Conditions: Hodgkin Disease Lymphoma, Large-Cell, Anaplastic
Keywords: Drug therapy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 39
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy, safety and pharmacokinetics (PK) of brentuximab vedotin as a single agent in Chinese participants with relapsed/refractory CD30+ Hodgkin Lymphoma (HL) or Systemic Anaplastic Large Cell Lymphoma (sALCL).

Detailed description:
The drug being tested in this study is called brentuximab vedotin. This study will look at efficacy, safety and PK of brentuximab vedotin in Chinese participants with relapsed/refractory CD30+ HL or sALCL.

The study will enroll approximately 30 patients. Participants will receive:

• Brentuximab vedotin 1.8 mg/kg

All participants will be administered IV infusion on Day 1 each 3-week cycle until the sooner of disease progression, unacceptable toxicity, or completion of 16 cycles.

This multi-center trial will be conducted in China only. The overall time to participate in this study is 3.5 years. Participants will make multiple visits to the clinic, and will be followed for overall survival (OS) every 12 weeks until death, withdrawal of consent, 18 months after end of treatment (EOT) or study closure, whichever occurs first.

Arms:
arm 1: Brentuximab vedotin 1.8 mg/kg, intravenous (IV) infusion on Day 1 of each 3-week cycle until the sooner of disease progression, unacceptable toxicity, or completion of 16 cycles.

Interventions: intervention 1: Brentuximab Vedotin
Intervention descriptions: intervention 1: Brentuximab vedotin IV infusion

Protocol document:
Prot_000.pdf: 


•
Title: A Phase 2, Single-Arm, Open-label Study of Brentuximab Vedotin in Chinese Patients With 
Relapsed/Refractory CD30-Positive Hodgkin Lymphoma (HL) or Systemic Anaplastic Large Cell 
Lymphoma (sALCL)
NCT Number: NCT02939014
Protocol Approve Date: 20 April 2016
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


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20 April 2016
CONFIDENTIAL
PROTOCOL
A Phase 2, Single-Arm, Open-label Study of Brentuximab Vedotin in Chinese Patients With 
Relapsed/Refractory CD30-Positive Hodgkin Lymphoma (HL) or Systemic Anaplastic 
Large Cell Lymphoma (sALCL)
Brentuximab Vedotin in Chinese Patients With Relapsed/Refractory CD30-Positive HL or 
sALCL
Sponsor:
Takeda Development Center Asia, Pte. Limited
21 Biopolis Road, Nucleos North Tower, Level 4, Singapore 138567
Study Number:
C25010
IND Number:
Not applicable
EudraCT Number:
Not applicable
Compound:
Brentuximab vedotin
Date:
20 April 2016
Original
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
1.1
Contacts
A separate contact information list will be provided to each site.
Serious adverse event and pregnancy reporting information is presented in Section 11.0, as is 
information on reporting product complaints.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
Contact
Serious adverse event and pregnancy reporting
See Section 11.0.
Medical Monitor
(medical advice on protocol and compound)
Responsible Medical Officer 
(carries overall responsibility for the conduct of the 
study)
PPD


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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 E6 Good Clinical Practice: 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.
PPD


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INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the investigator’s brochure 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.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 11.0 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Appendix B–Responsibilities of the Investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
2.0
STUDY SUMMARY ......................................................................................................9
3.0
STUDY REFERENCE INFORMATION ......................................................................14
3.1
Study-Related Responsibilities.................................................................................14
3.2
Coordinating Investigator.........................................................................................14
3.3
List of Abbreviations ...............................................................................................15
4.0
INTRODUCTION.........................................................................................................17
4.1
Background .............................................................................................................17
4.1.1
Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma ..............................17
4.1.2
Brentuximab Vedotin.........................................................................................18
4.1.3
Nonclinical Studies ............................................................................................19
4.1.4
Clinical Studies..................................................................................................19
4.1.5
Known or Potential Risks of Brentuximab Vedotin ............................................29
4.2
Rationale for the Proposed Study.............................................................................31
4.2.1
Rationale for Evaluation of HL and sALCL in One Study..................................31
4.2.2
Rationale for Dose .............................................................................................32
5.0
STUDY OBJECTIVES .................................................................................................33
5.1
Primary Objective....................................................................................................33
5.2
Secondary Objective................................................................................................33
6.0
STUDY ENDPOINTS...................................................................................................34
6.1
Primary Endpoints ...................................................................................................34
6.2
Secondary Endpoints ...............................................................................................34
7.0
STUDY DESIGN..........................................................................................................35
7.1
Overview of Study Design.......................................................................................35
7.2
Number of Patients ..................................................................................................35
7.3
Duration of Study ....................................................................................................35
8.0
STUDY POPULATION................................................................................................37
8.1
Inclusion Criteria .....................................................................................................37
8.2
Exclusion Criteria ....................................................................................................38
9.0
STUDY DRUG .............................................................................................................40
9.1
Study Drug Administration......................................................................................40


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9.2
Dose Modification Guidelines..................................................................................40
9.3
Excluded Concomitant Medications and Procedures ................................................43
9.4
Permitted Concomitant Medications and Procedures................................................43
9.5
Precautions and Restrictions ....................................................................................43
9.6
Management of Clinical Events ...............................................................................44
9.6.1
Nausea and/or Vomiting.....................................................................................44
9.6.2
Diarrhea.............................................................................................................44
9.6.3
Infusion-Related Reactions ................................................................................45
9.6.4
Peripheral Neuropathy .......................................................................................45
9.6.5
Suspected PML..................................................................................................45
9.7
Blinding and Unblinding..........................................................................................46
9.8
Description of Investigational Agents ......................................................................46
9.9
Preparation, Reconstitution, and Dispensation..........................................................46
9.10
Packaging and Labeling...........................................................................................46
9.11
Storage, Handling, and Accountability.....................................................................47
10.0
STUDY CONDUCT......................................................................................................48
10.1
Study Personnel and Organizations..........................................................................48
10.2
Arrangements for Recruitment of Patients................................................................48
10.3
Study Procedures.....................................................................................................48
10.3.1 Informed Consent...............................................................................................48
10.3.2 Enrollment .........................................................................................................48
10.3.3 Patient Demographics ........................................................................................49
10.3.4 Medical History .................................................................................................49
10.3.5 ECOG Performance Status.................................................................................49
10.3.6 Patient Height ....................................................................................................50
10.3.7 Weight ...............................................................................................................50
10.3.8 Vital Signs .........................................................................................................50
10.3.9 ECGs .................................................................................................................50
10.3.10
Clinical Laboratory Evaluations....................................................................50
10.3.11
Pregnancy Test .............................................................................................53
10.3.12
Concomitant Medications and Procedures.....................................................53
10.3.13
AEs...............................................................................................................54
10.3.14
Disease Assessment ......................................................................................54
10.3.15
PK Measurements.........................................................................................55
10.3.16
Immunogenicity Measurements ....................................................................55


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10.4
Completion of Treatment .........................................................................................55
10.5
Completion of Study................................................................................................55
10.6
Discontinuation of Treatment With Study Drug and Patient Replacement................56
10.7
Withdrawal of Patients From Study .........................................................................56
10.8
Study Compliance....................................................................................................57
10.9
Long-term Follow-up Assessments ..........................................................................57
11.0
ADVERSE EVENTS ....................................................................................................58
11.1
Definitions...............................................................................................................58
11.1.1 PTE Definition...................................................................................................58
11.1.2 AE Definition ....................................................................................................58
11.1.3 SAE Definition ..................................................................................................58
11.2
Procedures for Recording and Reporting AEs and SAEs..........................................59
11.3
Monitoring of AEs and Period of Observation .........................................................60
11.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........60
11.5
Procedures for Reporting Product Complaints..........................................................60
12.0
STUDY-SPECIFIC COMMITTEES .............................................................................62
13.0
DATA HANDLING AND RECORDKEEPING............................................................63
13.1
eCRFs......................................................................................................................63
13.2
Record Retention .....................................................................................................63
14.0
STATISTICAL METHODS..........................................................................................65
14.1
Statistical and Analytical Plans ................................................................................65
14.1.1 Analysis Populations..........................................................................................65
14.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................65
14.1.3 Efficacy Analysis...............................................................................................65
14.1.4 PK Analysis .......................................................................................................66
14.1.5 Immunogenicity Analysis...................................................................................66
14.1.6 ECG Analysis ....................................................................................................67
14.1.7 Safety Analysis ..................................................................................................67
14.1.8 Other Analyses...................................................................................................67
14.2
Interim Analysis and Criteria for Early Termination ................................................68
14.3
Determination of Sample Size..................................................................................68
15.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................69
15.1
Study-Site Monitoring Visits ...................................................................................69
15.2
Protocol Deviations..................................................................................................69
15.3
Quality Assurance Audits and Regulatory Agency Inspections ................................69


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16.0
ETHICAL ASPECTS OF THE STUDY........................................................................70
16.1
IRB and/or IEC Approval ........................................................................................70
16.2
Subject Information, Informed Consent, and Subject Authorization .........................71
16.3
Subject Confidentiality ............................................................................................72
16.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................72
16.4.1 Publication and Disclosure.................................................................................72
16.4.2 Clinical Trial Registration..................................................................................73
16.4.3 Clinical Trial Results Disclosure ........................................................................73
16.5
Insurance and Compensation for Injury....................................................................73
17.0
REFERENCES..............................................................................................................74
LIST OF IN-TEXT TABLES
Table 4.a
List of Completed Clinical Studies With Brentuximab Vedotin (as of February 
2016) .................................................................................................................20
Table 4.b
List of Ongoing Clinical Studies With Brentuximab Vedotin (as of February 
2016) .................................................................................................................24
Table 9.a
Criteria for Dose Adjustments and Delays..........................................................42
Table 9.b
Investigational Product.......................................................................................47
Table 10.a
Clinical Laboratory Evaluations .........................................................................53
LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................76
Appendix B
Responsibilities of the Investigator.....................................................................80
Appendix C
Investigator Consent to Use of Personal Information..........................................82
Appendix D
ECOG Scale for Performance Status ..................................................................83
Appendix E
New York Heart Association Functional Classification......................................84


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2.0
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Asia, Pte. Limited
Compound:
Brentuximab vedotin
Title of Protocol: A Phase 2, Single-Arm, Open-label 
Study of Brentuximab Vedotin in Chinese Patients With 
Relapsed/Refractory CD30-Positive Hodgkin Lymphoma 
(HL) or Systemic Anaplastic Large Cell Lymphoma 
(sALCL)
IND No.:
Not applicable
EudraCT No.:
Not applicable
Study Number: C25010
Phase: 2
Study Design:
This is a single-arm, open-label, multicenter, phase 2 study designed to evaluate the efficacy, safety, and 
pharmacokinetics (PK) of brentuximab vedotin as a single agent in Chinese patients with relapsed/refractory CD30+ 
HL or sALCL. Brentuximab vedotin will be administered as a single, 1.8 mg/kg intravenous (IV) infusion on Day 1 of 
each 3-week cycle. Patients will receive a maximum of 16 cycles if they do not meet the criteria for removal from the 
study. Patients will be assessed for overall response using the Revised Response Criteria for Malignant Lymphoma
[1]. Dedicated computed tomography (CT) scans (neck, chest, abdomen, and pelvis) will be performed at Baseline and 
at Cycles 2, 4, 7, 10, 13, and 16, and positron emission tomography (PET) scans will be performed at Baseline and at 
Cycles 4 and 7. No additional PET scanning is required beyond Cycle 7 unless clinically indicated. B symptoms will 
be assessed at Baseline and on Day 1 of each cycle. Patients may continue on study treatment until the sooner of 
disease progression, unacceptable toxicity, or completion of 16 cycles. Patients, including those who discontinue 
study treatment for any reason other than withdrawal of consent, will have safety follow-up assessments through 
30 days after the last dose of study drug (end of treatment [EOT]). Patients who discontinue study treatment with 
stable disease or better will be followed for progression-free survival (PFS) until disease progression, death, 
withdrawal of consent, or initiation of a new treatment, whichever occurs first. A CT scan will be performed every 
12 weeks for the first 12 months and at 18 months after the last dose (EOT). Patients will be followed for overall 
survival (OS) every 12 weeks until death, withdrawal of consent, or study closure, whichever occurs first. All patients 
will have the opportunity to be followed for 18 months after EOT. The study will be closed when all patients enrolled 
have completed the required follow-up. Toxicity will be evaluated according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03, effective 14 June 2010 [2]. Laboratory values, 
vital signs, and electrocardiograms will be obtained to evaluate the safety and tolerability of brentuximab vedotin. 
Serial blood samples for determination of the serum/plasma concentration and immunogenicity of brentuximab 
vedotin will be obtained at prespecified time points as described in Table B in Appendix A.
Primary Objectives:
To evaluate the efficacy and the safety of brentuximab vedotin in Chinese patients with relapsed/refractory CD30+ HL 
or sALCL.
Secondary Objectives:
To evaluate the PK and immunogenicity of brentuximab vedotin in Chinese patients with relapsed/refractory CD30+ 
HL or sALCL.
Subject Population: Chinese patients aged 18 years or older with relapsed/refractory CD30+ HL or sALCL.


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Number of Subjects:
Approximately 30 subjects (HL, approximately 22 subjects; 
sALCL, approximately 8 subjects). 
Number of Sites: 
Approximately 7 sites. 
Dose Level(s):
Brentuximab vedotin, 1.8 mg/kg, administered on Day 1 of 
each 21-day cycle.
Route of Administration:
IV
Duration of Treatment:
A maximum of 16 cycles (Approximately 12 months). 
Period of Evaluation:
Approximately 30 months, including 18 months of 
long-term follow-up.
Main Criteria for Inclusion:
1.
Male or female Chinese patients aged 18 years or older at the time of informed consent.
2.
Patients must have histologically confirmed CD30+ HL or sALCL. Immunohistochemistry or flow cytometry 
may be performed on either original diagnostic biopsy material or biopsy of relapsed disease, and pathology 
reports of CD30+ or their copies should be retained at the site.
3.
Patients with CD30+ HL or sALCL who have relapsed from or are refractory to previous treatments.
4.
Fluorodeoxyglucose-PET positive and measurable disease of at least 1.5 cm in the longest diameter by CT, as 
assessed by the site.
5.
Patients must have an Eastern Cooperative Oncology Group performance status of 0 or 1.
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.
Female patients 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.
Male patients, 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.
8.
Suitable venous access for the study-required blood sampling, including PK sampling.
9.
Patients must have the following required screening laboratory data. Patients must not have received 
recombinant granulocyte-colony stimulating factor or platelet transfusion within 1 week before the screening 
hematology assessment.
–
Absolute neutrophil count ≥1500/μL.
–
Platelet count ≥75,000/μL.
–
Serum bilirubin level ≤1.5 times the upper limit of the normal range (ULN).
–
Serum creatinine level ≤1.5 times the ULN.
–
Alanine aminotransferase and aspartate aminotransferase ≤2.5 times the ULN.
10.
Survival for 3 or more months must be expected.


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Main Criteria for Exclusion:
1.
Patients with current diagnosis of primary cutaneous ALCL (patients with other organ involvement who have 
transformed to sALCL are eligible).
2.
Female patients who are lactating and breast-feeding or have a positive serum pregnancy test during the 
screening period. 
3.
Patients with any active viral, bacterial, or fungal infection within 2 weeks before the first dose of brentuximab 
vedotin.
4.
Patients with cardiac failure categorized as Class III or IV according to the New York Heart Association criteria, 
uncontrolled coronary artery disease or uncontrolled arrhythmia despite of appropriate medical therapy, or a 
history of myocardial infarction within 6 months before the first dose of brentuximab vedotin.
5.
Patients with uncontrolled diabetes mellitus.
6.
Peripheral neuropathy ≥Grade 2 (NCI CTCAE version 4.03) [2].
7.
Patients with a history of another malignancy that has not been in remission for at least 3 years. The following are 
exempt from the 3-year limit:
–
Nonmelanoma skin cancer.
–
Curatively treated localized prostate cancer.
–
Cervical carcinoma in situ.
8.
Patients with known cerebral/meningeal disease (HL or any other etiology), including signs or symptoms of 
progressive multifocal leukoencephalopathy (see Section 9.6.5).
9.
Patients with a positive result in the screening test for human immunodeficiency virus antibody.
10.
Known hepatitis B virus (HBV) surface antigen seropositive or positive hepatitis C virus antibody. Note: patients 
who have positive HBV core antibody can be enrolled but must have an undetectable HBV viral load.
11.
Patients with a history of liver fibrosis or cirrhosis and clinical signs and symptoms indicating liver fibrosis or 
cirrhosis.
12.
Patients who have received autologous stem cell transplantation within 12 weeks before the first dose of 
brentuximab vedotin.
13.
Patients with a history of allogeneic stem cell transplantation.
14.
Patients who have received treatment for malignancies (including radiation, chemotherapy, and hormone 
therapy) within 4 weeks before the first dose of brentuximab vedotin and patients who have received treatment 
for malignancies with biologics (including molecular target drug) or radioisotopic therapy within 12 weeks 
before the first dose of brentuximab vedotin.
15.
Patients who have unresolved toxicity higher than Grade 1 (NCI CTCAE version 4.03) [2] attributed to any prior 
therapy/procedure (excluding alopecia or non-clinically significant and asymptomatic laboratory abnormalities).
16.
Patients who have received systemic corticosteroids at doses greater than the equivalent of 20 mg/day of 
prednisone within 1 week before the first dose of brentuximab vedotin.
17.
Patients who have received other investigational products within 4 weeks before the first dose of brentuximab 
vedotin.
18.
Patients who have received treatment with investigational medical devices within 4 weeks before the first dose of
brentuximab vedotin.
19.
Patients who have received previous treatment with brentuximab vedotin.
20.
Patients with a known hypersensitivity to any excipient contained in the drug formulation.
21.
Patients who have any kind of disorder that compromises the ability of the patient to give written informed 
consent and/or to comply with study procedures.
22.
Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would 


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CONFIDENTIAL
make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of the 
safety and toxicity of the prescribed regimens.
Main Criteria for Evaluation and Analyses:
The endpoints for this study are as follows.
•
Primary:
–
Overall response rate (ORR).
–
Safety: adverse events (AEs), assessments of clinical laboratory values, vital sign measurements.
•
Secondary:
–
Complete remission (CR) rate.
–
Duration of response (DOR).
–
PFS.
–
OS.
–
B symptom resolution rate.
–
Maximum observed plasma concentration (Cmax).
–
Time to reach Cmax (tmax).
–
Area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf).
–
Presence of antitherapeutic antibodies (ATA) and neutralizing antitherapeutic antibodies (nATA) to 
brentuximab vedotin.
Statistical Considerations:
The following analyses will be conducted separately for patients with HL and patients with sALCL unless otherwise 
stated.
Efficacy Analysis
Analyses of efficacy measures will be descriptive. The ORR, along with CR, and partial remission (PR) rates will be 
analyzed based on the assessment by the investigators per International Working Group criteria. Other efficacy
endpoints, including PFS, OS, and DOR, will also be analyzed.
PK Analysis
Descriptive statistics (number of patients, arithmetic mean, geometric mean, standard deviation, median, percentage 
of coefficient of variation, minimum, and maximum) will be used to summarize PK parameters of antibody-drug 
conjugate (ADC) and total antibody (TAb) in serum, and monomethylauristatin E (MMAE) in plasma. Arithmetic
mean of the plasma or serum concentration of MMAE, ADC, and TAb will be plotted over time. 
Immunogenicity Analysis
Immunogenicity parameters (ATA titer and nATA titer in serum) will be summarized using descriptive statistics. 
 
