Clinical trial NCT01990534
Conditions: Hodgkin Lymphoma
Keywords: Lymphoma Hodgkin Relapsed Refractory Antigens, CD30 Antibody-Drug Conjugate Antibodies, Monoclonal Monomethyl auristatin E Drug Therapy Immunotherapy Hematologic Diseases Additional Relevant MeSH terms: Lymphoma, Large B-Cell, Diffuse Lymphoma, Hodgkin Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Lymphoma, B-Cell Lymphoma, T-Cell Immunologic Factors Physiological Effects of Drugs Pharmacologic Actions
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2014-03-14; Completion date: 2020-03-12
Enrollment: 60 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase 4, single-arm, open-label, multicenter study is designed to evaluate the efficacy and safety of brentuximab vedotin as a single agent in adult participants with histologically confirmed CD30+ relapsed or refractory classical Hodgkin Lymphoma who have not received a prior stem cell transplantation (SCT) and are considered to be not suitable for SCT or multiagent chemotherapy at the time of study entry.

Detailed description:
The drug being tested in this study is called brentuximab vedotin. Brentuximab vedotin is being tested to treat people who have relapsed or refractory Hodgkin Lymphoma. This study will look at the overall response of people who took brentuximab vedotin.

The study will enroll 60 patients. Participants received:

• Brentuximab vedotin 1.8 mg/kg

This multicenter trial is being conducted worldwide. The overall time to participate in this study is approximately 6 to 7 years. Participants will make multiple visits to the clinic, and will be contacted by telephone every 3 months for 18 months after the end of treatment (EOT) for follow-up assessment of overall survival and then every 6 months until death, study closure, or 5 years after enrollment of the last participant.

Arms: arm 1: Brentuximab vedotin 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 in every 3-week cycle, until there is evidence of disease progression or unacceptable toxicity occurs (Up to 16 cycles). The dose could be decreased or delayed or discontinued in participants who develop treatment-associated non-hematologic, hematologic toxicity or peripheral neuropathy to brentuximab vedotin.
Interventions: intervention 1: Brentuximab Vedotin
Intervention descriptions: intervention 1: Brentuximab vedotin IV infusion

Protocol documents:
Prot_000.pdf: 



Title: A Single-arm Study of Brentuximab Vedotin in Patients With Relapsed or Refractory 
Hodgkin Lymphoma Who Are Not Suitable for Stem Cell Transplantation or Multiagent 
Chemotherapy
NCT Number: NCT01990534
Protocol Approve Date: 11 July 2013
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
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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 C25007, EudraCT:  2013-00232-10
1
CLINICAL STUDY PROTOCOL C25007
Brentuximab vedotin
A Single-arm Study of Brentuximab Vedotin in Patients With Relapsed or Refractory 
Hodgkin Lymphoma Who Are Not Suitable for Stem Cell Transplantation or Multiagent 
Chemotherapy
Protocol Number:
C25007
Indication:
Hodgkin lymphoma
Phase:
4
Sponsor:
Millennium Pharmaceuticals, Inc.
EudraCT Number:
2013-00232-10
Therapeutic Area:
Oncology
Protocol History
Original
11 July 2013
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street
Cambridge, MA  USA  02139
Telephone:  +1 (617) 679-7000
Approved by:
Note:  If this document was approved electronically, the electronic approval signatures may 
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Signature
Date DD Month  YYYY
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Clinical Study Protocol C25007, EudraCT:  2013-00232-10
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PROTOCOL SUMMARY
Study Title:  A Single-arm Study of Brentuximab Vedotin in Patients With Relapsed or Refractory 
Hodgkin Lymphoma Who Are Not Suitable for Stem Cell Transplantation or Multiagent 
Chemotherapy  
Name of Principal Investigator:  
 
