A Phase 4, Open-label, Single-Arm Study of Brentuximab Vedotin in Patients With Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma
Phase: PHASE4
Conditions: Lymphoma
Sponsor: Takeda




Title: A Phase 4, Open–label, Single-Arm Study of Brentuximab Vedotin in Patients With 
Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma
NCT Number: NCT01909934
Protocol Approve Date: 27 August 2021
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.

Brentuximab vedotin (ADCETRIS®) 
Clinical Study Protocol C25006 Amendment 2, EudraCT:  2012-004128-39
1
CLINICAL STUDY PROTOCOL C25006 AMENDMENT 2
Brentuximab vedotin
A Phase 4, Open–label, Single-Arm Study of Brentuximab Vedotin in Patients With 
Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma
Protocol Number:
C25006
Indication:
Relapsed or refractory systemic anaplastic large cell 
lymphoma
Phase:
4
Sponsor:
Takeda Development Center (TDC) Americas, Inc.
95 Hayden Avenue, Lexington, Massachusetts 02421 USA
TDC Americas, Inc. may be referred to in this protocol as 
“sponsor” or “Takeda”.
EudraCT Number:
2012-004128-39
Therapeutic Area:
Oncology
Protocol History
Amendment 2
27 August 2021
Amendment 1
15 March 2013
Original
29 November 2012
Approved by:
Note:  If this document was approved electronically, the electronic approval signatures may
be found at the end of the document.
Signature
Date 
DD Month YYYY
Signature
Date 
DD Month  YYYY
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
, Inc
Inc.
setts 024
etts 02
in this p
n this 
2
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Brentuximab vedotin (ADCETRIS®) 
Clinical Study Protocol C25006 Amendment 2, EudraCT:  2012-004128-39
2
Rationale for Amendment 2
The protocol is being amended to update the sponsor’s name and legal entity responsible for 
the study.
Purposes for Amendment 2
The purpose of this amendment is to:

Update the sponsor’s name and legal entity responsible for the study. 

Update the protocol signatories. 
For specific examples of changes in text and where the changes are located, see
Section 15.5.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Brentuximab vedotin (ADCETRIS®) 
Clinical Study Protocol C25006 Amendment 2, EudraCT:  2012-004128-39
3
PROTOCOL SUMMARY
Study Title: A Phase 4, Open-label, Single-Arm Study of Brentuximab Vedotin in Patients With 
Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma
Name of Principal Investigator:
Number of Patients:  At least 45 patients with histologically confirmed relapsed or refractory 
systemic anaplastic large-cell lymphoma (sALCL) will be enrolled in the study.
Study Objectives
Primary
! To assess the antitumor efficacy of single-agent brentuximab vedotin (1.8 mg/kg administered 
intravenously every 3 weeks) as measured by the overall objective response rate (ORR) in 
patients with relapsed or refractory sALCL following at least 1 multiagent chemotherapy 
regimen (CHOP or equivalent multiagent chemotherapy regimens with curative intent)
Secondary
! To determine duration of tumor control, including duration of response, progression-free 
survival (PFS), and complete remission (CR) rate with brentuximab vedotin
! To determine the proportion of patients receiving hematopoietic stem cell transplant (either 
autologous or allogeneic) after brentuximab vedotin therapy
! To determine overall survival (OS) with brentuximab vedotin
! To assess the safety and tolerability of brentuximab vedotin
! To assess the pharmacokinetics of brentuximab vedotin
! To determine the immunogenicity of brentuximab vedotin
Overview of Study Design:  This single-arm, open-label multicenter phase 4 clinical study seeks to 
evaluate the efficacy and safety of brentuximab vedotin as a single agent in patients with relapsed or 
refractory sALCL.  Its primary objective is to determine the antitumor efficacy of single-agent
brentuximab vedotin as measured by ORR in patients with relapsed or refractory sALCL following 
at least 1 multiagent chemotherapy regimen.
Brentuximab vedotin will be administered as a single intravenous (IV) infusion over 30 minutes on 
Day 1 of each 3-week cycle for up to a maximum of 16 cycles and should be administered for a
minimum of 8 cycles for patients who achieve stable disease or better.  Overall response will be 
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Brentuximab vedotin (ADCETRIS®) 
Clinical Study Protocol C25006 Amendment 2, EudraCT:  2012-004128-39
4
assessed by independent review facility (IRF) according to the International Working Group (IWG) 
Revised Response Criteria for Malignant Lymphoma (Cheson 2007).(1)  Patients who experience 
disease progression at any time will be withdrawn from study drug treatment. Computed 
tomography (CT) scans (chest, neck, abdomen, and pelvis) will be performed at baseline and 
Cycles 2, 4, 7, 10, 13, and 16, and positron emission tomography (PET) scans will be done at 
baseline, Cycles 4 and 7, and, for patients who discontinue study treatment without a post-baseline 
PET assessment, at End of Treatment (EOT).  Patients will have an EOT assessment 30 ± 7 days 
after receiving their final dose of study drug.  Survival and disease status will be assessed every 
3 months from EOT for 18 months, and then only OS will be assessed every 6 months thereafter 
until the sooner of death or study closure.
Study Population:  Male or female patients aged 18 years or older, with histologically confirmed 
relapsed or refractory sALCL who have previously received at least 1 multiagent chemotherapy 
regimen (CHOP or equivalent multiagent chemotherapy regimens with curative intent) will be 
enrolled.  Fluorodeoxyglucose (FDG)-avid disease by positron emission tomography (PET) and 
measurable disease of at least 1.5 cm by computed tomography ([CT] spiral preferred), as assessed 
by the site radiologist, are required.
Duration of Study:  Patients will complete a Screening period of up to 28 days and receive 
treatment with study drug for a minimum of 8 cycles and up to a maximum of 16 cycles.  Disease 
status (PFS and response) will be assessed every 3 months from EOT until the sooner of disease 
progression, death, or study closure.  OS will be assessed every 3 months from EOT for 18 months, 
then every 6 months thereafter until the sooner of death or study closure. The study will be closed 
when 50% of patients have had an OS event or 5◦years after enrollment of the last patient, whichever 
occurs first. The total study duration is approximately 6 to 7 years.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Brentuximab vedotin (ADCETRIS®) 
Clinical Study Protocol C25006 Amendment 2, EudraCT:  2012-004128-39
5
STUDY OVERVIEW DIAGRAM
S
C
R
E
E
N    
I
N
G
E
N
R
O
L
L
M
E
N
T
1.8 mg/kg IV brentuximab vedotin
q21days (Day 1 of each cycle)
Within 28 days of 
randomization
P
O
S
T
T
R
E
A
T
M
E
N
T
F/
U
30 ± 7 days 
after last dose 
of study drug
Patients achieving stable disease or better 
should receive a minimum of 8 cycles and 
up to a maximum of 16 cycles.
See Section 6.1 for more detail.
E
N
D 
O
F 
T
R
E
A
T
M
E
N
T
PFS + OS: 
q3 months 
until 18 mo 
post EOT
OS only: 
q6 months 
thereafter until 
study closure 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Brentuximab vedotin (ADCETRIS®) 
Clinical Study Protocol C25006 Amendment 2, EudraCT:  2012-004128-39
Confidential
6
SCHEDULE OF EVENTS
Screening
Enrollment
(date of first 
dose)
Each 3 Week Cycle
Additional 
Assessments 
at Cycles 2, 
4, 7, 10, 13, 
and 16 only
EOTa
PFSFUP/
OSFUPb
Day (D)
Within 24 
hours of first 
dose
D1
D2
D15
D15-21 of 
Cycle
30 ± 7 Days 
Post Last 
Dose
Visit Window
-28 to D1
+ 1D
± 5D
± 2 weeks
Screening/ Baseline
Informed consent
X
Enrollment
Inclusion/exclusion criteria 
X
Tumor specimen
Xc
Medical history 
X
Demographics
X
Safety Assessments
Height
X
Weight
X
X
X
Pregnancy testd
X
Xd
Vital signs
X
X
X
Physical examination with focused 
lymphoma assessmente
X
X
X
Xf
ECOG performance status
X
X
X
Hematology and serum chemistry
X
Xg
X
12-lead ECG
X
X
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

Brentuximab vedotin (ADCETRIS®) 
Clinical Study Protocol C25006 Amendment 2, EudraCT:  2012-004128-39
Confidential
7
Screening
Enrollment
(date of first 
dose)
Each 3 Week Cycle
Additional 
Assessments 
at Cycles 2, 
4, 7, 10, 13, 
and 16 only
EOTa
PFSFUP/
OSFUPb
Day (D)
Within 24 
hours of first 
dose
D1
D2
D15
D15-21 of 
Cycle
30 ± 7 Days 
Post Last 
Dose
Visit Window
-28 to D1
+ 1D
± 5D
± 2 weeks
Monitoring of concomitant 
medications and procedures
Recorded from signing informed consent form through 30 days after the last dose of study 
drug
Adverse event reporting
Recorded from first dose of study drug through 30 days after the last 
dose of study drug
Serious adverse events
Serious adverse eventsh will be collected from signing informed consent form through 
30 days after the last dose of study drug
Disease Assessments
Dedicated CT (spiral preferred) of 
chest, neck, abdomen, pelvisi
X
X
Xj
Xb
PET
X
Xk
Xk
B symptom assessment
Xl
Xj
Bone marrow biopsy
Xm
Xn
Survival/disease status and 
anticancer treatments for sALCL
Xo
Treatment
Brentuximab vedotin
administration 
X
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cles 2,
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Brentuximab vedotin (ADCETRIS®) 
Clinical Study Protocol C25006 Amendment 2, EudraCT:  2012-004128-39
Confidential
8
Screening
Enrollment
(date of first 
dose)
Each 3 Week Cycle
Additional 
Assessments 
at Cycles 2, 
4, 7, 10, 13, 
and 16 only
EOTa
PFSFUP/
OSFUPb
Day (D)
Within 24 
hours of first 
dose
D1
D2
D15
D15-21 of 
Cycle
30 ± 7 Days 
Post Last 
Dose
Visit Window
-28 to D1
+ 1D
± 5D
± 2 weeks
PK/
Biomarkersp
PK sample
X
Xr
Xr
X
Immunogenicity 
X
X
Abbreviations: AE = adverse event; ALK = anaplastic lymphoma kinase; BM = bone marrow; CR = complete response CT = computed tomography;
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; EOT = end of treatment; 
ICF = informed consent form; OSFUP = overall survival follow-up; PET = positron emission tomography; PFSFUP = progression-free survival 
follow-up; PK = pharmacokinetics; SD = stable disease.
Tests and procedures should be performed on schedule, but occasional changes are allowable (± 3 days) for administrative reasons unless indicated otherwise.
a EOT evaluations should be obtained before initiation of nonprotocol therapy.
b Patients who discontinue study treatment with SD or better will have CT scans done every 3 months from EOT for 18 months or until the sooner of disease 
progression, death, or study closure.  Overall survival data will be collected every 3 months from EOT for 18 months, then every 6 months thereafter until 
the sooner of death or study closure.
c Tumor tissue from the most recent post-diagnosis biopsy is preferred. Unstained slides or a paraffin-embedded block will be obtained after the patient has 
signed the ICF.  Patients without at least 10 histological slides from their most recent post-diagnosis biopsy will undergo a new tumor biopsy during 
screening.  This sample will be used to confirm sALCL diagnosis and ALK status.
d A serum or urine pregnancy test will be performed for women of childbearing potential during screening. If the screening test was performed more than 
4 days before the first dose of study drug, a serum or urine pregnancy test should be repeated. The results must be negative within 4 days before the first 
dose of brentuximab vedotin is administered. Additional pregnancy testing may be performed during the study at the discretion of the investigator, upon 
request of the IEC/IRB, or if required by local regulations.
e The focused lymphoma assessment will include a skin lesion assessment.
f
Once disease progression is documented, the physical exam and lymphoma assessment are not required.
g Cycle 1, Day 1 samples may be collected within 4 days before dosing to ensure patient eligibility on study Day 1.  In this situation it need not be repeated on 
Cycle 1, Day 1. Samples will be taken before dosing on Day 1 of each subsequent cycle.
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Brentuximab vedotin (ADCETRIS®) 
Clinical Study Protocol C25006 Amendment 2, EudraCT:  2012-004128-39
Confidential
9
Screening
Enrollment
(date of first 
dose)
Each 3 Week Cycle
Additional 
Assessments 
at Cycles 2, 
4, 7, 10, 13, 
and 16 only
EOTa
PFSFUP/
OSFUPb
Day (D)
Within 24 
hours of first 
dose
D1
D2
D15
D15-21 of 
Cycle
30 ± 7 Days 
Post Last 
Dose
Visit Window
-28 to D1
+ 1D
± 5D
± 2 weeks
h Includes serious pretreatment events. Serious pretreatment events will be reported to Takeda Pharmacovigilance or designee from the time of signing the 
ICF to first dose of study drug, but will not be recorded in the eCRF. See Section 10.3 of the study protocol for further SAE reporting details.
i
Response to treatment and disease status assessments will be evaluated according to the Revised Response Criteria for Malignant Lymphomas
(Cheson 2007) (1) and confirmed by an independent review facility.
j
Assessment should be repeated if not done within the previous 6 weeks.
k PET scan done at Cycles 4 and 7. No additional PET scans are required during the treatment period beyond Cycle 7, unless clinically indicated.  A PET 
scan should be done at EOT only for those patients who discontinue study treatment without a post-baseline PET assessment.
l
B symptoms will be assessed before dosing on Cycle 1, Day 1 and on Day 1 of each subsequent cycle.
m May be obtained within 60 days of first dose of brentuximab vedotin. If a positive BM biopsy was taken more than 60 days before the first dose and the 
patient has not received treatment in the interim, this does not need to be repeated.  When required, the BM biopsy will be obtained after the last dose of 
prior treatment and before the first dose of brentuximab vedotin.
n BM biopsy required to confirm response if BM positive at baseline.  BM biopsy should be obtained within 2 weeks after documentation of response.  BM 
biopsy does not need to be repeated once bone marrow is found to be negative.
o Patients who discontinue study treatment with SD or better will have disease status followup every 3 months from EOT for 18 months or until the sooner of 
disease progression, death, or study closure.  Overall survival data will be collected every 3 months from EOT until 18 months, then every 6 months 
 phone for patients with progressive disease during OSFUP.
p
q
r
Pharmacokinetics, serum biomarkers, and immunogenicity will be assessed as indicated in the following table below.
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ycles 2,
cles 2,
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, 10, 1
and 16 o
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rm
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Brentuximab vedotin (ADCETRIS®) 
Clinical Study Protocol C25006 Amendment 2, EudraCT:  2012-004128-39
Confidential
10
Pharmacokinetic, 
 and Immunogenicity Sampling Time Points
Cycle
Study 
Day
Time
Window
Relative Time
PK
Immunogenicity
Cycle 1
Day 1
Predose
within 2h
START of infusion
X
X
10 min
± 5 min
END of infusion
X
Day 2
24h
+ 1  day
START of infusion
X
Day 15
336h
± 5 days
START of infusion
X
Cycle 2
Day 1
Predose
within 2h
START of infusion
X
X
10 min
± 5 min
END of infusion
X
Cycle 3
Day 1
Predose
within 2h
START of infusion
X
X
10 min
± 5 min
END of infusion
X
Day 2
24h
+ 1  day
START of infusion
X
Day 15
336h
± 5 days
START of infusion
X
Cycle 4 and 
subsequent 
cycles
Day 1
Predose
within 2h
START of infusion
X
X
10 min
± 5 min
END of infusion
X
EOT
X
X
Abbreviations: Ab = antibody; EOT = end of treatment; h = hours; min = minutes; PK = pharmacokinetics.
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Brentuximab vedotin (ADCETRIS®) 
Clinical Study Protocol C25006 Amendment 2, EudraCT:  2012-004128-39
11
TABLE OF CONTENTS
LIST OF TABLES.............................................................................................................13
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ..........................................14
1. BACKGROUND AND STUDY RATIONALE..............................................................16
1.1 Scientific Background ..............................................................................................16
1.1.1 Systemic Anaplastic Large Cell Lymphoma.......................................................16
1.1.2 Study Drug ........................................................................................................19
1.2 Nonclinical Experience.............................................................................................19
1.3 Clinical Experience ..................................................................................................20
1.4 Study Rationale ........................................................................................................23
1.5 Potential Risks and Benefits .....................................................................................24
2. STUDY OBJECTIVES ..................................................................................................26
2.1 Primary Objective.....................................................................................................26
2.2 Secondary Objectives ...............................................................................................26
2.3 
................................................................................27
3. STUDY ENDPOINTS....................................................................................................27
3.1 Primary Endpoint .....................................................................................................27
3.2 Secondary Endpoints................................................................................................27
3.3 
................................................................................28
4. STUDY DESIGN...........................................................................................................28
4.1 Overview of Study Design........................................................................................28
4.2 Number of Patients...................................................................................................30
4.3 Duration of Study.....................................................................................................30
5. STUDY POPULATION.................................................................................................30
5.1 Inclusion Criteria......................................................................................................30
5.2 Exclusion Criteria.....................................................................................................33
6. STUDY DRUG..............................................................................................................34
6.1 Study Drug Administration.......................................................................................34
6.2 Dose-Modification Guidelines..................................................................................35
6.2.1 Recommended Brentuximab Vedotin Dose Modifications for Treatment-
associated Toxicity......................................................................................35
6.2.2 Criteria for Dose Interruption During a Cycle ....................................................36
6.2.3 Criteria for Beginning or Delaying a Subsequent Treatment Cycle.....................36
6.2.4 Criteria for Dose Reduction ...............................................................................37
6.2.5 Criteria for Discontinuation of Brentuximab Vedotin.........................................37
6.3 Excluded Concomitant Medications and Procedures.................................................37
6.4 Permitted Concomitant Medications and Procedures.................................................38
6.5 Precautions and Restrictions.....................................................................................38
6.6 Management of Clinical Events................................................................................40
6.7 Blinding and Unblinding ..........................................................................................41
6.8 Description of Investigational Agents.......................................................................41
6.9 Preparation, Reconstitution, and Dispensation ..........................................................41
6.10 Packaging and Labeling..........................................................................................42
6.11 Storage, Handling, and Accountability....................................................................42
7. STUDY CONDUCT ......................................................................................................43
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6.4 P
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6

