported using the Skindex-29 dermatology-
focused instrument were itching and sensitive skin, being annoyed by the disease, worry that it 
could get worse, affected interactions, and impairment in sexual life; the most frequent items 
reported using the EORTC QLQ-C30 oncology-focused instrument were fatigue, pain, and 
insomnia (Sampogna et al. 2009). 
4.1.3
Standard of Care
Common treatment goals in patients with CTCL include achieving symptom control, reducing 
disease burden, and minimizing treatment-related toxicity; however, there is no single drug or 
regimen considered to be standard of care, owing to the diversity of clinical presentations 
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(Kempf et al. 2011; Trautinger et al. 2006; Zinzani et al. 2016). Early-stage CTCL is typically 
managed using a variety of skin-directed therapies (SDTs). For early-stage MF (Stages IA-IIA), 
available SDTs include topical corticosteroids or mechlorethamine, local radiation, topical 
retinoids, and phototherapy. For patients with extensive plaque, tumor, or erythrodermic disease, 
total skin electron beam therapy (TSEBT) can also be effective. For pcALCL, surgical excision 
and local radiotherapy (but not TSEBT) are common treatments for patient with solitary or 
localized disease.
Although SDTs are often effective for managing early-stage CTCL, patients frequently require 
repeated treatment courses and maintenance regimens for ongoing disease control (Horwitz et al. 
2008). With advancing disease, response rates and progression-free intervals decrease (Dreyling 
et al. 2013; Herrmann et al. 1995). Systemic agents are commonly incorporated into the 
therapeutic regimen for patients with advanced-stage disease or other adverse prognostic 
features.
Methotrexate and bexarotene are widely used treatments across CTCL diagnoses. A recent 
multicenter, collaborative review of more than 800 patients with Stage IIB or higher MF found 
that bexarotene and methotrexate were the most commonly used systemic therapies worldwide 
(Quaglino et al. 2016). Bexarotene was approved in the European Union in 2001 
(EMEA/H/C/000326) for the treatment of patients with advanced stage CTCL who are refractory 
to at least 1 prior systemic therapy. Methotrexate was licensed in 2002 in the United Kingdom 
for use in non-Hodgkin lymphoma. Methotrexate is widely used off-label across the European 
Union for the treatment of CTCL. There have been no recent advances in standard of care 
treatment of CTCL. Overall, achievement of durable responses in patients with advanced CTCL 
has been elusive. In a retrospective analysis of 198 patients with MF or SS requiring systemic 
therapy, Hughes et al (2015) reported that the median number of systemic treatments 
administered was 3, with median time to next treatment of 3.9 months for all systemic 
chemotherapies and 5.4 months for all treatments considered (Hughes et al. 2015).
4.1.4
Rationale for the Use of Brentuximab Vedotin to Treat CTCL
Brentuximab vedotin is selected for treatment of CTCL on the basis of:

Favorable benefit: risk profiles observed in pivotal studies of brentuximab vedotin for the 
treatment of sALCL (SG035-0004) (Pro et al. 2012) and Hodgkin lymphoma (SG035-0003 
and SGN35-005) (Moskowitz et al. 2015; Younes et al. 2012).

Cutaneous responses observed in patients with sALCL with cutaneous manifestations in 
pivotal Study SG035-0004 (Advani et al. 2012; Pro et al. 2012).

Positive results from an investigator-initiated phase 2 study of SGN30 (the unconjugated 
anti-CD30 antibody component of brentuximab vedotin) in patients with pcALCL, LyP, or 
transformed MF (Duvic et al. 2009). 

Positive results from the phase 3 C25001 study in patients with CD30-positive (CD30+) 
CTCL. Treatment of CTCL with brentuximab vedotin led to a highly statistically significant 
improvement in the primary endpoint (the proportion of patients with objective response 
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lasting at least 4 months [ORR4]), as determined by an independent review of the Global 
Response Score (GRS), compared with the physician’s choice comparator arm (56.3% vs 
12.5%, p<0.001). 
4.2
Rationale for the Proposed Study
The indication of brentuximab vedotin treatment in patients with CD30+ MF or pcALCL who 
have received prior systemic treatment has been approved in China based on the global pivotal 
ALCANZA (C25001) study with local Chinese data waiver. This study is a postapproval 
commitment study required by the China Health Authority to collect efficacy and safety data in 
Chinese patients in this indication. Per China Health Authority requirement, at least 10 evaluable 
patients with CD30+ MF or pcALCL are needed for this postapproval commitment study.
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective is to determine the objective response rate (ORR) lasting at least 4 months 
with brentuximab vedotin in patients with CD30+ MF or pcALCL.
5.1.2
Secondary Objectives
The secondary objectives are:

To determine the complete response (CR) rate with brentuximab vedotin

To determine the ORR with brentuximab vedotin

To assess the duration of response with brentuximab vedotin.
5.1.3
Safety Objective
The safety objective is:

To assess the safety of brentuximab vedotin.
5.2
Endpoints
5.2.1
Primary Endpoint
The primary efficacy endpoint for this study is the ORR lasting at least 4 months with 
brentuximab vedotin in Chinese patients with CD30+ MF or pcALCL.
5.2.2
Secondary Endpoints
The secondary efficacy endpoints for this study are: 

CR rate with brentuximab vedotin.
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
ORR with brentuximab vedotin.

Duration of response (DOR) with brentuximab vedotin.
5.2.3
Safety Endpoints
The secondary safety endpoints for this study are: 

Incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs).

Changes from baseline in the patient’s vital signs.

Eastern Cooperative Oncology Group (ECOG) performance status.

Clinical laboratory results. 
6.0
STUDY DESIGN
6.1
Overview of Study Design
This is a phase 4, open-label, single-arm, multicenter, postapproval commitment study to be 
conducted in China. All patients must have histologically-confirmed CD30+ MF or pcALCL by 
local pathology assessment. CD30+ is defined as ≥10% target lymphoid cells demonstrating 
membrane, cytoplasmic, and/or Golgi staining pattern for CD30 at any intensity above 
background staining as noted on the corresponding negative control. Patients will receive 
treatment with brentuximab vedotin monotherapy on Day 1 of each 21-day cycle for up to 
16 cycles total. 
Objective response over the course of the study, per investigator assessment, will be assessed by 
global response score, which consists of skin evaluation (a modified severity weighted 
assessment tool [mSWAT]), nodal and visceral radiographic assessment, and detection of 
circulating Sézary cells (MF only). Objective response will be evaluated at the end of Cycles 3, 
6, 9, 12, and 15, and at the end of treatment (EOT) visit.
Safety will be evaluated according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 5.0, by the incidence of TEAEs, severity 
and type of adverse events, and by changes from baseline in the patient’s vital signs, ECOG 
performance status, and clinical laboratory results in the safety population. The study will be 
closed when all patients complete the EOT visit.
Toxicity will be evaluated according to NCI CTCAE, Version 5.0, effective 27 November 2017 
(NCI 2017).
6.2
Number of Patients
Approximately 10 evaluable patients will be enrolled and dosed in this study from approximately 
3 to 5 study centers in China. Enrollment is defined as a patient who has been confirmed as 
eligible to participate in the study and completed the related registration in the Interactive 
Response System (IxRS).
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6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Patients will receive treatment with brentuximab vedotin monotherapy on Day 1 of each 21-day 
cycle for up to 16 cycles total. 
Patients with progressive disease (PD) at any time during the study will be discontinued from 
study drug. Patients with mSWAT before assessment at the end of Cycle 3 will be allowed to 
continue therapy until the Cycle 3 assessment if, in the investigator’s opinion, the findings are 
due to tumor flare rather than PD. 
Duration of Follow-up: Patients will be screened up to 28 days before first dose of the study 
drug, receive study drug for up to 16 cycles, and will have an EOT assessment visit 30±2 days 
after receiving the final dose of study drug. 
6.3.2
End of Study/Study Completion Definition and Planned Reporting
The study will be closed when all patients complete the EOT visit.
The final analyses for the CSR will be performed after the last patient has completed the EOT 
visit, and the report will be prepared and submitted within the timeframe that is required by 
regulatory authorities. 
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures
Refer to Table 6.a for disclosures information for all primary and secondary endpoints.
Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame
Primary efficacy endpoint
ORR lasting at least 4 months with 
brentuximab vedotin in patients with 
CD30+ MF or pcALCL
Up to 48 weeks
Secondary efficacy endpoints
CR rate with brentuximab vedotin, the 
ORR with brentuximab vedotin, and 
the DOR with brentuximab vedotin
Up to 48 weeks
Safety endpoints
Incidence of TEAEs, severity and type 
of AEs (by NCI CTCAE, Version 5.0), 
changes from baseline in the patient’s 
vital signs, ECOG performance status, 
and clinical laboratory results
Up to 48 weeks
AEs: adverse events; CR: complete response; DOR: duration of response; ECOG: Eastern Cooperative Oncology 
Group; MF: mycosis fungoides; NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse 
Events; ORR: objective response rate; pcALCL: primary cutaneous anaplastic large cell lymphoma; TEAE: 
treatment-emergent adverse events.
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6.3.4
Total Study Duration
It is anticipated that this study will last for approximately 36 months – including enrollment, 
treatment, and follow-up (EOT visit 30±2 days after receiving the final dose of study drug).
6.3.5
Posttrial Access
Posttrial access to brentuximab vedotin is not planned for this study because patients will receive
study drug until PD, unacceptable toxicity, or completion of up to 16 cycles of brentuximab 
vedotin during the study, whichever occurs first. 
7.0
STUDY POPULATION
Procedures for rescreening patients are intended to be identical to the screening procedures.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened 1 more time which requires signing the informed consent form (ICF) again and 
repeating the screening procedures. 
7.1
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be enrolled in the study:
1. Patients aged 18 years or older with diagnosis of MF or pcALCL.
2. Histologically- confirmed CD30+ disease by local laboratory assessment and pathology 
review. CD30+, defined as ≥10% target lymphoid cells demonstrating membrane, 
cytoplasmic, and/or Golgi staining pattern for CD30 at any intensity above background 
staining as noted on the corresponding negative control. (A minimum of 10% staining in at 
least 1 sample is required. Percent positivity should be determined using percent neoplastic 
cells staining first. If neoplastic cells cannot be easily distinguished from non-neoplastic, then 
percent positivity should be determined using percent total lymphocytes staining.)
3. Patients with pcALCL who have received prior radiation therapy or at least 1 prior systemic 
therapy, or patients with MF who have received at least 1 prior systemic therapy for their 
disease.
4. ECOG performance status of ≤2 (refer to Appendix C).
5. Patients with uterus and ovary/ies who:

Are postmenopausal for at least 1 year before the screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed consent through 
6 months after the last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are 
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not acceptable methods of contraception. Female and male condoms should not be used 
together.)
Patients with testis/es, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment period 
and through 6 months after the last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception. Female and male condoms should not be used 
together.)
6. Voluntary written consent must be given before performance of any study-related procedure 
not part of standard medical care, with the understanding that consent may be withdrawn by 
the patient at any time without prejudice to future medical care.
7. Suitable venous access for the study-required blood sampling.
8. Clinical laboratory values as specified below within 4 days before the first dose of study 
drug: 

Total bilirubin must be 1.5 the upper limit of the normal range (ULN).

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) must be 3 ULN. 
AST and ALT may be elevated up to 5 ULN if their elevation can be reasonably 
ascribed to the presence of metastatic disease in liver. 