Number of Patients:  At least 60 patients with relapsed or refractory classical Hodgkin lymphoma 
(HL) who are considered to be not suitable for stem cell transplantation (SCT) or multiagent 
chemotherapy will be enrolled in this study at approximately 20 investigative sites in Europe and 
potentially other regions of the world.  
Study Objectives
Primary
To assess the antitumor efficacy, as determined by the objective response rate (ORR) of 
single-agent brentuximab vedotin 1.8 mg/kg administered intravenously (IV) every 3 weeks, 
in patients with relapsed or refractory classical HL who are considered to be not suitable for 
SCT or multiagent chemotherapy
Secondary
To determine the duration of tumor control, including the duration of response (DOR), 
progression-free survival (PFS), and complete remission (CR) rate by independent review 
facility (IRF) assessment after treatment with brentuximab vedotin
To determine the proportion of patients who receive hematopoietic SCT, either autologous 
stem cell transplantation (ASCT) or allogeneic stem cell transplantation (alloSCT) after 
treatment with brentuximab vedotin
To determine overall survival (OS) after treatment with brentuximab vedotin
To assess the safety and tolerability of brentuximab vedotin in this patient population
To assess the pharmacokinetics (PK) of brentuximab vedotin
To determine the immunogenicity of brentuximab vedotin
Tertiary/Exploratory
Overview of Study Design:  This phase 4, single-arm, multicenter study will evaluate the efficacy 
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Brentuximab Vedotin (ADCETRIS®)
Clinical Study Protocol C25007, EudraCT:  2013-00232-10
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and safety of brentuximab vedotin in adult patients 18 years or older with histologically confirmed 
CD30-positive (CD30+) relapsed or refractory classical HL who have not received a prior ASCT and 
are considered to be not suitable for SCT or multiagent chemotherapy at the time of study entry. 
Patients who are considered to be not suitable for SCT or multiagent chemotherapy include those 
who experience disease progression within 90 days of the earliest date of complete remission (CR) or 
complete remission unconfirmed (CRu) after the end of treatment with multiagent chemotherapeutic 
regimens and/or radiotherapy, or experience disease progression during frontline multiagent 
chemotherapy or alternatively, experience disease relapse after treatment with at least 
2 chemotherapeutic regimens, including any salvage treatments.  
Brentuximab vedotin will be administered as a single, outpatient, 1.8-mg/kg IV infusion on Day 1 of 
each 3-week cycle.  Patients with a CR, a partial remission (PR), or stable disease should receive a 
minimum of 8 cycles, and all patients will be given the opportunity to complete a maximum of 
16 cycles (see Section 15.1).  Dedicated computed tomography (CT) scans (spiral preferred) of chest, 
neck, abdomen, and pelvis will be performed at baseline and at Cycles 2, 4, 7, 10, 13, and 16; and 
fluorodeoxyglucose (FDG) positron-emission tomography (PET) scans will be done at baseline 
(screening) and at Cycles 4 and 7.  No additional PET scans are required during the treatment period 
after Cycle 7 unless they are clinically indicated.  A PET scan should be done at the end of treatment
only for those patients who discontinue study treatment without a postbaseline PET assessment.
Measures of anticancer activity will be assessed by an IRF according to the International Working 
Group (IWG) Revised Response Criteria for Malignant Lymphoma.(1)  Patients who experience 
disease progression at any time will discontinue receiving the study drug.  These patients will 
continue to be followed for overall survival (OS).  Patients with an objective response, either a CR or 
a PR, and who are eligible for an SCT may discontinue receiving brentuximab vedotin and proceed 
to an SCT.  These patients should receive at least 4 cycles of brentuximab vedotin before proceeding 
to SCT.  
Safety assessments will include the incidence and severity of AEs and changes in clinical laboratory 
values, vital signs measurements, and physical examination findings.  Toxicity will be evaluated 
according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE) version 4.03, effective 14 June 2010.
Patients may continue to receive the study treatment for a maximum of 16 cycles or until disease 
progression or unacceptable toxicity.  Patients will have an end-of-treatment (EOT) visit 30 days 
(± 7 days) after receiving their last dose of study drug.  Patients who discontinue the study treatment 
with a CR, a PR, or stable disease will have CT scans performed for assessment of PFS every 
3 months for 18 months after EOT or until the sooner of disease progression, death, or study closure.  
For patients who complete the 18-month PFS follow-up assessment period with a CR, a PR, or stable 
disease, a CT scan will be performed during the OS follow-up period at the time of disease
progression, and the results will be sent to the IRF.  Posttreatment follow-up assessments for OS will 
be performed every 3 months for 18 months after the EOT; thereafter, assessment for OS will 
continue every 6 months until the sooner of death, study closure, or 5 years after enrollment of the 