Brentuximab vedotin (ADCETRIS®) 
Clinical Study Protocol C25006 Amendment 2, EudraCT:  2012-004128-39
12
7.1 Study Personnel and Organizations...........................................................................43
7.2 Arrangements for Recruitment of Patients ................................................................43
7.3 Treatment Group Assignments .................................................................................43
7.4 Study Procedures......................................................................................................43
7.4.1 Informed Consent ..............................................................................................44
7.4.2 Patient Demographics ........................................................................................44
7.4.3 Medical History.................................................................................................44
7.4.4 Physical Examination.........................................................................................44
7.4.5 Patient Height ....................................................................................................44
7.4.6 Patient Weight ...................................................................................................44
7.4.7 Vital Signs .........................................................................................................44
7.4.8 Pregnancy Test ..................................................................................................45
7.4.9 Eastern Cooperative Oncology Group Performance Status.................................45
7.4.10 Tumor Specimen..............................................................................................45
7.4.11 Electrocardiogram............................................................................................45
7.4.12 Concomitant Medications and Procedures........................................................45
7.4.13 Adverse Events................................................................................................45
7.4.14 Enrollment .......................................................................................................45
7.4.15 Clinical Laboratory Evaluations.......................................................................46
7.4.16
7.4.17
7.4.18
7.4.19 Cost Assessment ..............................................................................................48
7.4.20 Pharmacokinetic Measurements.......................................................................48
7.4.21
7.4.22 Immunogenicity Measurements........................................................................49
7.5 Completion of Treatment..........................................................................................49
7.6 Completion of Study.................................................................................................49
7.7 Discontinuation of Treatment With Study Drug, and Patient Replacement................49
7.8 Withdrawal of Patients From Study..........................................................................51
7.9 Study Compliance ....................................................................................................51
7.10 Posttreatment Follow-up Assessments ....................................................................51
8. STATISTICAL AND QUANTITATIVE ANALYSES ..................................................52
8.1 Statistical Methods ...................................................................................................52
8.1.1 Determination of Sample Size............................................................................52
8.1.2 Randomization and Stratification .......................................................................52
8.1.3 Populations for Analysis ....................................................................................53
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data...........................54
8.1.5 Demographic and Baseline Characteristics.........................................................54
8.1.6
8.1.7
8.1.8 Pharmacokinetics/
............................................................................56
8.1.9 Safety Analysis ..................................................................................................57
8.1.10 Interim Analysis...............................................................................................58
9. STUDY COMMITTEES................................................................................................58
9.1 Data Safety Monitoring Board..................................................................................58
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10. ADVERSE EVENTS ...................................................................................................58
10.1 Definitions..............................................................................................................58
10.1.1 Pretreatment Event Definition..........................................................................58
10.1.2 Adverse Event Definition.................................................................................59
10.1.3 Serious Adverse Event Definition ....................................................................59
10.2 Procedures for Recording and Reporting Adverse Events and Serious
Adverse Events.................................................................................................60
10.3 Monitoring of Adverse Events and Period of Observation.......................................61
10.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events........62
11. ADMINISTRATIVE REQUIREMENTS .....................................................................62
11.1 Good Clinical Practice............................................................................................62
11.2 Data Quality Assurance ..........................................................................................62
11.3 Electronic Case Report Form Completion...............................................................63
11.4 Study Monitoring ...................................................................................................63
11.5 Ethical Considerations............................................................................................64
11.6 Patient Information and Informed Consent..............................................................64
11.7 Patient Confidentiality............................................................................................64
11.8 Investigator Compliance.........................................................................................64
11.9 On-site Audits ........................................................................................................65
11.10 Investigator and Site Responsibility for Drug Accountability................................65
11.11 Product Complaints ..............................................................................................65
11.12 Closure of the Study .............................................................................................66
11.13 Record Retention..................................................................................................66
12. USE OF INFORMATION............................................................................................67
13. INVESTIGATOR AGREEMENT................................................................................69
14. REFERENCES.............................................................................................................70
15. APPENDICES .............................................................................................................74
15.1 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status.........74
15.2 New York Heart Association Classification of Cardiac Disease ..............................74
15.3 Serious Adverse Event and Pregnancy Reporting Contact Information ...................75
15.4 Amendment 1 Detailed Summary of Changes.........................................................84
15.5 Amendment 2 Detailed Summary of Changes.........................................................94
LIST OF TABLES
Table 6-1   
Recommended Brentuximab Vedotin Dose Modifications for Treatment-
Associated Toxicity.....................................................................................35
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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
AE
adverse event
ALCL
anaplastic large cell lymphoma
ALK
anaplastic lymphoma kinase
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCT
autologous stem cell transplant
AST
aspartate aminotransferase
∀#∀
anti-therapeutic antibodies
BM
bone marrow
BMA
bone marrow aspirate
BUN
blood urea nitrogen
CBC
complete blood count
CHF
congestive heart failure
CR
complete remission
CT
computed tomography
CYP
cytochrome P450
DLBCL
diffuse large B-cell lymphoma
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOT
End of Treatment (visit)
EU
European Union
EMA
European Medicines Agency
FDA
United States Food and Drug Administration
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GGT
gamma glutamyl transferase
GM-CSF
granulocyte macrophage-colony stimulating factor
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
CCI
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Abbreviation
Term
IRB
institutional review board
IRF
independent review facility
IRR
infusion-related reactions
ITT
intent-to-treat
IV
intravenous; intravenously
IXRS
interactive voice and/or Web response system
JCV
John-Cunningham virus
LDH
lactate dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NHL
non-Hodgkin lymphoma
NYHA
New York Heart Association
PCR
polymerase chain reaction
PD
progressive disease (disease progression)
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
PR
partial response 
QOL
quality of life
SAE
serious adverse event
sALCL
systemic anaplastic large cell lymphoma
SCT
stem cell transplant
SD
stable disease
TDC Americas
Takeda Development Services, Americas
UK
United Kingdom
ULN
upper limit of the normal range
US
United States
WHO
World Health Organization
CCI
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1.   
BACKGROUND AND STUDY RATIONALE
1.1   
Scientific Background
CD30 is a cell surface antigen expressed on several malignancies including Hodgkin 
lymphoma (HL), anaplastic large cell lymphoma (ALCL), Kaposi’s sarcoma (KS), 
cutaneous T cell lymphomas (CTCL), a fraction of diffuse large B-cell lymphomas 
(DLBCL), some follicular lymphomas, and other lymphoproliferative diseases.(2, 3, 4, 5, 6)  
Brentuximab vedotin is an antibody drug conjugate (ADC) directed against the CD30 
antigen and is being developed to treat patients with CD30hematologic malignancies.  
Hodgkin lymphoma and ALCL are among the most common CD30malignancies.
Brentuximab vedotin received a conditional marketing authorization as ADCETRIS® in the 
European Union (EU) for the treatment of adult patients with relapsed or refractory sALCL;
and for the treatment of adult patients with relapsed or refractory CD30Hodgkin 
lymphoma (HL) following autologous stem cell transplant (ASCT) or following at least 2
prior therapies when ASCT or multiagent chemotherapy is not a treatment option.  
Brentuximab vedotin received an FDA approval in the United States (US) as ADCETRIS® 
for the treatment of patients with sALCL after failure of at least 1 prior multiagent 
chemotherapy regimen, for the treatment of patients with HL after failure of ASCT, and for 
the treatment of patients with HL who are not ASCT candidates after failure of at least 
2 multiagent chemotherapy regimens.
1.1.1   
Systemic Anaplastic Large Cell Lymphoma
Anaplastic large cell lymphoma (ALCL) is a very rare disease that accounts for 
approximately 3% of the cases of adult non-Hodgkin lymphoma (NHL). In 5 of the more 
populated European Union (EU) countries (United Kingdom [UK], France, Germany, Italy, 
and Spain), estimated overall incidence ranges from 180 (Spain) to 420 (Italy) new cases per 
year.(7, 8) There are 2 major, distinct presentations of ALCL:  a systemic disease (sALCL) 
involving lymph nodes and/or extranodal sites (gastrointestinal tract, soft tissues, lung, liver, 
bone) and a primary cutaneous form.(9, 10, 11)
Systemic ALCL is a subtype of mature T- and NK-cell lymphomas characterized by the 
uniform expression of the cell surface antigen CD30.(12, 13, 14)  In addition to CD30 
expression, sALCL has a number of histological and clinical similarities with HL.  Systemic 
ALCL tumors present with large blastic cells with horseshoe-kidney-shaped nuclei. These 
so-called hallmark cells are present in all sALCL variants.  However, sALCL may also 
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present with binucleated or multinucleated, pleiomorphic cells with prominent, often 
elongated nucleoli and abundant cytoplasm, similar to the Hodgkin and Reed-Sternberg cells 
of HL.(13, 14)  Of interest, the histopathology of both diseases is characterized by a variable 
amount of tumor tissue fibrosis/sclerosis, foci of necrosis, and a variable mixture of 
histiocytes, epithelioid cells, neutrophils, eosinophils, lymphocytes, and plasma cells.(15)  A 
differential diagnosis between both diseases is required in approximately 3% of cases 
(Hodgkin-like pattern sALCL) but this proportion can be higher for cases with a single 
mediastinal mass that mimics the presentation of the nodular sclerosis subtype of classical 
HL.(13, 16)  Furthermore, both diseases have similar expression of T-cell, B-cell, and 
activation antigens and cytokines that translates to a similar array of B symptoms.(17, 18)
Such similarities prompted the hypothesis of potential common steps in the tumorigenesis of 
both malignancies.(15)
There are also important differentiation features between both diseases.  In approximately 
50% to 80% of sALCL cases, the t(2;5)(p23;q35) chromosome translocation prompting the 
anaplastic lymphoma kinase (ALK) gene on chromosome 2 to fuse with the NPM 
(nucleophosmin) gene on chromosome 5 (ALK-positive) is detected.  In general, 
ALK-positive disease occurs in younger patients and has a superior overall survival and 
failure-free survival (FFS) rate compared to ALK-negative disease; in addition, 
ALK-positive patients are generally more responsive to frontline chemotherapy regimens.(10, 
19)  The majority of sALCL cases (70%) present clinically, independent of ALK status, with 
advanced stage disease (stage III-IV) characterized by peripheral and/or abdominal 
lymphadenopathy, often associated with extranodal infiltrates and bone marrow 
involvement. Patients often have B symptoms (75%), especially high fever.(13)
The International Peripheral T-cell Lymphoma Project reported the clinical and 
immunophenotypic characteristics of adult sALCL.(19)  As stated, the majority of newly 
diagnosed patients present with advanced stage disease and disease-related symptoms or 
B symptoms (fever, weight loss, night sweats).  While 75% to 85% of patients achieve an 
objective response (either CR or PR) with frontline anthracycline-based therapy, the long-
term prognosis for these patients is poor, particularly for the ALK-negative and high-risk 
ALK-positive population.  The 5-year OS and failure-free survival rates reported were 49% 
and 36% in the ALK-negative group, and 70% and 60% in the ALK-positive group, 
respectively.  Notably, the majority of treatment failures occurred in the first 1 to 2 years 
post diagnosis.
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Systemic ALCL is an extremely rare disease and relapsed or refractory sALCL is even less 
common; approximately half of sALCL patients develop recurrent disease following 
frontline therapy.(19)  There is consequently a paucity of comprehensive data describing the 
outcomes of these patients. However, it is generally accepted that when sALCL recurs it 
behaves aggressively and requires intensive treatment.  Due to its rarity, recurrent sALCL
has often been included as a subset of aggressive lymphomas in large prospective studies of 
salvage therapy.  As a result, limited data are available to estimate the benefit of salvage 
therapy in sALCL.  Multiple chemotherapy agents and combination regimens are used as 
second-line treatment for relapsed or refractory sALCL; however, a second complete 
remission with standard salvage chemotherapy such as ICE (ifosfamide, carboplatin, 
etoposide), which is also commonly used in relapsed and refractory HL, is achieved in less 
than 30% of patients.(20, 21, 22, 23, 24)  Some patients may benefit from high-dose therapy with
autologous stem cell transplant (ASCT); however, clinical benefit may be limited to only 
those with chemotherapy-sensitive disease,(25, 26, 27) and use of ASCT is not a standard 
practice in relapsed or refractory sALCL.  Acknowledging the limited therapeutic options 
for these patients, the National Comprehensive Cancer Network (NCCN) 2012 guidelines 
currently support enrollment on a clinical trial or the use of a second-line therapy regimen.  
From a short list, single-agent brentuximab vedotin is a second-line therapy recommended
for patients with relapsed or refractory sALCL.(28) Of 58 patients with relapsed or refractory 
sALCL, in the phase 2 study (SG035-0004) which supported the United States (US)
approval and the European conditional marketing authorization of brentuximab vedotin, an 
ORR of 86% was observed with 53% of patients achieving a CR.  Pralatrexate, a folate 
analog, was approved in the US for the treatment of patients with peripheral T-cell 
lymphoma (PTCL), which includes sALCL.  In the phase 2 study that supported approval
for pralatrexate, 109 patients were evaluable of which 17 sALCL patients were enrolled.  An 
ORR of 35% was observed in the 17 sALCL patients.(29, 30)  Similarly, the efficacy of 
romidepsin (which has also been approved in the US) was evaluated in 130 relapsed or 
refractory PTCL patients in a pivotal phase 2 study that resulted in an ORR of 25%.(31)
The European Society for Medical Oncology (ESMO) has no current guidelines available 
for the treatment of relapsed or refractory sALCL.  However, brentuximab vedotin has 
conditional marketing authorization in the EU as ADCETRIS® for adult patients with 
relapsed or refractory sALCL.
In summary, sALCL is a very rare, aggressive lymphoma that is potentially curable with
frontline multiagent chemotherapy; however, approximately half of sALCL patients develop 
recurrent disease for which many current multiagent or single-agent salvage therapies offer 
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little benefit.  Brentuximab vedotin is a single-agent therapy approved in the US and has a 