Safety Analysis
Safety will be evaluated by the incidence, severity, and type of AEs (eg, treatment-emergent AEs [TEAEs], 
drug-related TEAEs, Grade 3 or higher TEAEs, serious AEs) according to the Medical Dictionary for Regulatory 
Activities, and also by changes from Baseline in vital signs and clinical laboratory results using the safety population. 
Exposure to study drug, including the number of treated cycles, total amount of doses taken, and dose intensity, will be 
summarized.
CC
I


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Sample Size Justification:
The study will have approximately 30 evaluable patients including approximately 22 patients with HL and 
approximately 8 patients with sALCL. Based on the exact binomial CI calculations, a minimum of 9 responses 
observed from 22 evaluable patients with HL (ORR of 40.9%) will provide a 95% CI (20.7%, 63.6%); 5 responses 
observed from 8 evaluable patients with sALCL (ORR of 62.5%) will yield a 95% CI (24.5%, 91.5%). In both cases, 
the lower limits of the 95% CI for the ORR are greater than the threshold response rate of 20% obtained from the 
results of alternative therapies for the same indications.
HL (n=22)
sALCL (n=8)
Responses
ORR (%)
95% Exact CI
Responses
ORR (%)
95% Exact CI
8
36.4
(17.2
59.3)
4
50.0
(15.7
84.3)
9
40.9
(20.7
63.6)
5
62.5
(24.5
91.5)
10
45.5
(24.4
67.8)
6
75.0
(34.9
96.8)
11
50.0
(28.2
71.8)
7
87.5
(47.3
99.7)
12
54.5
(32.2
75.6)
8
100
(63.1
100.0)
13
59.1
(36.4
79.3)
For information purposes, response rates achieved in previous studies in relapsed/refractory HL and sALCL are 
referenced below.
ORR (CR+PR) by Independent Review Facility (95% CI)
Global Study SGN035-0003 (HL: n=102)
74.5 (64.9, 82.6)
Global Study SGN035-0004 (sALCL: n=58)
86.2 (74.6, 93.9)
Japan Study TB-BC010088 (HL: n=9)
66.7 (29.9, 92.5)
Japan Study TB-BC010088 (sALCL: n=5)
100 (54.9, 100)
Assuming similar ORR results to those in Study TB-BC010088 will be obtained, the expected response rates are 65% 
for HL and 80% for sALCL. With 22 patients with HL and 8 patients with sALCL, the study will have >99% and 
>94% probability, respectively, to detect an ORR greater than the 20% threshold (ie, ≥9 responses for HL and ≥5 
responses for sALCL).


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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 
Study-Related Responsibilities template. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
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 as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.


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3.3
List of Abbreviations
Abbreviation
Term
ABVD
doxorubicin+bleomycin+vinblastine+dacarbazine
ADC
antibody-drug conjugate
AE
adverse event
ALCL
anaplastic large cell lymphoma
ALK
anaplastic lymphoma kinase
allo-SCT
allogeneic stem cell transplantation
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATA
antitherapeutic antibodies
AUC
area under the concentration-time curve
auto-SCT
autologous stem cell transplantation
cAC10
anti-CD30 monoclonal antibody 
CHL
classical Hodgkin lymphoma
CHOP
cyclophosphamide+doxorubicin+vincristine+prednisone
Cmax
maximum observed concentration
CR
complete remission
CRO
contract research organization
CT
computed tomography
CYP
cytochrome P450
DLT
dose-limiting toxicity
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EOT
end of treatment
FDG
fluorodeoxyglucose
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HL
Hodgkin lymphoma
HRS
Hodgkin Reed-Sternberg
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee


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Abbreviation
Term
IRB
institutional review board
IRF
independent review facility
IV
intravenous(ly)
IWRS
interactive web response system
JCV
John Cunningham virus
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
MMAE
monomethylauristatin E
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
nATA
neutralizing antitherapeutic antibodies
NCCN
National Comprehensive Cancer Network
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NHL
non-Hodgkin lymphoma
NLPHL
nodular lymphocyte-predominant Hodgkin lymphoma
ORR
overall response rate
OS
overall survival
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
PR
partial remission
PTE
pretreatment event
Q3W
every 3 weeks
SAE
serious adverse event
sALCL
systemic anaplastic large cell lymphoma
SAP
statistical analysis plan
SD
stable disease
SJS
Stevens-Johnson syndrome
TAb
total antibody
TEAE
treatment-emergent adverse event
TEN
toxic epidermal necrolysis
tmax
time of first occurrence of Cmax
ULN
upper limit of the normal range
WHO
World Health Organization


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4.0
INTRODUCTION
4.1
Background
4.1.1
Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma
Lymphoma is the most common blood cancer. The 2 main forms of lymphoma are Hodgkin 
lymphoma (HL) and non-Hodgkin lymphomas (NHL). The World Health Organization (WHO) 
classification divides HL into 2 main subtypes: classical HL (CHL) and nodular 
lymphocyte-predominant HL (NLPHL). CHL is characterized by the presence of malignant 
Hodgkin Reed-Sternberg (HRS) cells in an inflammatory background, whereas NLPHL lacks 
HRS cells but is characterized by the presence of lymphocyte-predominant cells.
In 2015, it was estimated that 9050 new cases of HL were diagnosed in the United States and 1150 
patients died from the disease [3].
NHL is the major population of malignant lymphoma and is heterogeneous in nature originating in 
B lymphocytes, T lymphocytes, or natural killer cells. Anaplastic large cell lymphoma (ALCL) is 
a rare type of NHL (5% of all cases of NHLs) [4] but one of the more common subtypes of T-cell 
lymphoma. There are 3 distinctly recognized subtypes of ALCL: systemic anaplastic lymphoma 
kinase (ALK)-positive ALCL, systemic ALK-negative ALCL, and primary cutaneous ALCL. 
ALK-positive ALCL is most common in children and young adults. It is characterized by the 
overexpression of ALK protein, which is the result of chromosomal translocation [t(2;5)].
4.1.1.1
HL in China
In China, the 2008 annualized incidence of HL was 0.4/100,000, with a slight male predominance 
(0.5 men vs 0.3 women per 100,000 [5]. The incidence peak occurs in adults aged around 40 years.
HL is classified into Stage I to IV according to Ann-Arbor staging. In general, the treatment for HL 
in China follows the comprehensive clinical practice guidelines for the management of HL issued 
by the National Comprehensive Cancer Network (NCCN), except brentuximab vedotin, which has 
not been approved in China. HL is typically treated with chemotherapy as frontline therapy, and 
the doxorubicin+bleomycin+vinblastine+dacarbazine (ABVD) regimen has been adopted 
nationally and globally as a standard of care; vincristine instead of vinblastine is common in China. 
For early-stage HL (mainly Stage I or II), 4 to 6 cycles of the ABVD regimen are used in 
combination with radiotherapy to disease areas. For advanced HL (Stage III or IV), the 
bleomycin+etoposide+doxorubicin+cyclophosphamide+vincristine+procarbazine+prednisone
(BEACOPP) regimens might be a treatment option.
Approximately 30% to 40% of patients with advanced-stage HL will be refractory to initial 
therapy or will relapse. HL that has relapsed or is refractory to therapy is associated with 
significant patient morbidity and mortality [6,7]. Patients with HL experiencing relapse after 
achieving response to frontline therapy and those showing disease progression during frontline 
therapy or failing to achieve complete remission (CR) are unlikely to experience long-term, 
disease-free survival even after standard-dose chemotherapy as second-line therapy; observed 


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overall response rates (ORRs) are from 22% to 48% with the single use of gemcitabine or in 
combination use with rituximab for the treatment of patients with relapsed or refractory HL, both 
before and after autologous stem cell transplantation (auto-SCT) [8-11]. The survival rates are as 
low as 10% to 30% [12-14]. 
Therefore, patients with relapsed/refractory HL are treated with high-dose chemotherapy 
(radiotherapy). For patients who are not candidates for auto-SCT or do not have access to 
auto-SCT, or whose disease relapses following auto-SCT, no therapies have consistently resulted 
in substantive rates of durable remission or extension of overall survival (OS), which are currently 
10.7 months and 26.9 months, respectively [8,10]. Although other salvage chemotherapy and 
allogeneic stem cell transplantation (allo-SCT) have been attempted, no standard therapy is 
available yet for relapsed patients. Novel agents are therefore needed at an early date.
4.1.1.2
ALCL in China
In China, the 2008 annualized incidence of NHL was 2.1/100,000 with a slight male predominance 
(2.5 vs 1.7 per 100,000) [5], for an approximate annualized incidence of ALCL in China of 0.042 
to 0.11 per 100,000. ALCL is an aggressive disease that is potentially curable with frontline 
multiagent chemotherapy; however, 40% to 65% of patients will develop recurrent disease for 
which multi- or single-agent salvage therapy offers little benefit. OS is poor, with contemporary 
registry data showing a median OS of 3.3 months.
ALCL has a bimodal distribution in age of onset, with a first peak in the younger than 30 years of 
age group, with men accounting for a higher percentage than women, and a second peak in the 
older than 60 years of age group.
The cyclophosphamide+doxorubicin+vincristine+prednisone (CHOP) regimen or a CHOP-like 
regimen has been used as the standard frontline therapy for ALCL in China and other countries [4]. 
Second-line therapies for ALCL include single- or multi-agent salvage regimens, though the 
benefit is limited. Auto-SCT and allo-SCT have been used, but standard therapy has not yet been 
established for relapsed/refractory ALCL in any countries. Novel agents are therefore needed at an 
early date.
4.1.2
Brentuximab Vedotin
4.1.2.1
CD30 Antigen
CD30 is a transmembrane glycoprotein receptor, originally identified on HRS cells, belonging to a 
superfamily of tumor necrosis factor receptors. CD30 antigen is expressed on the surface of HRS 
cells, cells in ALCL, and in other T-cell lymphoproliferative disease. It is also slightly expressed 
on normal cells, such as activated T cells and various hematopoietic cells. The function of CD30 
has not been defined, but it is thought to be involved in both cellular death and proliferation [15]. 
The attention drawn to the usefulness of CD30 as a diagnostic marker for HL and ALCL and its 
apoptosis-induction activity have led to the investigation of CD30 as a new therapeutic target.


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In Western countries, CHL accounts for 90% to 95% and NLPHL accounts for 5% to 10% of all 
HL [16]. Therefore, 90% to 95% of HL is CD30 antigen positive. Almost 100% of ALCL is 
positive for CD30.
4.1.2.2
Antibody-Drug Conjugate Therapy and Brentuximab Vedotin
Brentuximab vedotin is an antibody drug conjugate (ADC) that targets CD30 and consists of the 
following: 1) anti-CD30 monoclonal antibody (cAC10), 2) a potent microtubule inhibitor 
monomethylauristatin E (MMAE), and 3) a linker cleavable by protease, through which cAC10 is 
conjugated to MMAE. The biological activity of brentuximab vedotin consists of several steps. 
First, after binding to CD30 on the surface of tumor cells, brentuximab vedotin is uptaken to the 
cells as ADC-CD30 complex and transported to lysosomes. Then, MMAE is released within the 
cells by a proteolytic reaction. Binding of MMAE to tubulin disrupts the microtubule network, 
leading to cell cycle arrest and apoptosis of CD30-expressing tumor cells.
As of February 2016, brentuximab vedotin has been approved for patients with 
relapsed/refractory, CD30-positive HL or systemic anaplastic large cell lymphoma (sALCL) in 62 
countries, including the United States, European Union, and Asian countries such as Korea, Japan, 
Taiwan, and Hong Kong.
Refer to the brentuximab vedotin Investigator’s Brochure (IB) for details.
4.1.3
Nonclinical Studies
Bone marrow cytopenia, depletion of lymphatic tissue, and associated decrease in blood cells in 
the peripheral blood were observed in rats and monkeys following repeated doses of brentuximab 
vedotin. These were consistent with inhibitory effects of MMAE on microtubules. Similar effects 
were seen following repeated doses of MMAE, while no related adverse effects were noted 
following repeat doses of cAC10. The no observable adverse effect level of brentuximab vedotin 
following repeated doses in rats and monkeys was estimated to be 0.5 mg/kg and 1 mg/kg, 
respectively. The highest nonseverely toxic dose of brentuximab vedotin following repeated doses 
in rats and monkeys was considered to be 5 mg/kg and 3 mg/kg, respectively. In a repeat-dose 
toxicity study in which rats were given the highest dose of 15 mg/kg of brentuximab vedotin for up 
to 1 month, changes were observed in bone marrow (cytopenia), thymus (depletion of lymphatic 
tissue), spleen (depletion of lymphatic tissue), liver (focal coagulation necrosis), intestine (single 
cell necrosis), testes (seminiferous tubule degeneration), and lung (alveolar histiocytosis). At the 
end of a recovery period of 4 weeks, the toxicity to all target organs were reversed except for 
testicular toxicity. The testicular toxicity in rats was partially reversed following a recovery period 
of 16 weeks.
Refer to the brentuximab vedotin IB for details.
4.1.4
Clinical Studies
Table 4.a and Table 4.b summarize completed and ongoing clinical studies of brentuximab 
vedotin.


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Table 4.a
List of Completed Clinical Studies With Brentuximab Vedotin (as of February 2016)
Study No.
Phase
Design
Study 
Objective
Diagnosis
Dosage (b-v) 
Frequency
Duration (a)
Primary 
Endpoint
Planned/
Treated/
Analyzed (b)
M:F
Median 
Age 
(Range)
Study Dates 
(c)
Sites/
Regions
Clinical Pharmacology Studies
SGN35-007
Phase 1
Open-label, 
single-arm
Clinical 
pharmacology
CD30+ 
hematologic 
malignancies
1.8 mg/kg IV
q3wk
16 cycles
Duration of 
ventricular 
repolarization
48/52/46
48%:52%
34.5 
(19–76)
Feb 10-Aug 
11
9/US, 
W 
Europe
SGN35-008A
Phase 1
Open-label, 
nonrandomized, 
3-arm, drug-drug 
interaction, 
excretion
Clinical 
pharmacology
CD30+ 
hematologic 
malignancies
1.2 or 1.8 
mg/kg IV
q3wk
2 cycles
PK parameters
36/56/45
59%:41%
33.5 
(16–71)
Dec 09–Jun 
10
7/US
SGN35-008B
Phase 1
Open-label, 
nonrandomized, 
hepatic or renal 
impairment
Clinical 
pharmacology
CD30+ 
hematologic 
malignancies
1.2 mg/kg IV
q3wk
2 cycles
PK parameters
12/17/17
Hepatic
57%:43%
55.0 
(22-72)
Renal
50%:50%
56.5 
(29-78)
Jan 10-May 
12
6/US
C25005
Phase 1
Open-label, 1:1 
randomized, single 
agent or with 
rifampicin
Metabolite 
quantification
Relapsed/ 
refractory classical 
HL or sALCL
1.8 mg/kg IV 
q3wk
16 cycles
PK parameters
20/20
≥18 and
≤75
Nov 13–Jun 
15
Europe
Footnotes are on last table page.


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Table 4.a
List of Completed Clinical Studies With Brentuximab Vedotin (as of February 2016) (continued)
Study No.
Phase
Design
Study 
Objective
Diagnosis
Dosage (b-v) 
Frequency
Duration (a)
Primary 
Endpoint
Planned/
Treated/
Analyzed (b)
M:F
Median 
Age 
(Range)
Study Dates 
(c)
Sites/
Regions
Efficacy and Safety Studies
SG035-0001
Phase 1
Open-label, 
single-arm, 
dose-escalation
Safety
CD30+ 
hematologic 
malignancies
0.1–3.6 
mg/kg IV
q3wk
NA
AEs; laboratory 
abnormalities
51/45/45
62%:38%
36 (20–87)
Nov 06–Jul 
09
4/US
SG035-0002
Phase 1
Open-label, 
single-arm, 
dose-escalation
Safety
CD30+ 
hematologic 
malignancies
0.4–1.4 
mg/kg IV 
q1wk
12 cycles
AEs, laboratory 
abnormalities
72/44/44
70%:30%
33 (12–82)
Mar 08-Feb 
10
5/US
SG035-0003
Phase 2
Open-label, 
single-arm
Efficacy and 
safety
HL
1.8 mg/kg IV
q3wk
16 cycles
ORR
100/102/102
47%:53%
31 (15–77)
Feb 09-Aug 
10 (d)
25/US, 
Canada,
W 
Europe
SG035-0004
Phase 2
Open-label, 
single-arm
Efficacy and 
safety
sALCL
1.8 mg/kg IV
q3wk
16 cycles
ORR
55/58/58
57%:43%
52 (14–76)
Jun 09–Jun 
11 (d)
22/US, 
Canada,
W 
Europe
SGN35-005
Phase 3
Randomized, 
double-blind, 
2-arm, placebo-
controlled
Efficacy and 
safety
HL
(high risk 
post-auto-SCT)
1.8 mg/kg or 
placebo IV 
q3wk
16 cycles
Progression-
free survival
322/327/329
53%:47%
32 (18-76)
Apr 10-Aug 
14 (d)
78/US, 
EU, 
Russia, 
Serbia
Footnotes are on last table page.


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Table 4.a
List of Completed Clinical Studies With Brentuximab Vedotin (as of February 2016) (continued)
Study No.
Phase
Design
Study 
Objective
Diagnosis
Dosage (b-v) 
Frequency
Duration (a)
Primary 
Endpoint
Planned/
Treated/
Analyzed (b)
M:F
Median 
Age 
(Range)
Study Dates 
(c)
Sites/
Regions
SGN35-006
Phase 2
Open-label, 
nonrandomized, 
2-arm
Efficacy and 
safety
CD30+ 
hematologic 
malignancies
1.2 or 1.8 
mg/kg IV
q3wk
NA
Retreatment 
arm (Report 
A): AEs, 
laboratory 
abnormalities, 
ORR
125(e)/32/34
(f)
47%:53%
37 (16–72)
Jul 09–Mar 
13
11/
10 US, 
1 France
Extension arm 
(Report B): 
AEs, laboratory 
abnormalities
125(e)/78/78
55%:45%
32 (15–78)
Jul 09–Mar 
13
14/US
SGN35-009
Phase 1
Open-label, 
2-arm, 
dose-escalation 
with ABVD/AVD
Safety
HL (treatment 
naïve)
0.6, 0.9, or 
1.2 mg/kg IV 
q2wk 
6 cycles
AEs, laboratory 
abnormalities
50-70/51/51
73%:27%
33 (18-59)
Jan 10–Sep 
12
4/US, 
Canada
TB-
BC010088 
Phase 1/2
Open-label, 
nonrandomized, 
single-arm, 2 part
Efficacy and 
safety in 
Japanese 
patients
CD30+ relapsed/ 
refractory HL or 
sALCL
1.2 or 1.8 
mg/kg IV
q3wk
16 cycles
Phase 1: DLT, 
AEs, weight, 
vital signs, 
ECGs, lab 
parameters
Phase 2: AEs, 
weight, vital 
signs, ECGs, 
lab parameters, 
and ORR
17–23/20/20
55%:45%
41 (22-88)
Oct 11-Oct 
13
5/Japan


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Table 4.a
List of Completed Clinical Studies With Brentuximab Vedotin (as of February 2016) (continued)
Study No.
Phase
Design
Study 
Objective
Diagnosis
Dosage (b-v) 
Frequency
Duration (a)
Primary 
Endpoint
Planned/
Treated/
Analyzed (b)
M:F
Median 
Age 
(Range)
Study Dates 
(c)
Sites/
Regions
Compassionate Use Programs
Single-patient 
IND use
NA
NA
HL
ALCL
1.8 mg/kg IV
q3wk
16 cycles
NA
NA/36/NA
NA
Aug 10–Jul 
11
NA/US
Canadian 
Special Access 
Program
NA
NA
HL
ALCL
1.8 mg/kg IV
q3wk
16 cycles
NA
NA/52/NA
NA
Oct 11–Jan 
13
Canada
AE=adverse event; AVD=doxorubicin+ vinblastine+dacarbazine; b-v=brentuximab vedotin; DLT=dose-limiting toxicity; ECG=electrocardiogram; EU=European 
Union; IND=Investigational New Drug (application); IV=intravenous(ly); NA=not applicable; PK=pharmacokinetic(s); qXwk=every X week(s); US=United 
States; W=Western.
(a) Maximum treatment duration represented as treatment cycles (1 cycle=q3wk, 1 dose/21-day cycle; q2wk, 2 doses/28-day cycle; or q1wk, 3 doses/28-day cycle).
(b) Contributed to evaluation of the primary endpoint.
(c) First patient visit (or first patient randomized) to last patient visit (as reported in the clinical study report).
(d) Long-term follow-up ongoing.
(e) Per the study design, this number represents the planned patients for the retreatment and extension arms combined.
(f) Includes 3 patients who were re-treated twice in this study.