last patient.
Study Population:  Male or female patients aged 18 years or older, with a histologically confirmed 
diagnosis of relapsed or refractory classical HL, a history of at least 1 prior systemic 
chemotherapeutic regimen, and considered to be not suitable for SCT or multiagent chemotherapy, 
according to 1 of the following criteria: disease progression within 90 days of the earliest date of CR
or CRu after the end of treatment with multiagent chemotherapeutic regimens and/or radiotherapy,
progressive disease during frontline multiagent chemotherapy, or disease relapse after treatment with 
at least 2 chemotherapeutic regimens, including any salvage treatments.  Patients must have 
bidimensional measurable disease, of at least 1.5 cm, as documented by radiographic technique 
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Clinical Study Protocol C25007, EudraCT:  2013-00232-10
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(spiral CT scan preferred), per IWG Revised Response Criteria for Malignant Lymphoma.(1)
Duration of Study:  Study enrollment is expected to take approximately 15 months.  Patients will 
complete a Screening period of up to 28 days and may receive a maximum of 16 cycles of 
brentuximab vedotin.  Patients will be followed for 30 days (7 days) after administration of the last 
dose of brentuximab vedotin to permit the detection of any delayed treatment-related AEs.  
For patients who discontinue the study treatment with a CR, a PR, or stable disease, posttreatment 
follow-up assessments for PFS will be performed every 3 months for 18 months after the EOT or 
until the sooner of disease progression, death, or study closure.  For patients who complete the 
18-month PFS follow-up assessment period with a CR, a PR, or stable disease, a CT scan will be 
performed during the OS follow-up period at the time of disease progression, and the results will be 
sent to the IRF.  Posttreatment follow-up assessments for OS will be performed every 3 months for 
18 months after the EOT; thereafter, assessment for OS will continue every 6 months until the sooner 
of death, study closure, or 5 years after enrollment of the last patient.  The total study duration is 
anticipated to be approximately 6 to 7 years.
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Clinical Study Protocol C25007, EudraCT:  2013-00232-10
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STUDY OVERVIEW DIAGRAM
S
C
R
E
E
N
I
N
G
E
N
R
O
L
L
M
E
N
T
Brentuximab vedotin
1.8 mg/kg IV infusion
every 3 weeks
E
N
D
O
F
T
R
E
A
T
M
E
N
T
V
I
S
I
T
P
O
S
T
T
R
E
A
T
M
E
N
T
F
O
L
L
O
W
-
U
P
Within 28 days of 
enrollment
Patients with a  CR, a PR, or 
stable disease should receive 
a minimum of 8 cycles and a 
maximum of 16 cycles. 
Additional treatment 
information is provided in 
Section 6.1.
Patients should receive a 
minimum of 4 cycles of  
study treatment before 
proceeding to stem cell 
transplantation.  
30 days 7 
daysafter 
last dose 
of study 
drug
Every 3 months for  a 
maximum of 18 months after 
EOT , then every 6 months 
until the sooner of death,  
study closure, or  5 years after 
enrollment of the last patient .
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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 
After Last 
Dose
Visit Window
D -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 assessment
X
X
X
Xe
ECOG performance status
X
X
X
Hematology and serum chemistry
X
Xf
X
12-lead ECG
X
Monitoring of concomitant 
medications and procedures
Recorded from signing the ICF through 30 days after the last dose of study drug
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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 
After Last 
Dose
Visit Window
D -28 to D1
+ 1D
± 5D
± 2 weeks
Adverse event reporting
Recorded from first dose of study drug through 30 days after the last 
dose of study drug.  All events related to PN, regardless of seriousness, 
will be followed for all changes in severity until resolution to baseline or 
study closure, whichever occurs first, and recorded in the eCRF.  
Serious adverse events
SAEsg will be collected from signing informed consent through 30 days after the last dose of 
study drug
Disease Assessments
Dedicated CT (spiral preferred) of 
chest, neck, abdomen, pelvish
X
X
Xi
Xb
FDG PET scan
Xj
Xj
Xj
Bone marrow biopsy
Xl
Xm
Survival/disease status and 
anticancer treatments for r/r HL
Xn
Treatment
Brentuximab vedotin administration 
X
PK/
Serum 
biomar
kers
PK sample
X
Xp
Xp
X
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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 
After Last 
Dose
Visit Window
D -28 to D1
+ 1D
± 5D
± 2 weeks
Immunogenicity 
X
X
Abbreviations:  AE = adverse event; BM = bone marrow; CR = complete remission; CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; eCRF = electronic case report form; EOT = end of treatment; FDG = fluorodeoxyglucose; HL = Hodgkin lymphoma; 
ICF = informed consent form; IEC = Independent Ethics Committee; 
 IRB = Independent Review Board; IRF = independent review 
facility; OS = overall survival; OSFUP = Overall survival follow-up; PET = positron emission tomography; PFSFUP = Progression-free survival follow-up; 
PK = pharmacokinetic(s); PN = peripheral neuropathy; r/r = relapsed or refractory; 
 