conditional marketing authorization in the EU and addresses this unmet medical need.
1.1.2   
Study Drug
Brentuximab vedotin (ADCETRIS®), is an antibody-drug conjugate (ADC) composed of the 
anti-CD30 chimeric immunoglobulin G1 (IgG1) monoclonal antibody cAC10 and the potent 
antimicrotubule drug monomethyl auristatin E connected by a protease-cleavable linker.  
cAC10 binds to the CD30 antigen, which has a very low expression on normal cells but is 
found on ALCL cells, the Hodgkin Reed-Sternberg (HRS) cells of HL, and on tumor cells of 
other varied lymphoproliferative disorders.
The European Medicines Agency (EMA) granted brentuximab vedotin a conditional 
marketing authorization as ADCETRIS® on 25 October 2012 for the treatment of adult 
patients with relapsed or refractory sALCL and for the treatment of adult patients with 
relapsed or refractory CD30HL after ASCT or after at least 2 previous treatments when 
ASCT or multiagent chemotherapy is not an option for treatment.  On 19 August 2011 the 
United States Food and Drug Administration (FDA) granted accelerated approval to 
brentuximab vedotin as ADCETRIS® for the treatment of patients with sALCL after failure 
of at least 1 prior multiagent chemotherapy regimen and for the treatment of patients with
HL after failure of ASCT or after failure of at least 2 prior multiagent chemotherapy 
regimens in patients who are not ASCT candidates.
1.2   
Nonclinical Experience
Brentuximab vedotin has the potential to target and selectively deliver the microtubule-
disrupting agent MMAE to CD30-expressing tumor cells.  In vitro, cytotoxicity studies 
showed that it selectively killed human CD30-positive HL and ALCL cells with nanomolar 
concentrations producing 50% inhibition (IC50 values).  Antitumor activity has been 
demonstrated in xenograft models derived from human CD30-positive HL and ALCL tumor 
cell lines.
The toxicity of multiple doses of brentuximab vedotin has been assessed in rats and 
monkeys. In both species, the primary test article-related toxicity was hypocellularity of the 
bone marrow and lymphoid depletion of the thymus. Microscopic lesions were also 
observed in the spleen in monkeys and rats, and in the lung, intestines, liver, and testes in 
rats. In addition, decreases in peripheral blood counts were observed in both species, and 
elevations in liver enzymes were seen in rats only. The most clinically significant toxicity in 
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monkeys was neutropenia, which resulted in secondary bacterial infections leading to early 
deaths after a single 6-mg/kg dose. Toxicity was dose-dependent, with a no-observable-
adverse-effect level (NOAEL) of brentuximab vedotin of 0.5 mg/kg in rats and 1 mg/kg in 
monkeys. Human equivalent doses (HED) are 0.32 and 0.08 mg/kg respectively.
Detailed information regarding the nonclinical pharmacology and toxicology of brentuximab 
vedotin may be found in the Investigator’s Brochure (IB).
1.3   
Clinical Experience
To date, the safety and efficacy of brentuximab vedotin have been evaluated in 738 patients
with sALCL, HL, and other CD30+ hematologic malignancies in completed 
company-sponsored studies. Clinical data have been collected from 2 completed phase 1 
dose escalation studies (SG035-0001 and SG035-0002), a pivotal phase 2 study in relapsed 
or refractory HL after ASCT (SG035-0003), and a pivotal phase 2 study in relapsed or 
refractory sALCL (SG035-0004), as further described in the following.  A phase 1 thorough 
QTc study (SGN35-007) and a phase 1 drug-drug interaction study (SG035-008A) have also 
been completed. Clinical trial data to date indicate that brentuximab vedotin has a tolerable 
and manageable safety profile in patients with CD30-positive hematologic malignancies.
Phase 1, Dose-Escalating Studies
In Study SG035-0001, a total of 45 patients with CD30-positive hematologic malignancies 
were treated with brentuximab vedotin at dose levels of 0.1 to 3.6 mg/kg administered 
intravenously every 3 weeks.  The most common adverse events (AEs) were fatigue (36%), 
pyrexia (33%), diarrhea, nausea, peripheral neuropathy, and neutropenia (22% each).  
Notable serious adverse events assessed by the investigator to be at least possibly related to 
treatment included anaphylaxis, myocardial infarction, and peripheral neuropathy. Of 
interest, 2 of 2 sALCL patients achieved a complete response.  The maximum tolerated dose 
(MTD) was determined to be 1.8 mg/kg administered intravenously (IV) over 30 minutes 
every 3 weeks.
In Study SG035-0002, 44 patients with CD30-positive hematologic malignancies, 5 of 
whom had sALCL were treated with brentuximab vedotin at dose levels of 0.4 to 1.4 mg/kg 
administered intravenously weekly for 3 of 4 weeks. This weekly regimen was designed to 
enable combination use with gemcitabine, efficacy with brentuximab vedotin monotherapy 
was deemed sufficient and the planned brentuximab vedotin/gemcitabine combination arm 
of the study was not pursued.  In relapsed or refractory HL patients receiving brentuximab 
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vedotin 1.2 mg/kg weekly for 3 of 4 weeks, the ORR and CR rates were 58% (95% CI:
27.7%-84.8%) and 25% (95% CI: 5.5%-57.2%), respectively.  For all patients, the most 
common adverse events were peripheral sensory neuropathy (66%), fatigue (52%), nausea 
(50%), diarrhea (32%), arthralgia (27%), pyrexia (25%), and decreased appetite, myalgia, 
and upper respiratory tract infection (23% each). The most frequent AE that led to dose 
modification or delay was peripheral sensory neuropathy. Acute infusion reaction AEs 
occurred in a total of 6 patients. Overall, 2 patients (14%) who had an acute infusion 
reaction also had antitherapeutic antibodies at any postbaseline visit. Brentuximab vedotin 
was generally safe and well-tolerated up to the maximum tolerated dose of 1.2 mg/kg 
administered weekly for 3 out of 4 weeks.
Phase 2 Studies
In SG035-0003, a pivotal phase 2, single-arm, open-label study in  patients with relapsed or 
refractory HL post ASCT, and SG035-0004, a pivotal phase 2, single-arm, open-label study
conducted in patients with relapsed or refractory sALCL, brentuximab vedotin was 
administered at a dose of 1.8 mg/kg every 3 weeks.  One-hundred two patients with relapsed 
and refractory HL and 58 patients with relapsed and refractory sALCL were exposed for a 
median duration of approximately 27weeks (9 cycles) and 20 weeks (6 cycles), respectively.  
Most patients (89%) in the two phase 2 studies were between the ages of 18 and 65 years.  
The primary endpoint of both studies was overall response rate (ORR) as assessed by an 
independent radiographic facility.  Key secondary endpoints included duration of response, 
OS, and PFS.  The key efficacy results in HL (SG035-0003) include ORR per IRF (75% 
[95% CI:  64.9%-82.6%]), CR rate (34% [95% CI:  25.2%-44.6%]), B symptom resolution 
rate (77%), and duration of response (DOR, 6.7 months).  Of interest, for those patients 
achieving a CR, the median DOR was 20.5 months.  Key efficacy points in sALCL 
(SG035-0004) include ORR (86% [95% CI:  74.6%-93.9%]), CR rate (53% [95% CI:  
39.6%-66.7%]), and B symptom resolution rate (82%).
Treatment-emergent AEs occurring in ≥20% of patients in the phase 2 studies (SG035-0004 
and SG035-0003) 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.  Approximately half of patients had treatment-emergent peripheral neuropathy, 
predominantly sensory neuropathy, with an onset and severity pattern consistent with a 
cumulative effect.  Dose delay and subsequent reduction to 1.2 mg/kg was generally 
effective in managing peripheral neuropathy.  Grades 3 and 4 neutropenia occurred in 13% 
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and 7% of patients, respectively; these events were typically of short duration and well 
managed by brief dose delays with growth factor support in some cases.
Infusion-related reactions (IRRs) were reported for 17 patients (11%) in the phase 2 
population (Studies SG035-0003 and SG035-0004), and were reported in similar proportions 
of HL and ALCL patients.  The preferred terms reported most frequently were chills in 
6 (4%) patients, nausea in 5 (3%) patients, dyspnoea and pruritus in 4 patients each (3%), 
and cough in 3 (2%) patients. All IRRs in the phase 2 population (Studies SG035-0003 and 
SG035-0004) were Grade 1 or 2 in severity. No serious IRRs, nor any events of 
anaphylaxis, were reported in the phase 2 population. All but 1 patient had their first IRR 
within the first 3 cycles (9 patients in Cycle 1; 6 patients in Cycle 2; and 1 patient in 
Cycle 3); 1 patient had a first IRR in Cycle 15. Of the 17 patients with IRRs reported by the 
investigator, 7 patients received no IRR prophylaxis and had no further IRRs reported, while 
10 received IRR prophylaxis. Of the 10 patients who received IRR prophylaxis, no 
additional IRRs were reported for 8 of these patients. Incidences of IRRs were also 
observed in the phase 1 studies. Most IRRs occurred within the first 2 cycles. Most IRRs in 
the phase 1 studies were Grade 1 or 2. Grade 3 IRRs occurred in 2 patients (both in phase 1 
dose-escalation safety studies). Two SAEs of anaphylaxis occurred, both in phase 1 safety 
(SG035-0001) and clinical pharmacology (SGN35-007) studies. One of these 2 cases of 
anaphylaxis resulted in treatment discontinuation. The other patient continued treatment 
with IRR prophylaxis and a longer infusion time.
The clinical laboratory parameters for which the most patients had new or worsening shifts 
to Grade 3 were low neutrophils (11%), lymphocytes (11%), platelets (6%), leukocytes 
(5%), and high glucose (6%).  Only 1 patient in the phase 2 studies had Grade 3 ALT and 
aspartate aminotransferase (AST).
In the phase 2 studies (SG035-0003 and SG035-0004), 31% of patients had a serious 
adverse event (SAE), 28% had an SAE of Grade 3 or higher, and 15% had an SAE that was 
determined by the investigator to be related to brentuximab vedotin.  The most common 
SAEs, reported in ≥ 2% of patients, were abdominal pain, disease progression (recurrent 
sALCL), pulmonary embolism, and septic shock.  A higher proportion of sALCL patients 
experienced SAEs, including deaths within 30 days of last dose, relative to HL patients, 
likely due to the older age and more aggressive nature of the malignancy in this patient 
population.
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A total of 9 deaths were reported within the safety evaluation period (within 30 days of the 
last dose of brentuximab vedotin) in 357 patients across the 6 phase 1 and phase 2 studies 
for which data are available.  Two patient deaths (0.6%) were considered related to study 
treatment.  One patient in study SG035-0001 who received 3.6 mg/kg in phase 1 died due to 
febrile neutropenia and presumed septic shock.  A second treatment-related death in study 
SG035-008A was attributed to pancytopenia, cytomegalovirus (CMV) infection, and 
intracranial hemorrhage.  This patient received 1.8-mg/kg brentuximab vedotin.  The 
remaining on study deaths were primarily related to disease progression in sALCL
(SG035-0004) patients.
Brentuximab vedotin has been shown to induce durable remissions in patients with HL both 
pre- and post-ASCT, and in patients with relapsed or refractory sALCL.  Progression-free 
survival results comparing PFS with brentuximab vedotin to PFS from prior systemic 
therapy indicate that PFS is significantly prolonged with brentuximab vedotin for both HL 
and sALCL.  A substantial number of HL and sALCL patients with B symptoms at baseline 
saw these symptoms resolve during treatment with brentuximab vedotin.  In addition, the 
large majority of sALCL patients presenting with cutaneous lesions at baseline experienced 
resolution of these symptoms after receiving brentuximab vedotin.
Further details on clinical studies with brentuximab vedotin are provided in the IB.
1.4   
Study Rationale
As described in Section 1.3, Study SG035-0004, a prior multicenter, open-label, phase 2 
study of 58 patients with relapsed or refractory sALCL was conducted at sites in North 
American and Western Europe.  In this study, brentuximab vedotin was administered at a 
dose of 1.8 mg/kg every 3 weeks for up to 16 cycles.  The primary endpoint was objective 
response rate (ORR) as assessed by an independent radiographic facility.  Key secondary 
endpoints included duration of response (DOR), overall survival (OS), progression-free 
survival (PFS), and B symptom resolution rate.  The ORR observed in this study was 86% 
(95% CI:  74.6%-93.9%), with a median DOR of 13.2 months (95% CI: 0.1-21.7).  The 
median PFS was 14.3 months (95% CI:  0.8%-23.6%), and 82% of patients experiencing 
B symptom at baseline experienced B symptom resolution.  This 58-patient study formed 
the basis for the US accelerated and EU conditional approvals of brentuximab vedotin as 
ADCETRIS® for the treatment of relapsed or refractory sALCL.  Confirmatory Study 
C25006 seeks to further evaluate the safety and efficacy of 1.8 mg/kg of brentuximab 
vedotin q3wk for up to 16 cycles in this patient population in countries outside North 
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America and is a Specific Obligation for conversion to full approval in the EU. This study 
will investigate a similar population of adult patients with relapsed or refractory sALCL that 
has failed at least 1 multiagent chemotherapy regimen and uses the same ORR primary 
endpoint as Study SG035-0004 (EudraCT No. 2008-006035-12).
1.5   
Potential Risks and Benefits
As detailed in Section 1.3 and Section 1.4, brentuximab vedotin monotherapy has 
demonstrated therapeutic activity in CD30+ hematological malignancies including HL and 
relapsed or refractory sALCL for which brentuximab vedotin was granted conditional 
marketing authorization in the EU by the EMA and accelerated approval in the US by the
FDA.
Brentuximab vedotin treatment causes a peripheral neuropathy that is predominantly 
sensory.  Cases of peripheral motor neuropathy have also been reported.  Brentuximab 
vedotin-induced peripheral neuropathy is typically cumulative and generally reversible.  In 
the SG035-0003 and SG035-0004 clinical trials, 54% of patients experienced any grade of 
neuropathy.  Of these patients, 49% had complete resolution, 31% had partial improvement, 
and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual 
neuropathy at the time the data cutoff date for clinical study reporting.  Monitoring patients 
for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, a burning 
sensation, neuropathic pain, or weakness is required. Patients experiencing new or 
worsening peripheral neuropathy may require brentuximab vedotin dose modifications, 
including a dose delay.
Infusion-related reactions, including anaphylaxis, have occurred with brentuximab 
vedotin.(32)  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.  If an infusion-related reaction occurs, the 
infusion should be interrupted and appropriate medical management instituted.  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.
Clinically significant laboratory abnormalities have been reported as adverse events per the 
phase 2 study protocols (SG035-0003 and SG035-0004).  Central laboratory data were 
collected only predose for each treatment cycle.  Few patients overall had postbaseline 
worsening to Grade 3 or higher in clinical laboratory values.  The clinical laboratory 
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parameters for which the most patients had new or worsening shifts to Grade 3 were low 
neutrophils (11%), lymphocytes (11%), platelets (6%), leukocytes (5%), and high glucose 
(6%).  Only 1 patient in the phase 2 studies had Grade 3 ALT and AST.
Any treatment that can decrease immune function may contribute to infections; patients are 
to be monitored for these events during the treatment period and up to and including 30 days 
after the last dose.
Complete blood counts (CBCs) 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 by dose delays, reductions, or discontinuations.
Tumor lysis syndrome may occur.  Patients with rapidly proliferating tumor 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.
Stevens-Johnson syndrome has been reported with brentuximab vedotin.  If Stevens-Johnson 
syndrome occurs, brentuximab vedotin must be discontinued and the appropriate medical 
therapy administered.
Progressive multifocal leukoencephalopathy (PML) has been reported with brentuximab 
vedotin use.  PML is a rare demyelinating disease of the brain that is caused by the John 
Cunningham virus (JCV).  It typically occurs in immunocompromised individuals and can 
be fatal.  Presenting features may include altered mental status, motor deficits such as
hemiparesis or ataxia, visual disturbances, or higher cortical dysfunction such as dysphasia 
or agnosia.  Seizures have also been reported in PML patients (approximately 20%).  The 
onset of neurological deficits may occur over weeks to months.  Cognitive decline without 
accompanying deficits in motor or sensory function is uncommon.  Optic nerve 
involvement, fever, and spinal cord disease are not typically associated with PML.  In 
addition, peripheral neuropathy, which has been reported with brentuximab vedotin 
treatment, is not commonly reported with PML.  If PML is suspected, a diagnostic work-up 
should be performed, as described in Section 6.6.
Preliminary population PK analyses of the effects of renal impairment on brentuximab 
vedotin metabolism suggest that no dose adjustments are necessary for patients with 
moderate renal impairment.
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Monomethyl auristatin E (MMAE) is primarily metabolized by CYP3A.   Patients who are 
receiving strong CYP3A4 inhibitors concomitantly with brentuximab vedotin should be 
closely monitored for adverse reactions.
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 6.5 for appropriate precautions following the 
administration of study medication.
Overall, considering the potential for therapeutic benefit of brentuximab vedotin in sALCL 
and the frequently limited treatment options available to these patients with this life 
threatening disease, as well as the manageable safety profile of brentuximab vedotin, the 
benefit-risk assessment is favorable.
2.   
STUDY OBJECTIVES
2.1   
Primary Objective
The primary objective is to assess the antitumor efficacy of single-agent brentuximab 
vedotin (1.8 mg/kg administered intravenously every 3 weeks) as measured by the overall 
objective response rate (ORR) in patients with relapsed or refractory sALCL following at 
least 1 multiagent chemotherapy regimen (CHOP or equivalent multiagent chemotherapy 
regimens with curative intent).
2.2   
Secondary Objectives
The secondary objectives include:

To determine duration of tumor control, including duration of response, progression-
free survival (PFS), and complete remission rate (CR) with brentuximab vedotin

To determine the proportion of patients receiving hematopoietic stem cell transplant
(SCT, either autologous or allogeneic) after brentuximab vedotin therapy

To determine overall survival (OS) with brentuximab vedotin

To assess the safety and tolerability of brentuximab vedotin

To assess the pharmacokinetics of brentuximab vedotin
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!
To determine immunogenicity of brentuximab vedotin
3.   
STUDY ENDPOINTS
3.1   
Primary Endpoint
The primary endpoint is ORR per independent review facility (IRF)
3.2   
Secondary Endpoints
The secondary endpoints include:
!
Duration of response per IRF
!
PFS per IRF
!
CR rate per IRF
!
Proportion of patients receiving hematopoietic stem cell transplant (SCT) following 
treatment with brentuximab vedotin
!
OS
CCI
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!
Type, incidence, severity, seriousness, and relatedness of adverse events, and 
laboratory abnormalities
!
Selected pharmacokinetic parameters
!
The presence of anti-therapeutic antibodies (ATA) to brentuximab vedotin
4.   
STUDY DESIGN
4.1   
Overview of Study Design
This single-arm, open-label, multicenter phase 4 clinical study seeks to evaluate the efficacy 
and safety of brentuximab vedotin as a single agent in adult patients with relapsed or 
refractory sALCL who have previously received at least 1 multiagent chemotherapy
regimen.  Its primary objective is to determine the antitumor efficacy of single-agent 
brentuximab vedotin as measured by ORR in patients with relapsed or refractory sALCL 
following at least 1 multiagent chemotherapy regimen.  A minimum of 45 patients will be 
treated in this study.
Brentuximab vedotin will be administered as a single outpatient 1.8-mg/kg IV infusion on 
Day 1 of each 3-week cycle.  Patients who achieve SD or better should receive a minimum 
CCI
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of 8 cycles and all patients will be given the opportunity to complete a maximum of
16 cycles.  Dedicated CT scans (spiral preferred) of chest, neck, abdomen, and pelvis will be 
performed at baseline and Cycles 2, 4, 7, 10, 13, and 16, and PET scans will be done at 
baseline, Cycles 4 and 7, and, for patients who discontinue study treatment without a post-
baseline PET assessment, at EOT.  Measures of anticancer activity will be assessed by an 
independent review facility (IRF) according to the International Working Group (IWG)
Revised Response Criteria for Malignant Lymphoma (Cheson 2007).(1)  Patients who 
experience disease progression at any time will be withdrawn from study drug treatment.  
Clinical laboratory samples will be taken before dosing on Day 1 of each 3-week cycle.  
Cycle 1, Day 1 clinical laboratory samples may be collected within 4 days before dosing to 
ensure patient eligibility on study Day 1.  Physical examination, including vital signs, 
weight, ECOG performance status, 
; brentuximab vedotin PK;
immunogenicity;
will be performed 
on Day 1 of each cycle.  In addition, a bone marrow biopsy is required to confirm responses 
in patients who have bone marrow involvement at baseline.  The follow-up bone marrow 
biopsy must be done within 2 weeks of documentation of response.  Once bone marrow is 
negative no further bone marrow evaluations are required.
Patients may continue on study treatment until disease progression or unacceptable toxicity.  
Patients who discontinue study treatment with SD or better will have CT scans done every
3 months for 18 months from EOT or until the sooner of disease progression, death, or study
closure.  Overall survival data will be collected every 3 months from EOT for 18 months, 
then every 6 months thereafter until the sooner of death or study closure.  The study will be 
closed when 50% of the patients have had an OS event or 5 years after enrollment of the last 
patient, whichever occurs first.
Additional efficacy endpoints will be evaluated 
Serum concentrations of brentuximab vedotin, ATA, and free drug (MMAE) will be 
measured.  
ed.  A possible dose response for any such effects as well as the 
presence of ATAs may be subsequently examined.
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Toxicity will be evaluated according to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), version 4.03, effective date 14 June 2010.(33)
Safety assessments will include the incidence and severity of adverse events and changes in 
clinical laboratory values, vital signs, and physical examination findings.
4.2   
Number of Patients
At least 45 patients with sALCL will be enrolled in this study from approximately 20 study 
centers.  The study will be conducted mainly in Europe, including Eastern Europe, and could 
include study centers in Latin America and possibly other regions.
Enrolled patients who do not receive study drug for any reason will not be replaced; 
however, additional patients may be enrolled to ensure a minimum of 45 patients with 
confirmed sALCL histology per central review.
4.3   
Duration of Study
Patients will complete a Screening period of up to 28 days and should receive treatment with 
study drug for a minimum of 8 cycles and up to a maximum of 16 cycles.  The final analysis 
of the primary endpoint will be conducted when all patients have had the opportunity to
complete 16 cycles of brentuximab vedotin and have had their EOT visit.  Study closure will 
occur when 50% of patients have had an OS event or 5 years after enrollment of the last
patient, whichever occurs first.  The total study duration is anticipated to be approximately 
6 to 7 years.
5.   
STUDY POPULATION
5.1   
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Patients with relapsed or refractory sALCL who have previously received at least 
1 multiagent chemotherapy regimen (CHOP or equivalent multiagent chemotherapy 
regimen with curative intent).
2. Histologically-confirmed sALCL based on local pathology report.  Refer to
Section 7.4.10 for details.
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3. Age greater than or equal to 18 years.
4. Patients must have bidimensional measurable disease of ≥1.5 cm as documented by 
radiographic technique (spiral CT preferred) per the International Working Group 
Revised Criteria for Response Assessment for Malignant Lymphoma.(1)
5. At least ONE of the following as evidence of relapsed or refractory sALCL:

Histologically-documented sALCL from a biopsy obtained at least 4 weeks 
subsequent to the most recently delivered prior treatment with radiation, 
chemotherapy, biologics, immunotherapy, and/or other investigational agents.

Interval tumor growth documented between 2 successive CT evaluations with the 
second evaluation occurring at least 4 weeks after delivery of any radiation, 
chemotherapy, biologics, immunotherapy, and/or other investigational agents.

FDG-avidity by PET in a new tumor mass on CT that is unlikely to have an 
alternative explanation.

Recurrent FDG-avidity by PET in a previously identified FDG-avid tumor mass 
on CT that had become negative.

FDG-avid tumor mass by PET in conjunction with sALCL-related symptoms 
such as pruritus, B symptoms, or weight loss > 10%, after infectious causes have 
been excluded.
6. Received any previous ASCT at least 12 weeks (3 months) before the first study 
dose prior to study entry.
7. Completed any previous treatment with radiotherapy, immunotherapy, 
chemotherapy, and/or other investigational agents at least 2 weeks prior to the first 
dose of brentuximab.
8. Patient has recovered to less than or equal to Grade 1 toxicity related to radiotherapy, 
immunotherapy, and chemotherapy unless evidence of toxicity is due to underlying 
disease.  If toxicity is related to underlying disease, less than or equal to Grade 2 
toxicity is acceptable.
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9. An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
(Refer to Section 15.1).
10. Suitable venous access for the study–required procedures.
11. 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 30 days after the last dose of study drug, or 

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable 
methods of contraception.)
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, or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, post-ovulation methods for the female partner] and withdrawal 
are not acceptable methods of contraception.)
12. 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.
13. Clinical laboratory values as specified below within 4 days before the first dose of 
study drug unless due to the presence of underlying lymphoma involvement, then 
patient must have recovered to less than or equal to Grade 2 toxicity:

Absolute neutrophil count ≥1,000/μL without growth factor support
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
Platelet count ≥50,000/μL without transfusion support unless thrombocytopenia 
is due to documented bone marrow involvement with lymphoma

Serum bilirubin level 1.5 the upper limit of normal (ULN) or 3 ULN for 
patients with an indirect hyperbilirubinemia due to Gilbert’s disease or 
documented hepatic involvement with lymphoma

Serum creatinine 1.5 ULN

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than 
or equal to 2.5 ULN
5.2   
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Previous treatment with brentuximab vedotin.
2. Previously received an allogeneic transplant.
3. Patients with current diagnosis of primary cutaneous ALCL (patients whose ALCL 
has transformed to sALCL are eligible).
4. Any of the following cardiovascular conditions or values within 6 months before the 
first dose of study drug:  
Myocardial infarction within 6 months before the first dose of study drug
New York Heart Association (NYHA) Class III or IV heart failure (Refer to 
Section 15.2).
Evidence of current uncontrolled cardiovascular conditions, including cardiac 
arrhythmias, congestive heart failure (CHF), angina, or electrocardiographic 
evidence of acute ischemia or active conduction system abnormalities
5. History of another primary malignancy that has not been in remission for at least 
3 years.  The following are exempt from the 3-year limits:  nonmelanoma skin 
cancer, curatively treated localized prostate cancer, and cervical carcinoma in situ on 
biopsy or a squamous intraepithelial lesion on PAP smear.
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6. Any active uncontrolled systemic viral, bacterial, or fungal infection
7. Any antimicrobial, antiviral, or antifungal therapy within 1 week prior to the first 
dose of brentuximab vedotin (routine prophylaxis is acceptable)
8. Treatment with any investigational products within 4 weeks before the first dose of 
study drug
9. Current therapy with other systemic anti-neoplastic or investigational agents.
10. Known cerebral/meningeal disease including signs or symptoms of progressive 
multifocal leukoencephalopathy (PML).
11. Female patients who are lactating and breastfeeding or have a positive serum or urine
pregnancy test during the screening period or a positive pregnancy test on Day 1 
before first dose of study drug.
12. Patients with dementia or an altered mental state that would preclude the 
understanding and rendering of informed consent.
13. Known hypersensitivity to recombinant proteins, murine proteins, or any excipient 
contained in the drug formulation.
14. Known human immunodeficiency virus (HIV) positive.
15. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C 
infection.
6.   
STUDY DRUG
6.1   
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented 
before drug administration.  Study drug will be administered only to eligible patients under 
the supervision of the investigator or identified subinvestigator(s).
Brentuximab vedotin will be administered on Day 1 of each 3-week cycle.  The dose of 
brentuximab vedotin is 1.8 mg/kg and is administered by outpatient IV infusion given over 
approximately 30 minutes.  Patients with stable disease or better should receive a minimum 
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of 8 cycles and, all patients will be given the opportunity to complete a maximum of up to 
16 cycles of brentuximab vedotin.  In the absence of infusion toxicities, the infusion rate for 
all patients must be calculated to achieve a 30-minute infusion period.  Brentuximab vedotin 
must not be administered as an IV push or bolus. Brentuximab vedotin should be 
administered through a dedicated IV line and cannot be mixed with other medications.
Dosing is based on patients’ weight; however, doses will be adjusted for patients who 
experience a ≥10% change in weight from baseline. Actual weight will be used except for 
patients weighing greater than 100 kg; dose will be calculated based on 100 kg for these 
individuals.  Brentuximab vedotin dose should be rounded to the nearest whole number of 
milligrams.
Further brentuximab vedotin administration information can be found in the Pharmacy 
Manual.
6.2   
Dose-Modification Guidelines
6.2.1   
Recommended Brentuximab Vedotin Dose Modifications for Treatment-
associated Toxicity
Table 6-1 details the recommended brentuximab vedotin dose modifications to be enacted in 
the event of treatment-associated toxicity.
Table 6-1   
Recommended Brentuximab Vedotin Dose Modifications for 
Treatment-Associated Toxicity
Nonhematologic
(Excluding Neuropathy)
Hematologic
Peripheral Neuropathy
Grade 1
Continue at same dose  
level
Continue at same dose level
Continue at same dose level
Grade 2
Continue at same dose 
level
Continue at same dose level
For Grade 2 neuropathy, 
withhold dose until toxicity is 
≤Grade 1 or has returned to 
baseline, then restart treatment 
at a reduced dose of 1.2 mg/kg 
every 3 weeks.
Grade 3
Withhold dose until 
toxicity is ≤ Grade 1 or 
has returned to baseline, 
then resume treatment at 
the same dose levela.
Withhold dose until toxicity is 
≤ Grade 2, or has returned to 
baseline, then resume treatment 
at the same dose level.b  
Consider growth factor support 
(G-CSF or GM-CSF) for 
treatment of neutropenia and 
prophylaxis in subsequent 
cycles.
Withhold dose until toxicity 
returns to Grade 1 or baseline, 
then restart treatment at a 
reduced dose of 1.2 mg/kg every 
3 weeks.
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Table 6-1   
Recommended Brentuximab Vedotin Dose Modifications for 
Treatment-Associated Toxicity
Nonhematologic
(Excluding Neuropathy)
Hematologic
Peripheral Neuropathy
Grade 4
Withhold dose until 
toxicity is ≤ Grade 1 or 
has returned to baseline, 
then reduce dose to 1.2 
mg/kg and resume 
treatment, or discontinue 
at the discretion of the 
investigator after 
discussion with the 
sponsor.a
Withhold dose until toxicity is 
≤ Grade 2, then resume 
treatment at the same dose 
level.  Consider growth factor 
support (G-CSF or GM-CSF) 
for treatment of neutropenia 
and prophylaxis in subsequent 
cycles.  For the second 
occurrence of Grade 4 toxicity 
(if neutropenia, while receiving 
growth factor support), 
withhold dose until toxicity is ≤ 
Grade 2, then reduce the dose 
to 1.2 mg/kg and resume 
treatment after discussion with 
the sponsor.b
Discontinue brentuximab 
vedotin
Abbreviations:  G-CSF = granulocyte-colony stimulating factor, GM-CFS = granulocyte macrophage-colony 
stimulating factor.
Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.03.
a Patients who develop clinically insignificant Grade 3 or 4 electrolyte laboratory abnormalities may continue 
study treatment without interruption.
b Patients who develop clinically insignificant Grade 3 or 4 lymphopenia may continue study treatment 
without interruption.
6.2.2   
Criteria for Dose Interruption During a Cycle
Please refer to Table 6-1 for further information.
6.2.3   
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
Treatment with brentuximab vedotin will use a cycle length of 3 weeks. For a new cycle of 
treatment to begin, all drug-related toxicity must have resolved per the guidelines provided 
in Table 6-1.
If the patient fails to meet the criteria for retreatment cited previously, 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 retreatment have been met.  The 
start of the next cycle may be delayed for up to 3 weeks 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 for study-drug-related toxicities require 
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discontinuation from study treatment, unless the sponsor agrees the benefit:risk assessment 
supports continued treatment.
6.2.4   
Criteria for Dose Reduction
Intrapatient dose reduction to 1.2 mg/kg may be allowed depending on the type and severity 
of toxicity described previously in Table 6-1 and following sponsor and investigator review 
of the available data.
Doses reduced for drug-related toxicity should generally not be re-escalated.  However, 
intrapatient re-escalation to the previous dose level may be permitted at the discretion of the 
investigator after discussion with the sponsor.
6.2.5   
Criteria for Discontinuation of Brentuximab Vedotin
At the time of study drug discontinuation, all study procedures outlined for the EOT visit 
will be completed.  The primary reason for study drug discontinuation will be recorded on 
the electronic case report form (eCRF).  Criteria for discontinuation of study are provided in
Section 7.7.  Please refer to Table 6-1 for further information regarding dosing requirements 
for patients who discontinue study drug due to toxicity.
If the sponsor and/or the investigator should discover conditions arising during the study that 
indicate it should be terminated, an appropriate schedule for termination will be instituted.
6.3   
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study:

Chemotherapy

Immunotherapy

No other investigational drug may be used during treatment on this study

Concurrent participation in another clinical trial of medical intervention is not 
allowed
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6.4   
Permitted Concomitant Medications and Procedures
The following medications and procedures are allowed during the study:

The use of topical steroids, inhalational steroids, and ophthalmic steroids is 
permitted.  Corticosteroids are permitted as part of a premedication regimen per 
institutional standards or to manage potential hypersensitivity.

Patients may receive concomitant hormonal therapy provided they have been on a 
stable dosage for at least 1 month prior to enrollment.  No restrictions are placed 
upon the use of hormonal contraceptives.

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.

Medications for infusion-related reactions, such as epinephrine, antihistamines, and 
corticosteroids should be available for immediate use.

Palliative radiation or surgery is permitted if other sites of measurable disease 
remain.
6.5   
Precautions and Restrictions 
CYP3A/4 Inhibitor Use
Monomethyl auristatin E (MMAE) is primarily metabolized by CYP3A.  Patients who are 
receiving strong CYP3A4 inhibitors concomitantly with brentuximab vedotin should be 
closely monitored for adverse reactions.  Please refer to the Study Manual for a list of 
examples of strong CYP3A4 inhibitors.
Infusion-Related Reactions
Infusion-related reactions may occur during the infusion of brentuximab vedotin.  The 
infusion should be administered at a site properly equipped and staffed to manage 
anaphylaxis should it occur.  The patient should be observed for 60 minutes following each
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 
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measures consistent with optimal patient care will be given throughout the study according 
to institutional standards.  Medications for infusion-related reactions, such as epinephrine 
and antihistamines should be available for immediate use.  However, routine premedication 
should not be administered prior to the first dose of brentuximab vedotin.
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 prior to each 30-minute brentuximab vedotin 
infusion.
Patients who experience a Grade 3 or 4 infusion-related reaction may potentially receive 
additional treatment with brentuximab vedotin at the discretion of the investigator after 
discussion with the sponsor.
If anaphylaxis occurs, the administration of brentuximab vedotin should be immediately and 
permanently discontinued and appropriate medical therapy administered.
Pregnancy
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 patients of reproductive age group 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 at the same time, from the time of signing the informed consent 
through 30 days after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
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post-ovulation methods] and withdrawal are not acceptable methods of 
contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:

Agree to practice effective barrier contraception during the entire study treatment 
period and through 6 months after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
post-ovulation methods for the female partner] and withdrawal are not acceptable 
methods of contraception.)
6.6   
Management of Clinical Events
Nausea and/or Vomiting
Although this study will not initially employ prophylactic anti-emetics, there is no 
prohibition against their use in the management of a patient who develops nausea and/or 
vomiting.  As in the prophylactic setting, 5-HT3 receptor antagonists and corticosteroids 
should be tried first.
Diarrhea
Prophylactic antidiarrheals will not be used in this protocol; however, patients will be 
instructed to take antidiarrheal medication(s) at physician’s discretion until they are 
diarrhea-free for at least 12 hours.  Fluid intake should be maintained to avoid dehydration.
Peripheral Neuropathy
AEs of peripheral neuropathy will be monitored closely throughout the study.  Events that 
are greater than Grade 1 in severity will result in brentuximab vedotin dose modification.
Suspected Progressive Multifocal Leukoencephalopathy (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.  Seizures have also been reported in PML patients (approximately 20%).  The 
onset of neurological deficits may occur over weeks to months.  See the IB for further 
details.
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If PML is suspected, hold further brentuximab vedotin dosing and undertake a diagnostic 
workup that may include (but is not limited to):

Neurologic examinations, as warranted.