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Table 4.b
List of Ongoing Clinical Studies With Brentuximab Vedotin (as of February 2016)
Study No.
Phase
Design
Study 
Objective
Diagnosis
Dosage (b-v) 
Frequency
Duration (a)
Primary 
Endpoint
Planned/
Enrolled (b)
Age
Study 
Dates (c) Regions
Efficacy and Safety Studies
SGN35-011
Phase 1
Open-label, 
nonrandomized, 
3-arm, with 
CHOP/CHP
Safety
CD30+ mature 
T-cell and Natural 
killer-cell 
neoplasms 
(treatment naive)
1.2 or 1.8 mg/kg 
IV
q3wk
16 cycles
AEs, laboratory 
abnormalities
52/39 (d)
≥18
Feb 11–
ongoing
US, W 
Europe
SGN35-012
Phase 2
Open-label, 
nonrandomized, 
3-part, single-agent or 
with rituximab
Efficacy and 
safety
NHL including 
DLBCL
1.8 mg/kg IV
q3wk
NA
Parts A and C: 
ORR
Part B: AEs, 
laboratory 
abnormalities
160/176 (d)
≥6
Aug 11–
ongoing
US, 
Canada
SGN35-013
Phase 2
Open-label, 
nonrandomized
Efficacy and 
safety
CD30+ non-
lymphomatous 
malignancies
1.8 or 2.4 mg/kg 
IVq3wk or
1.2 mg/kg IV 
q1wk
NA
ORR
80/83 (d)
≥6
Oct 11–
ongoing
US
SGN35-014
Phase 3 
Randomized, 
double-blind, 2-arm, 
A+CHP vs CHOP
Efficacy and 
safety
CD30+ mature 
T-cell lymphomas 
(treatment naïve)
1.8 mg/kg IV
q3wk
6-8 cycles
Progression-
free survival
450/363
≥18
Jan 13–
ongoing
US, Asia, 
Canada, 
Europe, 
Israel
SGN35-015
Phase 2
Open-label, 
nonrandomized, 
3-part, single agent or 
with dacarbazine or 
bendamustine
Efficacy and 
safety
HL (treatment 
naïve)
1.8 mg/kg IV
q3wk
16 cycles
ORR
80/72
≥60
Oct 12–
ongoing
US
Footnotes are on last table page.


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Table 4.b
List of Ongoing Clinical Studies With Brentuximab Vedotin (as of February 2016) (continued)
Study No.
Phase
Design
Study 
Objective
Diagnosis
Dosage (b-v) 
Frequency
Duration (a)
Primary 
Endpoint
Planned/
Enrolled (b)
Age
Study 
Dates (c) Regions
SGN35-016
Phase 1/2
Open-label, 
single-arm, with 
bendamustine
Efficacy and 
safety 
HL 
(post-frontline)
1.8 mg/kg IV
q3wk
16 cycles
CR rate
50/55 (d)
≥18
Jun 13–
ongoing
US
SGN35-017
Phase 2
Open-label, 
randomized,
3-part, with 
RCHOP/RCHP
Efficacy and 
safety
DLBCL 
(treatment naïve)
1.2 mg/kg or 
1.8 mg/kg IV
q3wk
Up to 6 cycles
CR rate, AEs, 
laboratory 
abnormalities
75/68
≥18
Aug 13–
ongoing
US
SGN35-022
Randomized, 
double-blind, 
dose-escalation
Efficacy and 
safety
SLE
0.3–1.8 mg/kg 
IV
q3wk
4 cycles
SRI response, 
AEs, laboratory 
abnormalities
40/10
≥18
US
SGN35-025
Open-label, 
single-arm with 
nivolumab
Efficacy and 
safety
HL 
(post-frontline)
1.2 mg/kg or
1.8 mg/kg IV
q3wk
4 cycles
CR rate, AEs, 
laboratory 
abnormalities
56–60/6
≥18
Oct 15–
ongoing
US
C25001
Phase 3
Open-label, 
randomized, 2-arm, 
single-agent vs 
physician’s choice of 
methotrexate or 
bexarotene
Efficacy, 
quality of life, 
and safety
CD30+ mycosis 
fungoides or 
primary cutaneous 
ALCL
1.8 mg/kg IV 
q3wk
16 cycles
ORR lasting 
≥4 months
124/132 (d)
≥18
Aug 12–
ongoing
US
Footnotes are on last table page.


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Table 4.b
List of Ongoing Clinical Studies With Brentuximab Vedotin (as of February 2016) (continued)
Study No.
Phase
Design
Study 
Objective
Diagnosis
Dosage (b-v) 
Frequency
Duration (a)
Primary 
Endpoint
Planned/
Enrolled (b)
Age
Study 
Dates (c) Regions
C25002
Phase 1/2
Open-label, dose 
escalation in pediatric 
patients
Phase 1: 
pediatric MTD 
and PK
Phase 2: ORR
Phase 1: CD30+ 
malignancies
Phase 2: r/r HL or 
sALCL
1.4 or 1.8 mg/kg 
IV 
q3wk
16 cycles
AEs, laboratory 
abnormalities, 
PK, ORR
42/33
≥2,<18 
ALCL
≥5,<18 
HL
Apr 12–
ongoing
US, W 
Europe
C25003
Phase 3
Open-label, 
randomized, 2-arm, 
A+AVD vs ABVD
Efficacy, 
quality of life, 
and safety
Advanced 
classical HL 
(treatment naïve)
1.2 mg/kg
IV
q2wk
6 cycles
Modified 
progression-
free survival per 
IRF
1240/1334 (d) ≥18
Nov 12–
ongoing
US, 
Canada, 
Europe, 
Asia
C25006
Phase 4
Open-label, 
single-arm
Efficacy and 
safety
sALCL
1.8 mg/kg IV 
q3wk
16 cycles
ORR per IRF
45/21
≥18
Feb 14–
ongoing
Europe, 
Latin 
America
C25007
Phase 4
Open-label, 
single-arm
Efficacy and 
safety
r/r HL not suitable 
for SCT or 
multiagent 
chemotherapy
1.8 mg/kg IV 
q3wk
16 cycles
ORR per IRF
60/60 (d)
≥18
Mar 14–
ongoing
Europe
Compassionate Use Programs and Other Studies
SGN35-010
Expanded 
Access 
Program
Open-label, treatment 
option
Safety and 
expanded 
access
HL, ALCL, 
CD30+ CTCL
1.8 mg/kg IV 
q3wk
NA
AEs
410/361
≥6
Sep 10–
ongoing
US, 
Europe
Footnotes are on last table page.


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Table 4.b
List of Ongoing Clinical Studies With Brentuximab Vedotin (as of February 2016) (continued)
Study No.
Phase
Design
Study 
Objective
Diagnosis
Dosage (b-v) 
Frequency
Duration (a)
Primary 
Endpoint
Planned/
Enrolled (b)
Age
Study 
Dates (c) Regions
Named Patient 
Program
NA
NA
HL, ALCL
1.8 mg/kg IV
q3wk
16 cycles
NA
NA/2561
NA
Nov 10–
ongoing
Global 
(ex-North 
America)
MA25101
Post-
authorization
Prospective 
observational cohort
Safety
CD30+ r/r HL or 
sALCL
Per label and 
routine practice
SAEs, AEs of 
special interest, 
and risk factors 
500/174
>18
Jun 13–
ongoing
Europe
Special Drug 
Use Survey 
(All-Patients 
Surveillance)
Prospective 
observational cohort
Efficacy and 
safety
CD30+r/r HL or 
ALCL
1.8 mg/kg IV 
q3wk 
16 cycles
AEs
140/293 (d)
NA
Apr 14–
ongoing
Japan
A+AVD=brentuximab vedotin+ doxorubicin+ vinblastine+dacarbazine; AE=adverse event; b-v=brentuximab vedotin; 
CHP=cyclophosphamide+doxorubicin+prednisone; CTCL=cutaneous T-cell lymphoma; DLBCL=diffuse large B-cell lymphoma; IRF=independent review 
facility; IV=intravenous(ly); MTD=maximum tolerated dose; NA=not applicable; PK=pharmacokinetic(s); PN=peripheral neuropathy; qXwk=every X week(s); 
r/r=relapsed/refractory; RCHOP= rituximab +cyclophosphamide+doxorubicin+vincristine+prednisone; RCHP= rituximab +
cyclophosphamide+doxorubicin+prednisone; SAE=serious adverse event; SCT=stem cell transplant; SLE= systemic lupus erythematosus; SRI= SLE Responder 
Index; US=United States; W=Western.
(a) Maximum treatment duration represented as treatment cycles (1 cycle=q3wk, 1 dose/21-day cycle; or q2wk, 2 doses/28-day cycle; or q1wk, 3 doses/28-day 
cycle).
(b) Approximate number of patients enrolled as of 31 October 2015.
(c) First patient visit to last patient visit.
(d) Enrollment completed.
CCI


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The results of the relevant clinical studies are summarized below. Refer to the brentuximab 
vedotin IB for details.

Phase 1 study (United States): Study SG035-0001
Study SG035-0001 was a phase 1 dose-escalation study in patients with CD30-positive 
relapsed/refractory hematopoietic neoplasms (0.1-3.6 mg/kg every 3 weeks [Q3W]). A total of 
45 patients were enrolled in each dose cohort and the maximum tolerated dose (MTD) was 
defined as 1.8 mg/kg. Dose-limiting toxicity (DLT) was observed in 1 of 12 patients in the 
1.8 mg/kg cohort (thrombocytopenia [Grade 4]), 3 of 12 patients in the 2.7 mg/kg cohort (acute 
renal failure [Grade 3], prostatitis [Grade 3], febrile neutropenia [Grade 3], and hyperglycemia 
[Grade 3]), and 1 of 1 patient in the 3.6 mg/kg cohort (febrile neutropenia and septic shock 
[Grade 5]). The most common treatment-emergent adverse events (TEAEs) (≥20%) were 
fatigue (36%), fever (33%), diarrhea, nausea, peripheral neuropathy, and neutropenia (22% 
each), and headache and vomiting (20% each). A number of patients achieved response, with 
an ORR of 40% (17/42) and a CR rate of 26%.

Phase 1/2 study (Japan): Study TB-BC010088
Study TB-BC010088 was a phase 1/2 study that evaluated single-agent brentuximab vedotin in 
Japanese patients with relapsed/refractory CD30-positive HL or sALCL (1.2 or 1.8 mg/kg 
Q3W). The phase 1 part of the study was a dose-escalation study that enrolled 6 patients 
sequentially into cohort 1 (3 patients; 2 patients with HL and 1 patient with sALCL) at 
1.2 mg/kg or into cohort 2 at 1.8 mg/kg (3 patients with HL). In this part, no DLT was observed 
in the 1.2 or 1.8 mg/kg dose cohorts, and the treatment was well tolerated. In the phase 2 part, 
14 patients (9 patients with HL and 5 patients with sALCL) received 1.8 mg/kg of brentuximab 
vedotin. The phase 2 part resulted in a high objective response rate in Japanese patients (67% 
for patients with HL and 100% for patients with sALCL), including CR for 56% of patients 
with HL and 80% of patients with sALCL with a manageable toxicity profile.

Pivotal phase 2 studies (United States, Canada, and Western Europa):
–
Study SG035-0003 was a phase 2, single-arm, open-label study in patients with 
relapsed/refractory HL after auto-SCT.
–
Study SG035-0004 was a phase 2 study conducted in patients with relapsed/refractory 
sALCL.
Brentuximab vedotin was administered at a dose of 1.8 mg/kg Q3W. One hundred two patients 
with relapsed/refractory HL and 58 patients with relapsed/refractory sALCL were enrolled in 
Study SG035-0003 and Study SG035-0004, respectively.
The key efficacy results in HL (SG035-0003) include ORR per an independent review facility 
(IRF) (75% [95% CI; 64.9, 82.6]), CR rate per IRF (34% [95% CI; 25.2, 44.6]), B symptom 
resolution rate (77%), and duration of response (DOR; 6.7 months). Key efficacy endpoints in 
sALCL (SG035-0004) include ORR per IRF (88% [95% CI, 74.6; 93.9]), CR rate per IRF 
(53% [95% CI, 39.6; 66.7]), and B symptom resolution rate (82%). Brentuximab vedotin has 


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been shown to induce durable remissions in patients with HL both before and after auto-SCT, 
and in patients with relapsed/refractory sALCL. Progression-free survival (PFS) results 
comparing PFS after brentuximab vedotin with PFS from prior systemic therapy indicate that 
PFS is significantly prolonged with brentuximab vedotin in both HL and sALCL. A substantial 
number of patients with HL and sALCL and B symptoms at Baseline saw these symptoms 
resolve during treatment with brentuximab vedotin. In addition, the large majority of patients 
with sALCL presenting with cutaneous lesions at Baseline experienced resolution of these 
symptoms after receiving brentuximab vedotin.
TEAEs occurring in ≥20% of patients in the phase 2 studies were peripheral sensory 
neuropathy (44%), fatigue (42%), nausea (41%), diarrhea (34%), pyrexia (31%), upper 
respiratory tract infection (28%), neutropenia (21%), and vomiting (20%). These events were 
primarily mild to moderate in severity and reversible. In the phase 2 studies, 31% of patients 
had a serious adverse event (SAE), 28% had a Grade 3 or higher SAE, and 15% had an SAE 
that was determined by the investigator to be related to brentuximab vedotin. The most 
common SAE preferred terms (2%) were abdominal pain, disease progression (recurrent 
sALCL), pulmonary embolism, and septic shock. A higher proportion of patients with sALCL 
experienced SAEs, including deaths within 30 days of the last dose, relative to patients with 
HL, likely due to the older age and more aggressive nature of the malignancy in this patient 
population. No deaths considered related to study treatment have been reported within the 
safety evaluation period (within 30 days after the last dose of brentuximab vedotin) in these 2 
phase 2 studies.
4.1.5
Known or Potential Risks of Brentuximab Vedotin

Brentuximab vedotin treatment causes peripheral neuropathy, both sensory and motor. 
Brentuximab vedotin-induced peripheral neuropathy is typically cumulative and generally 
reversible. Monitoring patients for symptoms of neuropathy, such as hypoesthesia, 
hyperesthesia, paresthesia, discomfort, a burning sensation, and neuropathic pain or weakness, 
is required. Patients experiencing new or worsening peripheral neuropathy may require 
brentuximab vedotin dose modifications, including a dose delay (see Table 9.a).

Complete blood counts should be monitored before each dose of brentuximab vedotin, and 
more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia. 
Prolonged (≥1 week) severe neutropenia can occur. If Grade 3 or 4 neutropenia develops, 
manage with dose delays, reductions, or discontinuations (see Table 9.a).

Infusion-related reactions, including anaphylaxis, have occurred with brentuximab vedotin. 
Monitoring of patients during infusion is required. If anaphylaxis occurs, the administration of 
brentuximab vedotin should be immediately and permanently discontinued and appropriate 
medical therapy administered. Patients who have experienced a prior infusion-related reaction 
should be premedicated according to institutional guidelines for subsequent infusions. 
Premedication may include acetaminophen, an antihistamine, and a corticosteroid.


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
Any treatment that can decrease immune function may contribute to malignancy and 
infections; patients are to be monitored for these events during the treatment period and up to 
and including 30 days after the last dose.

Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) have been reported with 
brentuximab vedotin. If SJS/TEN occurs, brentuximab vedotin must be discontinued and the 
appropriate medical therapy administered.

Tumor lysis syndrome may occur. Patients with rapidly proliferating tumors and high tumor 
burden are at risk of tumor lysis syndrome and should be closely monitored. If tumor lysis 
syndrome occurs, take medically appropriate measures.

Progressive multifocal leukoencephalopathy (PML) has been reported with brentuximab 
vedotin use. If PML is suspected, a diagnostic work-up should be performed as described in 
Section 9.6.5.

Concomitant use of brentuximab vedotin and bleomycin is contraindicated due to pulmonary 
toxicity. In a clinical study that studied brentuximab vedotin with bleomycin as part of a 
combination regimen (ABVD), the rate of noninfectious pulmonary toxicity was higher than 
the historical incidence reported with ABVD.
Pulmonary toxicity, including events of pneumonitis, interstitial lung disease, and acute 
respiratory distress syndrome, some with fatal outcomes, has been reported in patients 
receiving brentuximab vedotin monotherapy. Based on a cumulative review of all nonstudy 
derived events of acute pulmonary toxicity associated with brentuximab vedotin monotherapy 
and safety results in patients with HL after auto-SCT in Study SGN35-005, pulmonary toxicity 
associated with brentuximab vedotin treatment cannot be ruled out although clear evidence of 
a causal relationship was not found. Patients being treated with brentuximab vedotin should be 
closely and continuously monitored. If pulmonary toxicity is suspected, a prompt diagnostic 
evaluation should be performed, and patients should be treated appropriately. Consider 
holding brentuximab vedotin during evaluation and until symptomatic improvement.

Acute pancreatitis has been reported in patients treated with brentuximab vedotin and has 
contributed to fatal outcomes in some cases. Onset typically occurred after 1 to 2 doses of 
brentuximab vedotin. Early symptoms included severe abdominal pain, nausea, and vomiting. 
The majority of pancreatitis cases were complicated by other possible contributory factors, 
including cholelithiasis and alternate etiologies (eg, pancreatic lymphoma progression and
displacement of bile duct stent).

Approximately 10% of patients treated with brentuximab vedotin within the defined overall 
clinical study population have had an adverse event (AE) that was suggestive of a 
hepatobiliary disorder; <1% have experienced an SAE. Fatal outcomes have occurred; these 
cases were confounded by pre-existing liver disease, comorbidities, and concomitant 
medications with known hepatotoxic potential. The majority of hepatic AEs have been 
reported as Grade 1 to 2 in intensity. Increased liver enzymes have constituted the majority of 
hepatic AEs.


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
Gastrointestinal complications, including events of intestinal obstruction, ileus, enterocolitis, 
neutropenic colitis, erosion, ulcer, perforation, and hemorrhage, some with fatal outcomes, 
have been reported in patients treated with brentuximab vedotin. Some cases of 
gastrointestinal perforations were reported in patients with gastrointestinal involvement of 
underlying lymphoma. In the event of new or worsening gastrointestinal symptoms, perform a 
prompt diagnostic evaluation and treat appropriately.

The pharmacokinetic (PK) of brentuximab vedotin was studied in patients with hepatic or renal 
impairment. Patients with hepatic impairment (Child-Pugh class A to C) and patients with 
severe renal impairment (creatinine clearance lower than 30 mL/min) exhibited a trend toward 
moderate decreases in ADC exposure and increases in MMAE exposure. Therefore, patients 
with hepatic impairment and/or severe renal impairment at Baseline will not be enrolled in this 
study. Patients with hepatic or renal impairment during study treatment should be closely 
monitored for AEs and will be treated based on the local standard of care.

Co-administration of brentuximab vedotin with ketoconazole, a strong cytochrome P450 
(CYP) 3A4 and P-glycoprotein (P-gp) inhibitor, increased the exposure to the antimicrotubule 
agent MMAE by approximately 73% and did not alter the plasma exposure to brentuximab 
vedotin. Therefore, co-administration of brentuximab vedotin with strong CYP3A4 and P-gp 
inhibitors may increase the incidence of neutropenia. If neutropenia develops, refer to Table 
9.a.

Co-administration of brentuximab vedotin with rifampicin, a strong CYP3A4 inducer, did not 
alter the plasma exposure to brentuximab vedotin; however, it reduced exposure to MMAE by 
approximately 31%.

Co-administration of midazolam, a CYP3A4 substrate, with brentuximab vedotin did not alter 
the metabolism of midazolam; therefore, brentuximab vedotin is not expected to alter the 
exposure to medicines that are metabolized by CYP3A4 enzymes.