Serum creatinine must be 2.0 mg/dL and/or creatinine clearance or calculated creatinine 
clearance 30 mL/minute. (The Cockcroft-Gault formula is provided in Section 9.0.)
9. Patients must have radiographically or clinically measurable or evaluable disease. 
10. A 3-week washout period is required from previous treatments (with the exception of a 
12-week washout for antibody-directed or immunoglobulin-based immune therapy, or other 
monoclonal antibody therapies), unless it is not in the best interest of the patient in the 
opinion of the investigator. Individual cases should be discussed with the project clinician 
before enrollment. 
11. Recovered (ie, Grade 1 toxicity) from the reversible effects of prior antineoplastic therapy.
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study.
1. Patients who are lactating and breastfeeding or have a positive serum pregnancy test during 
the screening period or a positive urine pregnancy test on Day 1 before first dose of study 
drug.
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2. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially 
interfere with the completion of treatment according to this protocol.
3. Treatment with radiotherapy or other skin-directed therapy or any investigational products 
within 3 weeks before the first dose of study drug.
4. A concurrent diagnosis of systemic anaplastic large cell lymphoma (ALCL), or other non-
Hodgkin lymphoma (excluding LyP).
5. A concurrent diagnosis of SS or B2 disease. 
6. Corticosteroid therapy for the treatment of CTCL within 3 weeks of first dose of study drug.
7. Known hypersensitivity to recombinant proteins, murine proteins, or any excipient contained 
in the drug formulation.
8. Life-threatening illness unrelated to cancer.
9. Severe central nervous system (CNS), pulmonary, renal, or hepatic disease not related to the 
patient’s cancer. 
10. Known active cerebral/meningeal disease, including signs or symptoms of progressive 
multifocal leukoencephalopathy (PML).
11. Known human immunodeficiency virus (HIV) positive.
12. Known hepatitis B surface antigen positive or known or suspected active hepatitis C 
infection.
13. Any severe active systemic viral, bacterial, or fungal infection within 1 week before first 
study drug dose requiring systemic antimicrobial therapy. (Oral antibiotics for prophylaxis 
are allowed.)
14. Receiving antibody-directed or immunoglobulin-based immune therapy (eg, immunoglobulin 
replacement, other monoclonal antibody therapies) within 12 weeks of first study drug dose. 
15. Any of the following cardiovascular conditions or values within 6 months before the first 
dose of study drug: 

Myocardial infarction within 6 months of enrollment.

New York Heart Association (NYHA) Class III or IV heart failure (see Appendix D). 

Evidence of current uncontrolled cardiovascular conditions, including cardiac 
arrhythmias, congestive heart failure (CHF), angina, or electrocardiographic evidence of 
acute ischemia or active conduction system abnormalities.
16. History of another primary malignancy not in remission for at least 3 years. The following 
are exempt from the 3-year limit: completely resected in situ carcinoma, such as 
nonmelanoma skin cancer and cervical carcinoma in situ on biopsy or a squamous 
intraepithelial lesion on Pap smear. 
17. Oral retinoid therapy for any indication within 3 weeks of the first dose of study drug.
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18. Systemic therapy with Vitamin A in doses of greater than 15,000 IU (5,000 mcg) per day 
(equivalent to approximately 3 times recommended daily allowance [RDA]) within 3 weeks 
before the first dose of study drug.
19. History of pancreatitis or significant risk factors for developing pancreatitis (eg, prior 
pancreatitis, uncontrolled hyperlipidemia, excessive alcohol consumption, uncontrolled 
diabetes mellitus, biliary tract disease, and medications known to increase triglyceride levels 
or to be associated with pancreatic toxicity). 
20. Any other condition that, in the opinion of the investigator or project clinician, would 
interfere with a patient’s ability to receive or complete the study. 
21. Previous receipt of brentuximab vedotin.
8.0
STUDY DRUG
Investigational medicinal product: brentuximab vedotin. 
8.1
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented 
before drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s).
Study drug will be administered by intravenous (IV) infusion given over approximately 30 
minutes on Day 1 of each 21-day cycle. In the absence of infusion toxicities, the infusion rate for 
all patients must be calculated in order to achieve a 30-minute (approximate) infusion period. 
Brentuximab vedotin must not be administered as an IV push or bolus. Study drug will be 
administered through a dedicated IV line and cannot be mixed with other medications.
The dose of brentuximab vedotin is 1.8 mg/kg. Dosing is based on patients’ weight according to 
the institutional standard; however, doses will be adjusted for patients who experience a ≥10% 
change in weight from baseline. Actual weight will be used except for patients weighing greater 
than 100 kg; dose will be calculated based on 100 kg for these individuals. The dose will be 
rounded to the nearest whole number of milligrams.
Further brentuximab vedotin administration information can be found in the pharmacy manual.
8.2
Dose Modification Guidelines
No dose escalation of brentuximab vedotin is permitted in this study.
8.2.1
Criteria for Beginning or Delaying a Subsequent Treatment Cycle, and 
Discontinuation of Study Drug
Treatment with brentuximab vedotin will use a cycle length of 21 days. Dose modification 
guidelines are provided in Table 8.a.
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Table 8.a
Recommended Brentuximab Vedotin Dose Modifications for 
Treatment-Associated Toxicity
Nonhematologic (Excluding
Neuropathy)
Hematologic
Peripheral Neuropathy
Grade 1
Continue at same dose level
Continue at same dose level
Continue at same dose level
Grade 2
Continue at same dose level
Continue at same dose level
For Grade 2 neuropathy, withhold 
dose until toxicity is Grade ≤1 or has 
returned to baseline, then restart 
treatment at a reduced dose of 
1.2 mg/kg every 3 weeks.
Grade 3
Withhold dose until toxicity is 
Grade ≤1 or has returned to 
baseline, then resume 
treatment at the same dose 
level a.
Withhold dose until toxicity is 
Grade ≤2, or has returned to 
baseline, then resume treatment at 
the same dose level b. Consider 
growth factor support 
(G-CSF or GM-CSF) for treatment 
of neutropenia and prophylaxis in 
subsequent cycles.
Withhold dose until toxicity returns 
to Grade ≤1 or baseline, then restart 
treatment at a reduced dose of 
1.2 mg/kg every 3 weeks.
Grade 4
Withhold dose until toxicity is 
Grade ≤1 or has returned to 
baseline, then reduce dose to 
1.2 mg/kg and resume 
treatment, or discontinue at the 
discretion of the investigator 
after discussion with the
sponsor a.
Withhold dose until toxicity is
Grade ≤2, then resume treatment at 
the same dose level. Consider 
growth factor support (G-CSF or 
GM-CSF) for treatment of 
neutropenia and prophylaxis in 
subsequent cycles. For the second 
occurrence of Grade 4 toxicity (if 
neutropenia, while receiving growth 
factor support), withhold dose until 
toxicity is Grade ≤2, then reduce the 
dose to 1.2 mg/kg and resume 
treatment after discussion with the 
sponsor b.
Discontinue brentuximab vedotin
CTCAE: Common Terminology Criteria for Adverse Events; G-CSF: granulocyte-colony stimulating factor; GM-CFS:
granulocyte macrophage-colonystimulating factor; NCI: National Cancer Institute.
Grading based on the NCICTCAE, Version 5.0.
a Patients who develop clinically insignificant Grade 3 or 4 electrolyte laboratory abnormalities may continuestudy 
drug without interruption.
b Patients who develop clinically insignificant Grade 3 or 4 lymphopenia may continue study drug without interruption.
Please refer to Table 8.a for guidelines regarding discontinuation of study drug. 
8.2.2
Criteria for Dose Reduction
Intrapatient dose reduction to 1.2 mg/kg brentuximab vedotin will be allowed depending on the 
type and severity of toxicity.
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Doses reduced for drug-related toxicity should generally not be resumed. However, patients may 
resume the previous dose level at the discretion of the investigator after discussion with the 
sponsor. 
8.3
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study:

Any investigational agent other than brentuximab vedotin, including agents that are 
commercially available for indications other than CTCL (including bleomycin, where use is 
contraindicated due to pulmonary toxicity).

Any antineoplastic treatment with activity against CTCL other than study drug.

Any phototherapy including psoralen with ultraviolet light A (PUVA).

Any immunotherapy (eg, immunoglobulin replacement, any other monoclonal antibody 
therapy).

Radiation therapy (note that, in general, the requirement for local radiation therapy indicates 
PD).

Long-term systemic steroids. 
8.4
Permitted Concomitant Medications and Procedures
Patients may receive concomitant hormonal therapy provided they have been on a stable dosage 
for at least 1 month before enrollment. The use of platelet and/or red blood cell supportive 
growth factors or transfusions when applicable is allowed. The use of colony stimulating factors 
for the treatment of neutropenia per institutional practice is permitted during therapy. The use of 
systemic, topical, or inhaled corticosteroids during the study for reasons other than CTCL should 
be reviewed by the investigator and project clinician. The use of corticosteroids for the 
management of complications from infusion reactions and/or anaphylaxis is permitted. Topical 
corticosteroids to relieve CTCL symptoms are permitted on an as-needed basis. Patients may 
receive treatment for prior comorbidities and AEs which are expected not to interfere with the 
trial's evaluation. 
8.5
Precautions and Restrictions
It is not known what effects brentuximab vedotin has on human pregnancy or development of the 
embryo or fetus; therefore, patients participating in this study should avoid becoming pregnant or 
avoid impregnating a partner. Nonsterilized patients of reproductive age with a uterus and/or 
ovaries and nonsterilized patients with testes/testis should use effective methods of contraception 
through defined periods during and after study treatment as specified below.
Reproductively female patients must meet 1 of the following:

Postmenopausal for at least 1 year before the screening visit, OR

Surgically sterile, OR
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
If they are of childbearing potential, agree to practice 2 effective methods of contraception 
from the time of signing of the ICF through 6 months after the last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
Reproductively male patients, even if surgically sterilized (ie, status postvasectomy), must agree 
to 1 of the following:

Agree to practice effective barrier contraception during the entire study treatment period and 
through 6 months after the last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
8.6
Management of Clinical Events 
8.6.1
Nausea and/or Vomiting
Although this study will not initially employ prophylactic anti-emetics, there is no prohibition 
against their use in the management of a patient who develops nausea and/or vomiting. As in the 
prophylactic setting, 5-hydroxytryptamine 3 serotonin receptor (5-HT3) antagonists should be 
tried first. 
8.6.2
Diarrhea
Prophylactic antidiarrheals (eg, loperamide) are not recommended in this protocol; however, 
patients may be instructed to take antidiarrheal medications at physician’s discretion until they 
are diarrhea-free for at least 12 hours. Fluid intake should be maintained to avoid dehydration.
8.6.3
Management of Infusion-Related Reactions
Infusion-related reactions may occur during the infusion of brentuximab vedotin. The infusion 
should be administered at a site properly equipped and staffed to manage anaphylaxis should it 
occur. The patient should be observed closely during and for 60 minutes following the infusion 
of brentuximab vedotin. During this observation period, the IV line should remain open for at 
least 1 hour to allow administration of IV drugs if necessary. All supportive measures consistent 
with optimal patient care will be given throughout the study according to institution standards. 
Medications for infusion-related reactions, such as epinephrine and antihistamines should be 
available for immediate use.
Patients who experience a Grade 1 or 2 infusion-related reaction may receive subsequent 
brentuximab vedotin infusions with premedication consisting of acetaminophen (650 mg orally) 
and diphenhydramine (25-50 mg orally or 10-25 mg IV) or according to institutional standards, 
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administered 30 to 60 minutes before each 30-minute (approximate) brentuximab vedotin 
infusion. The planned use of steroids as premedication is prohibited.
If anaphylaxis occurs, brentuximab vedotin administration should be immediately and 
permanently discontinued. 
8.6.4
Management of Peripheral Neuropathy
AEs of peripheral neuropathy will be monitored closely and recorded throughout the study. 
Events that are greater than Grade 1 in severity will result in brentuximab vedotin dose 
modification which shown in Table 8.a. 
8.6.5
Management of PML
Signs and symptoms of PML may include altered mental status; motor deficits, such as 
hemiparesis or ataxia; visual disturbances; or higher cortical dysfunction, such as dysphasia or 
agnosia. See the Investigator’s Brochure for further details. 
If PML is suspected, hold further brentuximab vedotin dosing and undertake a diagnostic work-
up that may include (but is not limited to): 

Neurologic examinations, as warranted.

Brain magnetic resonance imaging (MRI): features suggestive of PML include presence of 
unifocal or multifocal lesions, mainly of the white matter, which are typically nonenhancing 
and do not have mass effect.

Polymerase chain reaction analysis: John Cunningham virus (JCV) DNA detectable in 
cerebrospinal fluid or there is evidence of JCV in a brain biopsy.