Brain magnetic resonance imaging (MRI):  Features suggestive of PML include 
presence of unifocal or multifocal lesions, mainly of the white matter, which are 
typically nonenhancing and do not have mass effect.

Polymerase chain reaction (PCR) analysis:  JCV DNA detectable in cerebrospinal 
fluid or there is evidence of JCV in a brain biopsy.

Neurology consultation.
If PML is confirmed, permanently discontinue treatment with brentuximab vedotin.
6.7   
Blinding and Unblinding
This is an open-label, single arm study. 
6.8  
Description of Investigational Agents
Brentuximab vedotin for Injection is a sterile, preservative-free, white to off-white 
lyophilized cake for reconstitution for IV administration.  Brentuximab vedotin for Injection 
is supplied in single-use, Type 1 borosilicate glass vials with FluroTec®-coated butyl rubber 
stoppers and aluminum seals.  Each vial of the product contains brentuximab vedotin, 
trehalose, sodium citrate, and polysorbate 80.  The lyophilized product, after reconstitution 
with 10.5 mL sterile Water for Injection, USP, yields 11 mL of brentuximab vedotin 
solution (5 mg/mL).
6.9   
Preparation, Reconstitution, and Dispensation
Brentuximab vedotin is an anticancer drug, and as with other potentially toxic compounds, 
caution should be exercised when handling brentuximab vedotin.
Recommended safety measures for handling and preparation include masks, protective 
clothing, gloves, and vertical laminar airflow safety cabinets.
Study treatment vials are single-use containers.  Any partially used vials or diluted dosing 
solutions are to be discarded using appropriate institutional drug disposal procedures 
according to the guidelines in the Study Manual.
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Study treatment must be reconstituted with the appropriate amount of sterile water for 
injection (see the Pharmacy Manual for details).  GENTLY swirl the vial until the contents 
are completely dissolved.  The vial must not be shaken or vigorously swirled; excess 
agitation may cause aggregate formation.  Visually inspect the reconstituted drug product for 
any particulate matter and discoloration.  
The required volume of 5 mg/mL reconstituted brentuximab vedotin solution needed must 
be calculated and withdrawn from the vial(s). The reconstituted solution should be added 
immediately to an infusion bag containing a minimum volume of 100 mL.  The dose for 
patients weighing greater than 100 kg should be calculated based on a weight of 100 kg.
There are no known incompatibilities between study treatment and polyvinyl chloride 
(PVC), ethyl vinyl acetate (EVA), polyolefin, or polyethylene (PE) bags.  The bag should be 
gently inverted to mix the solution.  The bag must not be shaken; excess agitation may 
cause aggregate formation.  Prior to administration, the reconstituted and diluted drug 
product should be inspected visually for any particulate matter and discoloration.
The formulation contains no preservative and is intended for single use only; infusion 
solutions should be prepared and transferred using aseptic technique in a biosafety hood.
Refer to the Directions for Use/Pharmacy Manual for more specific instructions on 
reconstitution and use.
6.10   
Packaging and Labeling
Vials of study treatment will be packaged in cardboard kits.  Each kit will contain 1 vial of 
investigational product.  Vials and kits will be labeled to meet country-specific regulatory 
requirements.
6.11   
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 
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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.
7.   
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.
7.1   
Study Personnel and Organizations
The contact information for the Takeda project clinician for this study, the central laboratory 
and any additional clinical laboratories, the coordinating investigator for each member 
state/country, the independent radiologic review facility, interactive voice and/or Web
response system (IXRS) provider, and the contract research organization (CRO) team may
be found in the Study Manual.  A full list of investigators is available in the sponsor’s 
investigator database.
7.2   
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).  It is not envisioned that prisoners (or other 
populations that might be subject to coercion or exploitation) will be enrolled into this study.
7.3   
Treatment Group Assignments 
This is an open label, nonrandomized study with no reference therapy.  Treatment group 
assignments are not applicable to this study.
7.4   
Study Procedures
Refer to the Schedule of Events for timing of assessments.  Additional details are provided 
as necessary in the sections that follow.
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7.4.1   
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.
7.4.2   
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening
per local regulations.
7.4.3   
Medical History
During the Screening period, a complete medical history will be compiled for each patient.  
The history will emphasize the background and progress of the patient’s malignancy and 
include a description of prior therapies for it.  In addition, concomitant medications will be 
recorded as specified in Section 7.4.12.
7.4.4   
Physical Examination
A physical examination will be completed per standard of care at the times specified in the 
Schedule of Events.
Physical examination will include a focused lymphoma assessment and an evaluation of 
skin, head, eyes, ears, nose, throat, nodes, heart, lungs, abdomen, back, extremities, and 
neurology.
7.4.5   
Patient Height
Height will be measured only during screening (within 28 days before the first dose of
brentuximab vedotin).
7.4.6   
Patient Weight
Weight will be measured at times specified in the Schedule of Events.  Dosing with 
brentuximab vedotin is based on patients’ weight; however, doses will be adjusted for
patients who experience a ≥10% change in weight from baseline (Section 6.1).
7.4.7   
Vital Signs
Vital sign measurements include seated (after 3-5 minutes in this position) measurements of 
diastolic and systolic blood pressure, heart rate, and oral temperature.
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7.4.8   
Pregnancy Test
A serum or urine pregnancy test will be performed for female patients of childbearing 
potential at times specified in the Schedule of Events.
7.4.9   
Eastern Cooperative Oncology Group Performance Status
ECOG performance status will be assessed at times specified in the Schedule of Events.  See 
Section 15.1 for ECOG grade classifications.
7.4.10   
Tumor Specimen
Tumor tissue from the most recent post-diagnosis biopsy is preferred.  Unstained slides or a 
paraffin-embedded block will be obtained after the patient has signed the ICF.  Patients 
without at least 10 histological slides from their most recent post-diagnosis biopsy will 
undergo a new tumor biopsy during screening.  This sample will be used to confirm sALCL 
diagnosis and ALK status.  Central laboratory results for sALCL diagnosis are not required 
prior to the first dose of study drug.  Refer to the Schedule of Events for details regarding 
tumor tissue collection.
7.4.11   
Electrocardiogram
A 12-lead electrocardiogram (ECG) will be administered at the time points specified in the 
Schedule of Events.
7.4.12   
Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will be
recorded in the eCRF as specified in the Schedule of Events.  Refer to Section 6.3 and 
Section 6.4 for a list of medications and therapies that are prohibited and/or allowed during 
the study.
7.4.13   
Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as 
specified in the Schedule of Events.  Refer to Section 10 for details regarding definitions, 
documentation, and reporting of pretreatment events, AEs, and SAEs.
7.4.14   
Enrollment
A patient is considered to be enrolled in the study when enrolled in the IXRS.
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Procedures for completion of the enrollment information are described in the Study Manual.
7.4.15   
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed centrally.  Decisions regarding eligibility 
and study dosing may be made using local laboratory results.  If local laboratory values are 
used for either eligibility or study dosing decisions, samples for central laboratory 
confirmation must be collected as specified in the Schedule of Events.
Handling and shipment of clinical laboratory samples will be outlined in the Study Manual.
Clinical laboratory evaluations will be performed as outlined in the following.
Clinical Chemistry and Hematology
Blood samples for analysis of the following clinical chemistry and hematological parameters 
will be obtained as specified in the Schedule of Events.
Hematology

Hemoglobin

Hematocrit

Platelet (count)

Leukocytes with differential

Neutrophils (absolute neutrophil count [ANC])
Serum Chemistry

Blood urea nitrogen 
(BUN)

Creatinine

Bilirubin (total)

Urate

Lactate dehydrogenase 
(LDH)

Gamma glutamyl 
transferase (GGT)

Phosphate

Albumin

Alkaline phosphatase 
(ALP)

Aspartate 
aminotransferase (AST)

Alanine 
aminotransferase (ALT)

Glucose 

Sodium

Potassium

Calcium

Chloride

Carbon dioxide (CO2)

Magnesium
7.4.16   
Disease Assessment
Response to treatment and disease status assessments will be evaluated according to the 
Revised Response Criteria for Malignant Lymphomas.(1)  Disease assessments will be 
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performed as specified in the Schedule of Events.  Records of disease assessments will be 
provided to the IRF for central review.
Computed tomography (CT), spiral preferred, with contrast as appropriate (chest, neck, 
abdomen, and pelvis), and positron emission tomography (PET) scans will be performed at 
time points described in the Schedule of Events.  Anatomical measurements (summed across 
target lesions) will be collected at baseline and each subsequent evaluation using an imaging 
modality consistent with that used at screening.  Objective assessments will be performed at 
each time point as described in the Schedule of Events.  When possible, the same qualified 
physician will interpret results to reduce variability.  Radiographic images will be 
maintained at the site, and test results and physician’s findings will be filed in patient source 
documents.
MRI scans may be substituted for CT scans only if a patient 1) has a glomerular filtration 
rate of less than 60 mL/min such that IV contrast presents a risk of renal failure, 2) develops 
anaphylaxis to IV contrast, or 3) becomes pregnant during long-term follow-up.  If use of 
MRI is required, a consistent scanning modality must be maintained.  Further detail may be 
found in the Imaging Manual.
B symptom assessments, including fever, night sweats, and weight loss, will be evaluated at 
the time points indicated in the Schedule of Events.
A bone marrow (BM) biopsy will be obtained for BM assessment as specified in the 
Schedule of Events.
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7.4.19   
Cost Assessment
The cost of treatment will be assessed through the collection 
.  Valuation of the 
costs will be undertaken separately.
7.4.20   
Pharmacokinetic Measurements
Pharmacokinetic measurements will be assessed for MMAE, ADC, and free antibody
(cAC10).  Pharmacokinetic parameters to be estimated may include the maximum 
concentration for MMAE (Cmax), and concentration at the end of infusion for brentuximab 
vedotin (Ceoi).  Population Pharmacokinetics methodologies may be used to determine PK 
parameters and covariates in this population.
All sampling times are relative to the end of infusion of brentuximab vedotin.  For sample 
collection time points refer to the Schedule of Events.  Details regarding the preparation, 
handling, and shipping of samples are provided in the Study Manual.
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7.4.22   
Immunogenicity Measurements
Blood for serum samples will be collected as specified in the Schedule of Events to evaluate 
ATA and neutralizing ATA as a safety assessment.  On dosing days, the blood samples for 
ATA and neutralizing ATA assessment must be collected before dosing. Neutralizing ATA 
assessment will be performed only for ATA-positive samples.  Details regarding the 
preparation, handling, and shipping of samples are provided in the Study Manual.
7.5   
Completion of Treatment
Patients will be considered to have completed study treatment if they complete 16 cycles of 
treatment with brentuximab vedotin.
7.6   
Completion of Study
Study closure will occur when enrollment is complete and 50% of patients have experienced 
OS events or 5 years after enrollment of the last patient, whichever occurs sooner.
Regardless of the duration of treatment, all patients will remain on study for follow-up after 
receiving the last dose of study treatment until they withdraw consent for further follow-up, 
are lost to follow-up, or until study closure.  The study is expected to close approximately
6 to 7 years after the first patient starts study treatment.
Refer to Section 7.10 for posttreatment follow-up schedule.
7.7   
Discontinuation of Treatment With Study Drug, and Patient Replacement
Study drug must be permanently discontinued for patients meeting any of the following 
criteria:
!
Completed maximum number of cycles per protocol
!
Progressive disease
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
Initiation of hematopoietic stem cell transplant

Withdrawal by subject
The reason justifying the study treatment withdrawal should be documented in the eCRF.
Patients who discontinue from study treatment will remain on study for follow-up unless 
they withdraw consent for the follow-up phase of the study.
Treatment with study drug may also be discontinued for any of the following reasons:

Adverse event

Symptomatic deterioration

Unsatisfactory therapeutic response

Protocol violation

Study terminated by sponsor

Lost to follow-up

Other
Once study drug has been discontinued, all study procedures outlined for the End of 
Treatment visit will be completed as specified in the Schedule of Events. The primary 
reason for study drug discontinuation will be recorded on the eCRF.  Some patients may 
discontinue study drug for reasons other than progressive disease before completing the full 
treatment course; these patients will remain in the study for posttreatment assessments as 
outlined in the Schedule of Events.
Enrolled patients who do not receive study drug for any reason will not be replaced; 
however, additional patients may be enrolled to ensure an adequate number of patients with 
histologically confirmed sALCL in the study.
All subsequent anticancer therapies will be recorded, regardless if they are initiated before 
or after progressive disease.
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7.8   
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