The effects of brentuximab vedotin on embryogenesis, reproduction, and spermatogenesis in 
humans are unknown. In addition, data about the effects of brentuximab vedotin in pregnant 
women are unavailable. Please see Section 9.5 for appropriate precautions triggered by the 
administration of study medication.
Refer to the brentuximab vedotin IB for details.
4.2
Rationale for the Proposed Study
4.2.1
Rationale for Evaluation of HL and sALCL in One Study
The mechanism and site of action of brentuximab vedotin are the same for both HL and sALCL 
because brentuximab vedotin exhibits antitumor effects by binding to CD30 on the surface of 
tumor cells. Additionally, the same tumor response criteria are used for both diseases. The 
therapeutic strategy is similar for relapsed/refractory HL and sALCL. The phase 2 studies showed 
that brentuximab vedotin has comparable antitumor effects in patients with relapsed/refractory HL 


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and sALCL, and there is no marked difference in safety profile. It is therefore appropriate to 
evaluate brentuximab vedotin in patients with relapsed/refractory HL and sALCL in one study.
4.2.2
Rationale for Dose
In Study SG035-0001 (first-in-human study), brentuximab vedotin doses from 0.1 to 3.6 mg/kg 
Q3W were evaluated. No DLT was observed in the cohorts up to 1.2 mg/kg Q3W. DLTs observed 
in 3 of 12 patients treated at the 2.7 mg/kg dose level included Grade 4 neutropenic fever, Grade 3 
prostatitis, Grade 3 hyperglycemia, and 1 case of unrelated acute renal failure. One occurrence of 
Grade 4 thrombocytopenia qualified as a DLT at the 1.8 mg/kg dose level. The MTD was defined 
as 1.8 mg/kg administered intravenously (IV) Q3W.
Tumor response (CR+partial remission [PR]) was observed at doses above 1.2 mg/kg Q3W. The 
subsequent clinical studies have used a dose of 1.8 mg/kg Q3W as the optimal dose.
In the phase 1 part of Study TB-BC010088 (Japan phase 1/2 study), brentuximab vedotin was 
evaluated at dose levels of 1.2 and 1.8 mg/kg administered Q3W to determine the phase 2 dose. No 
DLT was observed in the phase 1 part of this study, and the 1.8 mg/kg dose level was selected for 
the phase 2 part. The resulting tumor response at 1.8 mg/kg by the IRF was 67% (95% CI; 29.9,
92.5) for relapsed/refractory HL and 100% (95% CI; 54.9, 100.0) for relapsed/refractory sALCL. 
Tumor sizes were reduced in all subjects in the phase 2 part for whom measurements were 
available, and the safety profile was manageable.
The same brentuximab vedotin dosing schedule of 1.8 mg/kg Q3W was used in the Study 
SGN35-005 (global phase 3 study). The safety findings from this study were similar to those from 
pivotal phase 2 studies SG035-0003 and SG035-0004. At the time of the interim OS analysis, data 
are immature and limited by the small number of events observed within a relatively short 
follow-up period; however, the difference in median PFS in this study per IRF between the 
brentuximab vedotin arm and placebo arm was statistically significant by the stratified log rank 
test (p=0.001).
Based on these data, it is appropriate to use 1.8 mg/kg Q3W as the brentuximab vedotin dose in 
Chinese patients. This dose has been approved in 62 countries for patients with relapsed or 
refractory CD30-positive HL and sALCL.


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5.0
STUDY OBJECTIVES
5.1
Primary Objective
The primary objective is to evaluate the efficacy and the safety of brentuximab vedotin in Chinese 
patients with relapsed/refractory CD30+ HL or sALCL.
5.2
Secondary Objective
The secondary objective is to evaluate the PK and immunogenicity of brentuximab vedotin in 
Chinese patients with relapsed/refractory CD30+ HL or sALCL.


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6.0
STUDY ENDPOINTS
6.1
Primary Endpoints
The primary endpoints are:

ORR.

Safety: AEs, assessments of clinical laboratory values, and vital sign measurements.
6.2
Secondary Endpoints
The secondary endpoints are:

CR rate.

DOR.

PFS.

OS.

B symptom resolution rate.

Maximum observed plasma concentration (Cmax).

Time to reach Cmax (tmax).

Area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf).

Presence of antitherapeutic antibodies (ATA) and neutralizing antitherapeutic antibodies 
(nATA) to brentuximab vedotin.


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7.0
STUDY DESIGN
7.1
Overview of Study Design
This is a single-arm, open-label, multicenter, phase 2 study designed to evaluate the efficacy, 
safety, and PK of brentuximab vedotin as a single agent in Chinese patients with 
relapsed/refractory CD30+ HL or sALCL. Brentuximab vedotin will be administered as a single, 
1.8 mg/kg IV infusion on Day 1 of each 3-week cycle.
Patients will receive a maximum of 16 cycles if they do not meet the criteria for removal from the 
study. Patients will be assessed for overall response using the Revised Response Criteria for 
Malignant Lymphoma [1]. Dedicated computed tomography (CT) scans (neck, chest, abdomen, 
and pelvis) will be performed at Baseline and at Cycles 2, 4, 7, 10, 13, and 16, and positron 
emission tomography (PET) scans will be performed at Baseline and at Cycles 4 and 7. No 
additional PET scanning is required beyond Cycle 7 unless clinically indicated. B symptoms will 
be assessed at Baseline and on Day 1 of each cycle.
Patients may continue on study treatment until the sooner of disease progression, unacceptable 
toxicity, or completion of 16 cycles. Patients, including those who discontinue study treatment for 
any reason other than withdrawal of consent, will have safety follow-up assessments through 
30 days after the last dose of study drug (end of treatment [EOT]). Patients who discontinue study 
treatment with stable disease (SD) or better will be followed for PFS until disease progression, 
death, withdrawal of consent, or initiation of a new treatment, whichever occurs first. A CT scan 
will be performed every 12 weeks for the first 12 months and at 18 months after EOT. Patients will 
be followed for OS every 12 weeks until death, withdrawal of consent, or study closure, whichever 
occurs first. All patients will have the opportunity to be followed for 18 months after EOT. The 
study will be closed when all patients enrolled have completed the required follow-up.
Toxicity will be evaluated according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), version 4.03, effective 14 June 2010 [2]. Laboratory 
values, vital signs, and electrocardiograms (ECGs) will be obtained to evaluate the safety and 
tolerability of brentuximab vedotin. Serial blood samples for determination of the serum/plasma 
concentration and immunogenicity of brentuximab vedotin will be obtained at prespecified time 
points as described in Table B in Appendix A.
7.2
Number of Patients
It is expected that approximately 30 evaluable subjects (approximately 22 subjects with HL and
approximately 8 subjects with sALCL) will be enrolled in this study. The justification for the 
sample size is described in Section 14.3.
7.3
Duration of Study
The screening period will be up to 4 weeks, and the treatment period will be up to 16 cycles
(approximately 12 months). Patients will have safety follow-up assessments through 30 days after 
the last dose of brentuximab vedotin. All patients who discontinue brentuximab vedotin for any 


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reason other than withdrawal of full consent will undergo a long-term follow-up every 12 weeks 
after the safety follow-up assessments. Patients will be followed until all patients have had the 
opportunity to be followed for 18 months after EOT. The study will be closed when all patients 
enrolled have completed the required follow-up. It is expected that the study will last 
approximately 3.5 years.


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8.0
STUDY POPULATION
8.1
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Male or female Chinese patients aged 18 years or older at the time of informed consent.
2. Patients must have histologically confirmed CD30+ HL or sALCL. Immunohistochemistry or 
flow cytometry may be performed on either original diagnostic biopsy material or biopsy of 
relapsed disease, and pathology reports of CD30+ or their copies should be retained at the site.
3. Patients with CD30+ HL or sALCL who have relapsed from or are refractory to previous 
treatments.
4. Fluorodeoxyglucose (FDG)-PET positive and measurable disease of at least 1.5 cm in the 
longest diameter by CT, as assessed by the site.
5. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 
or 1.
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. Female patients 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.
Male patients, 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.
8. Suitable venous access for the study-required blood sampling, including PK sampling.
9. Patients must have the following required screening laboratory data. Patients must not have 
received recombinant granulocyte-colony stimulating factor (G-CSF) or platelet transfusion 
within 1 week before the screening hematology assessment.
–
Absolute neutrophil count ≥1500/μL.
–
Platelet count ≥75,000/μL.
–
Serum bilirubin level ≤1.5 times the upper limit of the normal range (ULN).
–
Serum creatinine level ≤1.5 times the ULN.


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–
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 times the 
ULN.
10. Survival for 3 or more months must be expected.
8.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Patients with current diagnosis of primary cutaneous ALCL (patients with other organ 
involvement who have transformed to sALCL are eligible).
2. Female patients who are lactating and breast-feeding or have a positive serum pregnancy test 
during the screening period.
3. Patients with any active viral, bacterial, or fungal infection within 2 weeks before the first dose 
of brentuximab vedotin.
4. Patients with cardiac failure categorized as Class III or IV according to the New York Heart 
Association criteria, uncontrolled coronary artery disease or uncontrolled arrhythmia despite 
of appropriate medical therapy, or a history of myocardial infarction within 6 months before 
the first dose of brentuximab vedotin.
5. Patients with uncontrolled diabetes mellitus.
6. Peripheral neuropathy ≥Grade 2 (NCI CTCAE version 4.03) [2].
7. Patients with a history of another malignancy that has not been in remission for at least 3 years. 
The following are exempt from the 3-year limit:
–
Nonmelanoma skin cancer.
–
Curatively treated localized prostate cancer.
–
Cervical carcinoma in situ.
8. Patients with known cerebral/meningeal disease (HL or any other etiology), including signs or
symptoms of PML (see Section 9.6.5).
9. Patients with a positive result in the screening test for human immunodeficiency virus (HIV)
antibody.
10. Known hepatitis B virus (HBV) surface antigen seropositive or positive hepatitis C virus 
(HCV) antibody. Note: patients who have positive HBV core antibody can be enrolled but 
must have an undetectable HBV viral load. 
11. Patients with a history of liver fibrosis or cirrhosis and clinical signs and symptoms indicating 
liver fibrosis or cirrhosis.
12. Patients who have received auto-SCT within 12 weeks before the first dose of brentuximab 
vedotin.
13. Patients with history of allo-SCT.


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14. Patients who have received treatment for malignancies (including radiation, chemotherapy,
and hormone therapy) within 4 weeks before the first dose of brentuximab vedotin and patients 
who have received treatment for malignancies with biologics (including molecular target drug) 
or radioisotopic therapy within 12 weeks before the first dose of brentuximab vedotin.
15. Patients who have unresolved toxicity higher than Grade 1 (NCI CTCAE version 4.03) [2]
attributed to any prior therapy/procedure (excluding alopecia or non-clinically significant and 
asymptomatic laboratory abnormalities).
16. Patients who have received systemic corticosteroids at doses greater than the equivalent of
20 mg/day of prednisone within 1 week before the first dose of brentuximab vedotin.
17. Patients who have received other investigational products within 4 weeks before the first dose 
of brentuximab vedotin.
18. Patients who have received treatment with investigational medical devices within 4 weeks 
before the first dose of brentuximab vedotin.
19. Patients who have received previous treatment with brentuximab vedotin.
20. Patients with a known hypersensitivity to any excipient contained in the drug formulation.
21. Patients who have any kind of disorder that compromises the ability of the patient to give 
written informed consent and/or to comply with study procedures.
22. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the 
investigator, would make the patient inappropriate for entry into this study or interfere 
significantly with the proper assessment of the safety and toxicity of the prescribed regimens.


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9.0
STUDY DRUG
9.1
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.
Brentuximab vedotin will be administered as an IV infusion over approximately 30 minutes on 
Day 1 of each 21-day cycle at a dose of 1.8 mg/kg. After Cycle 2, except when it takes longer for 
the subject to recover from toxicity that is possibly related to brentuximab vedotin after the most 
recent cycle (refer to Section 9.2), an administration window of -1 to +3 days is allowed. Patients 
with a tumor response (CR or PR) or SD for whom there are no safety concerns may receive up to 
16 cycles of brentuximab vedotin.
Brentuximab vedotin should not be given as a rapid IV dose or bolus injection. Brentuximab 
vedotin should be given through a dedicated infusion line and should not be mixed with other drug 
products.
The infusion line should be flushed with saline solution before and after brentuximab vedotin 
administration to avoid mixing with other drug products.
The dose of brentuximab vedotin will be calculated based on the subject’s actual body weight at 
Baseline, and the calculated brentuximab vedotin dose will be rounded to the nearest whole 
number. If the subject experiences a ≥10% change in body weight during the study, the dose 
should be adjusted. Note that if a patient weighs more than 100 kg, the dose for the patient will be 
calculated assuming the body weight to be 100 kg.
Patients will be monitored at bedside from the start of dosing for the first and second doses of 
brentuximab vedotin. Premedication to prevent infusion-related reactions may be used before 
dosing of brentuximab vedotin according to investigator discretion and institutional guidelines. 
Premedication use is further described in Section 9.6.3. If an infusion-related reaction occurs, 
continuation of brentuximab vedotin dosing will be based on the severity of the event and at the 
discretion of the investigator following discussion with the sponsor.
9.2
Dose Modification Guidelines
If treatment-related toxicity occurs, intrapatient dose reduction will be allowed to 1.2 mg/kg for 
each subject depending on the type and severity of the toxicity. If a patient requires further dose 
reductions, brentuximab vedotin will be permanently discontinued. Table 9.a provides the criteria 
for dose adjustments and delays for treatment-related toxicity. Toxicity will be evaluated 
according to the NCI CTCAE, version 4.03 [2].
If a patient fails to meet the criteria for re-treatment cited in Table 9.a, initiation of the next cycle of 
treatment should be delayed up to 1 week. At the end of that time, the patient should be 
re-evaluated to determine whether the criteria for re-treatment have been met. The start of the next 
cycle may be delayed for up to 3 weeks (6 weeks after the most recent dose) if additional time is 


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required for the patient to recover from treatment-related toxicity experienced during the current 
cycle. Delays of longer than 3 weeks (after Day 22) are prohibited without approval from the 
sponsor.
Doses reduced for treatment-related toxicity should generally not be re-escalated; however, 
intrapatient re-escalation to 1.8 mg/kg may be permitted at the discretion of the investigator after a 
discussion with the sponsor.


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Table 9.a
Criteria for Dose Adjustments and Delays
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Non-
hematologic
Continue at 
the same 
dose level
(1.8 mg/kg).
Continue at the same dose level
(1.8 mg/kg), except in the event of 
Grade 2 neuropathy.
For Grade 2 neuropathy, withhold 
dose until toxicity is ≤Grade 1 or 
has returned to baseline, then 
resume treatment at the same dose 
level (1.8 mg/kg). For the second 
occurrence of Grade 2 neuropathy, 
withhold dose until toxicity is 
≤Grade 1, then reduce the dose to 
1.2 mg/kg and resume treatment 
after discussion with the sponsor.
The investigator/subinvestigator will make 
decisions on the appropriateness of brentuximab 
vedotin treatment in subsequent cycles after 
discussion with the sponsor. For subjects who are 
determined to be able to continue treatment with 
brentuximab vedotin, continue treatment at the same 
dose level (1.8 mg/kg) or by reducing the dose to 
1.2 mg/kg. Confirm that toxicity is ≤Grade 1 or has 
returned to baseline before continuing treatment (a).
For Grade 3 or higher neuropathy, consider 
discontinuing treatment after discussion with the 
sponsor.
The investigator/subinvestigator will make decisions 
on the appropriateness of brentuximab vedotin 
treatment in subsequent cycles after discussion with 
the sponsor. For subjects who are determined to be able 
to continue treatment with brentuximab vedotin, 
confirm that toxicity is ≤Grade 1 or has returned to 
baseline, then continue treatment by reducing the dose 
to 1.2 mg/kg (a).
Hematologic
Continue at 
the same 
dose level
(1.8 mg/kg).
Continue at the same dose level
(1.8 mg/kg).
The investigator/subinvestigator will make 
decisions on the appropriateness of brentuximab 
vedotin treatment in subsequent cycles after 
discussion with the sponsor. For subjects who are 
determined to be able to continue treatment with 
brentuximab vedotin, continue treatment at the same 
dose level (1.8 mg/kg) or by reducing the dose to 
1.2 mg/kg. Confirm that toxicity is ≤Grade 2 or has 
returned to baseline before continuing treatment (b).
Consider growth factor support (G-CSF or 
GM-CSF) for treatment of neutropenia and 
prophylaxis in subsequent cycles.
The investigator/subinvestigator will make decisions 
on the appropriateness of brentuximab vedotin 
treatment in subsequent cycles after discussion with 
the sponsor. For subjects who are determined to be able 
to continue treatment with brentuximab vedotin, 
continue treatment at the same dose level (1.8 mg/kg)
or by reducing the dose to 1.2 mg/kg. Confirm that 
toxicity is ≤Grade 2 before continuing treatment (b).
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), 
the investigator/subinvestigator will make decisions on 
the appropriateness of brentuximab vedotin treatment 
in subsequent cycles after discussion with the sponsor. 
For subjects who are determined to be able to continue 
treatment with brentuximab vedotin, confirm that 
toxicity is ≤Grade 2, then continue treatment by 
reducing the dose to 1.2 mg/kg (b).
G-CSF= granulocyte colony-stimulating factor, GM-CSF= granulocyte macrophage colony-stimulating factor.
(a) Patients who develop Grade 3 or 4 electrolyte laboratory abnormalities may continue study treatment without dose delay.
(b) Patients who develop Grade 3 or 4 lymphopenia may continue study treatment without dose delay.


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9.3
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited from enrollment to completion of the 
safety follow-up assessments:

Antineoplastic agents other than brentuximab vedotin.

Any surgery requiring general anesthesia.

Radiotherapy.

Any other investigational drugs.

Any other investigational device.

Long-term treatment with corticosteroids at doses greater than the equivalent of 20 mg/day of 
prednisone.
9.4
Permitted Concomitant Medications and Procedures

Patients are allowed to receive treatment with corticosteroids at doses less than or equal to the 
equivalent of 20 mg/day of prednisone for longer than 1 month before enrollment. Intermittent 
use of corticosteroids for treating hypersensitivity reactions is permitted.

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.
Co-administration of brentuximab vedotin with ketoconazole, a strong CYP3A4 and P-gp 
inhibitor, increased the exposure to the antimicrotubule agent MMAE by approximately 73% and 
did not alter the plasma exposure to brentuximab vedotin. Therefore, co-administration of 
brentuximab vedotin with strong CYP3A4 and P-gp inhibitors may increase the incidence of 
neutropenia. If neutropenia develops, refer to Table 9.a.
Co-administration of brentuximab vedotin with rifampicin, a strong CYP3A4 inducer, did not alter 
the plasma exposure to brentuximab vedotin; however, it reduced exposure to MMAE by 
approximately 31%.
Co-administration of midazolam, a CYP3A4 substrate, with brentuximab vedotin did not alter the 
metabolism of midazolam; therefore, brentuximab vedotin is not expected to alter the exposure to 
medicines that are metabolized by CYP3A4 enzymes.
9.5
Precautions and Restrictions
It is not known what effects brentuximab vedotin has on human pregnancy or development of the 
embryo or fetus; therefore, female patients participating in this study should avoid becoming
pregnant, and male patients should avoid impregnating a female partner. Nonsterilized female 


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patients of reproductive age and male patients should use effective methods of contraception 
through defined periods during and after study treatment as specified below.
Female patients must meet 1 of the following:

Postmenopausal for at least 1 year before the screening visit, OR

Surgically sterile, OR

If they are of childbearing potential, agree to practice 2 effective methods of contraception 
from the time of signing of the informed consent form (ICF) through 6 months after the last 
dose of brentuximab vedotin.
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:

Practice effective barrier contraception during the entire study treatment period and through 
6 months after the last dose of brentuximab vedotin.
Contraception methods meeting the criteria defined above are provided below. If male condoms 
are used as a barrier method by male subjects, his partner must use an intrauterine devices (Copper 
T, or Progesteron T) or hormonal contraceptive (combined pills) instead of spermicide.
Barrier Methods (Each Time the 
Subject Has Intercourse)
Intrauterine Devices
Hormonal Contraceptives

Male condom PLUS spermicide.