Neurology consultation.
If PML is confirmed, treatment with brentuximab vedotin should be discontinued permanently.
8.7
Blinding and Unblinding
This is an open-label and single-arm study. 
8.7.1
Electrocardiogram
A 12-lead electrocardiogram (ECG) will be performed at the time points specified in the 
schedule of events. 
8.8
Description of Investigational Agents
Brentuximab vedotin for injection is a sterile, preservative-free, white to off-white lyophilized 
cake for reconstitution for IV administration. Brentuximab vedotin for Injection is supplied by 
the sponsor in single-use, Type 1 borosilicate glass vials with FluroTec-coated butyl rubber 
stoppers and aluminum seals. Each vial of the product contains brentuximab vedotin, trehalose, 
sodium citrate, and polysorbate 80. The lyophilized product, after reconstitution with 10.5 mL 
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sterile Water for Injection, United States Pharmacopeia (USP), yields 11 mL of brentuximab 
vedotin solution (5 mg/mL).
8.9
Preparation, Reconstitution, and Dispensation
Recommended safety measures for handling and preparation include masks, protective clothing, 
gloves, and vertical laminar airflow safety cabinets.
Study drug vials are single-use containers. Any partially used vials or diluted dosing solutions 
are to be discarded using appropriate institutional drug disposal procedures according to the 
guidelines in the pharmacy manual. 
The required volume of 5 mg/mL reconstituted brentuximab vedotin solution needed must be 
calculated and withdrawn from the vials. The reconstituted solution should be added 
immediately to an infusion bag containing a minimum volume of 100 mL. The dose for patients 
weighing greater than 100 kg should be calculated based on a weight of 100 kg. 
Study drug must be reconstituted with the appropriate amount of Sterile Water for Injection, USP 
(see pharmacy manual for details).
There are no known incompatibilities between study drug and polyvinyl chloride (PVC), ethyl 
vinyl acetate (EVA), polyolefin, or polyethylene (PE) bags.
The formulation contains no preservative and is intended for single use only; infusion solutions 
should be prepared and transferred using aseptic technique in a biosafety hood. 
Refer to the pharmacy manual for more specific instructions on reconstitution and use. 
8.10
Packaging and Labeling
Vials of study drug will be packaged in cardboard kits. Each kit will contain 1 vial of 
investigational product. Vials and kits will be labeled to meet country-specific regulatory 
requirements.
8.11
Storage, Handling, and Accountability
Vials containing study drug must be refrigerated at 2oC to 8oC in a secure location (eg, locked 
room) accessible only to the pharmacist, the investigator, or a duly designated person. 
Study drug does not contain preservatives; therefore, opened and reconstituted vials of study 
drug must be used within 24 hours when stored under refrigeration at 2oC to 8oC. Reconstituted 
study drug should not be stored at room temperature. It is recommended that study drug vials and 
solutions be protected from direct sunlight until the time of use. Reconstituted vials must not 
be shaken. 
Drug accountability instructions are provided in the pharmacy manual. 
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9.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and the International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines.
9.1
Study Personnel and Organizations
The contact information for the project clinician for this study, the local laboratory, the 
coordinating investigator for each member state/country, and may be found in the Investigator 
Site File. A full list of investigators is available in the sponsor’s investigator database. 
For 24-hour contact information, please refer to the Patient identification (ID) Card. 
9.2
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the institutional review board (IRB)/
independent ethics committee (IEC). 
9.3
Study Procedures
Refer to the schedule of events (Appendix A) for timing of assessments. Additional details are 
provided as necessary in the sections that follow.
9.3.1
Informed Consent
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care.
9.3.2
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening.
9.3.3
Medical History
During the screening period, a complete medical history will be compiled for each patient. The 
history will emphasize the background and progress of the patient’s malignancy and include a 
description of prior therapies for it. In addition, concomitant medications will be recorded as 
specified in Section 9.3.9.
9.3.4
Physical Examination
A physical examination will be completed per standard of care at the times specified in the 
schedule of events (Appendix A). A complete physical examination must be performed at 
screening, the extent of which should be consistent with medical history and the patient’s 
underlying disease. Subsequent physical examinations may be directed to relevant findings. 
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9.3.5
Patient Height
Height will be measured only during screening.
9.3.6
Patient Weight
Weight will be measured at screening, on Day 1 of each treatment cycle, and at EOT. 
9.3.7
Vital Signs
Vital signs measurement will be performed at the times specified in the Schedule of Events 
(Appendix A). Vital sign measurements include measurements of diastolic and systolic blood 
pressure, heart rate, and body temperature. Blood pressure should be determined with the patient 
in a seated position after the patient has been sitting quietly for 5 minutes.
9.3.8
Pregnancy Test
A serum pregnancy (choriogonadotropin beta) test will be completed for all reproductively 
female patients of childbearing potential during screening; this test must be negative for the 
patient to be enrolled. A urine pregnancy test will be performed before dosing on Day 1 of all 
cycles. The results of any pregnancy test must be negative before dosing on Day 1 of all cycles.
Additional pregnancy tests may be performed during the study at the discretion of the 
investigator, if requested by an IEC/IRB or if required by local regulations. 
9.3.9
Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will 
recorded in the electronic case report form (eCRF) from screening through 30 days after the last 
dose of brentuximab vedotin. See Section 8.3 and Section 8.4 for a list of medications and 
therapies that are prohibited or allowed during the study.
9.3.10
Adverse Events
Monitoring of adverse events (AEs), serious and nonserious, will be conducted throughout the 
study as specified in the schedule of events. Refer to Section 10.0 for details regarding 
definitions, documentation, and reporting of AEs and SAEs.
9.3.11
Enrollment
A patient is considered to be enrolled in the study when they have been confirmed as eligible to 
participate in the study and completed the related registration in IxRS system. 
Procedures for completing enrollment information are described in the study manual.
Patients who screen fail may later be rescreened once with prior sponsor approval. Any patient 
who is rescreened after screen failure must, in addition to the failed test, repeat only those 
screening tests that have fallen outside the specified screening period, as outlined in the Schedule 
of Events (Appendix A). 
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9.3.12
ECG
A 12-lead ECG will be administered at the time points specified in the Schedule of Events 
(Appendix A). ECG assessments are to be performed with the patient supine and rested for 5 
minutes. 
9.3.13
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally. Clinical laboratory evaluations will be 
performed as outlined in Section 9.3.13.1.
Sézary cell results must be available from the local lab to determine eligibility and treatment 
decisions. 
9.3.13.1
Clinical Chemistry, Hematology, and Urinalysis
Blood samples for analysis of the clinical chemistry and hematology parameters shown in 
Table 9.a and urine samples for analysis of the parameters shown in Table 9.b will be obtained as 
specified in the Schedule of Events (Appendix A).
Table 9.a
Clinical Chemistry and Hematology Tests
Hematology
Serum Chemistry
Hematocrit
Hemoglobin
Leukocytes with differential
ANC
Platelet (count)
Albumin
ALP
ALT
AST
Bilirubin (total)
BUN
Calcium
Creatinine
Lipase
Chloride
GGT)
Glucose
LDH
Magnesium
Phosphate
Potassium
Sodium
Urate
Amylase
ANC: absolute neutrophil count; ALP: alkaline phosphatase; ALT: alanine aminotransferase; aspartate 
aminotransferase; BUN: blood urea nitrogen; GGT: gamma glutamyl transferase; LDH: lactate dehydrogenase.
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Table 9.b
Clinical Urinalysis Tests
Urinalysis
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
pH
Protein
Specific gravity
Turbidity and color
Urobilinogen
If creatinine clearance is to be estimated, the Cockroft-Gault formula will be employed as 
follows:
For female patients, the result of the formula above should be multiplied by 0.85. 
For transgender patients, use the sex at birth for patients not using hormone therapy or for 
patients who have used hormone therapy for <6 months; use the current gender for patients who 
have used hormone therapy for ≥6 months. 
9.3.14
Disease Assessment
A GRS of CR, partial response (PR), stable disease (SD), PD, and relapse will be determined 
based on sequential tumor burden assessments of body compartments (skin, lymph nodes, 
viscera, and blood for MF patients) as further described below. 
Response will be determined by a composite assessment of total tumor burden:

Cutaneous disease (mSWAT) (Section 9.3.15.1.1).

Lymph node involvement (Section 9.3.15.1.3).

Visceral involvement (Section 9.3.15.1.3).