Death

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.
The reason(s) for withdrawal must be documented in the patient’s medical records.  The 
investigators will make every reasonable effort to keep each patient on the study until all 
planned treatments and assessments have been performed.  Final treatment assessments will 
be performed before any other therapeutic intervention if possible.  Patients who withdraw 
from study treatment with SD or better will continue to be followed for PFS and will have 
CT scans done every 3 months for 18 months from EOT or until the sooner of disease 
progression, death, or study closure.  Overall survival data will be collected every 3 months 
from EOT for 18 months, then every 6 months thereafter until the sooner of death or study 
closure.  Additionally, any planned alternative treatments should be documented on the 
patient’s medical records and CRF.
7.9   
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.
7.10   
Posttreatment Follow-up Assessments
Posttreatment follow-up for all patients consists of a physical exam, QOL assessments, 
CT scan, and collection of survival/disease status and anticancer treatment for sALCL as 
specified in the Schedule of Events.
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Patients who discontinue study treatment with SD or better will have CT scans done every 
3 months from EOT for 18 months or until the sooner of disease progression, death, or study 
closure.  Overall survival data will be collected every 3 months from EOT for 18 months, 
then every 6 months thereafter until the sooner of death or study closure.  The study will be 
closed when 50% of the patients have had an OS event or 5 years after enrollment of the last 
patient, whichever occurs first.
NOTE:  Related SAEs must be reported to the Takeda Department of Pharmacovigilance or 
designee.  This includes deaths that the investigator considers related to study drug that 
occur during the posttreatment follow-up.  Refer to Section 10 for details regarding 
definitions, documentation, and reporting of SAEs.
8.   
STATISTICAL AND QUANTITATIVE ANALYSES
8.1   
Statistical Methods
Statistical analyses will be primarily descriptive and graphical in nature.  For continuous 
variables, descriptive statistics will be used including n, mean, median, standard deviation, 
minimum, and maximum. For categorical variables, frequencies and percentages will be 
used for the analyses. The Kaplan-Meier survival curves will be provided along with their 
two-sided 95% CIs for time-to-event data.
No formal statistical hypothesis testing will be performed.
The statistical methods are outlined below; analysis details will be provided in the statistical 
analysis plan (SAP). The formal SAP will be developed and finalized before database lock.
8.1.1   
Determination of Sample Size
A minimum of 45 patients with relapsed or refractory sALCL will be enrolled in the study.  
Based on previous study results, with a sample size of 45, observing 31 (69%) objective 
responses (complete or partial remission) would provide a 95% confidence (two-sided) that 
the true ORR is greater than 53%.
8.1.2   
Randomization and Stratification
This is an open-label, single-arm study.  Randomization and stratification are not applicable 
to this study.
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8.1.3   
Populations for Analysis
The populations used for analysis will include the following:
Intent-to-Treat
The Intent-to-Treat (ITT) analysis population includes all patients enrolled in the study.  The 
ITT analysis population will be used for the primary efficacy analysis.  Secondary and 
additional efficacy endpoints will also be analyzed using this analysis set.
Per-Protocol
The Per-Protocol analysis population includes all patients who receive at least 1 dose of 
brentuximab vedotin and who have measurable disease at baseline, the correct histological 
cancer type per central pathology review, and no other major protocol deviations that could 
potentially affect tumor response. The Per-Protocol analysis population will be used for 
analyses of the primary efficacy endpoint.
Safety
The Safety analysis population includes all patients who receive at least 1 dose of 
brentuximab vedotin.  The Safety analysis population will be used for all safety analyses as 
well as for patient demographics and baseline disease characteristics.
Pharmacokinetic
Patients with sufficient dosing and pharmacokinetic concentration-time data to reliably
estimate pharmacokinetic parameters will be included in the Pharmacokinetic analysis
population.
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8.1.4   
Procedures for Handling Missing, Unused, and Spurious Data
All available efficacy and safety data will be included in data listings and tabulations.  The 
relevance of missing sample data will be assessed.  Details on any sensitivity analyses and 
data handling details regarding issues such as missing data will be discussed in the SAP.
Data that are potentially spurious or erroneous will be examined according to standard data 
management operating procedures.
8.1.5   
Demographic and Baseline Characteristics
Demographics, baseline characteristics, and prior medications will be summarized.  Selected 
listings will also be provided.
8.1.6   
Efficacy Analysis
The primary and secondary efficacy endpoints will be summarized. The corresponding two-
sided 95% confidence intervals will be presented for selected efficacy endpoints. The 
standard survival analysis techniques of Kaplan-Meier method will be utilized for time-to-
event including during of response, duration of response in the subset of patients achieving 
CR, PFS per IRF, time to response, time to CR, time to progression, and OS.
The primary efficacy analysis will use the ITT population.  Secondary and additional 
efficacy endpoints will be analyzed using ITT population as well.
To investigate the impact of informative events, sensitivity analyses are planned for selected 
efficacy endpoints such as ORR, duration of response, PFS, and OS by switch of therapy 
and withdrawal/discontinuation of informed consent.
Detailed methodology will be provided in the SAP.
8.1.6.1   
Primary Efficacy Analyses
The primary efficacy endpoint is the overall ORR per IRF in patients with relapsed or 
refractory sALCL following frontline treatments.
The ORR per IRF and its two-sided 95% exact confidence interval will be calculated using 
the F distribution method.(34)  This endpoint may also be tabulated by covariates such as sex, 
age, race, categorized weight (≤ 100 kg and > 100 kg), prior treatment, and ECOG 
performance status, etc.  The maximum percent reduction in the sum of the products of the 
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largest diameters (SPD) of the nodes or nodal masses being followed for response 
assessment will be graphically displayed.
The primary efficacy endpoint will also be analyzed using per-protocol population.
The ORR per investigator and its two-sided 95% exact confidence interval will also be 
calculated.  The difference of objective responses between assessments by IRF and 
investigator will be tabulated.
8.1.6.2   
Secondary Efficacy Analyses
The complete remission rate per IRF will be derived and its two-sided 95% exact confidence 
interval will be calculated using the F distribution method.(34)
Duration of response per IRF, duration of response per IRF in the subset of patients 
achieving complete remission, progression free survival per IRF, and overall survival will be 
estimated using Kaplan Meier methodology and Kaplan-Meier plots will be provided.  The 
median duration of response per IRF, duration of response per IRF in the subset of patients 
achieving CR, PFS per IRF, OS and their two-sided 95% CI by Brookmeyer and Crowley(35)
will be calculated.  These endpoints may also be summarized by covariates such as sex, age, 
race, ALK status, categorized weight, prior treatment, and ECOG performance status, etc.
Descriptive statistics will be used to present percent of patients receiving stem cell 
transplantation (SCT) following treatment with brentuximab vedotin.
These efficacy endpoints per investigator will be similarly analyzed.
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8.1.8   
Pharmacokinetics/Biomarkers
Pharmacokinetic Analysis
Pharmacokinetics of antibody drug-conjugate (brentuximab vedotin), total antibody, and 
unconjugated drug (MMAE) will be derived from serum or plasma concentrations versus 
time data for all subjects who met study inclusion criteria, received study drug, and had 
evaluable and adequate PK data.  The reporting of pharmacokinetic parameters will be 
determined based on the final parameter analysis on the available data.
Immunogenicity
All patients who were administered at least 1 dose of brentuximab vedotin will be evaluated 
for antitherapeutic antibody (ATA) development.  A list/table of ATA status will be 
provided.  Antibody neutralizing status (neutralizing or not neutralizing) will also be listed 
for patients who have positive antibody status.
Immunogenicity information, including ATA and neutralizing ATA, will be summarized in 
descriptive statistics as applicable.
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8.1.9   
Safety Analysis
8.1.9.1   
Safety Analysis
The safety population will be used for all safety analyses.
8.1.9.2  
Adverse Events
Safety will be evaluated by the incidence of AEs, treatment-emergent AEs, severity and type 
of AEs, and by changes from baseline in the patient’s vital signs, weight, ECOG 
performance status, clinical laboratory results, and ECG. Exposure to study drug and 
reasons for discontinuation will be tabulated. Total dose and duration of treatment will be 
summarized and listed. Dose modifications will also be summarized and listed.
Treatment-emergent AEs that occur after administration of the first dose of study drug and 
through 30 days after the last dose of study drug will be tabulated.
AEs will be summarized according to the Medical Dictionary for Regulatory Activities 
(MedDRA) by primary system organ class (SOC), high-level term, preferred term (PT), 
severity, and relationship to study medication. The relationship to study medication will be 
classified as “related” or “unrelated”. All AEs will be listed with the pertinent patient 
information.
AEs will include the following categories

Treatment-emergent AEs

Drug-related treatment-emergent AEs

Grade 3 or higher treatment-emergent AEs

Grade 3 or higher drug-related treatment-emergent AEs

The most commonly reported treatment-emergent AEs (ie, those events reported by 
10% of all patients)

SAEs
AEs leading to dose modification, study medication discontinuation, or patient withdrawal 
will be summarized and listed in the same manner.
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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.
ECOG performance status information will be summarized.
All medications taken by subjects during the course of the study will be recorded. 
Concomitant medications will be summarized by the World Health Organization (WHO) 
Drug Dictionary substance name. A listing of all concomitant medications taken by subjects 
will be provided.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities 
and to further define the safety profile of brentuximab vedotin.
Electrocardiogram Analysis
A listing of ECG results will be provided for each patient by visit.
8.1.10   
Interim Analysis
No formal interim analysis is planned for this study.
9.   
STUDY COMMITTEES
9.1   
Data Safety Monitoring Board
An independent data monitoring committee (IDMC) will not be required for this study.
10.   
ADVERSE EVENTS
10.1   
Definitions
10.1.1   
Pretreatment Event Definition
A pretreatment event 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.
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10.1.2   
Adverse Event Definition
Adverse event (AE) means any untoward medical occurrence in a patient or subject 
administered a pharmaceutical product; the untoward medical occurrence does not 
necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product whether 
or not it is related to the medicinal product.  This includes any newly occurring event, or a 
previous condition that has increased in severity or frequency since the administration of 
study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.
10.1.3   
Serious Adverse Event Definition
Serious AE (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 below 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 1 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 
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treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse; any organism, virus, or infectious particle (eg, prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or nonpathogenic, is 
considered an infectious agent.
In this study, intensity for each AE, including any lab abnormality, will be determined using 
the NCI CTCAE, Version 4.03, effective date 14 June 2010.(33)  Clarification should be 
made between a serious AE (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.
10.2   
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events
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 10.3 for the 
period of observation).  Any clinically relevant deterioration in laboratory assessments or 
other clinical finding is considered an AE.  When possible, signs and symptoms indicating a 
common underlying pathology should be noted as 1 comprehensive event.
Regardless of causality, SAEs and serious pretreatment events (as defined in Section 10.1) 
must be reported (see Section 10.3 for the period of observation) by the investigator to the 
Takeda Department of Pharmacovigilance 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 pretreatment event may be requested by Takeda.  SAE 
report information must be consistent with the data provided on the eCRF.
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SAE and Pregnancy Reporting Contact Information,
please refer to Section 15.3
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).
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 date 14 June 2010.(33)  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?
10.3   
Monitoring of Adverse Events and Period of Observation
AEs, both nonserious and serious (which includes all deaths), 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.

Treatment-related AEs will be reported from first dose of study drug through 30 days 
after administration of the last dose of study drug and monitored for resolution 
through event resolution or study closure, and recorded in the eCRFs.

Serious pretreatment events will be reported to the Takeda Department of 
Pharmacovigilance or designee from the time of the signing of the ICF up to first 
dose of study drug, but will not be recorded in the eCRF.
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
Related and unrelated SAEs will be reported to the Takeda Department of 
Pharmacovigilance or designee from the first dose of study drug through 30 days 
after administration of the last dose of study drug and recorded in the eCRF.  After 
this period, only related SAEs must be reported to the Takeda Department of 
Pharmacovigilance or designee.  SAEs should be monitored until they are resolved 
or are clearly determined to be due to a patient’s stable or chronic condition or 
intercurrent illness(es). Any SAE that occurs between 30 days post last dose of 
study drug and study closure that the investigator considers to be related to study 
drug therapy must be reported to the Takeda Department of Pharmacovigilance & 
Risk Management or designee.
10.4   
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study, she must inform the investigator immediately and permanently discontinue study 
drug.  The sponsor must also be contacted immediately by faxing a completed Pregnancy 
Form to the Takeda Department of Pharmacovigilance or designee (see Section 10.2).  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 Department of Pharmacovigilance or designee
(see Section 10.2).  Every effort should be made to follow the pregnancy for the final 
pregnancy outcome.
11.   
ADMINISTRATIVE REQUIREMENTS
11.1   
Good Clinical Practice
The study will be conducted in accordance with the ICH-GCP and the appropriate regulatory 
requirement(s).  The investigator will be thoroughly familiar with the appropriate use of the 
study drug as described in the protocol and the IB.
11.2   
Data Quality Assurance
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
patient.  Study data will be entered into an eCRF by site personnel using a secure, validated, 
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web-based electronic data capture (EDC) application.  Takeda will have access to all data 
upon entry in the EDC application.
Study monitors will discuss instances of missing or uninterpretable data with the 
investigator for resolution.  Any changes to study data will be made to the eCRF and 
documented via an electronic audit trail associated with the affected eCRF.
11.3   
Electronic Case Report Form Completion 
Takeda or designee will provide the study sites with secure access to and training on the 
EDC application, sufficient to permit site personnel to enter or correct information in the 
eCRFs for the patients for whom they are responsible.
eCRFs will be completed for each study patient.  It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the 
patient’s eCRF.
The investigator, or designated representative, should complete the eCRF as soon as 
possible after information is collected.
The investigator must provide through the EDC application formal approval of all the 
information in the eCRFs and changes to the eCRFs to endorse the final submitted data for 
the patients for which he or she is responsible.  The audit trail entry will show the user’s 
identification information and the date and time of the correction.
Takeda, or a designee, will retain the eCRF data and corresponding audit trails.  A copy of 
the final archival eCRF in the form of a compact disk (CD) or other electronic media will be 
placed in the investigator’s study file.
11.4   
Study Monitoring
Monitoring and auditing procedures developed or approved by Takeda will be followed to 
comply with GCP guidelines.
All information recorded on the eCRFs for this study must be consistent with the patient’s 
source documentation.  During the course of the study, the study monitor will make study 
site visits to review protocol compliance, verify eCRFs against source documentation, assess 
drug accountability, and ensure that the study is being conducted according to pertinent 
regulatory requirements.  The review of medical records will be performed in a manner that 
ensures that patient confidentiality is maintained.
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11.5   
Ethical Considerations
The study will be conducted in accordance with applicable regulatory requirement(s) and 
will adhere to GCP standards.  The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the patients.  The study will 
be conducted only at sites where IRB/IEC approval has been obtained.  The protocol, IB, 
ICF, advertisements (if applicable), written information given to the patients (including 
diary cards), safety updates, annual progress reports, and any revisions to these documents 
will be provided to the IRB/IEC by the investigator or the sponsor, as allowed by local 
regulations.
11.6   
Patient Information and Informed Consent
After the study has been fully explained, written informed consent will be obtained from 
either the patient or his/her guardian or legal representative before study participation.  The 
method of obtaining and documenting the informed consent and the contents of the consent 
must comply with the ICH-GCP and all applicable regulatory requirements.
11.7   
Patient Confidentiality
To maintain patient privacy, all eCRFs, study drug accountability records, study reports, and 
communications will identify the patient by initials where permitted and/or by the assigned 
patient number.  The patient’s confidentiality will be maintained and will not be made 
publicly available to the extent permitted by the applicable laws and regulations.
11.8  
Investigator Compliance
The investigator will conduct the trial in compliance with the protocol provided by Takeda
and given approval/favorable opinion by the IRB/IEC and the appropriate regulatory 
authority(ies).  Modifications to the protocol are not to be made without agreement of both 
the investigator and Takeda.  Changes to the protocol will require written IRB/IEC 
approval/favorable opinion before implementation, except when the modification is needed 
to eliminate an immediate hazard or hazards to patients.  Takeda, or a designee, will submit 
all protocol modifications to the appropriate regulatory authority(ies) in accordance with the 
governing regulations.
When immediate deviation from the protocol is required to eliminate an immediate hazard 
or hazards to patients, the investigator will contact Takeda, or a designee, if circumstances 
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permit, to discuss the planned course of action.  Any departures from the protocol must be 
documented.
11.9   
On-site Audits
Regulatory authorities, the IEC/IRB, and/or Takeda may request access to all source 
documents, eCRFs, and other study documentation for on-site audit or inspection.  Direct 
access to these documents must be guaranteed by the investigator, who must provide support 
at all times for these activities.
11.10   Investigator and Site Responsibility for Drug Accountability
Accountability for the study drug at the trial site is the responsibility of the investigator.  
Drug accountability records indicating the drug’s delivery date to the site, inventory at the 
site, use by each patient, and amount returned to Takeda, or a designee (or disposal of the 
drug, if approved by Takeda) will be maintained by the clinical site. Takeda or its designee 
will review drug accountability at the site on an ongoing basis.
All material containing study drug will be treated and disposed of in accordance with 
governing regulations.
11.11   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 identify a potential product complaint situation should immediately contact MedComm 
Solutions (see below) and report the event.  Whenever possible, the associated product 
should be maintained in accordance with the label instructions pending further guidance 
from a Takeda Quality representative.
For Product Complaints,
call MedComm Solutions at
877-674-3784 (877 MPI DRUG)
(US and International)
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 PPD (refer to Section 10.2).
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11.12   Closure of the Study
Within 90 days of the end of the study, the sponsor will notify the competent authorities and 
the IECs in all member states where the study is being carried out that the study has ended.
Within 1 year of the end of the study, a summary of the clinical trial results will be 
submitted to the competent authorities and IECs in all member states involved in the study.
Study participation by individual sites or the entire study may be prematurely terminated if, 
in the opinion of the investigator or Takeda, there is sufficient reasonable cause.  Written 
notification documenting the reason for study termination will be provided to the 
investigator or Takeda by the terminating party.
Circumstances that may warrant termination include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to patients

Failure to enter patients at an acceptable rate

Insufficient adherence to protocol requirements

Insufficient, incomplete, and/or unevaluable data

Determination of efficacy based on interim analysis

Plans to modify, suspend or discontinue the development of the study drug
Should the study be closed prematurely, the site will no longer be able to access the EDC 
application, will not have a right to use the EDC application, and will cease using the 
password or access materials once their participation in the study has concluded.  In the 
event that any access devices for the EDC application have been provided, these will be 
returned to Takeda once the site’s participation in the study has concluded.
Within 15 days of premature closure, Takeda must notify the competent authorities and 
IECs of any member state where the study is being conducted, providing the reasons for 
study closure.
11.13   Record Retention
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s).  Records will be retained for at least 2 years after the last 
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marketing application approval or 2 years after formal discontinuation of the clinical 
development of the investigational product or according to applicable regulatory 
requirement(s).  If the investigator withdraws from the responsibility of keeping the study 
records, custody must be transferred to a person willing to accept the responsibility and 
Takeda notified.
12.   
USE OF INFORMATION
All information regarding brentuximab vedotin supplied by Takeda to the investigator is 
privileged and confidential information.  The investigator agrees to use this information to 
accomplish the study and will not use it for other purposes without consent from Takeda.  It 
is understood that there is an obligation to provide Takeda with complete data obtained 
during the study.  The information obtained from the clinical study will be used toward the 
development of brentuximab vedotin and may be disclosed to regulatory authority(ies), 
other investigators, corporate partners, or consultants as required.
Upon completion of the clinical study and evaluation of results by Takeda, the hospital or 
institution and/or investigator may publish or disclose the clinical trial results pursuant to the 
terms contained in the applicable Clinical Trial Agreement.
It is anticipated that the results of this study will be presented at scientific meetings and/or 
published in a peer-reviewed scientific or medical journal.  A Publications Group 
comprising Takeda employees and study investigators will be formed to oversee the 
publication of the study results, which will reflect the experience of all participating study 
centers.  Subsequently, individual investigators may publish results from the study in 
compliance with their agreements with Takeda.
A prepublication manuscript or abstract is to be provided to Takeda a minimum of 30 days 
before the intended submission date of the manuscript or abstract to a publisher. Within 
30 days after receipt by Takeda of the notification, Takeda shall inform the study centers
whether it has objections to the publication for reasons including, but not limited to, those 
defined below:

If patentable subject matter is disclosed, the publication shall be delayed for a period 
not to exceed 90 days from Takeda’s receipt of the proposed publication to allow 
time for the filing of patent applications covering patentable subject matter. 
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
If confidential information is contained in any proposed publication or public 
disclosure, such confidential information will be removed at Takeda’s request.
The overall principal investigator will be the last author on abstracts and publications of the 
data generated from this study.  Other authors will be listed according to number of patients 
enrolled to the study.  If the principal investigator has the highest enrollment, he/she may 
choose to be either first or last author. This policy may be changed with the agreement of 
both the investigators and Takeda.
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13.   
INVESTIGATOR AGREEMENT
I have read Protocol C25006 Amendment 2:  A Phase 4, Open-label, Single-Arm Study of 
Brentuximab Vedotin in Patients With Relapsed or Refractory Systemic Anaplastic Large 
Cell Lymphoma.
I agree to conduct the study as detailed herein and in compliance with International 
Conference on Harmonisation Guidelines for Good Clinical Practice and applicable 
regulatory requirements and to inform all who assist me in the conduct of this study of their 
responsibilities and obligations.
Principal investigator printed name
Principal investigator signature
Date
Investigational site or name of institution and 
location (printed)
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14.   
REFERENCES
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Horie R, Watanabe T. CD30: expression and function in health and disease. 
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Younes A, Carbone A. CD30/CD30 ligand and CD40/CD40 ligand in malignant 
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Gardner LJ, Polski JM, Evans HL, Perkins SL, Dunphy CH. CD30 expression in 
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anaplastic large-cell lymphoma in adults: clinical presentation, immunophenotype,
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Jacobsen E. Anaplastic large-cell lymphoma, T-/null-cell type. Oncologist 
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Filippa DA, Ladanyi M, Wollner N, Straus DJ, O'Brien JP, Portlock C, et al. CD30 
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Stein H, Foss HD, Durkop H, Marafioti T, Delsol G, Pulford K, et al. CD30(+) 
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Weisenburger DD, Anderson JR, Diebold J, Gascoyne RD, MacLennan KA, Muller-
Hermelink HK, et al. Systemic anaplastic large-cell lymphoma: results from the non-
Hodgkin's lymphoma classification project. Am J Hematol 2001;67(3):172-8.
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Stein H, Mason DY, Gerdes J, O'Connor N, Wainscoat J, Pallesen G, et al. The 
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malignancies are derived from activated lymphoid cells. Blood 1985;66(4):848-58.
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Delsol G, Falini B, Muller-Hermelink H, Campo E, Jaffe E, Gascoyne R, et al. 
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Harris N, Jaff E, Pileri S, Stein H, et al., editors. WHO classification of Tumours of 
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Research on Cancer (IARC); 2008. p. 312-6.
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Mason D, Harris N, Delsol G, Stain H, Campo E, Kinney M, et al. Anaplastic Large 
Cell Lymphoma, ALK negative In: Swerdlow S, Campo E, Harris N, Jaffe E, Pileri 
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lymphoid tissues. Lyon, France: International Agency for Research on Cancer 
(IARC); 2008. p. 317-9.
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Orscheschek K, Merz H, Hell J, Binder T, Bartels H, Feller AC. Large-cell 
anaplastic lymphoma-specific translocation (t[2;5] [p23;q35]) in Hodgkin's disease: 
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16.
Pileri A, Poggi S, Sabattini E, Falini B, Stein H. Anaplastic large cell lymphoma 
Hodgkin's like. Current Diagnostic Pathology 1995;2(1):57-8.
17.
Merz H, Houssiau FA, Orscheschek K, Renauld JC, Fliedner A, Herin M, et al. 
Interleukin-9 expression in human malignant lymphomas: unique association with 
Hodgkin's disease and large cell anaplastic lymphoma. Blood 1991;78(5):1311-7.
18.
Jucker M, Abts H, Li W, Schindler R, Merz H, Gunther A, et al. Expression of 
interleukin-6 and interleukin-6 receptor in Hodgkin's disease. Blood 
1991;77(11):2413-8.
19.
Savage KJ, Harris NL, Vose JM, Ullrich F, Jaffe ES, Connors JM, et al. ALK-
anaplastic large-cell lymphoma is clinically and immunophenotypically different 
from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: 
report from the International Peripheral T-Cell Lymphoma Project. Blood 
2008;111(12):5496-504.
20.
Wilson WH, Bryant G, Bates S, Fojo A, Wittes RE, Steinberg SM, et al. EPOCH 
chemotherapy: toxicity and efficacy in relapsed and refractory non-Hodgkin's 
lymphoma. Journal of Clinical Oncology 1993;11(8):1573-82.
21.
Cabanillas F, Rodriguez MA. MINE-ESHAP salvage therapy for recurrent and 
refractory lymphomas. Seminars in Hematology 1994;31(2 Suppl 3):30.
22.
Velasquez WS, McLaughlin P, Tucker S, Hagemeister FB, Swan F, Rodriguez MA, 
et al. ESHAP--an effective chemotherapy regimen in refractory and relapsing 
lymphoma: a 4-year follow-up study. Journal of Clinical Oncology 1994;12(6):1169-
76.
23.
King K, Younes A. Ifosfamide- and paclitaxel-based treatment of relapsed and 
refractory lymphoma. Seminars in Oncology 2000;27(1 Suppl 1):14-22.
24.
Hertzberg MS, Crombie C, Benson W, Taper J, Gottlieb D, Bradstock KF. 
Outpatient fractionated ifosfamide, carboplatin and etoposide as salvage therapy in 
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relapsed and refractory non-Hodgkin's and Hodgkin's lymphoma. Annals of 
Oncology 2006;17 Suppl 4:iv25-30.
25.
Gisselbrecht C, Bosly A, Lepage E, Reyes F, Philip T, Haioun C, et al. Autologous 
hematopoietic stem cell transplantation in intermediate and high grade non-
Hodgkin's lymphoma: a review. Annals of Oncology 1993;4 Suppl 1:7-13.
26.
Moskowitz CH, Nimer SD, Glassman JR, Portlock CS, Yahalom J, Straus DJ, et al. 
The International Prognostic Index predicts for outcome following autologous stem 
cell transplantation in patients with relapsed and primary refractory intermediate-
grade lymphoma. Bone Marrow Transplantation 1999;23(6):561-7.
27.
Shipp MA, Abeloff MD, Antman KH, Carroll G, Hagenbeek A, Loeffler M, et al.
International Consensus Conference on High-Dose Therapy with Hematopoietic 
Stem Cell Transplantation in Aggressive Non-Hodgkin's Lymphomas: report of the 
jury. Journal of Clinical Oncology 1999;17(1):423-9.
28.
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice 
Guidelines in Oncology (NCCN Guidelines):  Non-Hodgkin's Lymphomas Version 
3.2012.  2012.
29.
Malik SM, Liu K, Qiang X, Sridhara R, Tang S, McGuinn WD, Jr., et al. Folotyn 
(pralatrexate injection) for the treatment of patients with relapsed or refractory 
peripheral T-cell lymphoma: U.S. Food and Drug Administration drug approval 
summary. Clinical Cancer Research 2010;16(20):4921-7.
30.
O'Connell S. In Vivo Antitumor Activity of TAK-733, MLN8237, and Gemcitabine 
Administered Alone or in Combination to Female Nude Mice Bearing Panc-1 
Human Pancreatic Epithelial Carcinoma Xenografts. San Diego (CA, USA): Takeda 
San Diego, Inc; 2011. Report No.: TAK-733-10027.
31.
Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, et al. Results from a 
pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral 
T-cell lymphoma after prior systemic therapy. J Clin Oncol 2012;30(6):631-6.
32.
Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL, et al. 
Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J 
Med 2010;363(19):1812-21.
33.
U.S. Department of Health and Human Services, National Institutes of Health 
National Cancer Institute. Common Terminology Criteria for Adverse Events 
(CTCAE). Version 4.03. 14 June 2010.
34.
Collett D. Statistical inference for binary data. In: Modelling Binary Data. London, 
England: Chapman and Hall; 1991. p. 23-26.
35.
Brookmeyer R, Crowley J. A confidence interval for the median survival time. 
Biometrics 1982;38:29-41.
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36.
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.
37.
The Criteria Committee of New York Heart Association. Nomenclature and Criteria 
for Diagnosis of Diseases of the Heart and Great Vessels. 9 ed. Boston, MA: Little, 
Brown & Co; 1994.
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15.   
APPENDICES
15.1   
Eastern Cooperative Oncology Group (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. Am J Clin Oncol 1982; 5 (6):649-55.(36)
15.2   
New York Heart Association Classification of Cardiac Disease
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence 
of cardiovascular 
disease.
II
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of 
minimal cardiovascular 
disease.
III
Patients with cardiac disease resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary activity 
causes fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of 
moderately severe 
cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or the 
anginal syndrome may be present even at rest.  If any physical activity 
is undertaken, discomfort is increased.
Objective evidence of 
severe cardiovascular 
disease.
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for Diagnosis 
of Diseases of the Heart and Great Vessels.  9th Ed.  Boston, MA:  Little, Brown & Co; 1994:253-256.(37)
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15.3   
Serious Adverse Event and Pregnancy Reporting Contact Information
Please refer to Section 10 of the study protocol for complete details on AE/SAE 
definitions and reporting (including pregnancy and birth defects).
International (Countries Outside United States and Canada)
(24 hours/7 days a week)
Phone/ Helpline Instructions
To place a call using World Phone (WP)
1. Get a line with dial tone
2. Dial the Worldwide access number (international toll free number listed below)
3. Listen for tone/chime and menu; enter five digit WP access code listed beside 
applicable Worldwide access number below.
American Samoa 
Anguilla 
Antigua 
Argentina  
Aruba
Austria
Australia
Bahamas
Bahrain
Bangladesh
Barbados
Belarus
Belgium
Belize
Bermuda 
Bolivia 
Brazil
British Virgin Islands
Brunei
Bulgaria
Cayman Islands
Chile
PPD
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Te
mber lis
ber lis
ss code
ss cod
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om
Co
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No
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da 
da 
:
via 
ia 
da
razil
razil
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Britis
Brit
Ta
o
Bru
Br
of
y o
B
y
mmercial Use Only and Subject to 

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China
Colombia
Cook Islands
Costa Rica
Croatia
Cyprus
Czech Republic
Denmark
Dominica
Dominican Republic
Ecuador
Egypt
El Salvador
Estonia
Fiji
Finland
France
French Antillies
French Guiana
Gabon
Georgia
Germany
Ghana
Greece
Grenada
Guam
Guatemala
Guyana
Haiti
PPD
Property of Takeda: For Non-Com
C
on
N
or
Antillie
ntill
F
ch Gui
h Gu
da
abon
bon
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Georg
Geor
Ta
Ger
G
f T
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G
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y o
y o
y
of Use
ommercial Use Only and Subject to the Applicable Terms of U

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Honduras
Hong Kong
Hungary
Iceland
India
Indonesia
Iran
Iraq
Ireland
Israel
Italy
Ivory Coast
Jamaica
Japan
Jordan
Kazakhstan
Kenya
Latvia
Lebanon
Liechtenstein
Lithuania
Luxembourg
Macau
Macedonia
Malaysia
Malta
Marshall Islands
Mexico
Micronesia
Monaco
Montserrat
Morocco
Netherlands
Netherlands Antilles
New Zealand
PPD
Property of Takeda: For Non-Com
Co
-C
: F
shall Is
hall 
da
exico
exico
ke
Micro
Mic
Ta
o
Mo
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M
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of Use
y
ommercial Use Only and Subject to the Applicable Terms of

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Nicaragua
Norway
Pakistan
Panama
Paraguay
Peru
Philippines
Poland
Portugal
Puerto Rico
Romania
Russia
Rwanda
Saipan
Sakhalin Islands
San Marino
Saudi Arabia
Senegal
Singapore
Slovak Republic
South Africa
South Korea
Spain
Sri Lanka
St. Kitts/Nevis
St. Lucia
St. Pierre & Miquelon
St. Vincent
Sweden
Switzerland
Taiwan
Thailand
Tonga Islands
PPD
Property of Takeda: For Non-Com
Fo
nka
ka
: F
t. Kitts/
t. Kitts
ke
St. Lu
St. L
Ta
St. 
St
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S
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of Use
f
of
o
y
ommercial Use Only and Subject to the Applicable Terms of

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Trinidad & Tobago
Turkey
Turks & Caicos
Ukraine
United Arab Emirates
United Kingdom
Uruguay
U.S. Virgin Islands
Uzbekistan
Vatican City
Venezuela
Vietnam
Zimbabwe
International 
(Countries Outside United States & Canada)
Reporting via Fax
All SAEs (regardless of their relationship to study drug), must be reported within 
24 hours of knowledge of the event by FAX to the appropriate PPD PVG safety fax 
number:
To fax using World Phone (WP)
1. Get a line with a dial tone
2. Dial the Worldwide access number (international toll free number listed below)
3. Listen for tone/chime and menu; enter five digit WP access code listed beside 
applicable worldwide access number below.
4. Note: Some fax machines may require pushing the “pause” or “add digit” or “star” 
button either 2 or 3 times before entering the 5 digit access code.
American Samoa 
Anguilla 
Antigua 
Argentina 
Aruba
Austria
Australia
Bahamas
Bahrain
Bangladesh
Barbados
Belarus
PPD
PPD
Property of T
Au
Aus
f Takeda: For Non-Commercial Use Only and Subject to the
th
ates &
ates &
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X to th
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and m
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Au
Austria
str
Ta
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s of Use
f
of
o
s
the Applicable Terms o

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Belgium
Brazil
British Virgin Islands
Brunei
Bulgaria
Cayman Islands
Chile
China
Colombia
Cook Islands
Costa Rica
Croatia
Cyprus
Czech Republic
Denmark
Dominica
Dominican Republic
Ecuador
Egypt
El Salvador
Estonia
Fiji
Finland
France
French Antillies
French Guiana
Gabon
Georgia
Germany
PPD
Property of Takeda: F
ador
ador
For Non-Com
om
on
F
Esto
Es
f T
o
F
o
y o
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of Use
f
of
mmercial Use Only and Subject to the Applicable Terms of

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Ghana
Greece
Grenada
Guam
Guatemala
Guyana
Haiti
Honduras
Hong Kong
Hungary
Iceland
India
Indonesia
Iran
Iraq
Ireland
Israel
Italy
Ivory Coast
Jamaica 
Japan
Jordan
Kazakhstan
Kenya
Latvia
Lebanon
Liechtenstein
Lithuania
Luxembourg
Macau
Macedonia
Malaysia
Malta
Marshall Islands
Mexico
Micronesia
PPD
Property of Takeda: For Non-Com
om
Co
-C
Non
N
stein
ein
Fo
nia
nia
:
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Macau
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Mace
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Ma
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of Use
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mmercial Use Only and Subject to the Applicable Terms of

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Monaco
Montserrat
Morocco
Netherlands
Netherlands Antilles
New Zealand
Nicaragua
Norway
Pakistan
Panama
Paraguay
Peru
Philippines
Poland
Portugal
Puerto Rico
Romania
Russia
Rwanda
Saipan
Sakhalin Islands
San Marino
Saudi Arabia
Senegal
Singapore
Slovak Republic
South Africa
South Korea
Spain
Sri Lanka
St. Kitts/Nevis
St. Lucia
St. Pierre & Miquelon
PPD
Property of Takeda: For Non-Com
n-C
No
a
r N
y o
of Use
of
o
mmercial Use Only and Subject to the Applicable Terms of

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St. Vincent
Sweden
Switzerland
Taiwan
Thailand
Tonga Islands
Trinidad & Tobago
Turkey
Turks & Caicos
Ukraine
United Arab Emirates
United Kingdom
Uruguay
U.S. Virgin Islands
Uzbekistan
Vatican City
Venezuela
Vietnam
Zimbabwe
If there are difficulties using the international toll free access, please fax SAEs to the 
back-up RightFax number below.  Note that this number is dialed direct and not toll 
free.
Please refer to Section 10 of the study protocol for complete details on AE/SAE 
definitions and reporting (including pregnancy and birth defects).
PPD
PPD
Property of Takeda: For Non-Commercial Use Only a
nationa
ation
nly
of Use
Note th
Note t
n-C
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r to S
definiti
defin
and Subject to the Applicable Terms of
Commercial U

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15.4   Amendment 1 Detailed Summary of Changes
THE PRIMARY SECTION(S) OF THE PROTOCOL AFFECTED BY THE CHANGES 
IN AMENDMENT 1 ARE INDICATED.  THE CORRESPONDING TEXT HAS BEEN 
REVISED THROUGHOUT THE PROTOCOL.
Purpose:  Specify that a minimum of 45 patients with histologically confirmed systemic
anaplastic large cell lymphoma (sALCL) will be enrolled
The primary change denoting minimum number occurs in Section 4.1, Overview of Study 
Design:
Formerly 
read:
Approximately 45 patients will be treated in this study.
Now 
reads:
A minimum of 45 patients will be treated in this study.
Sections that also contain this change are:

Protocol Summary

Section 4.2, Number of Patients

Section 8.1.1, Determination of Sample Size
The primary change denoting histology occurs in Section 4.2, Number of Patients:
Formerly 
read:
Enrolled patients who do not receive study drug for any reason will not be 
replaced; however, additional patients may be enrolled to ensure an adequate 
number of evaluable patients with sALCL in the study.
Now 
reads:
Enrolled patients who do not receive study drug for any reason will not be 
replaced; however, additional patients may be enrolled to ensure a minimum
of 45 patients with confirmed sALCL histology per central review.
Sections that also contain this change are:

Protocol Summary

Section 7.7, Discontinuation of Treatment With Study Drug, and Patient
Replacement
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Purpose:  Increase the duration of disease status follow-up (minimum not formerly stated 
but now 18 months after End of Treatment [EOT]) and overall survival (OS) follow-up 
(minimum not formerly stated but now until the sooner of 50% of patients having OS 
events or 5 years after enrollment of the last patient); these changes extend the predicted 
study duration approximately 4 years
The primary change occurs in Section 4.1, Overview of Study Design:
Formerly 
read:
Patients who discontinue study treatment with SD or better will have CT 
scans done every 3 months for 2 years and then every 6 months thereafter 
until disease progression, death, or study closure. Overall survival will be 
followed until the sooner of death or study closure.
Now 
reads:
Patients who discontinue study treatment with SD or better will have CT 
scans done every 3 months for 18 months from EOT or until the sooner of
disease progression, death, or study closure.  Overall survival data will be 
collected every 3 months from EOT for 18 months, then every 6 months 
thereafter until the sooner of death or study closure.  The study will be 
closed when 50% of the patients have had an OS event or 5 years after 
enrollment of the last patient, whichever occurs first.
Sections that also contain this change are:

Protocol Summary

Schedule of Events

Section 7.8, Withdrawal of Patients From Study

Section 7.10, Posttreatment Follow-up Assessments
Purpose:  Note that sensitivity analyses of selected efficacy endpoints such as overall 
response rate, duration of response, progression-free survival, and OS are planned to 
investigate any impact of events such as switching therapy, study withdrawal, or 
withdrawal of informed consent
The change occurs in Section 8.1.6, Efficacy Analysis:
Added 
text:
The primary efficacy analysis will use the ITT population.  Secondary and 
additional efficacy endpoints will be analyzed using ITT population as well.
To investigate the impact of informative events, sensitivity analyses are 
planned for selected efficacy endpoints such as ORR, duration of 
response, PFS, and OS by switch of therapy and 
withdrawal/discontinuation of informed consent.
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Purpose:  Specify that positron emission tomography (PET) scan should be done at EOT 
only for those patients who discontinue study treatment without a post-baseline PET 
assessment
The primary change occurs in Section 4.1, Overview of Study Design:
Formerly 
read:
Dedicated CT scans (spiral preferred) of chest, neck, abdomen, and pelvis 
will be performed at baseline and Cycles 2, 4, 7, 10, 13, and 16, and PET 
scans will be done at baseline and Cycles 4 and 7.
Now 
reads:
Dedicated CT scans (spiral preferred) of chest, neck, abdomen, and pelvis 
will be performed at baseline and Cycles 2, 4, 7, 10, 13, and 16, and PET 
scans will be done at baseline, Cycles 4 and 7, and, for patients who
discontinue study treatment without a post-baseline PET assessment, at 
EOT.
Sections that also contain this change are:

Protocol Summary

Schedule of Events
Purpose:  Clarify that patients should be observed for infusion-related reactions for 
60 minutes following every brentuximab vedotin infusion
The change occurs in Section 6.5, Precautions and Restrictions, Infusion-Related 
Reactions:
Formerly 
read:
The patient should be observed for 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.
Now 
reads:
The patient should be observed for 60 minutes following each 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.
Purpose:  Add the warning that brentuximab vedotin administration should immediately 
and permanently be discontinued in the event of anaphylaxis
The primary change occurs in Section 6.5, Precautions and Restrictions:
Added 
text:
Patients who experience a Grade 3 or 4 infusion-related reaction may 
potentially receive additional treatment with brentuximab vedotin at the 
discretion of the investigator after discussion with the sponsor.
If anaphylaxis occurs, the administration of brentuximab vedotin should 
be immediately and permanently discontinued and appropriate medical 
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therapy administered.
Section 1.5, Potential Risks and Benefits, also contains this change.
Purpose:  Remove the assessment of B symptoms during screening and the progression-
free survival follow-up period (PFSFUP)/overall survival follow-up period (OSFUP) and 
specify that B symptoms must be assessed before dosing on Cycle 1, Day 1 and on Day 1 
of each subsequent cycle, remove the assessment of health care utilization during 
screening and PFSFUP/OSFUP, and remove the assessment of quality-of-life (QOL) 
measures during screening
The changes summarized below occur in the Schedule of Events:
Deleted 
text:

Xs were removed from the B symptoms assessment row in the 
screening and PFSFUP/OSFUP columns

The X was removed from the health care utilization row in the 
screening and PFSFUP/OSFUP columns

The X was removed from the quality of life assessments row in the 
screening column.
Added
text:
Footnote “l”: B symptoms will be assessed before dosing on Cycle 1, Day 1 
and on Day 1 of each subsequent cycle.
Purpose:  Remove the stipulation that serum pregnancy testing must be beta human 
chorionic gonadotropin (-hCG) testing
The primary change occurs in Section 7.4.8,Pregnancy Test:
Deleted 
text:
A serum -hCG or urine pregnancy test will be performed for female patients 
of childbearing potential at times specified in the Schedule of Events.
Sections that also contain this change are:

Schedule of Events

LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Purpose:  Specify that serious adverse events that occur between 30 days after the last 
dose of brentuximab vedotin and study closure that the investigator considers related to 
brentuximab vedotin will be reported to the Takeda Department of Pharmacovigilance & 
Risk Management or its designee
The change occurs in Section 10.3, Monitoring of Adverse Events and Period of 
Observation:
Formerly 
read:
Any SAE that occurs at any time after completion of the study and the 
designated follow-up period that the investigator considers to be related to 
study drug therapy must be reported to the Takeda Department of 
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Pharmacovigilance & Risk Management or designee.
Now 
reads:
Any SAE that occurs between 30 days post last dose of study drug and
study closure that the investigator considers to be related to study drug 
therapy must be reported to the Takeda Department of Pharmacovigilance & 
Risk Management or designee.
Purpose:  Specify that a tumor specimen from patients’ most recent post-diagnosis biopsy 
is preferred
The primary change occurs in Section 7.4.10, Tumor Specimen:
Formerly 
read:
If available, tumor tissue collected at the time of original diagnosis or 
subsequent procedures (unstained slides or a paraffin-embedded block) will 
be obtained after the patient has signed the informed consent form (ICF).  
Patients who have an archived tumor specimen or histological slides will not 
need to undergo a biopsy at the time of screening.  If archived tissue cannot 
be obtained, a biopsy should be performed at screening.  This sample will be 
used to confirm sALCL diagnosis and ALK status by central laboratory 
review.
Now 
reads:
Tumor tissue from the most recent post-diagnosis biopsy is preferred.  
Unstained slides or a paraffin-embedded block will be obtained after the 
patient has signed the ICF.  Patients without at least 10 histological slides 
from their most recent post-diagnosis biopsy will undergo a new tumor 
biopsy during screening. This sample will be used to confirm sALCL
diagnosis and ALK status by central laboratory review.
The Schedule of Events footnote “c” also contains this change.
Purpose:  Remove the nonspecific symptom “discomfort” from the list of neuropathy 
symptoms for which patients should be monitored
The change occurs in Section 1.5, Potential Risks and Benefits:
Deleted 
text:
Of the patients who reported neuropathy, 51% had residual neuropathy at the 
time the data cutoff date for clinical study reporting.  Monitoring patients for 
symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, 
discomfort, a burning sensation, neuropathic pain, or weakness is required.
Purpose:  Remove “malignancy” as a symptom for which patients should be specially 
observed during the treatment period and up to 30 days after the last brentuximab vedotin 
dose
The change occurs in Section 1.5, Potential Risks and Benefits:
Deleted 
Any treatment that can decrease immune function may contribute to 
malignancy and infections; patients are to be monitored for these events 
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text:
during the treatment period and up to and including 30 days after the last 
dose.
Purpose:  Clarify in the inclusion criteria that, for male patients, the described methods of 
periodic abstinence apply to the female partner
The primary change occurs in Section 5.1, Inclusion Criteria, criterion 11:
Added 
text:
Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice true abstinence, when this is in line with the 
preferred and usual lifestyle of the subject.  (Periodic 
abstinence [eg, calendar, ovulation, symptothermal, post-
ovulation methods for the female partner] and withdrawal 
are not acceptable methods of contraception.)
Section 6.5, Precautions and Restrictions, Pregnancy also contains this change.
Purpose:  Add a criterion excluding patients who have received any investigational 
products within 4 weeks before the first dose of brentuximab vedotin
The primary change occurs in Section 5.2, Exclusion Criteria, new criterion 8:
Added
text:
8.
Treatment with any investigational products within 4 weeks 
before the first dose of study drug
The latter portion of the Exclusion Criteria was also reorganized to better accommodate 
this change.
Purpose:  Align the recommended brentuximab vedotin dose modification to be enacted 
in the event of Grade 2 neuropathy with that in the European Union Summary of Product 
Characteristics (Specifically, brentuximab vedotin dosing should be restarted at a reduced 
dose level upon recovery to Grade 1 or baseline; restarting at the previous dose level 
upon recovery for the first occurrence of Grade 2 neuropathy is no longer permitted.)
The change occurs in Section 6.2.1, Recommended Brentuximab Vedotin Dose 
Modifications for Treatment-associated Toxicity, in Table 6-1 Recommended 
Brentuximab Vedotin Dose Modifications for Treatment-Associated Toxicity
Formerly 
read:
For Grade 2 neuropathy, withhold dose until toxicity is ≤Grade 1 or has 
returned to baseline, then resume treatment at the same dose level.  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.
Now 
reads:
For Grade 2 neuropathy, withhold dose until toxicity is ≤Grade 1 or has 
returned to baseline, restart treatment at a reduced dose of 1.2 mg/kg every 
3 weeks.
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Purpose:  Specify that enrollment may occur either through an interactive voice response 
system or an interactive Web response system (IXRS)
The primary change occurs in Section 7.1, Study Personnel and Organizations:
Formerly 
read:
The contact information for the Takeda project clinician for this study, the 
central laboratory and any additional clinical laboratories, the coordinating 
investigator for each member state/country, the independent radiologic review 
facility, interactive voice response system (IVRS) provider, and the contract 
research organization (CRO) team may be found in the Study Manual.
Now 
reads:
The contact information for the Takeda project clinician for this study, the 
central laboratory and any additional clinical laboratories, the coordinating 
investigator for each member state/country, the independent radiologic review 
facility, interactive voice and/or Web response system (IXRS) provider, and 
the contract research organization (CRO) team may be found in the Study 
Manual.
Sections that also contain this change are:

LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS

Section 7.4.14, Enrollment
Purpose:  Clarify the instructions for dispensation of reconstituted brentuximab vedotin
The change occurs in Section 6.9, Preparation, Reconstitution, and Dispensation:
Formerly 
read:
The appropriate amount of reconstituted study treatment will be withdrawn 
from the vial(s) and diluted in a 150 to 250 mL infusion bag containing 0.9% 
Sodium Chloride Injection, USP.
Now 
reads:
The required volume of 5 mg/mL reconstituted brentuximab vedotin 
solution needed must be calculated and withdrawn from the vial(s). The 
reconstituted solution should be added immediately to an infusion bag 
containing a minimum volume of 100 mL.  The dose for patients weighing 
greater than 100 kg should be calculated based on a weight of 100 kg.
Purpose:  Specify seated rather than supine measurements of vital signs
The change occurs in Section 7.4.7, Vital Signs:
Formerly 
read:
Vital sign measurements include supine (after 3-5 minutes in this position) 
measurements of diastolic and systolic blood pressure, heart rate, and oral 
temperature.
Now 
reads:
Vital sign measurements include seated (after 3-5 minutes in this position) 
measurements of diastolic and systolic blood pressure, heart rate, and oral 
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temperature.
Purpose:  Add gamma glutamyl transferase (GGT) and alkaline phosphatase (ALP) to the 
serum chemistry panel
The change occurs in Section 7.4.15, Clinical Laboratory Evaluations, in the table of 
serum chemistry evaluations:
Added 
text:

Gamma glutamyl transferase (GGT)

Alkaline phosphatase (ALP)
Purpose:  Move “unsatisfactory therapeutic response” from a mandatory to a voluntary 
reason for discontinuation of treatment with study drug and add the voluntary reason of 
“symptomatic deterioration”
The changes occur in Section 7.7, Discontinuation of Treatment With Study Drug, and 
Patient Replacement:
Formerly 
read:
Study drug must be permanently discontinued for patients meeting any of the 
following criteria:

Completed maximum number of cycles per protocol

Progressive disease

Initiation of hematopoietic stem cell transplant

Withdrawal by subject

Unsatisfactory therapeutic response
The reason justifying the study treatment withdrawal should be documented 
in the eCRF.
Patients who discontinue from study treatment will remain on study for 
follow-up unless they withdraw consent for the follow-up phase of the study.
Treatment with study drug may also be discontinued for any of the following 
reasons:

Adverse event

Protocol violation

Study terminated by sponsor

Lost to follow-up

Other
Now 
reads:
Study drug must be permanently discontinued for patients meeting any of the 
following criteria:

Completed maximum number of cycles per protocol

Progressive disease

Initiation of hematopoietic stem cell transplant
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
Withdrawal by subject
The reason justifying the study treatment withdrawal should be documented 
in the eCRF.
Patients who discontinue from study treatment will remain on study for 
follow-up unless they withdraw consent for the follow-up phase of the study.
Treatment with study drug may also be discontinued for any of the following 
reasons:

Adverse event

Symptomatic deterioration

Unsatisfactory therapeutic response

Protocol violation

Study terminated by sponsor

Lost to follow-up

Other
Purpose:  Specify that all subsequent anticancer therapies will be recorded, regardless if 
they are initiated before or after the onset of progressive disease
The change occurs in Section 7.7, Discontinuation of Treatment With Study Drug, and 
Patient Replacement:
Added 
Text:
All subsequent anticancer therapies will be recorded, regardless if they are 
initiated before or after progressive disease.
Purpose:  Delete “completed study” from the list of reasons a patient may be withdrawn 
from the study and remove the requirement that Takeda or their designee must be notified 
in writing if a patient is withdrawn from study treatment or the study itself
The change occurs in Section 7.8, Withdrawal of Patients From Study:
Deleted 
text:
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

Completed study 

Death

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.
Takeda or their designee must be notified in writing if a patient is withdrawn 
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from study treatment or from the study.  The reason(s) for withdrawal must be 
documented in the patient’s medical records.
Purpose:  Specify that serious adverse events in countries other than the United States 
and Canada must be reported within 24 hours (formerly “1 working day” in the SAE 
reporting appendix)
The change occurs in Appendix 15.3, Serious Adverse Event and Pregnancy Reporting 
Contact Information:
Formerly 
read:
All SAEs (regardless of their relationship to study drug), must be reported
within 1 working day of knowledge of the event by FAX to the appropriate 
PPD PVG safety fax number:
Now 
reads:
All SAEs (regardless of their relationship to study drug), must be reported
within 24 hours of knowledge of the event by FAX to the appropriate PPD 
PVG safety fax number:
Purpose:  Remove the term “pharmacodynamic” throughout the protocol
The primary change occurs in Section 8.1.8, Pharmacokinetics/Biomarkers:
Formerly 
read:
Now 
reads:
Sections that also contain this change are:
!
Schedule of Events
!
Section 4.2, Number of Patients
!
Section 8.1.1, Determination of Sample Size
!
Section 8.1.3, Populations for Analysis
CCI
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Purpose:  Correct typographical errors, punctuation, grammar, and formatting
These changes are not listed individually.
15.5
Amendment 2 Detailed Summary of Changes
THE PRIMARY SECTION OF THE PROTOCOL AFFECTED BY THE CHANGES IN 
AMENDMENT 2 ARE INDICATED.  THE CORRESPONDING TEXT HAS BEEN 
REVISED THROUGHOUT THE PROTOCOL.
Purpose:  Update the sponsor’s name and legal entity responsible for the study. 
The primary change occurs on the Title Page:
Formerly 
read:
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street
Cambridge, MA  USA  02139
Now 
reads:
Takeda Development Center (TDC) Americas, Inc.
95 Hayden Avenue, Lexington, Massachusetts 02421 USA
TDC Americas, Inc. may be referred to in this protocol as “sponsor” or 
“Takeda”.
CCI
Property of Takeda: For Non-Commercial Use Only and Subj
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