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. If EOT evaluations are completed before 30 days±7 days after the last 
treatment, the site will conduct a phone screen 30 to 37 days after the patient’s last treatment to ensure that no changes in the AE profile have occurred.
b Patients who discontinue study treatment with a CR, a PR, or stable disease will have CT scans done every 3 months for 18 months after EOT or until the 
sooner of disease progression, death, or study closure.  For patients who complete the PFSUP period with a CR, a PR, or stable disease, a CT scan will be 
performed during OSFUP at the time of progressive disease, and the results will be sent to the IRF.  Assessment for OS will be performed every 3 months 
for 18 months after the EOT; thereafter, assessment for OS will continue every 6 months until the sooner of death, study closure, or 5 years after enrollment 
of the last patient.  
c Tumor tissue from the most recent biopsy is preferred.  Unstained slides or a paraffin-embedded block will be obtained after the patient has signed the ICF.  
Patients who cannot provide at least 10 histological slides from their most recent biopsy will undergo a new tumor biopsy during screening.  This sample 
will be used to confirm HL and CD30+ status by central laboratory review.  
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 Once disease progression is documented, the physical examination is not required.
f
Cycle 1, Day 1 samples may be collected within 4 days before dose administration 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 dose administration on Day 1 of each 3-week cycle at Cycles 2 through 16.
g Includes SAEs reported before treatment with the study drug. SAEs pretreatment will be reported to Millennium Pharmacovigilance or designee from the 
time of signing the ICF to time of administration of the first dose of study drug, but will not be recorded on the eCRF. After the 30-day posttreatment 
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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 
After Last 
Dose
Visit Window
D -28 to D1
+ 1D
± 5D
± 2 weeks
period, SAEs that are considered to be related to the study drug must continue to be reported to the Millennium Department of Pharmacovigilance or 
designee for the duration of the study.  See Section 10.3 of the study protocol for further SAE reporting details.
h Response to treatment and disease status assessments will be evaluated according to the Revised Response Criteria for Malignant Lymphomas(1) and 
confirmed by an IRF.
i
Assessment should be repeated if the procedure was not done within the previous 6 weeks.
j
PET scan done at baseline (screening) and at Cycles 4 and 7. No additional PET scans are required during the treatment period after Cycle 7, unless 
clinically indicated. A PET scan should be done at EOT only for those patients who discontinue study treatment without a postbaseline PET assessment.  
k
l
May be obtained within 60 days of administration of the 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 procedure does not need to be repeated.  A BM biopsy is required only for patients 
with previous known BM involvement or suspected infiltration suspicious of bone marrow involvement.  When required, the BM biopsy will be obtained 
after the last dose of prior treatment and before the first dose of brentuximab vedotin.
m BM biopsy required to confirm a CR if the patient is BM positive at baseline. BM biopsy should be obtained within 2 weeks after documentation of a CR.  
BM biopsy does not need to be repeated once bone marrow is found to be negative.
n Patients will be followed for PFS every 3 months for a maximum of 18 months after the EOT.  Assessment for OS will be done every 3 months for a 
maximum of 18 months after the EOT visit; thereafter, assessment for OS will continue every 6 months until the sooner of death or study closure or a 
maximum of 5 years after enrollment of the last patient.  See Section 7.10 for posttreatment follow-up assessments.  Information may be collected by
telephone for patients with progressive disease during PFSFUP/OSFUP.
o
 