Blood (MF patients only) (Section 9.3.15.1.4).
–
Sézary cells will be enumerated by morphology and immunophenotyping.
9.3.15
Response Assessment
9.3.15.1
Cutaneous Disease Response Assessment
9.3.15.1.1
mSWAT
mSWAT will be used for MF and pcALCL and will be performed as specified in the Schedule of 
Events.
The mSWAT score calculation method and skin lesion definitions for MF and pcALCL are 
provided in Table 9.c. 
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Table 9.c
mSWAT
Body Region
% BSA in Body 
Region
Assessment of Involvement in Patient’s Skin
Patcha
Plaqueb
Tumorc
Head 
7
Neck 
2
Anterior trunk 
13
Arms 
8
Forearms 
6
Hands 
5
Posterior trunk 
13
Buttocks 
5
Thighs 
19
Legs 
14
Feet 
7
Groin 
1
Subtotal of lesion BSA
Weighting factor
x1
x2
x4
Subtotal lesion BSA x
weighting factor
BSA: body surface area; mSWAT: modified Severity Weighted Assessment Tool. 
mSWAT score equals summation of each column line.
a Any size lesion without induration or significant elevation above the surrounding uninvolved skin; poikiloderma 
may be present.
b Any size lesion that is elevated or indurated; crusting, ulceration, or poikiloderma may be present.
c Any solid or nodular lesion 1 cm in diameter with evidence of deep infiltration in the skin and/or vertical growth. 
The mSWAT score will be calculated as follows:
Sum percentage of total body surface (TBSA) from all body regions affected by patches x 
severity-weighting factor of 1
+ Sum percentage of TBSA from all body regions affected by plaques x severity-weighting 
factor of 2
+ Sum percentage ofTBSA from all body regions affected by tumors x severity-weighting factor 
of 4
= Total mSWAT (maximum score = 400)
Figure 9.a presents the mSWAT percentage of TBSA for the 12 main body areas to assess 
disease burden in MF and pcALCL (Mann et al. 2007; Stevens et al. 2002). The body is divided 
into 12 regions with preassigned percentage of TBSA based on methodology used to assess 
burns (Lund and Browder 1944). The extent of skin disease is assessed for each region and 
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quantified using the patient's palm as a "ruler" to measure the percentage of TBSA involvement 
within each region: 
Patient's palm with 4 fingers and including the thumb, and measured from wrist to fingertips, is 
approximately 1% of TBSA.
Figure 9.a
mSWAT Percentage of TBSA for 12 Main Body Areas
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Table 9.d
Response in Skin
Response
Definition
CR
100% clearance of skin lesionsa
PR
50%-99% clearance of skin disease from baseline
No new tumors in patients without tumors at baseline (MF)
No new tumors (pcALCL)
SD
<25% increase to <50% clearance in skin disease from baseline
No new tumors in patients without tumors at baseline (MF)
PDb
≥25% increase in skin disease from baseline, or
Loss of response: in those with CR or PR, increase of skin score of
greater than the sum of nadir plus 50% baseline score, or
New tumors in patients without tumors at baseline (MF)
Relapse
Any disease recurrence in those with complete response
Source: Response criteria for MF are per Olsen 2011 (Olsen et al. 2011b), and for pcALCL per Kempf 2011 (Kempf 
et al. 2011).
CR: complete response; MF: mycosis fungoides; pcALC: primary cutaneous anaplastic large cell lymphoma; PD: 
progressive disease; PR: partial response; SS: Sézary syndrome. 
a A biopsy of normal appearing skin is unnecessary to assign a complete response. However, a skin biopsy should be 
performed on a representative area of the skin if there is any question of residual disease (persistent erythema or 
pigmentary change) where otherwise a complete response would exist. If histologic features are suspicious or 
suggestive of MF/SS, the response should be considered a PR only.
b Whichever criterion occurs first.
9.3.15.1.2
Photographs 
Each of the designated index lesions (up to a total of 5) and lesions selected for biopsy will be 
serially photographed at screening; before dosing on Day 1 of Cycles 1, 2, and 3; at the end of 
every cycle beginning at Cycle 3 (Days 16-21, or before dosing on Day 1 of subsequent cycles); 
within 30 days after the last dose of study drug. Full body global photographs, including head, 
trunk, legs, front, back, and side, will be taken at the same time points indicated above. 
9.3.15.1.3
Lymph Node and Visceral Evaluation
Lymph nodes and visceral involvement will be assessed by a computed tomography (CT) scan, 
and responses are defined in Table 9.e and Table 9.f.
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Table 9.e
Response in Lymph Nodes a
Response
Definition
CR
All lymph nodes are now ≤1.5 cm b in greatest transverse (long axis) diameter by method used to 
assess lymph nodes at baseline or biopsy negative for lymphoma. In addition, lymph nodes that 
show lymphoma involvement by biopsy c and ≤1.5 cm b in long axis diameter and >1 cm in short 
axis at baseline, must now be ≤1 cm in diameter of the short axis or biopsy negative for 
lymphoma
PR
Cumulative reduction ≥50% of the SPD of each abnormal lymph node at baseline and no new 
lymph node >1.5 cm b in the diameter of the long axis or >1.0 cm in the short axis if the long axis 
is 1-1.5 cm diameter
SD
Fails to attain the criteria for CR, PR, and PD
PD d
(1) ≥50% increase in SPD from baseline of lymph nodes, or
(2) Any new node >1.5 cm b in greatest transverse diameter or >1 cm in the short axis diameter if 
1-1.5 cm in long axis that is proven to be lymphoma histologically c, or
(3) Loss of response: in those with PR (or CR if pcALCL), >50% increase from nadir in SPD of 
lymph nodes 
Relapse
Any new lymph node >1.5 cm b in the long axis diameter:
In those with CR (pcALCL)
In those with CR proven to be lymphoma histologically c (MF)
Source: (Olsen et al. 2011a), (Kempf et al. 2011), and (Cheson et al. 2007).
CR: complete response; EORTC: European Organisation for Research and Treatment of Cancer; ISCL: International 
Society for Cutaneous Lymphomas; MF: mycosis fungoides; pcALCL primary cutaneous anaplastic large cell 
lymphoma; PD: progressive disease PR: partial response; SD: stable disease; SPD: sum of the maximum linear 
dimension (major axis) X longest perpendicular dimension (minor axis); USCLC: United States Cutaneous 
Lymphoma Consortium.
a Peripheral and central lymph nodes.
b Response criteria are similar for patients with MF and pcALCL. However, per the EORTC, ISCL and USCLC 
consensus recommendations for the treatment of non-MF primary cutaneous CD30+ lymphoproliferative disorders 
(Kempf et al. 2011), an abnormal lymph node is considered ≥1.5 cm and should be considered when assessing nodal 
response in patient with pcALCL. 
c For patients with MF, lymphoma involvement is defined as N3 (ie, partial or complete effacement of lymph node 
architecture by atypical or frankly neoplastic cells)
d Whichever criterion occurs first.
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Table 9.f
Response in Viscera 
Response
Definition
CR
Liver or spleen or any organ considered involved at baseline should not be enlarged on physical 
exam and should be considered normal by imaging; no nodules should be present on imaging of 
liver or spleen. Any posttreatment mass must be determined by biopsy to be negative for 
lymphoma
PR
≥50% regression in any splenic or liver nodules, or in measurable disease (SPD) in any organs 
abnormal at baseline. No increase in size of liver or spleen and no new sites of involvement
SD
Fails to attain the criteria for CR, PR, or PD
PDa
(1) >50% increase in size (SPD) of any organs involved at baseline, or
(2) New organ involvement, or
(3) Loss of response: in those with PR (or CR if pcALCL), >50% increase from nadir in the size 
(SPD) of any previous organ involvement 
Relapse
New organ involvement in those with CR
Source: (Olsen et al. 2011b) and (Kempf et al. 2011). 
CR: complete response; PR: partial response; SPD: sum of the maximum linear dimension (major axis) X longest 
perpendicular dimension (minor axis); SD: stable disease; SPD: sum of the maximum linear dimension (major axis) 
X longest perpendicular dimension (minor axis); PD: progressive disease.
a Whichever criterion occurs first.
Contrast CT scans of the neck, chest, abdomen, and pelvis will be obtained at screening and 
during the study or if clinically indicated as specified in the Schedule of Events (Appendix A) 
and Section 6.1. All CT scans will be taken with IV contrast (unless contraindicated) and they 
will be of diagnostic quality. Specific disease sites that cannot be adequately imaged by CT may 
be documented by MRI. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scans 
will be performed at screening only, unless clinically indicated. Anatomical measurements 
(summed across target lesions) will be collected at baseline and each subsequent evaluation 
using an imaging modality consistent with that used at screening. 
Objective assessments will be performed at each time point as described in the Schedule of 
Events (Appendix A). When possible, the same qualified physician will interpret results to 
reduce variability. Radiographic images will be maintained at the site, and test results and 
physician’s findings will be filed in patient source documents. 
9.3.15.1.4
Blood Assessment
MF involvement in blood is defined in Appendix E. SS is defined as meeting T4 plus B2 criteria, 
Appendix E (Olsen et al. 2011b). 
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Table 9.g
Response in Blood
Response a
Definition
CR b
B0
PR c
>50% decrease in quantitative measurements of blood tumor burden from baseline in those with 
high tumor burden at baseline (B2)
SD
Fails to attain criteria for CR, PR, or PD
PD d
B0 to B2
or
>50% increase from baseline and at least 5,000 neoplastic cells/µL
or
Loss of response: in those with PR who were originally B2 at baseline, >50% increase from nadir 
and at least 5,000 neoplastic cells/µL
Relapse
Increase of neoplastic blood lymphocytes to ≥B1 in those with CR
CR: complete response; PD: progressive disease.PR: partial response; SD: stable disease.
a As determined by absolute numbers of neoplastic cells/µL.
b If a bone marrow biopsy was performed at baseline and determined to unequivocally be indicative of 
lymphomatous involvement, then to confirm a global CR where blood assessment now meets criteria for B0, a repeat 
bone marrow biopsy must show no residual disease or the response should be considered a PR only.
c There is no PR in those with B1 disease at baseline as the difference within the range of neoplastic cells that define 
B1 is not considered significant and should not affect determination of global objective response.
d Whichever criterion occurs first.
9.3.15.1.5
Global Response Score
GRS is an assessment whereby each component of the TNM(B) staging (skin, nodes, viscera, 
and blood for MF), has been given its own definition of response. Due to the primacy of the 
response in the skin in CTCL, no patient with a global objective response should have less than a 
PR in the skin. The global response score definition is provided in Table 9.h. 
Response to treatment (CR, PR, SD, PD, relapse) will be monitored on a continual basis. For all 
treated patients, GRS will be assessed at the end of Cycles 3, 6, 9, 12, and 15 (Days 16-21 or 
before dosing on Day 1 of the subsequent cycle); at EOT. GRS will be determined based upon 
the most recent disease assessments for each component (mSWAT, CT scans, Sezary cell count 
for MF patients). For patients without baseline nodal/visceral involvement, the schedule for 
obtaining CT scans will likely not correlate with the timing of GRS determinations; thus, the 
nodal/visceral response component should be based upon the most recent CT scan findings 
before the GRS assessment time point. Additional unscheduled GRS determinations may occur 
following a change in response in skin or at the time of a CT scan. Relapse will be categorized in 
the study endpoints definition as recurrent disease in patients with complete response. 
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Table 9.h
Global Response Score
Global Score
Definition
Skin
Nodes
Blood
Viscera
CR
Complete disappearance of all 
clinical evidence of disease
CR
All categories have CR/NI
PR
Regression of measurable disease 
CR
All categories do not have a CR/NI and no 
category has a PD 
PR
No category has a PD and if any other 
category involved at baseline, at least one 
has a CR or PR 
SD
Failure to attain CR, PR or PD 
representative of all disease
PR
No category has a PD and if any other 
category involved at baseline, no CR or PR 
in any
SD
CR/NI,PR,SD in any category and no 
category has a PD 
PD
Progressive disease
PD in any category
Relapse
Recurrence disease in prior CR
Relapse in any category 
CR: complete response; GRS: Global Response Score; NI: noninvolved; PD: progressive disease; PR: partial 
response; SD: stable disease.
For the purpose of this study, patients with B1 involvement at baseline (but no node or viscera), who reach a PR in 
skin and stable B1, will be considered to have reached PR for the GRS.
9.3.16
Skin Biopsies
For enrollment, patients will be required to undergo skin biopsies, (a total of at least 2 samples 
from separate lesions for MF, and 1 sample for pcALCL) during screening for confirmation of 
CD30 expression. Samples may be obtained up to 28 days before the first dose of brentuximab 
vedotin; in the event that a patient rescreens, repeat skin biopsies should be discussed with the 
sponsor, project clinician, or designee. CD30+ is defined as ≥10% target lymphoid cells 
demonstrating membrane, cytoplasmic, and/or Golgi staining pattern for CD30 at any intensity 
above background staining as noted on the corresponding negative control. A minimum of 10% 
staining in at least 1 sample is required. Percent positivity should be determined using percent 
neoplastic cells staining first. If neoplastic cells cannot be easily distinguished from non-
neoplastic, then percent positivity should be determined using percent total lymphocytes 
staining. 
9.4
Completion of Study Treatment (for Individual Patients)
Patients will be considered to have completed study treatment if they meet any of the following 
criteria:

Complete up to 16 cycles of treatment with brentuximab vedotin. 
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9.5
Completion of Study (for Individual Patients)
Regardless of the duration of treatment, all patients will remain on study until they complete the 
EOT visit, or they withdraw consent, are lost to follow-up, death, or until study closure. The 
study is expected to close approximately 3 years after the first patient starts study drug.
9.6
Discontinuation of Treatment With Study Drug and Patient Replacement
Study drug should be discontinued for patients meeting any of the following criteria:

Completed 16 cycles of brentuximab vedotin therapy. 

PD.
Treatment with study drug may also be discontinued for any of the following reasons: 

AE.

Protocol deviation.

Study terminated by sponsor.

Withdrawal by patient.

Lost to follow-up.

Other.
Once study drug has been discontinued, all study procedures outlined for the EOT visit will be 
completed as specified in the Schedule of Events (Appendix A). The primary reason for study 
drug discontinuation will be recorded on the eCRF. 
Note that some patients may discontinue study drug for reasons other than PD before completing 
the full treatment course. 
Additional patients may be enrolled to ensure an adequate number of evaluable patients in the 
study, ie, approximately 10 evaluable patients. 
9.7
Withdrawal of Patients From Study
A patient may be discontinued from the study (during treatment cycle or follow-up) for any of 
the following reasons: 

Lost to follow-up.

Study terminated by sponsor.

Withdrawal by patient.

Death. 

Other.
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The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database.
The sponsor or their designee must be notified if a patient is withdrawn from study drug or from 
the study. The reason(s) for withdrawal should be documented in the patient’s medical records 
and eCRF. The investigators must make every reasonable effort to keep each patient on the study 
until all planned treatments and assessments have been performed. Final treatment assessments 
will be performed before any other therapeutic intervention if possible. Additionally, any 
planned alternative treatments should be documented on the patient’s medical records and eCRF. 
9.8
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision of 
the investigator or identified subinvestigator(s). The appropriate study personnel will maintain 
records of study drug receipt and dispensing.
10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1
AE Definition
AE means any untoward medical occurrence in a patient or subject administered a 
pharmaceutical product; the untoward medical occurrence does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product whether or not it is related to the medicinal product. 
This includes any newly occurring event or a previous condition that has increased in severity or 
frequency since the administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.
10.1.2
SAE Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).
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
Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life-threatening, or require hospitalization, but may be considered serious when, 
on the basis of appropriate medical judgment, it may jeopardize the patient, require medical 
or surgical intervention to prevent one of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse; any organism, virus, or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
10.2
Procedures for Recording and Reporting AEs and SAEs
All AEs spontaneously reported by the patient or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will 
be recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). 
Any clinically relevant deterioration in laboratory assessments or other clinical finding is 
considered an AE. When possible, signs and symptoms indicating a common underlying 
pathology should be noted as a single comprehensive event.
Regardless of causality, AEs or SAEs must be reported (see Section 10.3 for the period of 
observation) by the investigator to the sponsor's Global Pharmacovigilance department or 
designee within 7 calendar days for AEs, or 24 hours for SAEs, after becoming aware of the 
event. This will be done by transmitting an electronic data capture (EDC) AE or SAE report. If 
transmission of an EDC SAE report is not feasible, then a completed Takeda paper-based AE or 
SAE form will be sent via fax or email. A sample of the paper-based SAE form and processing 
directions are in the study manual. Information in the AE or SAE report or form must be 
consistent with the data provided on the eCRF.
If information not available at the time of the first report becomes available at a later date, then 
the investigator will transmit a follow-up EDC SAE report (or a paper-based SAE form if an 
EDC SAE report is not feasible) or provide other documentation immediately within 24 hours of 
receipt, while follow-up AE report is transmitted within 7 days of receipt. Copies of any relevant 
data from the hospital notes (eg, ECGs, laboratory tests, discharge summary, postmortem results) 
should be sent to the addressee, if requested.
All AEs and SAEs should be followed up until resolution, SD, loss to follow up, withdrawal of 
consent, or permanent outcome of the event. The timelines and procedure for follow-up reports 
are the same as those for the initial report.
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
the patient was enrolled in the trial are not to be considered AEs unless the condition deteriorated 
in an unexpected manner during the trial; eg, surgery was performed earlier or later than planned.
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For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the relationship of the event to study drug administration. 
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using 
the NCI CTCAE, Version 5.0, effective 27 November 2017 (NCI 2017). The criteria are 
provided in the study manual.
Relationship of the event to study drug administration (ie, its causality) will be determined by 
the investigator responding yes (related) or no (unrelated) to this question: is there a reasonable 
possibility that the AE is associated with the study drug? The causal assessment can be based on 
but not limited to suggestive time or dose relationship, plausible temporal association, or 
biological plausibility (pharmacological and pathological mechanism).
10.3
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:

AEs will be reported from the first dose of study drug through 30 days after administration of 
the last dose of study drug. All events relating to peripheral neuropathy regardless of 
seriousness will be followed for all changes in severity until resolution to baseline or study 
closure, whichever occurs first, and recorded in the eCRF. 