Cap (plus spermicidal cream or 
jelly) PLUS male condom and 
spermicide.

Diaphragm (plus spermicidal 
cream or jelly) PLUS male 
condom and spermicide.

Copper T PLUS condom or 
spermicide.

Progesterone T PLUS condom or 
spermicide.

Implants.

Hormone injections.

Combined pills.

Minipills.

Patches.

Vaginal ring PLUS male condom 
and spermicide.
9.6
Management of Clinical Events
9.6.1
Nausea and/or Vomiting
Although this study will not require prophylactic antiemetics, there is no prohibition against their 
use.
9.6.2
Diarrhea
Prophylactic antidiarrheals will not be used in this protocol; however, patients will be instructed to 
take antidiarrheal medication(s) at their physician’s discretion until they are diarrhea-free for at 
least 12 hours. Fluid intake should be maintained to avoid dehydration.


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9.6.3
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 an infusion-related 
reaction, including anaphylaxis should it occur. The patient should be observed for approximately 
60 minutes following the first 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, 
administered 30 to 60 minutes before each 30-minute brentuximab vedotin infusion.
9.6.4
Peripheral Neuropathy
AEs of peripheral neuropathy will be monitored closely throughout the study. These events may 
include, but are not limited to, peripheral sensory neuropathy, peripheral motor neuropathy, 
paresthesia, hypoesthesia, polyneuropathy, muscular weakness, and demyelinating 
polyneuropathy. Such events, regardless of seriousness, will be followed for all changes in 
severity until the sooner of resolution to baseline or study closure and recorded in the electronic 
case report form (eCRF). Events that are higher than Grade 1 will result in brentuximab vedotin 
dose modification as shown in Table 9.a.
9.6.5
Suspected 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 
IB for further details.
If PML is suspected, hold further dosing and undertake a diagnostic work-up including (but not 
limited to):

Neurologic examinations, as warranted.

Brain magnetic resonance imaging (MRI): Features suggestive of PML include the 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 evidence of JCV in a brain biopsy.

Neurology consultation.
If PML is confirmed, permanently discontinue treatment with brentuximab vedotin.


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9.7
Blinding and Unblinding
This is an open-label study.
9.8
Description of Investigational Agents
Brentuximab vedotin is manufactured by BSP Pharmaceuticals S.p.A (formerly named BSP 
Pharmaceuticals S.r.l.) (Italy) under the manufacturing license issued by Takeda Pharma A/S 
(Denmark).
Brentuximab vedotin is a sterile, preservative-free, white to off-white lyophilized cake or powder 
supplied in single-use vials. Each vial contains brentuximab vedotin, trehalose, sodium citrate, and 
polysorbate 80.
For further details, see the IB.
9.9
Preparation, Reconstitution, and Dispensation
Brentuximab vedotin is supplied in single-use glass vials and will be reconstituted in the vial with 
10.5 mL of sterile water for injection. The appropriate amount of reconstituted brentuximab 
vedotin should be withdrawn from the vial and diluted in an infusion bag containing saline solution 
to produce a final brentuximab vedotin concentration of 0.4 to 1.8 mg/mL. For further details, see 
the Pharmacy Manual.
Parenteral drug products should be inspected visually for particulate matter and discoloration 
before administration whenever the solution and container permit.
Brentuximab vedotin is an anticancer drug, and as with other potentially toxic compounds, caution 
should be exercised when handling brentuximab vedotin.
9.10
Packaging and Labeling
The specifications and storage conditions of brentuximab vedotin are provided in Table 9.b.
Brentuximab vedotin vials will be packaged as single-use cartons. Each carton will contain 1 vial 
of the investigational product, and the vial and carton will be labeled to meet the requirements of 
the China Food and Drug Administration.


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Table 9.b
Investigational Product
Investigational product
Brentuximab vedotin
Content
50 mg/vial
Concentration
5 mg/mL (after reconstitution)
Container
Clear, colorless, glass vial
Packing unit
1 vial/carton
Property
Sterile white to off-white lyophilized cake or powder. Reconstituted products are clear 
or slightly opaque.
Protection from light
Reconstituted products should be protected from light until preparation.
Storage
Refrigeration (2°C-8°C)
Manufacturer and country
9.11
Storage, Handling, and Accountability
Vials containing study treatment 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 treatment does not contain preservatives; therefore, opened and reconstituted vials of study 
treatment must be used within 24 hours when stored under refrigeration at 2oC to 8oC. 
Reconstituted study treatment should not be stored at room temperature. It is recommended that 
study treatment 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.
CCI


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10.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines.
10.1
Study Personnel and Organizations
The contact information for the clinical laboratories, the coordinating investigator, the interactive 
web response system (IWRS) provider, and the contract research organization (CRO) is presented
in the attachment. A full list of investigators is available in the sponsor’s investigator database.
10.2
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).
10.3
Study Procedures
Refer to the Schedule of Events (Appendix A) for the study procedures. Additional details are 
provided as necessary in the sections that follow.
10.3.1 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. All the 
results of examinations (eg, HIV, HBV, HCV), imaging studies (eg, CT or MRI), tumor histology 
(CD30+ HL or sALCL, and ALK status for patients with sALCL), and bone marrow examination 
that were performed as part of routine care before informed consent has been signed may be used 
as screening data if the informed consent is obtained from the patient and the tests are performed 
within 28 days (14 days for bone marrow examination) before the first dose.
10.3.2
Enrollment
The investigator or investigator’s designee will access the IWRS at the screening visit to obtain a 
unique subject identification number. A subject is considered to be eligible to enter the enrollment 
visit when the eligibility criteria are met. The subject identification numbers will be used 
consistently throughout the entire study and must not be changed.
Subjects who do not meet eligibility criteria within the screening period will not be eligible for 
enrollment. However, subjects may be rescreened at the discretion of the investigator/ 
subinvestigator, provided that the subject has not been registered as a screen failure. If a subject is 
being rescreened, the investigator/subinvestigator must obtain additional written informed consent 
to reconfirm the subject’s consent to participate in this study. Subjects may be rescreened only 


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once. Subjects who will not be rescreened or are determined not eligible after rescreening must be 
considered screen failures.
The first dose of brentuximab vedotin should be started within 7 days after enrollment. If the first 
dose cannot be started within 7 days, screening can be repeated after reconsenting. 
10.3.3 Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during the screening 
period (Days -28 to 0).
10.3.4 Medical History
During the screening period (Days -28 to 0), 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 and procedures 
will be recorded as specified in Section 10.3.12.
Medical history will be evaluated for the following categories of clinically significant diseases or 
procedures that have been resolved or completed by the day before the first dose of brentuximab 
vedotin:
1. Any diseases that meet the exclusion criteria (including all that were resolved before 
enrollment).
2. Any diseases or procedures within the past 3 months that do not fall within category 1, except 
transient diseases (eg, upper respiratory inflammation, common cold, headache, diarrhea).
3. Any other diseases that are considered to possibly affect the evaluation of drug efficacy.
Complications will also be evaluated for any symptoms or diseases that are present at the first dose 
of brentuximab vedotin. Complications include clinically relevant abnormalities in laboratory 
tests, 12-lead ECGs, or physical findings. Details of complications (diagnostic results, whenever 
possible) should be given.
10.3.5 ECOG Performance Status
ECOG performance status (see Appendix D) will be measured during the screening and treatment 
periods. The timing of assessments will be as follows:

Screening period: Days -28 to 0.

Cycles 1 and 2: Days 1, 8, and 15; to be performed before study treatment on Day 1.

Cycle 3 and subsequent cycles: Days 1 and 15; to be performed before study treatment on 
Day 1.

Safety follow-up period: on the 30th day (±7 days) after the last dose of brentuximab vedotin. 


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10.3.6 Patient Height
Height will be measured only during screening (within 28 days before the first dose of study drug).
10.3.7 Weight
Weight will be measured during the screening and treatment periods. The timing of assessments 
will be as follows:

Screening period: Days -28 to 0.

Cycle 1: Day 1 within 3 days before study treatment.

Cycle 2 and subsequent cycles: Day 1 of each cycle within 1 day before study treatment.

Safety follow-up period: on the 30th day (±7 days) after the last dose of brentuximab vedotin.
10.3.8 Vital Signs
Vital sign measurements include blood pressure in the sitting position, pulse rate, and axillary
temperature. The timing of assessments will be as follows:

Screening period: Days -28 to 0.

Cycles 1 and 2: Days 1, 8, and 15; to be measured on Day 1 of Cycles 1 and 2 at predose, 
15 minutes (±5 minutes) and 30 minutes (±5 minutes) after the start of study drug infusion and 
at the end of dosing (±10 minutes).

Cycle 3 and subsequent cycles: Days 1 and 15; to be measured on Day 1 of Cycle 3 and 
subsequent cycles at predose and at the end of dosing (-5 minutes to +10 minutes).

Safety follow-up period: on the 30th day (±7 days) after the last dose of brentuximab vedotin.
10.3.9
ECGs
A 12-lead ECG will be administered as follows:

Screening period: Days -14 to 0; the screening ECG within 3 days of study dose on Day 1 of 
Cycle 1 may be substituted for the ECG on Day 1 of Cycle 1.

Cycle 1: Day 1 within 3 days before study treatment and after completion of the infusion 
(+2 hour).

Cycle 2 and subsequent cycles: Day 1 of each cycle within 1 day before study treatment.

Safety follow-up period: on the 30th day (±7 days) after the last dose of brentuximab vedotin.
10.3.10
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally. Clinical laboratory evaluations will be 
performed as outlined in this section.


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10.3.10.1
Clinical Chemistry, Hematology, and Urinalysis
Blood samples for analysis of the clinical chemistry and hematological parameters and urine 
samples for analysis of the parameters shown in Table 10.a will be collected. The timing of the 
assessments will be as follows:
Hematology

Screening period: Days -14 to 0; screening testing within 3 days of study dose on Day 1 of 
Cycle 1 may be substituted for testing on Day 1 of Cycle 1.

Cycles 1 and 2: Days 1, 2, 4, 8, and 15; the testing on Day 1 of Cycle 1 is to be performed 
within 3 days before study treatment and the testing on Day 1 of Cycle 2 is to be performed 
within 1 day before study treatment.

Cycle 3 and subsequent cycles: Days 1 and 15; the testing on Day 1 of each cycle is to be 
performed within 1 day before study treatment on Day 1.

Safety follow-up period: on the 30th day (±7 days) after the last dose of brentuximab vedotin.
Chemistry A

Screening period: Days -14 to 0; screening testing within 3 days of study dose on Day 1 of 
Cycle 1 may be substituted for testing on Day 1 of Cycle 1.

Cycles 1 and 2: Days 1, 8, and 15; the testing on Day 1 of each cycle is to be performed within 
3 days before study treatment and the testing on Day 1 of Cycle 2 is to be performed within 1 
day before study treatment.

Cycle 3 and subsequent cycles: Days 1 and 15; the testing on Day 1 of each cycle is to be 
performed within 1 day before study treatment.

Safety follow-up period: on the 30th day (±7 days) after the last dose of brentuximab vedotin.
Samples of glucose must be taken under fasting conditions (at least 4 hours after a meal) at 
screening and on Day 1 of Cycle 1. At other time points, although fasting levels (at least 4 hours 
after a meal) should be measured as a rule, nonfasting levels are also permitted; if a nonfasting 
level is measured, meal times must be recorded on the source document.
Chemistry B

Screening period: Days -14 to 0.

Safety follow-up period: on the 30th day (±7 days) after the last dose of brentuximab vedotin.
Samples of total cholesterol and triglycerides must be taken under fasting conditions (at least 
4 hours after a meal) at screening. At other time points, although fasting levels (at least 4 hours 
after a meal) should be measured as a rule, nonfasting levels are also permitted; if a nonfasting 
level is measured, meal times must be recorded on the source document.


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Coagulation

Screening period: Days -14 to 0; screening testing within 3 days of study dose on Day 1 of 
Cycle 1 may be substituted for testing on Day 1 of Cycle 1.

Cycle 1: Days 1 and 15; the testing on Day 1 to be performed within 3 days before study 
treatment.

Cycle 2 and subsequent cycles: Day 1 of each cycle; to be performed within 1 day before study 
treatment.

Safety follow-up period: on the 30th day (±7 days) after the last dose of brentuximab vedotin.
Viral test

Screening period: Day -28 to 0.
For patients who are HBV core antibody positive/HBV surface antigen negative/HBV surface 
antibody negative at screening, it is recommended to follow-up for HBV-DNA levels per local 
practice.
Urinalysis

Screening period: Day -14 to 0.

Cycle 2 and subsequent cycles: Day 1 of each cycle; to be performed within 1 day before study 
treatment.

Safety follow-up period: on the 30th day (±7 days) after the last dose of brentuximab vedotin.


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Table 10.a
Clinical Laboratory Evaluations
Tests
Panels
Hematology
Red blood cells, hemoglobin content, hematocrit, white blood cells, platelets, differential white 
blood cells (neutrophils, eosinophils, basophils, lymphocytes, monocytes), reticulocyte
Chemistry A (a)
Sodium, potassium, chloride, albumin, calcium, phosphorus, glucose, BUN, uric acid, creatinine, 
total bilirubin, AST, ALT, ALP, LDH, GGT
Chemistry B (b)
HbA1c, total cholesterol, triglycerides, TSH, FT3, FT4
Coagulation test
INR, PT, APTT
Viral test
HIV antibody, HBV surface antigen, HBV surface antibody, HBV core antibody, HBV DNA if 
appropriate, HCV antibody
Urinalysis
pH, protein, glucose, ketones, blood, urobilinogen
ALP=alkaline phosphatase, ALT=alanine aminotransferase, APTT=activated partial thromboplastin time,
AST= aspartate aminotransferase, BUN=blood urea nitrogen, FT3=free triiodothyronine, FT4=free thyroxine, 
GGT=gamma-glutamyl transpeptidase, HbA1c=hemoglobin A1c, HBV=hepatitis B virus, HCV= hepatitis C virus,
HIV= human immunodeficiency virus, INR=international normalized ratio, LDH=lactate dehydrogenase, 
PT=prothrombin time, TSH= thyroid-stimulating hormone. 
(a) Samples for glucose must be taken under fasting conditions (at least 4 hours after a meal) at screening and on Day 
1 of Cycle 1. At other time points, although fasting levels (at least 4 hours after a meal) should be measured as a rule, 
nonfasting level are also permitted; if a nonfasting level is measured, meal times must be recorded on the source 
document.
(b) Samples for total cholesterol and triglycerides must be taken under fasting conditions (at least 4 hours after a meal) 
at screening. At other time points, although fasting levels (at least 4 hours after a meal) should be measured as a rule, 
nonfasting levels are also permitted; if a nonfasting level is measured, meal times must be recorded on the source 
document.
10.3.11 Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at screening within 
2 weeks before the first dose of brentuximab vedotin. The results from this test must be available 
and negative before the first dose of brentuximab vedotin is administered. Timing of assessments 
will be as follows:

Screening period: Days -14 to 0.

Safety follow-up period: on the 30th day (±7 days) after the last dose of brentuximab vedotin.
10.3.12 Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will recorded 
in the eCRF from the first dose of study medication through the safety follow-up visit. During 
outpatient treatment, the use of medications other than brentuximab vedotin and/or medical 
procedures will be elicited every visit. See Section 9.3 and Section 9.4 for a list of medications and 
therapies that are prohibited and/or allowed, respectively, during the study.


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10.3.13 AEs
Monitoring of AEs, serious and nonserious, will be conducted throughout the study. Changes in 
severity of peripheral neuropathy should be monitored in detail.
Refer to Section 11.0 for details regarding definitions, documentation, and reporting of 
pretreatment events (PTEs), AEs, and SAEs.
10.3.14 Disease Assessment
Tumor response will be evaluated according to the Revised Response Criteria for Malignant 
Lymphoma [1].
All imaging will be performed with contrast, except for subjects in whom contrast imaging is 
difficult because of hypersensitivity to contrast medium, bronchial asthma, renal impairment, or 
other conditions.
Measurable lesions are those that meet all the following criteria:

Lymph nodes diagnosed as lymphoma lesions, or nodular masses involving extranodal organs 
on CT imaging.

Lesions that can be accurately measured in 2 perpendicular directions on CT cross-sectional 
images.

Lesions with longest diameter ≥1.5 cm on CT cross-sectional images.

FDG-PET positive lesions.
As many as 6 target lesions will be selected among the measurable lesions, whether nodal or 
extranodal, in order of decreasing longest diameter on CT cross-sectional images.
B symptoms will be assessed at prespecified time points as described in the Schedule of Events
(Appendix A).
Bone marrow aspirate or biopsy will be performed within 2 weeks before the first dose of 
brentuximab vedotin (it is not necessary to repeat these procedures in patients with a positive bone 
marrow aspirate or biopsy performed after the most recent antineoplastic therapy). For patients 
with bone marrow involvement at Baseline, bone marrow aspirate or biopsy is required to confirm 
the CR status. Bone marrow aspirate or biopsy samples will be collected within 2 weeks after CT 
scans. Further bone marrow assessments are not required after bone marrow aspirate or biopsy 
becomes negative.
Timing of CT scans will be as follows:

Screening period: Days -28 to 0.

Cycles 2, 4, 7, 10, 13, and 16: Days 15 through 21 (before study treatment in the next cycle).


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Subjects who discontinue study treatment or assessments for the reasons stated in Section 10.6
other than progressive disease (PD) and have not undergone assessment within the past 6 weeks 
should have tumor response assessed during the safety follow-up whenever possible.
Subjects who discontinue study treatment for any reason other than PD will have CT scans every 
12 weeks (±14 days) for the first 12 months and at 18 months after EOT until disease progression, 
death, withdrawal of consent, or initiation of a new treatment, whichever occurs first.
Subjects with symptoms suggestive of PD should be evaluated radiographically to assess disease 
status at the time the symptoms occur whenever possible.
PET scans will be performed at baseline and on Days 15 through 21 of Cycles 4 and 7 (before 
study treatment of next cycle). No additional PET scanning is required beyond Cycle 7 unless 
clinically indicated.
Refer to the study manual for the details of CT/PET scans for the assessment of antitumor effect.
10.3.15 PK Measurements
Blood samples for PK (ADC and total antibody [TAb] in serum, MMAE in plasma) will be taken 
at prespecified time points as described in Table B (Appendix A).
Refer to Sample Management Plan and Laboratory Manual for PK sample collection, processing, 
storage condition, and shipment.
10.3.16 Immunogenicity Measurements
Blood samples for immunogenicity (in serum) assessments will be taken at prespecified time 
points as described in Table B (Appendix A). On dosing days, the blood samples for 
immunogenicity assessments must be collected before dosing.
Detailed information about the immunogenicity blood volume, blood sample collection, 
processing, storage conditions, and shipment will be provided in the Sample Management Plan 
and Laboratory Manual.
Positive ATA screening samples will be further tested for true positivity. Confirmed true positive 
ATA samples will be further characterized for neutralizing activity.
10.4
Completion of Treatment
Patients will be considered to have completed study treatment if they complete 16 cycles of 
treatment with brentuximab vedotin or if they experience PD. Patients who discontinue study 
treatment for any reason other than withdrawal of consent will have safety follow-up assessments 
through 30 days (±7 days) after receiving their last dose of brentuximab vedotin.
10.5
Completion of Study
Patients will be considered to have completed the study if they complete 16 cycles of treatment 
with brentuximab vedotin and have completed the 18-month follow-up or have died.


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10.6
Discontinuation of Treatment With Study Drug and Patient Replacement
Treatment with study drug may be discontinued for any of the following reasons:

AE.

Protocol violation.

PD.

Study terminated by sponsor.

Withdrawal by subject.

Lost to follow-up.

Administrative decision by the investigator/subinvestigator or the sponsor.

Pregnancy.

Completed 16 cycles of treatment at response (CR or PR) or SD.