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Pharmacokinetic, Serum Biomarkers, and Immunogenicity Sampling Time Points
Cycle
Study 
Day
Time
Window
Relative Time
PK
Immunogenicity
Cycle 1
Day 1
Predose
within 2 h
START of infusion
X
X
10 min
± 5 min
END of infusion
X
Day 2
24 h
+ 1 day
START of infusion
X
Day 15
336 h
± 5 days
START of infusion
X
Cycle 2
Day 1
Predose
within 2 h
START of infusion
X
X
10 min
± 5 min
END of infusion
X
Cycle 3
Day 1
Predose
within 2 h
START of infusion
X
X
10 min
± 5 min
END of infusion
X
Day 2
24 h
+ 1 day
START of infusion
X
Day 15
336 h
± 5 days
START of infusion
X
Cycle 4 through 
16
Day 1
Predose
within 2 h
START of infusion
X
X
10 min
± 5 min
END of infusion
X
EOT
X
X
Abbreviations: EOT = end of treatment; h = hours; 
; min = minutes; PK = pharmacokinetics; 
; 
 
.
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TABLE OF CONTENTS
LIST OF TABLES..................................................................................................................13
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ............................................14
1. BACKGROUND AND STUDY RATIONALE ................................................................18
1.1 Scientific Background ..................................................................................................18
1.1.1 Relapsed or Refractory Hodgkin Lymphoma........................................................18
1.1.2 Brentuximab Vedotin.............................................................................................19
1.2 Preclinical Experience ..................................................................................................20
1.3 Clinical Experience.......................................................................................................20
1.3.1 Patients With Relapsed or Refractory HL and No Prior Autologous Stem 
Cell Transplantation........................................................................................22
1.4 Study Rationale.............................................................................................................23
1.5 Potential Risks and Benefits.........................................................................................23
2. STUDY OBJECTIVES ......................................................................................................26
2.1 Primary Objective.........................................................................................................26
2.2 Secondary Objectives ...................................................................................................26
2.3 Tertiary/Exploratory Objectives...................................................................................27
3. STUDY ENDPOINTS........................................................................................................27
3.1 Primary Endpoint..........................................................................................................27
3.2 Secondary Endpoints ....................................................................................................27
3.3 Tertiary/Exploratory Endpoints....................................................................................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.....................................................................................................31
5.1 Inclusion Criteria ..........................................................................................................31
5.2 Exclusion Criteria.........................................................................................................34
6. STUDY DRUG...................................................................................................................36
6.1 Study Drug Administration ..........................................................................................36
6.2 Dose-Modification Guidelines .....................................................................................36
6.2.1 Recommended Brentuximab Vedotin Dose Modifications for 
Treatment-associated Toxicity........................................................................36
6.2.2 Criteria for Dose Interruption During a Cycle.......................................................37
6.2.3 Criteria for Beginning or Delaying a Subsequent Treatment Cycle......................38
6.2.4 Criteria for Dose Reduction...................................................................................38
6.2.5 Criteria for Discontinuation of Brentuximab Vedotin...........................................38
6.3 Excluded Concomitant Medications and Procedures ...................................................39
6.4 Permitted Concomitant Medications and Procedures...................................................39
6.5 Precautions and Restrictions.........................................................................................39
6.6 Management of Clinical Events ...................................................................................41
6.7 Blinding and Unblinding ..............................................................................................42
6.8 Description of Investigational Agents ..........................................................................43
6.9 Preparation, Reconstitution, and Dispensation of Brentuximab Vedotin.....................43
6.10 Packaging and Labeling..............................................................................................44
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6.11 Storage, Handling, and Accountability.......................................................................44
7. STUDY CONDUCT...........................................................................................................44
7.1 Study Personnel and Organizations..............................................................................44
7.2 Arrangements for Recruitment of Patients ...................................................................44
7.3 Treatment Group Assignments.....................................................................................45
7.4 Study Procedures ..........................................................................................................45
7.4.1 Informed Consent ..................................................................................................45
7.4.2 Patient Demographics............................................................................................45
7.4.3 Medical History .....................................................................................................45
7.4.4 Physical Examination ............................................................................................45
7.4.5 Patient Height ........................................................................................................45
7.4.6 Patient Weight........................................................................................................46
7.4.7 Vital Signs..............................................................................................................46
7.4.8 Pregnancy Test.......................................................................................................46