Serious pretreatment events will be reported to the sponsor's Department of 
Pharmacovigilance or designee from the time of the signing of the ICF up to first dose of 
study drug, but will not be recorded in the eCRF. Investigators will send initial and follow-up 
paper-based SAE forms of serious pretreatment events within 24 hours of becoming aware of 
via fax or email. 

Related and unrelated SAEs will be reported to the sponsor's Department of 
Pharmacovigilance or designee from the first dose of study drug through 30 days after 
administration of the last dose of study drug and recorded in the eCRF. After this period only 
related SAEs must be reported to the sponsor's Department of Pharmacovigilance or 
designee. SAEs should be monitored until they are resolved or are clearly determined to be 
due to a patient’s stable or chronic condition or intercurrent illness(es). 
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, 
she must inform the investigator immediately and permanently discontinue study drug. The 
sponsor must also be contacted immediately by sending a completed pregnancy form to the 
sponsor's Global Pharmacovigilance department or designee. The pregnancy must be followed 
for the final pregnancy outcome.
If a reproductively male patient impregnates a partner during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by sending a completed pregnancy 
form to the sponsor's Global Pharmacovigilance department or designee. Every effort should be 
made to follow the pregnancy for the final pregnancy outcome.
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10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or email addresses provided below.
A medication error is a preventable event that involves an identifiable patient and leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the phone numbers or email addresses provided below.
Call Center
Phone Number
Email
Fax
DLSS
1-844-662-8532 
Non-toll-free number: 
1-510-740-1273 
GlobalOncologyMedinfo@takeda.com 
1-800-881-6092
Product complaints and medication errors in and of themselves are not AEs. If a product 
complaint or a medication error results in an AE or SAE, then the AE or SAE should be reported. 
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and IRBs and
IECs, as applicable, in accordance with national regulations in the countries where the study is
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted to the regulatory authorities as expedited reports
within 7 days for fatal and life-threatening events and within 15 days for other serious events, 
and serious ADRs will be submitted to the regulatory authorities within 15 days and other ADRs 
within 30 days, unless otherwise required by national regulations. The sponsor will also prepare 
an expedited report for other safety issues where these might materially alter the current benefit-
risk assessment of an investigational medicinal product or that would be sufficient to consider 
changes in the investigational medicinal product’s administration or in the overall conduct of the 
trial. The investigational site also will forward a copy of all expedited reports to his or her IRB or 
IEC in accordance with national regulations. 
11.0
STUDY-SPECIFIC COMMITTEES
11.1
Independent Data Monitoring Committee
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.
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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the data management plan. 
If selected for coding, AEs, medical history, and concurrent conditions will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the WHO 
Drug Dictionary.
12.1
eCRFs 
Completed eCRFs are required for each subject who signs an ICF.
The sponsor or designee will provide the study sites with secure access to and training on the 
EDC application, sufficient to permit site personnel to enter or correct information in the eCRFs 
for the patients for whom they are responsible.
eCRFs will be completed for each study patient. It is the investigator’s responsibility to ensure 
the accuracy, completeness, clarity, and timeliness of the data reported in the patient’s eCRF.
The investigator, or designated representative, should complete the eCRF as soon as possible 
after information is collected.
The investigator must provide through the EDC application formal approval of all the 
information in the eCRFs and changes to the eCRFs to endorse the final submitted data for the 
patients for which he or she is responsible. The audit trail entry will show the user’s 
identification information and the date and time of the correction.
The sponsor, or a designee, will retain the eCRF data and corresponding audit trails. A copy of 
the final archival eCRF in the form of a compact disk (CD) or other electronic media will be 
placed in the investigator’s study file. 
12.2
Record Retention
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s). Records will be retained for at least 2 years after the data approval or 
2 years after formal discontinuation of the clinical development of the investigational product or 
according to applicable regulatory requirement(s). If the investigator withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person willing to 
accept the responsibility and sponsor notified.
13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
Descriptive summaries and analyses will be performed for all efficacy and safety assessments. A 
statistical analysis plan (SAP) will be prepared and signed off and will provide further details 
regarding the definition of analysis variables and analysis methodology to address all study 
objectives.
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13.1.1
Analysis Sets
The following analysis sets are defined in the study. If a patient will not be included in an 
analysis set, it should be decided before database lock. 
Full analysis set 
All efficacy analyses will be based on the full analysis set (FAS), which is defined as all enrolled 
patients identified as CD30 positive and received at least 1 dose of the study drug.
Response-evaluable set
The response-evaluable population will include a subset of the FAS patients with measurable 
disease at baseline and with at least 1 post-baseline response assessment. Patients who were 
discontinued due to death before a post-baseline evaluation happens, will be used for analyses of 
response.
Safety analysis set
The safety analysis set will consist of all enrolled patients who receive at least 1 dose of study 
drug.
13.1.2
Analysis of Demographics and Other Baseline Characteristics
Descriptive statistics will be provided on demographics and baseline characteristics, including 
gender, age, body weight, height, medical history, prior medication, and other parameters, if 
needed. 
13.1.3
Efficacy Analysis
All primary efficacy evaluations for the primary and secondary efficacy endpoints will be 
conducted using the FAS. In addition, sensitivity analysis may be performed using response-
evaluable population as appropriate.
13.1.3.1
Analysis of Primary Efficacy Endpoints
The primary endpoint, ORR4, proportion of patients achieving an objective response that lasts at 
least 4 months will be summarized. The 95% CI of the ORR4 will be provided. Patients whose 
first response occurs after the start of subsequent anti-cancer therapy but otherwise meet the 
primary endpoint criteria will be excluded. No imputation will be conducted for missing data. 
13.1.3.2
Analyses of Secondary Efficacy Endpoints
CR rate is defined as the proportion of patients who achieved a CR as their best response on 
study. The 95% CI of the CR will be provided. No imputation will be conducted for missing 
data. 
ORR will be analyzed in a similar fashion as the primary endpoint.
Duration of response is defined as the time between first documentation of response and PD. 
Duration of response will be summarized using the Kaplan-Meier method with the associated 
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95% CIs when estimable. The analysis will only include responders. Detailed censoring 
approaches for the analysis of DOR will be provided in the SAP.
13.1.4
Safety Analysis
Safety will be evaluated by the incidence of TEAEs, SAEs, ECOG and by changes from baseline 
in the patient’s vital signs and clinical laboratory results using the safety analysis set. Exposure 
to study drug, including the number of treated cycles, total amount of doses taken, and dose 
intensity, will be summarized.
TEAEs, defined as AEs that occur after administration of the first dose of study drug and through 
30 days after the last dose of study drug, will be tabulated. A listing of deaths and TEAEs 
resulting in study drug discontinuation will be provided. All reported AEs will be listed along 
with the date of onset, date of resolution (if resolved), CTCAE grade, and relationship to study 
drug. Summary information (the number and percent of patients) by System Organ Class, High 
Level Term, and Preferred Term will be tabulated for the following categories:

TEAEs.

Drug-related TEAEs.

Grade 3 or higher TEAEs.

Grade 3 or higher drug-related TEAEs.

TEAEs leading to study drug modification and discontinuation.