Initiation of subsequent stem cell transplant

Other.
Once study drug has been discontinued, all study procedures outlined for the safety follow-up 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.
Reasons that may cause a subject to be replaced include but are not limited to:

Patient does not meet Inclusion Criterion 2.

Patient has not taken at least 1 dose of brentuximab vedotin.

Patient is not response evaluable according to the Revised Response Criteria for Malignant 
Lymphoma [1].
10.7
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

Lost to follow-up.

Study terminated by sponsor.

Withdrawal by subject.

Other.
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.


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The sponsor or designee must be notified in writing if a patient is withdrawn from study treatment 
or from the study. The reason(s) for withdrawal must be documented in the patient’s medical 
records. The investigators should make every reasonable effort to keep each patient on the study 
until all planned treatments and assessments have been performed. If a patient withdraws from 
study treatment, every attempt should be made to follow the patient until death or study closure. 
Final treatment assessments should be performed before any other therapeutic intervention when
possible. Additionally, any planned alternative treatments should be documented in the patient’s 
medical records and eCRF.
10.8
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.
10.9
Long-term Follow-up Assessments
Patients who discontinue study treatment with SD or better will be followed for PFS until disease 
progression, death, withdrawal of consent, or initiation of a new treatment, whichever occurs first. 
A CT scan will be performed every 12 weeks (±14 days) for the first 12 months and at 18 months 
after the EOT. Patients will be followed for OS every 12 weeks (±14 days) until death, withdrawal 
of consent, or study closure, whichever occurs first. Survival information may be collected by 
methods including, but not limited to, telephone, e-mail, or mail. Patients will be followed until all 
patients have had the opportunity to be followed for 18 months after EOT. The study will be closed 
when all patients enrolled have completed the required follow-up.


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11.0
ADVERSE EVENTS
11.1
Definitions
11.1.1 PTE Definition
A PTE is any untoward medical occurrence in a patient or subject who has signed informed 
consent to participate in a study but before administration of any study medication; it does not 
necessarily have to have a causal relationship with study participation.
11.1.2 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.
11.1.3 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 11.2 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).

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, 
based on appropriate medical judgment, 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, 


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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.
In this study, intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, version 4.03, effective 14 June 2010 [2]. Clarification should be made between an 
SAE and an AE that is considered severe in intensity (Grade 3 or 4) because the terms serious and 
severe are NOT synonymous. The general term severe is often used to describe the intensity 
(severity) of a specific event; the event itself, however, may be of relatively minor medical 
significance (such as a Grade 3 headache). This is NOT the same as serious, which is based on 
patient/event outcome or action criteria described above, and is usually associated with events that 
pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) does not 
necessarily need to be considered serious. For example, a white blood cell count of 1000/mm3 to 
less than 2000 is considered Grade 3 (severe) but may not be considered serious. Seriousness (not 
intensity) serves as a guide for defining regulatory reporting obligations.
11.2
Procedures for Recording and Reporting AEs and SAEs
All AEs spontaneously reported by the patient and/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 11.3 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 1 comprehensive event.
Regardless of causality, SAEs and serious PTEs (as defined in Section 11.1) must be reported (see 
Section 11.3 for the period of observation) by the investigator to the Takeda Global 
Pharmacovigilance department or designee (contact information provided below). This should be 
done by faxing the SAE Form within 24 hours after becoming aware of the event. The SAE Form, 
created specifically by Takeda, will be provided to each clinical study site. A sample of the SAE 
Form may be found in the Study Manual. Follow-up information on the SAE or serious PTE may 
be requested by Takeda. SAE report information must be consistent with the data provided on the 
eCRF.
SAE Reporting Contact Information
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 intensity of the 
event and the relationship of the event to study drug administration. For serious pretreatment 
events, the investigator must determine both the intensity of the event and the relationship of the 
event to study procedures.
Intensity for each AE, including any lab abnormality, will be determined using the NCI CTCAE, 
version 4.03, effective 14 June 2010 [2]. The criteria are provided in the Study Manual.
Relationship to study drug administration will be determined by the investigator responding yes 
or no to this question: Is there a reasonable possibility that the AE is associated with the study 
drug?
11.3
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 and recorded in the eCRFs.

Serious PTEs will be reported to the Takeda Global Pharmacovigilance department or 
designee from the time of the signing of the ICF up to the first dose of study drug, but will not 
be recorded in the eCRF.

Related and unrelated SAEs will be reported to the Takeda Global Pharmacovigilance 
department 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 Takeda Global Pharmacovigilance department 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).
11.4
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 faxing a completed Pregnancy Form to the Takeda Global 
Pharmacovigilance department or designee (see Section 11.2). The pregnancy must be followed 
for the final pregnancy outcome.
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed Pregnancy Form 
to the Takeda Global Pharmacovigilance department or designee (see Section 11.2). Every effort 
should be made to follow the pregnancy for the final pregnancy outcome.
11.5
Procedures for Reporting Product Complaints
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 


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identify a potential product complaint situation should immediately report this via the phone 
numbers or email addresses below:
Product
Call center
Phone number
E-mail
Fax
ADCETRIS
Product complaints in and of themselves are not AEs. If a product complaint results in an SAE, an 
SAE form should be completed and sent to 
 (refer to Section 11.2)
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12.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.


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13.0
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, PTEs, 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.
13.1
eCRFs 
Completed eCRFs are required for each subject who is enrolled in the study.
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor, CRO partners, and 
regulatory authorities. Investigative sites must complete eCRFs in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
13.2
Record Retention
The investigator agrees to keep the records stipulated in Section 13.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated ICFs, subject authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copy of eCRFs, including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from regulatory 
authorities, the sponsor or its designees. Any source documentation printed on degradable thermal 
sensitive paper should be photocopied by the site and filed with the original in the subject’s chart 
to ensure long term legibility. Furthermore, ICH E6 Section 4.9.5 requires the investigator to retain 


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essential documents specified in ICH E6 (Section 8) until at least 2 years after the last approval of 
a marketing application for a specified drug indication being investigated or, if an application is 
not approved, until at least 2 years after the investigation is discontinued and regulatory authorities 
are notified. In addition, ICH E6 Section 4.9.5 states that the study records should be retained until 
an amount of time specified by applicable regulatory requirements or for a time specified in the 
Clinical Study Site Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.


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14.0
STATISTICAL METHODS
14.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized before database lock. The SAP will 
provide further details regarding the definition of analysis variables and analysis methodology to 
address all study objectives. The primary analysis for the clinical study report including the 
primary and the secondary endpoints will be conducted when all patients have had the opportunity 
to receive 16 cycles of treatment and have had EOT assessments. The final analysis will be 
conducted at the time of study closure.
14.1.1 Analysis Populations
Safety/Modified Intent-to-Treat Population
The safety/modified intent-to-treat (mITT) population consists of all subjects who have 
measurable lesions at Baseline and receive at least 1 dose of brentuximab vedotin. The 
safety/mITT population will be used for analyses of efficacy, safety, and patient demographic and 
baseline disease characteristics, unless otherwise stated.
Per-protocol Population
The per-protocol population consists of all subjects who have measurable lesions at Baseline and 
no protocol deviations determined by the project clinician. The per-protocol population will be 
used for secondary analyses of tumor response.
PK Population
The PK analysis population consists of patients with sufficient dosing and PK data to reliably 
estimate PK parameters as determined by the clinical pharmacologist. The PK population will be 
used for all PK analyses.
14.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographics and baseline characteristics will be summarized, including sex, age, race, weight, 
height, medical history, prior medication, and other parameters as appropriate. No inferential 
statistics will be conducted.
14.1.3 Efficacy Analysis
Efficacy will be analyzed using the safety/mITT population for HL and sALCL patients
separately.
Primary efficacy endpoint:

The ORR, defined as the proportion of patients who have achieved CR or PR by EOT.
Secondary efficacy endpoints:

The CR rate, defined as the proportion of patients who have achieved CR by EOT.


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!
DOR, defined as the time between the first documentation of objective tumor response (CR or 
PR) and the first subsequent documentation of objective tumor progression or death due to any 
cause, whichever occurs first.
!
PFS, defined as the time from the start of study treatment to the first documentation of 
objective tumor progression or to death due to any cause, whichever occurs first.
!
OS.
!
B symptom resolution rate.
Pertinent variables will be summarized descriptively. Continuous variables will be summarized, 
including the number of subjects, mean, standard deviation, median, minimum, and maximum 
values; for categorical variables, the frequency and percentage per category will be summarized. 
Two-sided exact 95% CIs will be computed using appropriate techniques for ORR and CR. 
Time-to-event variables will be summarized by the Kaplan-Meier method with the associated 95% 
CIs when estimable.
14.1.4 PK Analysis
Descriptive statistics (number of patients, arithmetic mean, geometric mean, standard deviation, 
median, percentage of coefficient of variation, minimum, and maximum) will be used to 
summarize ADC and TAb in serum, and MMAE in plasma.
The following PK parameters of ADC, MMAE, and TAb will be estimated where applicable:
!
Cmax: maximum observed concentration (measured value).
!
tmax: time of first occurrence of Cmax.
!
AUC0-21d: AUC for the 21-day dosing interval.
!
t1/2: terminal elimination half-life.
!
AUC0-inf: AUC from time 0 to infinity.
!
CL: total clearance after intravenous administration, calculated using the observed value of the 
last quantifiable concentration.
!
Vss: volume of distribution at steady state after intravenous administration, calculated using the 
observed value of the last quantifiable concentration.
Arithmetic mean of the plasma or serum concentration of MMAE, ADC and TAb will be plotted 
over time.
14.1.5 Immunogenicity Analysis
Immunogenicity information, including ATA and nATA, will be summarized using descriptive 
statistics as applicable (based on the SAP). 
 
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14.1.6 ECG Analysis
A summary of ECG abnormalities will be presented by visit. ECG intervals (QT, corrected QT 
QTcB [Bazett] and QTcF [Frederica], PR, QRS, and RR) and ventricular rate will be summarized 
at each scheduled time point, along with change from Baseline.
14.1.7 Safety Analysis
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes from 
Baseline in the patient’s vital signs and clinical laboratory results using the safety population. 
Exposure to study drug, including the number of treated cycles, total amount of doses taken, and 
dose intensity will be summarized.
TEAEs 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.
AEs will be tabulated according to the MedDRA and will include the following categories:

TEAEs.

Drug-related TEAEs.

Grade 3 or higher TEAEs.

Grade 3 or higher drug-related TEAEs.

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 post-Baseline value. Graphical displays of key safety parameters, such as scatter plots 
of Baseline versus worst post-Baseline values, may be used to understand the brentuximab vedotin 
safety profile.
Descriptive statistics for the actual values (and/or the changes from Baseline) of vital signs (eg, 
blood pressure, pulse rate, and axillary temperatures) and weight over time will be tabulated by 
scheduled time point. ECOG performance status scores over time will also be tabulated.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities and to 
further define the safety profile of brentuximab vedotin.
14.1.8 Other Analyses
Important protocol deviations and the number of subjects with important protocol deviations will 
be tabulated for enrolled subjects with HL, with sALCL, and for the combined populations.


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14.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
14.3
Determination of Sample Size
The study will enroll approximately 30 evaluable patients, including approximately 22 patients 
with HL and approximately 8 patients with sALCL. For information purposes, response rates 
achieved in previous studies in relapsed/refractory HL and sALCL are referenced below.
ORR (CR+PR) by IRF (95% CI)
Global Study SGN035-0003 (HL: n=102)
74.5 (64.9, 82.6)
Global Study SGN035-0004 (sALCL: n=58)
86.2 (74.6, 93.9)
Japan Study TB-BC010088 (HL: n=9)
66.7 (29.9, 92.5)
Japan Study TB-BC010088 (sALCL: n=5)
100 (54.9, 100)
The observed response rates and the 95% exact CIs for 22 patients with HL and 8 patients with 
sALCL are summarized as follows.
HL (n=22)
sALCL (n=8)
Responses
ORR (%)
95% Exact CI
Responses
ORR (%)
95% Exact CI
8
36.4
(17.2
59.3)
4
50.0
(15.7
84.3)
9
40.9
(20.7
63.6)
5
62.5
(24.5
91.5)
10
45.5
(24.4
67.8)
6
75.0
(34.9
96.8)
11
50.0
(28.2
71.8)
7
87.5
(47.3
99.7)
12
54.5
(32.2
75.6)
8
100
(63.1
100.0)
13
59.1
(36.4
79.3)
Based on the exact binomial CI calculations, a minimum of 9 responses observed from 
22 evaluable patients with HL (ORR of 40.9%) will provide a 95% CI (20.7%, 63.6%); 5
responses observed from 8 evaluable patients with sALCL (ORR of 62.5%) will yield a 95% CI
(24.5%, 91.5%). In both cases, the lower limits of the 95% CIs are greater than the threshold 
response rate of 20% obtained from the results of alternative therapies for the same indications.
Assuming similar ORR results to those in Study TB-BC010088 will be obtained, the expected 
response rates are 65% for HL and 80% for sALCL. With 22 patients with HL and 8 patients with 
sALCL, the study will have >99% and >94% probability, respectively, to detect an ORR greater 
than the 20% threshold (ie, ≥9 responses for HL and ≥5 responses for sALCL).


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15.0
QUALITY CONTROL AND QUALITY ASSURANCE
15.1
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 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study medication, subject medical records, informed consent documentation, documentation of 
subject 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.
15.2
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 IEC, 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 primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol.
15.3
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 regulatory agencies, including 
those of foreign governments (eg, the United States Food and Drug Administration, the United 
Kingdom Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals and 
Medical Devices Agency of Japan). If the study site is contacted for an inspection by a regulatory 
body, the sponsor should be notified immediately. The investigator and institution guarantee 
access for quality assurance auditors to all study documents as described in Section 15.1.


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16.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (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.
16.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable local requirements of each 
participating region. 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/or 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 exact protocol title, 
number, and version date; identify versions of other documents (eg, ICF) reviewed; and state the 
approval date. 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 
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 its 
designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.


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16.2
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, as well as 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. In the event 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 or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines 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 entering into the study. The subject or the subject’s legally acceptable representative 
should be instructed to sign using their legal names, not nicknames, using blue or black ballpoint 
ink. The investigator must also sign and date the ICF and subject authorization (if applicable) at 
the time of consent and before subject entering 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 
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 


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revised consent was obtained should be recorded in the subject’s medical record, and the subject 
should receive a copy of the revised ICF.
16.3
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 only be linked to 
the sponsor’s clinical study database or documentation 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, the United States Food and Drug Administration, the United Kingdom 
Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals and Medical Devices 
Agency of Japan), 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 16.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
16.4
Publication, Disclosure, and Clinical Trial Registration Policy
16.4.1 Publication and Disclosure
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/or 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 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.


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16.4.2 Clinical Trial Registration
In order 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 ClinicalTrials.gov or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, country, and recruiting status will be registered 
and available for public viewing.
For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the 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.
16.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
16.5
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 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee.


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17.0
REFERENCES
1.
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
response criteria for malignant lymphoma. J Clin Oncol 2007;25(5):579-86.
2.
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. U.S. 
Department of Health and Human Services National Cancer Institute. 14 June 2010.
3.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 
2015;65(1):5-29.
4.
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Non-Hodgkin's 
Lymphomas. Version 2.2016. National Compresive Cancer Network. 2016.
5.
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide 
burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127(12):2893-917.
6.
Horning SJ, Chao NJ, Negrin RS, Hoppe RT, Long GD, Hu WW, et al. High-dose therapy 
and autologous hematopoietic progenitor cell transplantation for recurrent or refractory 
Hodgkin's disease: analysis of the Stanford University results and prognostic indices. 
Blood 1997;89(3):801-13.
7.
Kleiner S, Kirsch A, Schwaner I, Kingreen D, Schwella N, Huhn D, et al. High-dose 
chemotherapy with carboplatin, etoposide and ifosfamide followed by autologous stem 
cell rescue in patients with relapsed or refractory malignant lymphomas: a phase I/II study. 
Bone Marrow Transplant 1997;20(11):953-9.
8.
Santoro A, Bredenfeld H, Devizzi L, Tesch H, Bonfante V, Viviani S, et al. Gemcitabine in 
the treatment of refractory Hodgkin's disease: results of a multicenter phase II study. J Clin 
Oncol 2000;18(13):2615-9.
9.
Zinzani PL, Bendandi M, Stefoni V, Albertini P, Gherlinzoni F, Tani M, et al. Value of 
gemcitabine treatment in heavily pretreated Hodgkin's disease patients. Haematologica 
2000;85(9):926-9.
10.
Venkatesh H, Di Bella N, Flynn TP, Vellek MJ, Boehm KA, Asmar L. Results of a phase II 
multicenter trial of single-agent gemcitabine in patients with relapsed or 
chemotherapy-refractory Hodgkin's lymphoma. Clin Lymphoma 2004;5(2):110-5.
11.
Oki Y, Pro B, Fayad LE, Romaguera J, Samaniego F, Hagemeister F, et al. Phase 2 study of 
gemcitabine in combination with rituximab in patients with recurrent or refractory 
Hodgkin lymphoma. Cancer 2008;112(4):831-6.
12.
Schmitz N, Pfistner B, Sextro M, Sieber M, Carella AM, Haenel M, et al. Aggressive 
conventional chemotherapy compared with high-dose chemotherapy with autologous 
haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a 
randomised trial. Lancet 2002;359(9323):2065-71.


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13.
Linch DC, Winfield D, Goldstone AH, Moir D, Hancock B, McMillan A, et al. Dose 
intensification with autologous bone-marrow transplantation in relapsed and resistant 
Hodgkin's disease: results of a BNLI randomised trial. Lancet 1993;341(8852):1051-4.
14.
Longo DL, Duffey PL, Young RC, Hubbard SM, Ihde DC, Glatstein E, et al. 
Conventional-dose salvage combination chemotherapy in patients relapsing with 
Hodgkin's disease after combination chemotherapy: the low probability for cure. J Clin 
Oncol 1992;10(2):210-8.
15.
Wahl AF, Klussman K, Thompson JD, Chen JH, Francisco LV, Risdon G, et al. The 
anti-CD30 monoclonal antibody SGN-30 promotes growth arrest and DNA fragmentation 
in vitro and affects antitumor activity in models of Hodgkin's disease. Cancer Res 
2002;62(13):3736-42.
16.
NCCN. Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Hodgkin 
Lymphoma Version 2. 2015.