SAEs.
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change from 
baseline in clinical laboratory parameters) will be presented for all scheduled measurements over 
time. Mean laboratory values over time will be plotted for key laboratory parameters. Shift tables 
for laboratory parameters will be generated based on changes in NCI CTCAE, grade from 
baseline to the worst postbaseline value.
Descriptive statistics for the actual values (and/or the changes from baseline) of vital signs (eg, 
diastolic and systolic blood pressure, heart rate, and body temperature) and weight over time will 
be tabulated by scheduled time point. ECG will be presented in a listing. ECOG performance 
status scores over time will also be tabulated.
Additional and unplanned safety analyses may be performed as the study is conducted. Those 
additional analyses, if deemed necessary, will be presented in the listing and documented in the 
CSR and may not need to be prespecified. 
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned. 
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13.3
Determination of Sample Size
Per China Health Authority requirement, approximately 10 evaluable patients with CD30+ MF 
or pcALCL are needed for this post approval commitment study.
14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee including, but not limited to, the investigator’s binder, study medication, patient 
medical records, informed consent documentation, documentation of patient authorization to use 
personal health information (if separate from the ICFs), and review of eCRFs and associated 
source documents. It is important that the investigator and other study personnel are available 
during the monitoring visits and that sufficient time is devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of the primary 
study assessment.
The sponsor will assess any protocol deviation; if it is likely to affect to a significant degree the 
safety and rights of a subject or the reliability and robustness of the data generated, it may be 
reported to regulatory authorities as a serious breach of GCP and the protocol.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected,
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by a regulatory agency. If the 
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study site is contacted for an inspection by a regulatory agency, the sponsor should be notified 
immediately. The investigator and institution guarantee access for quality assurance auditors to 
all study documents as described in Section 14.1.
15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual patients (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the responsibilities of the investigator that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable ICH- GCP guidelines, state and 
federal/local requirements and regulations of each participating region/country. The sponsor or 
designee will require documentation noting all names and titles of members who make up the 
respective IRB or IEC. If any member of the IRB or IEC has direct participation in this study, 
written notification regarding his or her abstinence from voting must also be obtained.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the ICF, and, if applicable, subject recruitment materials and advertisements and other 
documents required by all applicable laws and regulations must be submitted to a central or local 
IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and subject 
informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study, ie, before shipment of the sponsor-supplied drug or study-specific 
screening activity. The IRB or IEC approval must refer to the study by its exact protocol title, 
number, and version date; identify versions of other documents (eg, ICF) reviewed; and state the 
approval date. If required by country or regional regulations or procedures, approval from the 
competent regulatory authority will be obtained before commencement of the study or 
implementation of a substantial amendment. The sponsor will notify site once the sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor has 
received permission from the competent authority to begin the trial. Until the site receives 
notification, no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by subjects, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor (or 
designee).
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Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, subject authorization form (if applicable), and subject 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF and the subject information sheet (if applicable) further explain the nature of 
the study, its objectives, and potential risks and benefits, and the date informed consent is given. 
The ICF will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical 
care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and, if applicable, the subject authorization form. The ICF, subject authorization form (if 
applicable), and subject information sheet (if applicable) must be approved by both the IRB or 
IEC and the sponsor before use.
The ICF, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, subject 
authorization form (if applicable), and subject information sheet (if applicable) to the subject. 
Information should be given in both oral and written form whenever possible and in the manner 
deemed appropriate by the IRB or IEC. If the subject is not capable of rendering adequate 
written informed consent, then the subject’s legally acceptable representative may provide such 
consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity 
to: (1) inquire about details of the study and (2) decide whether to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines that he or she will 
participate in the study, then the ICF and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and before the subject enters into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using a ballpoint pen with either blue or black ink. The investigator must also sign and date the 
ICF and subject authorization (if applicable) at the time of consent and before the subject enters 
into the study; however, the sponsor may allow a designee of the investigator to sign to the 
extent permitted by applicable law.
Once signed, the original ICF, subject authorization form (if applicable), and subject information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the subject signs the informed consent in the subject’s medical record. Copies of the 
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signed ICF, the signed subject authorization form (if applicable), and subject information sheet 
(if applicable) shall be given to the subject.
All revised ICFs must be reviewed and signed by relevant subjects or the relevant subject’s 
legally acceptable representative in the same manner as the original informed consent. The date 
the revised consent was obtained should be recorded in the subject’s medical record, and the 
subject should receive a copy of the revised ICF.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will be linked to the 
sponsor’s clinical study database or documentation only via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s
unique identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (eg, US Food and Drug Administration, United Kingdom 
Medicines and Healthcare Products Regulatory Agency, Japan Pharmaceuticals and Medical 
Devices Agency), the sponsor’s designated auditors, and the appropriate IRBs and IECs to 
review the subject’s original medical records (source data or documents) including, but not 
limited to, laboratory test result reports, ECG reports, admission and discharge summaries for 
hospital admissions occurring during a subject’s study participation, and autopsy reports. Access 
to a subject’s original medical records requires the specific authorization of the subject as part of 
the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
identifying personal information removed, eg, subject name, address, and other identifier fields 
not collected on the subject’s eCRF.
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
Publication 
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
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accordance with this section and the clinical study site agreement. In the event of any 
discrepancy between the protocol and the clinical study site agreement, the clinical study site 
agreement will prevail.
15.4.2
Clinical Trial Registration
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations, and guidance, Takeda will, at a minimum, register 
interventional clinical trials it sponsors anywhere in the world on www.ClinicalTrials.gov or 
other publicly accessible websites on or before start of study, as defined by Takeda 
policy/standards. Takeda contact information, along with investigator’s city, state (for Americas 
investigators), country, and recruiting status will be registered and available for public viewing. 
As needed, Takeda and investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants in finding a clinical trial by helping them locate trial sites 
closest to their homes by providing the investigator name, address, and phone number via 
email/phone or other methods preferred by callers requesting trial information. Once subjects 
receive investigator contact information, they may call the site requesting enrollment into the 
trial. The investigative sites are encouraged to handle the trial inquiries according to their 
established subject screening process. If the caller asks additional questions beyond the topic of 
trial enrollment, they should be referred to the sponsor.
Any investigator who objects to Takeda providing this information to callers must provide 
Takeda with a written notice requesting that their information not be listed on the registry site. 
15.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on www.ClinicalTrials.gov, and other publicly 
accessible websites (including the Takeda corporate site) and registries, as required by Takeda 
policy/standards, applicable laws, and/or regulations.
Data Sharing
The sponsor is committed to responsible sharing of clinical data with the goal of advancing 
medical science and improving patient care. Qualified independent researchers will be permitted 
to use data collected from patients during the study to conduct additional scientific research, 
which may be unrelated to the study drug or the patient’s disease. The data provided to external 
researchers will not include information that identifies patients personally.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to clinical study 
subjects. Refer to the clinical study site agreement regarding the sponsor’s policy on subject 
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compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the sponsor or sponsor’s designee. 
16.0
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Relapsed or Refractory Hodgkin's Lymphoma. J Clin Oncol, 30(18), 2183-9.
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Appendix A
Schedule of Events
Screening a
Cycle 1
(21-Day Cycle)
Cycle 2
(21-Day Cycle)
Cycle 3-16
(21-Day Cycle)
EOT/ET
Cycle (C) Day (D)
Visit Window
-28 to D-1
C1 D1
C2 D1
Cx D1
Cx D16-21
30 (±2) days after last dose
Informed consent
X
Inclusion/exclusion
X
Demographics
X
Medical history
X
Complete physical exam
X
Height
X
Weight b
X
X
X
X
X
Pregnancy test c
X
X
X
X
Vital signs d
X
X d
X
X
X
Physical exam including focused 
lymphoma assessment
X e
X
X
X
ECOG performance status
X
X
X
X
X
Hematology/serum chemistry f
X
X
X
X
Urinalysis
X
12-lead ECG
X
X g
mSWAT and photography h
X
X
X
X
X
X
Circulating Sézary cells
X
X i
X i
X
FDG-PET j
X
CT k
X
X k
X k
Skin biopsy l (CD30 expression)
X
Biopsies for disease assessment
X
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Screening a
Cycle 1
(21-Day Cycle)
Cycle 2
(21-Day Cycle)
Cycle 3-16
(21-Day Cycle)
EOT/ET
Cycle (C) Day (D)
Visit Window
-28 to D-1
C1 D1
C2 D1
Cx D1
Cx D16-21
30 (±2) days after last dose
Disease status m
X
X
Brentuximab vedotin 
administration
X
X
X
Monitoring of concomitant 
medications and procedures
Recorded from screening through 30 days after the last dose of study drug.
AE n
Recorded from first dose of study drug through 30 days after the last dose of study drug.
AE: adverse event; CBC: complete blood cell; CR: complete response, CT: computed tomography; ECG: electrocardiogram; ECOG: Eastern Cooperative 
Oncology Group; EOT: end of treatment; ET: early termination; FDG: fluorodeoxyglucose; ICF: informed consent form; IEC: independent ethics committee. 
IRB: institutional review board; MF: mycosis fungoides; mSWAT: modified severity weighted assessment tool; pcALCL: primary cutaneous anaplastic large cell 
lymphoma; PD: progressive disease; PET: positron emission tomography; PR: partial response; SD: stable disease.
Tests and procedures should be performed on schedule, but occasional changes are allowable (±3 days) for holidays, vacations, and other administrative reasons. 
If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this time, the patient may 
continue the study only with the written permission of the project clinician.
a Screening must occur within 28 days before enrollment.
b Weight will be measured at screening, on Day 1 of each treatment cycle, and at EOT. The brentuximab vedotin dose will be adjusted for patients who 
experience a ≥10% change in weight from baseline. 
c A serum beta-human chorionic gonadotropin pregnancy test will be performed during screening only for patients of childbearing potential. A urine pregnancy 
test will be performed before dosing on Day 1 of all cycles. The results of any pregnancy test must be negative before dosing on Day 1 of all cycles. Additional 
pregnancy testing may be performed during the study at the discretion of the investigator, upon request of the IEC/IRB, or if required by local regulations.
d Perform vital signs measurement at screening, before dosing on Day 1 of each cycle, and at EOT. On Cycle 1 Day 1 only, also perform vital signs 
measurements at 1 hour (± 10 minutes) postdose for patients receiving brentuximab vedotin. Blood pressure should be determined with the patient in a seated 
position after the patient has been sitting quietly for 5 minutes.
e The Cycle 1 Day 1 physical examination is not required if the complete physical examination performed at screening was conducted within 4 days before 
treatment. A limited physical exam may be administered at the treating physician’s discretion. 
f A blood sample for hematology and serum chemistry will be obtained at screening, before dosing on Day 1 of all cycles, and at EOT. For screening, labs must 
be performed within 4 days of treatment, and do not need to be repeated before dosing. Hematology panel includes complete blood count with differential 
consisting of the following: hemoglobin, hematocrit, platelet count, leukocytes with differential, and neutrophils (absolute neutrophil count). Machine counts are 
acceptable. Serum chemistry panel includes: sodium, potassium, chloride, blood urea nitrogen, creatinine, total bilirubin, alkaline phosphatase, aspartate 
transaminase, alanine transaminase, lactate dehydrogenase, albumin, glucose, urate (uric acid), calcium, phosphate, magnesium, gamma glutamyl transferase, 
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Screening a
Cycle 1
(21-Day Cycle)
Cycle 2
(21-Day Cycle)
Cycle 3-16
(21-Day Cycle)
EOT/ET
Cycle (C) Day (D)
Visit Window
-28 to D-1
C1 D1
C2 D1
Cx D1
Cx D16-21
30 (±2) days after last dose
amylase, and lipase. 
g A 12-lead ECG will be obtained at screening and on Cycle 1 Day 1 (predose). ECG assessments are to be performed with the patient supine and rested for 5 
minutes.
h The mSWAT should follow guidelines from Olsen, et al, 2011 (Olsen et al. 2011b), for analysis and response. Each of the designated index lesions (up to a total 
of 5) and lesions selected for biopsy will be serially photographed at screening; before dosing on Day 1 of Cycles 1, 2, and 3; at the end of every cycle beginning 
at Cycle 3 (Days 16-21 or before dosing on Day 1 of the subsequent cycle); within 30 days after the last dose of study drug. Full body global photographs 
including head, trunk, legs, front, back, and side, will be taken at the same time points indicated above.
i A blood sample for Sézary cell enumeration in patients with MF will be collected at screening; at the time of response assessments at the end of Cycles 3, 6, 9, 
12, and 15 (Days 16-21 or before dosing on Day 1 of the subsequent cycle); at EOT; If the screening sample was obtained within 4 days before treatment, it does 
not need to be repeated on Cycle 1, Day 1. The Sézary cell sample will be evaluated per pathologist and will not be used for dosing decisions; the slide should be 
prepared from the same vial of blood sent for CBC testing. Investigators should ensure the result of a Sézary cell sample sent for local testing is available before
dosing. 
j FDG-PET scans will be taken at screening. No further FDG-PET scans will be required unless they are clinically indicated. FDG-PET scans taken within 8 
weeks before signing the ICF may be used as the screening FDG-PET scan.
k CT scans of the neck, chest, abdomen, and pelvis will be obtained at screening, at the end of Cycles 3, 6, 9, 12, and 15 (Days 16-21 or before dosing on Day 1 
of the subsequent cycle); and at EOT. CT scans taken within 4 weeks before screening as routine can be used as screening evaluation. 
l Skin biopsies with a minimum of 2-mm diameter (at least 2 samples from separate lesions for patients with MF, and at least 1 sample for patients with pcALCL) 
will be obtained at screening (within 28 days before treatment) to confirm tumor specific CD30+ expression. In the event that a patient is rescreened, repeat skin 
biopsies should be discussed with the sponsor, project clinician, or designee.
m Response to treatment (CR, PR, SD, PD, relapse) will be monitored on a continual basis. For all treated patients, global response score will be assessed at the 
end of Cycles 3, 6, 9, 12, and 15 (Days 16-21 or before dosing on Day 1 of the subsequent cycle), at EOT. Additional unscheduled global response score 
determinations may occur following a change in response in skin or at the time of a CT scan. 
n All events relating to peripheral neuropathy regardless of seriousness will be followed for all changes in severity until resolution to baseline or study closure, 
whichever occurs first.
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. 
The investigator agrees to assume the following responsibilities:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this 
individual or party is qualified to perform those trial-related duties and functions and should 
implement procedures to ensure the integrity of the trial-related duties and functions 
performed and any data generated.
4. Ensure that study-related procedures, including study-specific (nonroutine/nonstandard 
panel) screening assessments, are NOT performed on potential subjects before the receipt of 
written approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform 
to ICH and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB/IEC all changes in research activity and 
all anticipated risks to subjects. Make at least yearly reports on the progress of the study to 
the IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in ICH and local regulations, are 
met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a subject authorization section 
that describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not 
include such a subject authorization, then the investigator must obtain a separate subject 
authorization form from each subject or the subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
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11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied
drugs, and return all unused sponsor-supplied drugs to the sponsor.
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix C
ECOG Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair.
5
Dead.
Source: (Oken et al. 1982).
ECOG: Eastern Cooperative Oncology Group.
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Appendix D
NYHA Classification of Cardiac Disease 
The following table presents the NYHA classification of cardiac disease:
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of physical 
activity. Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain.
No objective evidence of 
cardiovascular disease.
II
Patients with cardiac disease resulting in slight limitation of physical activity. 
They are comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain.
Objective evidence of 
minimal cardiovascular 
disease.
III
Patients with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of 
moderately severe 
cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of heart failure or the anginal 
syndrome may be present even at rest. If any physical activity is undertaken, 
discomfort is increased.
Objective evidence of 
severe cardiovascular 
disease.
Source: (The Criteria Committee of New York Heart Association 1994).
NYHA: New York Heart Association. 
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Modified ISCL/EORTC Revisions to the TNMB Classification of MF/SS
TNMB Stages
Description of TNMB
B1
Low blood tumor burden: >5% of peripheral blood lymphocytes are atypical (Sézary) cells but 
does not meet the criteria of B2
B1a
Clone negative
B1b
Clone positive
B2
High blood tumor burden: ≥1,000/µL Sézary cells with positive clone‡; one of the following can 
be substituted for Sézary cells: CD4/CD8 ≥10, CD4+CD7- cells ≥40% or CD4+CD26- cells ≥30%
Source: (Olsen et al. 2011b).
EORTC: European Organisation for Research and Treatment of Cancer ISCL: International Society for Cutaneous 
Lymphomas; MF: mycosis fungoides; NCI: National Cancer Institute SS: Sézary syndrome; TNMB: tumor-mode-
metastasis-blood.
*Patch = any sized lesion without induration or significant elevation above the surrounding uninvolved skin: 
poikiloderma may be present. Plaque = any sized lesion that is elevated or indurated: crusting or poikiloderma may 
be present.
Tumor = any solid or nodular lesion ≥1 cm in diameter with evidence of deep infiltration in the skin and/or vertical 
growth.
† Lymph node classification has been modified from 2007 ISCL/EORTC consensus revisions (Kim et al. 2007) to 
include central nodes. Lymph nodes are qualified as abnormal if >1.5 cm in diameter.
‡ The clone in the blood should match that of the skin. The relevance of an isolated clone in the blood or a clone in 
the blood that does not match the clone in the skin remains to be determined.
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SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN
Study Number: C25029
Study Title: A Phase 4, Single Arm, Open Label, Multicenter Study of Brentuximab Vedotin 
Treatment of Chinese Patients With CD30-Positive Cutaneous T-Cell Lymphoma
Phase: Phase 4
Version: Final 1.0
Date: 13-Jul-2022
Prepared by: 
Based on: A Phase 4, Single Arm, Open Label, Multicenter Study of Brentuximab Vedotin 
Treatment of Chinese Patients With CD30-Positive Cutaneous T-Cell Lymphoma
Protocol Version: Original
Protocol Date: 31-Jan-2022
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda.
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Approval Signatures
Date
Prepared by:  
, Clinical Biostatistics
Date
Approved by:
, Clinical Biostatistics
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REVISION HISTORY
Version 
Approval Date
Primary Rationale for Revision
Final 1.0
[Not Applicable]
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TABLE OF CONTENTS
APPROVAL SIGNATURES ......................................................................................................2
1.0
OBJECTIVES, ENDPOINTS AND ESTIMANDS..........................................................9
1.1
Objectives..................................................................................................................9
1.1.1
Primary Objective..............................................................................................9
1.1.2
Secondary Objective(s)......................................................................................9
1.1.3
Safety Objective(s) ............................................................................................9
1.1.4
Additional Objective(s)......................................................................................9
1.2
Endpoints...................................................................................................................9
1.2.1
Primary Endpoint(s)...........................................................................................9
1.2.2
Secondary Endpoint(s).......................................................................................9
1.2.2.1
Secondary Endpoints(s) .............................................................................9
1.2.2.2
Other Secondary Endpoint(s).....................................................................9
1.2.3
Exploratory Endpoint(s).....................................................................................9
1.2.4
Safety Endpoints..............................................................................................10
1.2.5
Other Endpoints...............................................................................................10
1.3
Estimand(s)..............................................................................................................10
2.0
STUDY DESIGN..........................................................................................................10
3.0
STATISTICAL HYPOTHESES AND DECISION RULES...........................................10
4.0
SAMPLE-SIZE DETERMINATION.............................................................................10
5.0
ANALYSIS SETS.........................................................................................................10
5.1
Safety Analysis Set..................................................................................................10
5.2
Full Analysis Set......................................................................................................11
5.3
Response-evaluable set ............................................................................................11
6.0
STATISTICAL ANALYSIS..........................................................................................11
6.1
General Considerations............................................................................................11
6.2
Disposition of Subjects ............................................................................................11
6.3
Demographic and Other Baseline Characteristics.....................................................12
6.3.1
Demographics and Baseline Characteristics .....................................................12
6.3.2
Medical History...............................................................................................12
6.4
Prior Medications and Concomitant Medications .....................................................12
6.4.1
Prior Medications ............................................................................................12
6.4.2
Concomitant Medications ................................................................................12
6.5
Efficacy Analysis.....................................................................................................12
6.5.1
Primary Endpoint(s) Analysis ..........................................................................13
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6.5.1.1
Derivation of Endpoint(s) ........................................................................13
6.5.1.2
Main Analytical Approach.......................................................................13
6.5.1.3
Sensitivity Analysis .................................................................................13
6.5.1.4
Supplementary Analyses..........................................................................13
6.5.2
Secondary Endpoint(s) Analysis ......................................................................13
6.5.2.1
Derivation of Endpoint(s) ........................................................................14
6.5.2.2
Main Analytical Approach.......................................................................14
6.5.2.3
Sensitivity Analysis .................................................................................14
6.5.2.4
Supplementary Analyses..........................................................................14
6.5.3
Other Secondary Endpoints Analysis ...............................................................14
6.5.4
Subgroup Analyses ..........................................................................................14
6.6
Safety Analysis........................................................................................................15
6.6.1
Adverse Events................................................................................................15
6.6.1.1
Adverse Events........................................................................................15
6.6.1.2
Serious Adverse Events ...........................................................................15
6.6.1.3
Deaths .....................................................................................................15
6.6.1.4
Adverse Events Resulting in Discontinuation of Study Drug....................15
6.6.1.5
Laboratory Data.......................................................................................16
6.6.1.6
Electrocardiograms..................................................................................16
6.6.1.7
Vital Signs...............................................................................................16
6.6.1.8
Eastern Cooperative Oncology Group Performance Status.......................16
6.6.2
Other Safety Analysis ......................................................................................16
6.6.3
Extent of Exposure and Compliance ................................................................17
6.6.4
Treatment Modifications..................................................................................17
6.7
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses................................17
6.8
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis...................................................................................................................17
6.9
Other Analyses ........................................................................................................17
6.10
Interim Analyses......................................................................................................17
6.11
Data Monitoring Committee/Internal Review Committee.........................................17
7.0
REFERENCES..............................................................................................................17
8.0
CHANGES TO PROTOCOL PLANNED ANALYSES ................................................18
9.0
APPENDIX...................................................................................................................18
9.1
Changes From the Previous Version of the SAP.......................................................18
9.2
Data Handling Conventions .....................................................................................18
9.2.1
General Data Reporting Conventions...............................................................18
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9.2.2
Definition of Baseline......................................................................................18
9.2.3
Definition of Visit Windows............................................................................18
9.3
Analysis Software....................................................................................................19
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ABBREVIATIONS
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
BSA
Body Surface Area
CR
Complete Response
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
DOR
Duration of Response
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
FAS
Full Analysis Set
GRS 
Global Response Score
HLT
High Level Term
HR
Hazard Ratio
HRQoL 
Health-Related Quality of Life
IRC
Internal Review Committee
KM
Kaplan-Meier
LLN
Lower Limit of Normal
LOCF
Last Observation Carried Forward
MedDRA
Medical Dictionary for Regulatory Activities
MF 
Mycosis Fungoides
mSWAT 
Modified Severity Weighted Assessment Tool
NCI
National Cancer Institute
OC
Observed Cases
ORR
Objective Response Rate
OS 
Overall Survival
pcALCL 
Primary Cutaneous Anaplastic Large Cell Lymphoma
PD 
Progressive Disease/Disease Progression
PET 
Positron Emission Tomography
PK
Pharmacokinetic
PML 
Progressive Multifocal Leukoencephalopathy
PR 
Partial Response
PRO
Patient-Reported Outcomes
PT
Preferred Term
Q1
25th Percentile
Q3
75th Percentile
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QOL
Quality of Life
SAE
Serious Adverse Event
sALCL 
Systematic Anaplastic Large Cell Lymphoma
SAP
Statistical Analysis Plan
SD 
Stable Disease
SMQ
Standardised Meddra Queries
SOC
System Organ Class
TEAE 
Treatment-Emergent Adverse Event
WHO 
World Health Organization
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1.0
OBJECTIVES, ENDPOINTS AND ESTIMANDS
1.1
Objectives
1.1.1
Primary Objective
The primary objective is to determine the objective response rate (ORR) lasting at least 4 months
with brentuximab vedotin in patients with CD30+ MF or pcALCL.
1.1.2
Secondary Objective(s)