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Appendix A
Schedule of Events
Table A
Schedule of Events
Screening Period
Treatment Period
Safety 
Follow-up
Long-term 
Follow-up
Screening Enroll-
ment
Cycle 1
Cycle 2
Cycle 3 and 
Subsequent Cycles
Basis Date:
Number of Days 
Starting on Day 1 of 
Each Cycle
-28 
to 0
-14 
to 0 -7 to 0
1
2
3
4
8
11
15
1
2
4
8
15
15 to 
21j
1
15
15 to 
21j
Day 30
after final
doseo
Every 12 
weeks
Visit Window
±1D
±1D -1D to +3D
±3D ±3D
-1D to 
+3D
±3D
±7D
±14D
Informed consent
x
Enrollmenta
x
Demographics
x
Medical history
x
Brentuximab vedotin 
administrationb
x
xb
xb
ECOG performance 
statusc
x
x
x
x
x
x
x
x
x
x
Height
x
Weight
x
X
xs
xs
x
Vital signsd
x
x
x
x
x
x
x
x
x
x
12-lead ECG
x
Xi
xs
xs
x
Hematology
x
X
x
x
x
x
xs
x
x
x
x
xs
x
x
Chemistry Ae
x
X
x
x
xs
x
x
xs
x
x
Chemistry Bf
x
x
Coagulation
x
X
x
xs
xs
x
Viral test
x
Urinalysis
x
xs
xs
x
Pregnancy test
x
x
Concomitant 
medications/ procedures
AEs
SAE
CT scan
x
x
xl
xp
xq
PET scan
x
xm
(xm)
B symptom assessment
x
x
x
x
xp


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Screening Period
Treatment Period
Safety 
Follow-up
Long-term 
Follow-up
Screening Enroll-
ment
Cycle 1
Cycle 2
Cycle 3 and 
Subsequent Cycles
Basis Date:
Number of Days 
Starting on Day 1 of 
Each Cycle
-28 
to 0
-14 
to 0 -7 to 0
1
2
3
4
8
11
15
1
2
4
8
15
15 to 
21j
1
15
15 to 
21j
Day 30
after final
doseo
Every 12 
weeks
Visit Window
±1D
±1D -1D to +3D
±3D ±3D
-1D to 
+3D
±3D
±7D
±14D
Bone marrow aspirate or 
biopsy
xh
xn
xn
(xn)
PKg
x
x
x
x
x
x
x
x
x
x
x
x
xk
x
Immunogenicityg
x
x
xk
x
Survival follow-up
xr
CT= computed tomography, ECOG PS=Eastern Cooperative Oncology Group performance status, ECG=electrocardiogram, IWRS=interactive web response system, PET=positron 
emission tomography, PK=pharmacokinetics, SAE=serious adverse events. 
Tests and procedures should be performed on schedule, but occasional changes may be allowed (± 3 days) for holidays, vacations, and other administrative reasons. If the study 
schedule is shifted, assessments must be shifted to ensure collection of assessments is completed prior to dosing. 
X=Within 3 days before the first dose. Screening tests within 3 days before the study dose on Day 1 of Cycle 1 may be substituted for testing on Day 1 of Cycle 1.
(a) The investigator or investigator’s designee will access the IWRS at the screening visit to obtain a unique subject identification number. A subject is considered to be eligible to 
enter the enrollment visit when eligibility criteria are met. The subject identification numbers will be used consistently throughout the entire study and must not be changed.
(b) The start of the next cycle may be delayed for up to 3 weeks (up to 6 weeks from the current administration of brentuximab vedotin) if additional time is required for the patient to 
recover from study treatment-associated toxicity experienced during the current cycle. Delays of greater than 3 weeks (after Day 22) are prohibited without approval from the sponsor.
(c) Assessments on Day 1 of each cycle must be administered before dose of the study treatment.
(d) On Day 1 of Cycles 1 and 2, vital signs must be measured and recorded at the following times: predose; 15 (±5) minutes, and 30 (±5) minutes after the start of infusion; and upon 
completion of the infusion (±10 minutes). On Day 1 of Cycle 3 and subsequent cycles, vital signs must be measured and recorded at the following times: before the start of infusion 
and upon completion of the infusion (-5 to +10 minutes).
(e) Samples of glucose must be taken under fasting conditions (at least 4 hours after a meal) at screening and on Day 1 of Cycle 1. At other time points, although fasting levels (at least 
4 hours after a meal) should be measured as a rule, nonfasting levels are also permitted; if a nonfasting level is measured, the meal times must be recorded on the source document.
(f) Samples of total cholesterol and triglycerides must be taken under fasting conditions (at least 4 hours after a meal) at screening. At other time points, although fasting levels (at least 
4 hours after a meal) should be measured as a rule, nonfasting levels are also permitted; if a nonfasting level is measured, the meal times must be recorded on the source document.
(g) See Table B for details regarding PK and immunogenicity draws and windows. Immunogenicity samples must be taken before dosing.
(h) In patients with a positive bone marrow aspirate or biopsy following the most recent treatment of malignant tumor, bone marrow aspirate or biopsy do not need to be repeated.
(i) ECG on Day 1 of Cycle 1 within 3 days before study treatment and after completion of the infusion (+2 hours).
(j) On Days 15-21 after study drug dose of each cycle and before study drug dose of the next cycle.
(k) Sampling for PK and immunogenicity will be taken every 2 cycles after Cycle 3. 
(l) CT scan will be performed every 3 cycles after Cycle 4 (Cycles 4, 7, 10, 13 and 16). It does not need to be performed at Cycle 3.
(m) PET scan will be performed at Cycles 4 and 7. No additional PET scanning is required beyond Cycle 7 unless clinically indicated.
(n) For patients with bone marrow involvement at Baseline, bone marrow aspirate or biopsy is required to confirm the CR status. Bone marrow aspirate or biopsy samples will be 
collected within 2 weeks after CT scans. Further bone marrow assessments are not required after bone marrow aspirate or biopsy becomes negative.


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(o) Safety follow-up assessments should be performed before initiation of subsequent antineoplastic therapy.
(p) If possible, CT scans and B symptom assessments should be performed if not done within the previous 6 weeks.
(q) Patients who discontinue study treatment with SD or better will be followed for PFS until disease progression, death, withdrawal of consent, or initiation of a new treatment, 
whichever occurs first. A CT scan will be performed every 12 weeks (±14 days) for the first 12 months and at 18 months after EOT.
(r) Patients will be followed for OS every 12 weeks (±14 days) until death, withdrawal of consent, or study closure, whichever occurs first. 
(s) The testing on Day 1 is to be performed within 1 day before study treatment.


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Table B
Serial Sample Breakdown
Cycle
Study Day
Time
Window
PK
Immunogenicity
Cycle 1
Day 1
Predose
Within 2 hr
x
x
10 min after the end of brentuximab vedotin infusion
±5 min
x
4 hr after the end of brentuximab vedotin infusion
±30 min
x
Day 2
24 hr after the end of brentuximab vedotin infusion
±1 hr
x
Day 3
48 hr after the end of brentuximab vedotin infusion
±2 hr
x
Day 4
72 hr after the end of brentuximab vedotin infusion
±2 hr
x
Day 8
168 hr after the end of brentuximab vedotin infusion
±3 hr
x
Day 11
240 hr after the end of brentuximab vedotin infusion
±3 hr
x
Day 15
336 hr after the end of brentuximab vedotin infusion
±3 hr
x
Cycle 2
Day 1
Predose
Within 2 hr
x
x
10 min after the end of brentuximab vedotin infusion
±5 min
x
4 hr after the end of brentuximab vedotin infusion
±30 min
x
Day 2
24 hr after the end of brentuximab vedotin infusion
±1 hr
x
Day 4
72 hr after the end of brentuximab vedotin infusion
±2 hr
x
Day 8
168 hr after the end of brentuximab vedotin infusion
±3 hr
x
Day 15
336 hr after the end of brentuximab vedotin infusion
±3 hr
x
Cycle 3 and 
subsequent 
cycles
Day 1
Predose
Within 2 hr
xa
xa
10 min after the end of brentuximab vedotin infusion
±5 min
xa
–
Safety 
follow-up
x
x
(a) To be performed every 2 cycles after Cycle 3 and subsequent cycles.


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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. Ensure that study-related procedures, including study specific (non routine/non standard 
panel) screening assessments are NOT performed on potential subjects, before the receipt of 
written approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
ICH, and local regulatory requirements.
6. 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.
7. Ensure that requirements for informed consent, as outlined in ICH and local regulations, are 
met.
8. 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.
9. 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.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.


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12. 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
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.


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Appendix D
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 self-care. Totally confined to bed or 
chair.
5
Dead
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria 
of the Eastern Cooperative Oncology Group. American Journal of Clinical Oncology 1982;5(6):649-55.


Brentuximab vedotin
Study No. C25010
Page 84 of 84
Protocol 
20 April 2016
CONFIDENTIAL
Appendix E
New York Heart Association Functional Classification
Class I
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation 
or dyspnea.
Class II
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in 
fatigue, palpitation or dyspnea.
Class III
Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes 
fatigue, palpitation or dyspnea.
Class IV
Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency may 
be present even at rest. If any physical activity is undertaken, discomfort is increased.


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SAP_001.pdf: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 2, Single-Arm, Open-label Study of Brentuximab Vedotin in Chinese Patients 
With Relapsed/Refractory CD30-Positive Hodgkin Lymphoma (HL) or Systemic Anaplastic 
Large Cell Lymphoma (sALCL)
NCT Number: NCT02939014
SAP Approve Date:  30 August 2018
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: C25010
A Phase 2, Single-Arm, Open-label Study of Brentuximab Vedotin in Chinese Patients With
Relapsed/Refractory CD30-Positive Hodgkin Lymphoma (HL) or Systemic Anaplastic
Large Cell Lymphoma (sALCL)
PHASE 2
Version: Final
Date: 30 August 2018
Prepared by:
Based on:
Protocol Version: Original
Protocol Date: 20 April 2016
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.
PPD


C25010
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1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.


C25010
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2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
List of In-Text Tables............................................................................................................4
List of In-Text Figures...........................................................................................................4
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objectives ....................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Additional Objectives ................................................................................................7
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS...............................................................................................9
5.1
Primary Endpoints .....................................................................................................9
5.2
Secondary Endpoints .................................................................................................9
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................10
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................11
7.1
General Principles....................................................................................................11
7.1.1
Definition of Study Days....................................................................................11
7.1.2
Definition of Study Visit Windows ....................................................................12
7.1.3
Conventions for Missing Adverse Event Dates...................................................12
7.1.4
Conventions for Missing Concomitant Medication Dates...................................12
7.2
Analysis Sets ...........................................................................................................13
7.2.1
Safety/Modified Intent-to-Treat Population........................................................13
7.2.2
Per-protocol Population......................................................................................13
7.2.3
PK Population....................................................................................................13
7.2.4
Immunogenicity Population ...............................................................................13
7.3
Disposition of Subjects ............................................................................................13
7.3.1
Protocol Deviations............................................................................................13
7.4
Demographic and Other Baseline Characteristics.....................................................14
7.5
Medical History and Concurrent Medical Conditions...............................................14
7.6
Medication History and Concomitant Medications...................................................15
7.7
Study Drug Exposure and Compliance.....................................................................15
7.8
Efficacy Analysis.....................................................................................................16
7.8.1
Primary Efficacy Endpoint(s).............................................................................16


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7.8.2
Secondary Efficacy Endpoint(s).........................................................................16
7.8.3
Additional Efficacy Endpoint(s).........................................................................17
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................17
7.9.1
Pharmacokinetic Analysis ..................................................................................17
7.9.2
Pharmacodynamic Analysis ...............................................................................18
7.10
Other Outcomes.......................................................................................................18
7.10.1 Immunogenicity Analysis...................................................................................18
7.11
Safety Analysis........................................................................................................19
7.11.1 Adverse Events ..................................................................................................19
7.11.2 Clinical Laboratory Evaluations .........................................................................20
7.11.3 Vital Signs .........................................................................................................21
7.11.4 12-Lead ECGs ...................................................................................................21
7.11.5 Other Observations Related to Safety.................................................................21
7.12
Interim Analysis ......................................................................................................21
7.13
Changes in the Statistical Analysis Plan...................................................................22
8.0
REFERENCES..............................................................................................................23
LIST OF IN-TEXT TABLES
Table 6.a
ORRs in the Global Pivotal Studies and the Japan Study....................................10
Table 6.b
ORRs and the 95% Exact CIs for Various Number of Responses .......................10
Table 7.a
Imputation Rules for Missing AE Start Dates.....................................................12
LIST OF IN-TEXT FIGURES
None


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3.0
LIST OF ABBREVIATIONS
ADC
antibody-drug conjugate
AE
adverse event
ALCL
anaplastic large cell lymphoma
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATA
antitherapeutic antibodies
ATC
Anatomical Therapeutic Chemical classification
AUC
area under the concentration-time curve
CI
confidence interval
CL
clearance
Cmax
maximum observed concentration
CR
complete response
CSR
clinical study report
CT
computed tomography
CTMS
clinical trial management system
CV
coefficient of variation
DCR
Disease control rate
DOR
duration of response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EOT
end of treatment
HL
Hodgkin lymphoma
IRF
independent review facility
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
MMAE
monomethylauristatin E
nATA
neutralizing antitherapeutic antibodies
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
ORR
overall response rate
OS
overall survival
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
RDI
relative dose intensity
SAE
serious adverse event
sALCL
systemic anaplastic large cell lymphoma
SAP
statistical analysis plan


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SD
stable disease
SPD
sum of products of diameters
StdDev
standard deviation
SMQ
standardised MedDRA queries
TAb
total antibody
TEAE
treatment-emergent adverse event
tmax
time of first occurrence of Cmax
WHO
World Health Organization


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4.0
OBJECTIVES
4.1
Primary Objectives
The primary objective is to evaluate the efficacy and the safety of brentuximab vedotin in 
Chinese patients with relapsed/refractory CD30+ HL or sALCL.
4.2
Secondary Objectives
The secondary objective is to evaluate the PK and immunogenicity of brentuximab vedotin in 
Chinese patients with relapsed/refractory CD30+ HL or sALCL.
4.3
Additional Objectives
Not applicable.
4.4
Study Design
This is a single-arm, open-label, multicenter, phase 2 study designed to evaluate the efficacy, 
safety, and PK of brentuximab vedotin as a single agent in Chinese patients with 
relapsed/refractory CD30+ HL or sALCL. Brentuximab vedotin will be administered as a single, 
1.8 mg/kg IV infusion on Day 1 of each 3-week cycle.
Patients will receive a maximum of 16 cycles if they do not meet the criteria for removal from 
the study. Patients will be assessed for overall response using the Revised Response Criteria for 
Malignant Lymphoma [1]. Dedicated computed tomography (CT) scans (neck, chest, abdomen, 
and pelvis) will be performed at Baseline and at Cycles 2, 4, 7, 10, 13, and 16, and positron 
emission tomography (PET) scans will be performed at Baseline and at Cycles 4 and 7. No 
additional PET scanning is required beyond Cycle 7 unless clinically indicated. B symptoms will 
be assessed at Baseline and on Day 1 of each cycle.
Patients may continue on study treatment until the sooner of disease progression, unacceptable 
toxicity, or completion of 16 cycles. Patients, including those who discontinue study treatment 
for any reason other than withdrawal of consent, will have safety follow-up assessments through 
30 days after the last dose of study drug until end of treatment (EOT). Patients who discontinue 
study treatment with stable disease (SD) or better will be followed for PFS until disease 
progression, death, withdrawal of consent, or initiation of a new treatment other than the stem 
cell transplantation (SCT), whichever occurs first. A CT scan will be performed every 12 weeks 
for the first 12 months and at 18 months after EOT. Patients will be followed for OS every 
12 weeks until death, withdrawal of consent, or study closure, whichever occurs first. All 
patients will have the opportunity to be followed for 18 months after EOT. The study will be 
closed when all patients enrolled have completed the required follow-up.
Toxicity will be evaluated according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), version 4.03, effective 14 June 2010 [2]. Laboratory 
values, vital signs, and electrocardiograms (ECGs) will be obtained to evaluate the safety and 
tolerability of brentuximab vedotin. Serial blood samples for determination of the serum/plasma 


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concentration and immunogenicity of brentuximab vedotin will be obtained at prespecified time 
points as described in Table B in Appendix A of the Study Protocol.


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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints

ORR.

Safety: AEs, assessments of clinical laboratory values, and vital sign measurements.
5.2
Secondary Endpoints

CR rate.

DOR.

PFS.

OS.

B symptom resolution rate.

Maximum observed plasma concentration (Cmax).

Time to reach Cmax (Tmax).

Area under the plasma concentration-time curve from time 0 to infinity (AUC∞).

Presence of antitherapeutic antibodies (ATA) and neutralizing antitherapeutic antibodies 
(nATA) to brentuximab vedotin.


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6.0
DETERMINATION OF SAMPLE SIZE
The study will enroll approximately 30 evaluable patients, including approximately 22 patients 
with HL and approximately 8 patients with sALCL. For information purposes, the ORRs 
achieved in previous studies in relapsed/refractory HL and sALCL are referenced below.
Table 6.a
ORRs in the Global Pivotal Studies and the Japan Study 
ORR (CR+PR) by IRF (95% CI)
Global Study SGN035-0003 (HL: n=102)
74.5 (64.9, 82.6)
Global Study SGN035-0004 (sALCL: n=58)
86.2 (74.6, 93.9)
Japan Study TB-BC010088 (HL: n=9)
66.7 (29.9, 92.5)
Japan Study TB-BC010088 (sALCL: n=5)
100 (54.9, 100)
Some observed response rates and the 95% exact CIs for 22 patients with HL and 8 patients with 
sALCL are summarized as follows.
Table 6.b
ORRs and the 95% Exact CIs for Various Number of Responses
HL (n=22)
sALCL (n=8)
Responses
ORR (%)
95% Exact CI
Responses
ORR (%)
95% Exact CI
8
36.4
(17.2
59.3)
4
50.0
(15.7
84.3)
9
40.9
(20.7
63.6)
5
62.5
(24.5
91.5)
10
45.5
(24.4
67.8)
6
75.0
(34.9
96.8)
11
50.0
(28.2
71.8)
7
87.5
(47.3
99.7)
12
54.5
(32.2
75.6)
8
100
(63.1
100.0)
13
59.1
(36.4
79.3)
Based on the exact binomial CI calculations, a minimum of 9 responses observed from 
22 evaluable patients with HL (ORR of 40.9%) will provide a 95% CI (20.7%, 63.6%); 
5 responses observed from 8 evaluable patients with sALCL (ORR of 62.5%) will yield a 95%
CI (24.5%, 91.5%). In both cases, the lower limits of the 95% CIs are greater than the threshold 
response rate of 20% obtained from the results of alternative therapies for the same indications.
Assume similar ORR results to those in the Japan Study TB-BC010088 will be obtained, eg, the 
expected response rates are 65% for HL and 80% for sALCL. With 22 patients with HL and 
8 patients with sALCL, the study will have >99% and >94% probability, respectively, to observe 
an ORR such that the lower limit of its 95% exact CI is still greater than the 20% threshold 
(ie, observe ≥9 responses for HL and ≥5 responses for sALCL).


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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
In general, descriptive statistics (number of observations, mean, standard deviation [StdDev], 
median, minimum, and maximum) will be used to summarize continuous variables. Frequency 
and percentage will be used to summarize categorical variables. Time-to-event data will be 
analyzed using the Kaplan-Meier method and results will be summarized by the 25th, 50th 
(median), and 75th percentiles, if estimable, with associated 2-sided 95% confidence intervals, as 
well as the percentage of censored observations. 
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (StdDev) will be presented to 2 more decimal places than the recorded data. 
Confidence intervals about a parameter estimate will be presented using the same number of 
decimal places as the parameter estimate.
Unless otherwise specified, safety and efficacy data will be summarized in the following 
3 groups: patients with r/r HL only, patients with r/r sALCL only, all patients. Analyses 
pertaining to pharmacokinetics and immunogenicity will be summarized by treatment cycle at 
the prespecified time points. 
The baseline value is defined as the value collected at the time closest to, but prior to, the start of 
study drug administration, unless otherwise specified. A windowing convention may be used to 
determine the analysis value for a given study visit for observed data analyses. 
All available efficacy and safety data will be included in data listings and tabulations. Data that 
are potentially spurious or erroneous will be examined under the auspices of standard data 
management operating procedures. In general, there will be no imputation of missing data. For 
time-related endpoints, subjects who have no specified events will be censored as specified for 
each respective endpoint in Section 7.8. Imputation rules for missing dates of AEs and 
concomitant medications are detailed in Sections 7.1.3 and 7.1.4.
The primary analysis for the clinical study report including the primary and the secondary 
endpoints will be conducted when all patients have had the opportunity to receive 16 cycles of 
treatment and have had EOT assessments. The results will be summarized in the primary CSR. 
The final analysis will be conducted when all patients have had the opportunity to be followed 
for 18 months after EOT. These results will be summarized in the CSR Addendum. 
SAS Version 9.4 (or higher) will be used for all analyses. 
7.1.1
Definition of Study Days
Study Day 1 is defined as the date on which a subject is administered their first dose of the study 
medication. Other study days are defined relative to the Study Day 1 with Day 1 being Study 
Day 1 and Day -1 being the day prior to Study Day 1.