To determine the complete response (CR) rate with brentuximab vedotin.

To determine the ORR with brentuximab vedotin.

To assess the Duration of response (DOR) with brentuximab vedotin.
1.1.3
Safety Objective(s)

To assess the safety of brentuximab vedotin.
1.1.4
Additional Objective(s)
Not applicable.
1.2
Endpoints
1.2.1
Primary Endpoint(s)
The primary efficacy endpoint for this study is the ORR lasting at least 4 months (ORR4) with 
brentuximab vedotin in Chinese patients with CD30+ MF or pcALCL.
1.2.2
Secondary Endpoint(s) 
1.2.2.1
Secondary Endpoints(s)
The secondary efficacy endpoints are: 

CR rate with brentuximab vedotin.

ORR with brentuximab vedotin.

Duration of response with brentuximab vedotin.
1.2.2.2
Other Secondary Endpoint(s)
Not applicable.
1.2.3
Exploratory Endpoint(s)
Not applicable.
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1.2.4
Safety Endpoints
The secondary safety endpoints are: 

Incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs).

Changes from baseline in the patient’s vital signs.

Eastern Cooperative Oncology Group (ECOG) performance status.

Clinical laboratory results.
1.2.5
Other Endpoints
Not applicable.
1.3
Estimand(s)
Not applicable.
2.0
STUDY DESIGN
This is a phase 4, open-label, single-arm, multicenter, postapproval commitment study to be
conducted in China. All patients must have histologically-confirmed CD30+ MF or pcALCL by
local pathology assessment. CD30+ is defined as ≥10% target lymphoid cells demonstrating
membrane, cytoplasmic, and/or Golgi staining pattern for CD30 at any intensity above
background staining as noted on the corresponding negative control. Patients will receive
treatment with brentuximab vedotin monotherapy on Day 1 of each 21-day cycle for up to 16 
cycles total.
Objective response over the course of the study, per investigator assessment, will be assessed by
global response score, which consists of skin evaluation (a modified severity weighted
assessment tool [mSWAT]), nodal and visceral radiographic assessment, and detection of
circulating Sezary cells (MF only). Objective response will be evaluated at the end of Cycles 3, 6, 
9, 12, and 15, and at the end of treatment (EOT) visit.
Approximately 10 evaluable patients will be enrolled and dosed in this study from approximately
3 to 5 study centers in China.
3.0
STATISTICAL HYPOTHESES AND DECISION RULES 
Not Applicable.
4.0
SAMPLE-SIZE DETERMINATION
Per China Health Authority requirement, approximately 10 evaluable patients with CD30+ MF 
or pcALCL are needed for this post approval commitment study.
5.0
ANALYSIS SETS
5.1
Safety Analysis Set
The safety analysis set will consist of all enrolled patients who receive at least 1 dose of study 
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drug.
5.2
Full Analysis Set
Full analysis set (FAS) is defined as all enrolled patients identified as CD30 positive and 
received at least 1 dose of the study drug. FAS will be used for the primary and secondary 
efficacy analyses unless specified otherwise.
5.3
Response-evaluable set
The response-evaluable population will include a subset of the FAS patients with measurable
disease at baseline and with at least 1 post-baseline response assessment. Patients who were
discontinued due to death before a post-baseline evaluation happens, will be used for analyses of 
response.
6.0
STATISTICAL ANALYSIS
6.1
General Considerations
There is no pre-planned hypothesis testing for this study. Analysis for this study will mostly be 
descriptive. 2-sided 95% confidence intervals will be presented, where applicable. 
Where applicable, variables will be summarized descriptively by study visit. For the categorical 
variables, the counts and proportions of each possible value will be presented. The denominator 
for the proportion will be based on the number of subjects who provided non missing responses 
to the categorical variable. For continuous variables, the number of subjects with non-missing 
values, mean, median, SD, minimum, and maximum values will be tabulated. For time-to-event 
variables, the summary statistics will include median time to event-free survival, 25th and 75th 
percentiles and number of patients at risk at specified time points.
In general, missing data will be treated as missing and no data imputation will be applied, unless 
otherwise specified.
6.2
Disposition of Subjects
The disposition of patients includes the number and percentage of patients for the following 
categories: patients treated (safety population), patients in the FAS population, patients in the 
Response-Evaluable population, patients discontinued from study treatment, and patients 
discontinued from the study. All percentages will be based on the number of patients treated.
The primary reason for study and treatment discontinuation will also be summarized in this table.
A listing will present data concerning patient disposition.
A by-subject listing of protocol deviations will be provided.
Patient eligibility including inclusion criteria that are not met and exclusion criteria that are met 
at enrollment will be summarized for all enrolled patients.  
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6.3
Demographic and Other Baseline Characteristics
6.3.1
Demographics and Baseline Characteristics
Demographic and baseline characteristics will be summarized for all patients treated. Baseline 
demographics and baseline characteristics to be evaluated will include age, gender, race, height, 
weight, body surface area (BSA), primary diagnosis (MF or pcALCL), Eastern Cooperative 
Oncology Group (ECOG) performance status (0, 1, 2), Ann Arbor staging and other parameters 
as appropriate.
The formulation for BSA is:
BSA = sqrt(height(cm) x weight (kg) / 3600).
No inferential statistics will be generated.
6.3.2
Medical History
Medical history will be listed for all patients.
6.4
Prior Medications and Concomitant Medications 
6.4.1
Prior Medications
Prior medications are defined as the medication(s) used during screening phase but discontinued 
prior to the first dose of study drug. 
Prior medications will be coded by generic term using World Health Organization (WHO) Drug 
Dictionary. The number and percentage of normal subjects taking concomitant medications will 
be tabulated by Anatomical Therapeutic Chemical (ATC) classification pharmacological 
subgroup and WHO drug generic term. Prior medications will also be listed for all patients.
6.4.2
Concomitant Medications
Concomitant medication is defined as a medication where any amount of drug was taken 
between the first day of study drug and 30 days after the last dose of study drug.
Concomitant medications will be coded by generic term using World Health Organization (WHO) 
Drug Dictionary. The number and percentage of normal subjects taking concomitant medications 
will be tabulated by Anatomical Therapeutic Chemical (ATC) classification pharmacological 
subgroup and WHO drug generic term. Concomitant medications will also be listed for all 
patients. 
Concomitant procedures will not be coded but will be presented in a data listing.
6.5
Efficacy Analysis
All efficacy evaluations will be conducted using the FAS population unless specified otherwise.
The response-evaluable population will be used for the sensitivity analyses of ORR4, CR rate,
ORR and duration of response, as needed.
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6.5.1
Primary Endpoint(s) Analysis
6.5.1.1
Derivation of Endpoint(s)
The primary endpoint of this study is ORR4. ORR4 is defined as the proportion of patients 
achieving an objective response that lasts at least 4 months (i.e., duration from first response to 
last response is ≥4 months) on study. 
Patients whose first response occurs after the start of subsequent anti-cancer therapy but 
otherwise meet the primary endpoint criteria will be excluded from numerator. 
For objective response, a patient must achieve a CR or PR. The objective response will be 
considered maintained for patients with a previous CR who experience recurrent disease (i.e. 
Relapse) unless the criteria for progressive disease are met. Determination of objective response 
will be based on a global response score (GRS), which consists of skin evaluation (mSWAT 
assessment) by investigator, nodal and visceral radiographic assessment, and detection of 
circulating Sezary cells (MF only). 
GRS will be assessed at the end of Cycles 3, 6, 9, 12, and 15 (Days 16-21 or before dosing on 
Day 1 of the subsequent cycle), at EOT. GRS will be determined based upon the most recent 
disease assessments for each component (mSWAT, CT scans, Sezary cell count for MF patients). 
For patients without baseline nodal/visceral involvement, the nodal/visceral response component 
should be based upon the most recent CT scan findings before the GRS assessment time point. 
Additional unscheduled GRS determinations may occur following a change in response in skin 
or at the time of a CT scan. Relapse will be categorized in the study endpoints definition as 
recurrent disease in patients with complete response.
6.5.1.2
Main Analytical Approach
The count, proportion as well as the 95% CI of the ORR4 will be presented. No imputation will 
be conducted for missing data. Patients who do not have any post baseline response assessment 
as specified in the protocol, or patients who have no response before dropout, will be counted as 
non-responders.
6.5.1.3
Sensitivity Analysis
Sensitivity analysis will be performed using Response-Evaluable population to assess the 
robustness of the primary analysis.
6.5.1.4
Supplementary Analyses
Not applicable. 
6.5.2
Secondary Endpoint(s) Analysis
CR rate, ORR, and DOR are designated as secondary endpoints.
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6.5.2.1
Derivation of Endpoint(s)
CR rate is defined as the proportion of patients who achieved a CR as their best response on
study. 
Overall response rate (ORR) is defined as the proportion of patients who achieve CR or PR on 
study.
Duration of response (DOR) is defined as the time between first documentation of response and 
PD (or death in the absence of disease progression).
6.5.2.2
Main Analytical Approach
CR and ORR will be analyzed in a similar fashion as the primary endpoint.
No imputation will be conducted for missing data. Patients who do not have any post baseline 
response assessment as specified in the protocol will be counted as non-responders. Patients 
whose first response occurs after the start of subsequent anti-cancer therapy but otherwise meet 
the primary endpoint criteria will be excluded from numerator.
DOR will be summarized using the Kaplan-Meier method with the associated 95% CIs when 
estimable. The analysis of DOR will only include responders. Patients who are lost to follow-up, 
withdraw consent, or discontinue treatment due to undocumented PD after the last adequate 
disease assessment will be censored at the last disease assessment. 
If the patient starts new antineoplastic therapy before PD, the patient is treated as progressed at 
the date of assessment at which PD was documented.
If death or PD occurs after a missed visit, then the patient is treated as progressed at the date of 
death or PD. Patients without baseline and/or no sufficient post baseline data for disease 
assessment and with no death recorded will be censored at the date of the first dose. If PD is 
documented between scheduled visits, then the date of the documented PD is the date of 
progression. 
6.5.2.3
Sensitivity Analysis
Sensitivity analyses will be performed for CR, ORR and DOR based on the Response-Evaluable 
population.
6.5.2.4
Supplementary Analyses
Not applicable. 
6.5.3
Other Secondary Endpoints Analysis 
Not applicable. 
6.5.4
Subgroup Analyses 
Not applicable. 
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6.6
Safety Analysis
Safety evaluations will be based on the incidence, severity, type of adverse events (AEs),
clinically significant changes, or abnormalities in the subject’s physical examination, vital signs, 
ECOG performance status, and clinical laboratory results.
These analyses will be performed using the safety population.
6.6.1
Adverse Events
6.6.1.1
Adverse Events
Treatment-emergent AEs (TEAEs) will be tabulated by primary System Organ Class (SOC),
High Level Term (HLT), and Preferred Term (PT). A TEAE is defined as any AE that occurs 
after administration of the first dose of study drug and up through 30 days after the last dose of 
study drug. AEs will be tabulated according to the most recent version of the Medical Dictionary 
for Regulatory Activities (MedDRA) by SOC, HLT, and PT and will include the following 
categories:

TEAEs

Study drug-related TEAEs

Grade 3 or higher TEAEs

Grade 3 or higher drug-related TEAEs

TEAEs leading to study drug modification and discontinuation.

Serious AEs (SAEs), including study drug-related SAEs

AEs of peripheral neuropathy identified by the broad search MedDRA SMQ “Peripheral 
neuropathy”
Additional analyses of peripheral neuropathy may also be presented.
6.6.1.2
Serious Adverse Events
The number and percentage of subjects experiencing at least 1 treatment-emergent SAE will be 
summarized by MedDRA primary SOC, HLT, and PT.
In addition, a by-subject listing of the SAEs will be presented.
6.6.1.3
Deaths
A by-subject listing of the deaths will be presented. A summary of deaths will be provided with 
number and percentage of patients.
6.6.1.4
Adverse Events Resulting in Discontinuation of Study Drug
A by-subject listing of AEs resulting in discontinuation of study drug will be presented.
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6.6.1.5
Laboratory Data
For the purposes of summarization in both the tables and listings, all laboratory values will be 
converted to standardized units. If a lab value is reported using a nonnumeric qualifier (e.g., less 
than (<) a certain value, or greater than (>) a certain value), the given numeric value will be used 
in the summary statistics, ignoring the nonnumeric qualifier.
If a subject has repeated laboratory values for a given time point, the value from the last
evaluation will be used.
All laboratory data recorded in the eCRF will be listed.
The actual values in clinical laboratory parameters (hematology and serum chemistry) will be 
summarized at baseline and over time; summary statistics for change from baseline in laboratory 
parameters will also be presented.
In addition, hematology and serum chemistry parameters will be summarized in shift tables
comparing the baseline visit to the worst post baseline value (National Cancer Institute [NCI] 
Common Terminology Criteria for Adverse Events [CTCAE] grade, version 5.0 for the 
following parameters if applicable.

Hematology: hemoglobin, platelet count, neutrophils (absolute neutrophil count [ANC]), 
lymphocyte counts, and leukocyte counts

Chemistries: bilirubin (total), alkaline phosphatase (ALP), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), amylase, and lipase.
Urinalysis results will be presented in a listing.
6.6.1.6
Electrocardiograms
Electrocardiogram results will be presented in a listing.
6.6.1.7
Vital Signs
The actual values of vital sign parameters, including blood pressure, heart rate, temperature and 
weight when available, will be summarized over time.
6.6.1.8
Eastern Cooperative Oncology Group Performance Status
Eastern Cooperative Oncology Group performance status and change from baseline will be
summarized. Shifts from baseline to the worst postbaseline score will be tabulated. Patients who 
have ECOG performance scores that worsen postbaseline compared to baseline will be listed 
with other pertinent patient information.
6.6.2
Other Safety Analysis 
Pregnancy testing results will be presented in a by-subject listing.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities and to 
further define the safety profile of study drugs.
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6.6.3
Extent of Exposure and Compliance
The exposure to study drug will be characterized by total amount of dose taken in mg, total
number of dose taken, number of treated cycles, duration of treatment, numbers and percentages 
of patients in treated cycle categories (1, 2…,16), and dose intensity (mg/week).
Dose intensity (mg/week) will be calculated as total dose administered (mg)/(3 * number of
treated cycles) where a treated cycle is defined as a 21-day period during which the patient
received any amount of brentuximab vedotin (scheduled for a single dose in a 21-day cycle). The 
duration of treatment is defined as time from the first study dose to 21 days after the last study 
dose ([last dose date + 21] – first dose date) of brentuximab vedotin.
Relative dose intensity (%) will be calculated as (Total Dose Administered/Total Dose Expected) 
* 100 and summarized.
All extent-of-exposure data will be summarized as continuous variables in the safety population. 
Study drug administration and exposure information will also be presented in a by-subject data 
listing.
6.6.4
Treatment Modifications
Action on study drug (including dose reduction) will be summarized by cycle, and overall.
6.7
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses
Not applicable. 
6.8
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis
Not applicable. 
6.9
Other Analyses
Not applicable. 
6.10
Interim Analyses
No interim analysis is planned.
6.11
Data Monitoring Committee/Internal Review Committee
No steering committee, data safety monitoring committee, or clinical endpoint committee will be
used in this study.
7.0
REFERENCES
Not applicable.
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8.0
CHANGES TO PROTOCOL PLANNED ANALYSES
Not applicable.
9.0
APPENDIX 
9.1
Changes From the Previous Version of the SAP
SAP Section 
Impacted Text (shown in 
bold)
Change 
Rationale for Change
9.2
Data Handling Conventions 
9.2.1
General Data Reporting Conventions 
Unless otherwise specified, the following conventions will be applied to all analyses:

Mean and median values will be formatted to one more decimal place than the measured 
value. Standard deviation values will be formatted to two more decimal places than the 
measured value, and minimum and maximum values will be presented to the same number 
of decimal places as the measured value. If the measured value is large (eg, > 100), fewer 
decimal places may be displayed.

CIs intervals will be presented using the same number of decimal places as the parameter 
estimate.

Percentages will be rounded to one decimal place;

All p-values reported will be 2-tailed and rounded to 3 decimal places prior to assessment of 
statistical significance. If a p-value is less than 0.001 it will be reported as “<0.001.” If a p-
value is greater than 0.999 it will be reported as “>0.999.”

1 month = 30.4375 days. Month is calculated as (days/30.4375) rounded to 1 decimal place;

1 year = 365.25 days. Year is calculated as (days/365.25) rounded to 1 decimal place.
9.2.2
Definition of Baseline 
Unless otherwise specified, the baseline value is defined as the value collected at the time closest 
to, but before, the start of study drug administration.
9.2.3
Definition of Visit Windows 
All data will be categorized based on the scheduled visit at which they were collected. These 
visit designators are predefined values that appear as part of the visit tab in the electronic case 
report form (eCRF).
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9.3
Analysis Software 
SAS version 9.4 (or higher) will be used for all analyses.
For non-commercial use only


For non-commercial use only