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7.1.2
Definition of Study Visit Windows
All data will be categorized based on the scheduled visit at which it was collected. These visit 
designators are predefined values that appear as part of the visit tab in the eCRF.
7.1.3
Conventions for Missing Adverse Event Dates
Missing or partial AE start dates will be imputed according to the following rules.
Table 7.a
Imputation Rules for Missing AE Start Dates
Non- missing Missing
Estimated
Month and
Year
Day
Day of first dose date of STUDY DRUG, if month and year of onset date are the
same as month and year of date of first dose.
The last day of the month, if the month and year of onset date are before the
month and year of date of first dose of STUDY DRUG.
The first day of the month, if the month and year of onset date are after the month
and year of date of first dose of STUDY DRUG.
Year
Day and Month
Day and month of first dose date of STUDY DRUG, if the year of onset date is 
the same as the year of date of first dose of STUDY DRUG.
December 31st, if the year of onset date is prior to the year of date of first dose of
STUDY DRUG.
January 1st, if the year of onset date is after the year of date of first dose of
STUDY DRUG.
Day, Month and 
Year
Date of first dose of STUDY DRUG
Missing or partial AE stop dates will be imputed according to the following rules. If only the day 
is missing, use 15th of the month; if both month and day are missing, use June 30th. For a record 
with a complete start date and a partial stop date, if the estimated stop date would become earlier 
than the start date, the stop date will not be estimated.
If AE stop date is not missing and AE stop date < estimated start date, let estimated onset date = 
AE stop date.
All dates presented in listings are recorded dates without imputation.
7.1.4
Conventions for Missing Concomitant Medication Dates
If only the day is missing, use 15th of the month; if both month and day are missing, use 
June 30th. For a record with a complete start date and a partial stop date, if the imputed stop date 
would become earlier than the start date, the stop date will not be estimated. 
All dates presented in listings are recorded dates without imputation.


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7.2
Analysis Sets
7.2.1
Safety/Modified Intent-to-Treat Population
The safety/modified intent-to-treat (mITT) population consists of all subjects who have 
measurable lesions at Baseline and receive at least 1 dose of brentuximab vedotin. The 
safety/mITT population will be used for analyses of efficacy, safety, and patient demographics 
and baseline disease characteristics, unless otherwise stated.
7.2.2
Per-protocol Population
The per-protocol population consists of all subjects who have measurable lesions at Baseline and 
no significant protocol deviations determined by the project clinician. The per-protocol 
population will be used for sensitivity analyses of tumor response.
7.2.3
PK Population
The PK analysis population consists of patients with sufficient dosing and PK data to reliably 
estimate PK parameters as determined by the clinical pharmacologist. The PK population will be 
used for all PK analyses.
7.2.4
Immunogenicity Population
The Immunogenicity population consists of patients who receive at least 1 dose of brentuximab 
vedotin and have ATA status assessment at Baseline, and at least one postbaseline sample.
7.3
Disposition of Subjects
Disposition of patients will be tabulated with the number and percentage of patients for the 
following categories: patients in each of the study populations in Section 7.2, patients 
discontinued from the study drug treatment, primary reason to discontinue from the study drug 
treatment, patients discontinued from the study, and primary reason to discontinue from the 
study. All percentages will be based on the number of patients in the safety/mITT population. 
A listing will be used to present data concerning patient disposition.
7.3.1
Protocol Deviations
Protocol deviation will be collected by clinical team and entered into clinical trial management 
system (CTMS). Important protocol deviation criteria will be established as “Major” in Protocol 
Deviation and patients with important protocol deviations will be identified and documented 
before database lock. Important protocol deviations and the number of subjects with important
protocol deviations will be tabulated for enrolled patients with HL, with sALCL, and for the 
combined populations.


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7.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized for patients in the safety/mITT
population by disease type. Baseline demographic data to be evaluated will include sex, age, 
race, ethnicity, body weight, height, and BMI. The formulation for BMI is:
BMI =
The following baseline disease characteristics will be summarized for patients in the safety/mITT 
population by disease type.
At initial diagnosis

Age at initial diagnosis.

Evidence of Bone Marrow Involvement.

Evidence of Extranodal Involvement.

Ann Arbor Stage.
At Study Entry

Time since initial diagnosis.

History of Bone Marrow Involvement.

Evidence of Extranodal Involvement.

Ann Arbor Stage.

B Symptoms.
7.5
Medical History and Concurrent Medical Conditions
A complete medical history will be compiled for each patient during the screening period prior to 
the first dose of brentuximab vedotin. General medical history of all patients will be presented in 
a by-patient listing in reported terms. 
Concurrent medical conditions that will be assessed include B symptoms (persistent fever, 
drenching night sweats, and unexplained weight loss >10%) and clinical evaluations of palpable 
liver and spleen. These assessments will be presented over time in by-patient listings. 
B symptom resolution rate is defined as the proportion of patients with lymphoma-related 
B symptom(s) at baseline who achieve resolution of all B symptoms at any time during the 
treatment period. For patients with any B symptom at Baseline, B symptom resolution rate and 
the 95% exact CI will be summarized.
2)
(
)
(
m
height
kg
weight


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7.6
Medication History and Concomitant Medications
Medication history including prior antineoplastic therapy, prior surgery, prior radiation, and prior 
transplant procedure information that have been received prior to the first dose of brentuximab 
vedotin, if available, will be presented in by-patient listings. The number and percentage of 
patients with any prior event will be tabulated by disease type based on the safety/mITT 
population. The best response to last prior therapy will also be tabulated by disease type. For 
ordering purposes, prior therapies with partial end date will have the date imputed as the last day 
of the month or December 31st if the month is also unknown, but no later than the date of first 
dose of study drug. All dates presented in listings are recorded dates without imputation.
Concomitant medication is defined as any medication administered between the first dose of the 
study drug and the EOT visit. Concomitant medications will be coded by preferred term using 
the World Health Organization (WHO) Drug Dictionary (March 2012 Version or higher). The 
number and percentage of patients taking concomitant medications will be tabulated by 
Anatomical Therapeutic Chemical (ATC) classification pharmacological subgroup and WHO 
drug generic term. Patients are counted once for each ATC pharmacological subgroup and once 
for each WHO generic term.
Subsequent anticancer therapies received after EOT will be tabulated separately. 
Concomitant procedures will not be coded, instead will be presented in a by-patient listing.
7.7
Study Drug Exposure and Compliance
The exposure to brentuximab vedotin will be characterized by total amount of dose taken (mg), 
number of treated cycles, duration of treatment (days), and relative dose intensity (RDI, %). 
Total amount of dose taken (mg) is the summation of actual doses (prepared dose (mg) × (actual 
volume / prepared volume)). Total dose expected (mg) is the summation of expected doses (dose 
level initially assigned multiply by weight used for dosing calculation). Dose intensity
(mg/kg/week) is total dose (mg/kg) / (duration of treatment in days /7). Relative dose intensity 
(RDI) is 
RDI (%) = 
 	
	
 (//)
    (.  !/"!) 
#$ %& ' &( ) ×+
 × 100%
A treated cycle is defined as a 21-day period, during which the patient receives any amount of 
brentuximab vedotin (scheduled for single dose in 21-day period). The duration of treatment is 
defined as time from the first study dose to 21 days after the last study dose, or death date, 
whichever is earlier:
Duration of treatment = min(Last dose date + 21, death) - First dose date
Action on study drug (including dose reduced, increased, missed, delayed, interrupted, held, or 
discontinued permanently) will be summarized by Cycle 1 through 16. Percentage will be 
calculated based on the number of patients treated during each cycle.


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Dosing data including dose modification and action on drug will also be presented in a by-
patient, by-cycle listing. 
7.8
Efficacy Analysis
ORR, CR and PR rates, DOR, PFS, and OS will primarily be conducted using the safety/mITT 
population. Sensitivity analyses of the efficacy endpoints including ORR, CR and PR rates, and 
DOR will also be evaluated using the Per-protocol population. All efficacy data will be 
summarized by disease type outlined in Section 7.1.
7.8.1
Primary Efficacy Endpoint(s)
The primary efficacy endpoint is the ORR of patients who achieve a CR or PR as determined by 
the investigator using PET scans, CT scans, and clinical assessment according to IWG revised 
response criteria. 
ORR per investigator (CR+PR) will be summarized with 2-sided 95% exact confidence intervals 
using the safety/mITT population. A sensitivity analysis of ORR per investigator will also be 
summarized using the Per-protocol population.
The sum of products of diameters (SPD) for up to 6 of the largest dominant nodes or nodal 
masses will be quantitatively identified at baseline and subsequent response assessments. A 
waterfall plot will be used to characterize the best percent change of SPD from Baseline in target 
lesions for individual patients. 
No formal hypothesis testing will be conducted with respect to ORR. 
7.8.2
Secondary Efficacy Endpoint(s)
CR rate per investigator will be summarized with 2-sided 95% exact confidence intervals using 
the safety/mITT population. A sensitivity analysis of CR rate per investigator will also be 
summarized using the Per-protocol population
DOR and PFS will be estimated base on the investigator assessments using PET scans, CT scans, 
as well as clinical evaluations according to the IWG revised response criteria. DOR will 
primarily be summarized using the subset of patients with a CR or PR in the safety/mITT 
population; a sensitivity analysis of DOR will also be summarized using the subset of patients 
with a CR or PR in the Per-protocol population. PFS and OS will be summarized using the 
safety/mITT population.
DOR in subjects with a CR or PR is defined as the time from start of the first documentation of 
objective tumor response (CR or PR) to the first subsequent documentation of objective tumor 
progression or to death due to any cause, whichever comes first. DOR will be censored on the 
day of the last assessment of measured lesions documenting absence of PD for patients who do 
not have objective tumor progression and are still on study at the time of analysis, are given 
antitumor treatment other than the study treatment or SCT, or are removed from study prior to 
documentation of objective tumor progression.


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PFS is defined as the time from the first dose until disease progression or death due to any cause, 
whichever occurs first. PFS will be censored on the day of the last assessment of measured 
lesions documenting absence of PD for patients who do not have objective tumor progression 
and are still on study at the time of analysis, are given antitumor treatment other than the study 
treatment or SCT, or are removed from study prior to documentation of objective tumor 
progression. Patients lacking an evaluation of tumor response after their first dose will have their 
event time censored at the day of first dose.
OS is defined as the time from the first dose until death due to any cause. In the absence of 
confirmation of death, survival time will be censored at the last date the patient is known to be 
alive. Patients lacking data beyond the day of first dose will have their survival time censored at 
the day of first dose. 
DOR, PFS, and OS will be analyzed using the Kaplan-Meier method, the 25th, 50th (median), 
and 75th percentiles, if estimable, will be presented along with the associated 2-sided 95% 
confidence intervals. The results will also be presented in figures (Kaplan-Meier plots). 
For patients with any B symptom at Baseline, B symptom resolution rate and the 95% exact CI 
will be summarized.
Efficacy data will also be listed by patient.
7.8.3
Additional Efficacy Endpoint(s)
Disease control rate (DCR) per investigator (CR+PR+SD) will be summarized with 2-sided 95% 
exact confidence intervals using the safety/mITT population. A sensitivity analysis of DCR per 
investigator will also be summarized using the Per-protocol population.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
Pharmacokinetic analysis will be conducted using the PK population.
Serum concentrations of brentuximab vedotin (ADC) and total therapeutic antibody (TAb), and 
plasma concentrations of monomethyl auristatin E (MMAE) will be determined using validated 
assays.
Descriptive statistics (eg, number of patients, arithmetic mean, geometric mean, StdDev, median, 
percentage of coefficient of variation (%CV), minimum, and maximum) will be used to 
summarize serum concentrations of ADC and TAb, and plasma concentrations of MMAE at each 
prespecified time point in Cycle 1 through 16. The mean concentrations-time profiles of ADC, 
TAb, and MMAE will be plotted over time and in greater detail for Cycles 1 and 2. The complete 
set of the same data (Cycles 1-16 or up to the cycle where N ≥3) will also be plotted for ADC on 
a single plot. Similar plots will be provided for TAb and MMAE. Individual patient 
concentration data will be listed and plotted over time by cycle.


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Noncompartmental analysis for the determination of PK parameters such as tmax, Cmax, AUC21D, 
AUC∞, t1/2z, CL, and Vss will be performed as data permit for ADC and TAb. The PK parameters 
of tmax, Cmax, AUC21D, AUC∞, and t1/2z will be estimated for MMAE. These parameters will be 
summarized by cycle. The summary statistics will consist of N, mean, StdDev, %CV, median, 
min, max, and geometric mean. Individual patient values of the parameters will be listed by 
cycle.
More exploratory plots may be presented in the CSR as needed.
7.9.2
Pharmacodynamic Analysis
Not applicable.
7.10
Other Outcomes
7.10.1 Immunogenicity Analysis
Immunogenicity will be summarized using the Immunogenicity population (Section 7.2.4). 
Descriptive statistics will be used to summarize patients in the following categories: ATA 
negative, transiently ATA positive, persistently ATA positive, low or high ATA titer, and 
negative or positive nATA.

ATA Negative – defined as patients who do not have a confirmed positive ATA status in any 
postbaseline assessment.

Transiently ATA positive – defined as patients who have confirmed positive ATA status in 
1 or 2 postbaseline assessments. 

Persistently ATA positive – defined as patients who have confirmed positive ATA status in 
more than 2 postbaseline assessments.

High ATA titer – defined as patients who have at least one postbaseline ATA titer >25.

Low ATA titer – defined as patients whose postbaseline ATA titer numbers are all ≤25.

nATA negative – defined as patients who do not have positive nATA in any postbaseline 
ATA positive sample.

nATA positive – defined as patients who have positive nATA in any postbaseline ATA 
positive sample. 
ATA status, ATA titer and nATA will be listed by patient. ATA titer (high or low) and nATA 
status (nATA negative or positive) will also be tabulated for patients who are transiently or 
persistently ATA positive.
For effect of ATA and nATA on efficacy, the proportions of patients in CR and PR may be 
summarized within each ATA response status (negative, transiently positive, persistently 
positive) and nATA status by disease type. The same analysis may be repeated based on ATA 
titer (high, >25; low, ≤25). In addition, patient level ATA and efficacy (overall response) data 
may be listed together. 


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For effect of ATA and nATA on safety, patient incidence of AEs (preferred term) by ATA 
response status (negative, transiently positive, persistently positive) and nATA status may be 
provided for both HL and sALCL. The same analysis may be repeated based on ATA titer (high, 
>25; low, ≤25).
 
7.11
Safety Analysis
Safety will be evaluated by the incidence of treatment-emergent AEs (TEAEs), severity and type 
of AEs, and by changes from baseline in the patient’s vital signs, neurotoxicity assessment, 
ECGs, and clinical laboratory results. Exposure to study drug and reasons for discontinuation 
will also be tabulated.
These analyses will be performed using the safety/mITT population.
7.11.1 Adverse Events
AEs will be tabulated according to the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 19.0 or higher by system organ class, high-level terms, preferred terms and severity. 
AEs with missing start and/or end dates will be imputed according to rules specified in 
Section 7.1.3. TEAEs are defined as any AEs that occur after administration of the first dose of 
brentuximab vedotin and up through 30 days after the last dose. Patients who experience the 
same AE more than once will have that event counted only once within each system organ class, 
once within each high-level term, and once for each preferred term. AEs will be summarized and 
will include the following categories: 
!
TEAEs.
!
Drug-related TEAEs.
!
Grade 3 or higher TEAEs.
!
Grade 3 or higher drug-related TEAEs.
!
TEAEs resulting in study drug discontinuation.
!
SAEs.
!
AEs of peripheral neuropathy identified by the broad search MedDRA SMQ “Peripheral 
neuropathy”.
Treatment-emergent AEs will be tabulated by system organ class, high-level term and preferred 
term. The most commonly reported treatment-emergent AEs (ie, those events reported by ≥10% 
of all patients) will be tabulated by preferred term. Additional analyses of peripheral neuropathy 
may also be presented.
CCI


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7.11.1.1 Serious Adverse Events
The number and percentage of patients experiencing at least 1 treatment-emergent SAE will be 
summarized by MedDRA (Version 19.0 or higher) primary system organ class, high-level term, 
and preferred term. Drug-related SAE assessed by the investigator will be summarized similarly.
In addition, a by-subject listing containing all SAEs will be presented, regardless of treatment-
emergent AE status.
7.11.1.2 Peripheral Neuropathies
Peripheral Neuropathy (PN) is defined by the peripheral neuropathy SMQ broad search. The 
incidence of treatment-emergent PN and treatment-emergent drug-related PN will each be 
summarized by preferred term and severity. The incidence of peripheral motor neuropathy will 
also be calculated. Time to onset, resolution and improvement of PN events will be summarized. 
Individual plot by preferred term for treatment-emergent peripheral neuropathy (SMQ) may be 
presented.
7.11.1.3 Deaths
A by-subject listing of the deaths will be presented. All deaths occurring on-study and during 
follow-up will be displayed (regardless of treatment-emergent AE status). On-study death is 
defined as a death that occurs between the first dose of brentuximab vedotin and 30 days after 
the last dose.
7.11.1.4 Adverse Events Resulting in Discontinuation of Study Drug
AEs resulting in discontinuation of study drug will be presented in a by-patient listing and also in 
a summary table by system organ class, high-level term and preferred term.
7.11.2 Clinical Laboratory Evaluations
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.
If a patient has repeated laboratory values for a given time point, the value from the latest 
evaluation will be used. If the report lab values contain a nonnumeric qualifier, eg, > or <, the 
given numeric portion will be used in summary statistics.
The parameters to be analyzed are as follows:

Hematology: Red blood cells, hemoglobin content, hematocrit, white blood cells, platelets, 
differential white blood cells (neutrophils, eosinophils, basophils, lymphocytes, monocytes), 
reticulocyte.

Serum chemistry: Sodium, potassium, chloride, albumin, calcium, phosphorus, glucose, 
BUN, uric acid, creatinine, total bilirubin, AST, ALT, ALP, LDH, GGT, HbA1c, total 
cholesterol, triglycerides, TSH, FT3, FT4.


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
Coagulation: INR, PT, APTT.
Shift tables for laboratory parameters will be generated based on changes in NCI CTCAE grades 
from Baseline to the worst postbaseline value.
7.11.3 Vital Signs 
Descriptive statistics for the actual values (and/or the changes from baseline) of vital signs 
(eg, blood pressure, pulse rate, and axillary temperatures) and weight will be tabulated over time. 
A by-patient listing will also be presented.
7.11.4 12-Lead ECGs
ECG (QT, corrected QT [QTcB and QTcF], PR,QRS, and RR) intervals, and ventricular rate will 
be summarized at each scheduled time point, along with mean change from baseline to 
posttreatment time point. 
The corrected QT interval will be computed using Bazett’s formula and Fridericia’s formula. The 
Bazett and Fridericia corrected QT interval is calculated as
/012 (msec) =/0/(77)1/2 and /01< (msec) =/0/(77)1/3
respectively, where RR is presented in the unit of sec. No decimal place will be presented in the 
derived dataset and TLF outputs.
In addition, a categorical analysis of QTc intervals will be performed for each time point. The 
number and percentage of patients in each QTc interval (<450 msec, 450 to 480 msec, 480 to 
500 msec, and ≥500msec) will be summarized at Baseline and each of the subsequent time 
points. Categories of changes from Baseline (≥30 msec and ≥60 msec) will be summarized as 
well.
In addition, Overall interpretation of ECG results (normal, not clinically significant abnormal, 
clinically significant abnormal) is collected by eCRF according to the scheduled measurements. 
Shifts in ECG interpretation will be presented as cross-tabulations of numbers of patients with 
normal, not clinically significant abnormal and clinically significant abnormal ECG 
interpretation results (and will include categories for missing and totals).
7.11.5 Other Observations Related to Safety
Pregnancy test results will be provided in a by-patient listing, if applicable.
ECOG performance status scores over time will also be tabulated. A by-patient listing of ECOG 
performance scores will be presented by time. 
7.12
Interim Analysis
Not applicable.


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7.13
Changes in the Statistical Analysis Plan 
Disease control rate per investigator (CR+PR+SD) that was not included in the efficacy endpoint 
in the protocol will be summarized.
The Immunogenicity population that was not defined in the protocol has been clearly defined in 
this SAP.


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8.0
REFERENCES
1. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
response criteria for malignant lymphoma. J Clin Oncol 2007;25(5):579-86.
2. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. U.S. 
Department of Health and Human Services National Cancer Institute. 14 June 2010.


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