7.4.9 Eastern Cooperative Oncology Group Performance Status...................................46
7.4.10 Tumor Specimen Measurements .........................................................................46
7.4.11 Electrocardiograms..............................................................................................46
7.4.12 Concomitant Medications and Procedures ..........................................................47
7.4.13 Adverse Events ....................................................................................................47
7.4.14 Enrollment ...........................................................................................................47
7.4.15 Clinical Laboratory Evaluations..........................................................................47
7.4.16 Disease Assessment.............................................................................................48
7.4.17 Pharmacokinetic Measurements ..........................................................................49
7.4.18 Serum Biomarkers ...............................................................................................49
7.4.19 Immunogenicity...................................................................................................49
7.4.20 Health Care Utilization Data Collection..............................................................49
7.4.21 Cost Assessment ..................................................................................................50
7.5 Completion of Treatment..............................................................................................50
7.6 Completion of Study.....................................................................................................50
7.7 Discontinuation of Treatment With Study Drug, and Patient Replacement.................50
7.8 Withdrawal of Patients From Study .............................................................................51
7.9 Study Compliance.........................................................................................................52
7.10 Posttreatment Follow-up Assessments (Progression-Free Survival and Overall 
Survival) ...............................................................................................................52
8. STATISTICAL AND QUANTITATIVE ANALYSES.....................................................53
8.1 Statistical Methods .......................................................................................................53
8.1.1 Determination of Sample Size...............................................................................53
8.1.2 Randomization and Stratification ..........................................................................54
8.1.3 Populations for Analysis........................................................................................54
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data ............................55
8.1.5 Demographic and Baseline Characteristics ...........................................................55
8.1.6 Efficacy Analysis...................................................................................................55
8.1.7 Health Care Utilization Data..................................................................................56
8.1.8 Pharmacokinetics/Biomarkers ...............................................................................57
8.1.9 Safety Analysis ......................................................................................................57
8.1.10 Interim Analysis...................................................................................................58
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9. STUDY COMMITTEES....................................................................................................59
9.1 Data Safety Monitoring Board .....................................................................................59
10. ADVERSE EVENTS........................................................................................................59
10.1 Definitions ..................................................................................................................59
10.1.1 Pretreatment Event Definition .............................................................................59
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 .....................................................................................................61
10.3 Monitoring of Adverse Events and Period of Observation ........................................62
10.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ........62
11. ADMINISTRATIVE REQUIREMENTS ........................................................................63
11.1 Good Clinical Practice................................................................................................63
11.2 Data Quality Assurance..............................................................................................63
11.3 Electronic Case Report Form Completion..................................................................63
11.4 Study Monitoring........................................................................................................64
11.5 Ethical Considerations................................................................................................64
11.6 Patient Information and Informed Consent ................................................................64
11.7 Patient Confidentiality................................................................................................64
11.8 Investigator Compliance.............................................................................................65
11.9 On-site Audits.............................................................................................................65
11.10 Investigator and Site Responsibility for Drug Accountability .................................65
11.11 Product Complaints and Medication Errors .............................................................65
11.12 Closure of the Study .................................................................................................66
11.13 Record Retention ......................................................................................................67
12. USE OF INFORMATION................................................................................................67
13. INVESTIGATOR AGREEMENT ...................................................................................69
14. REFERENCES .................................................................................................................70
15. APPENDICES ..................................................................................................................73
15.1 Response Definitions for Clinical Studies..................................................................73
15.2 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status..........74
15.3 New York Heart Association Classification of Cardiac Disease ...............................74
15.4 Serious Adverse Event and Pregnancy Reporting Contact Information ....................74
LIST OF TABLES
Table 6-1   
Dose Modification Guidelines for Brentuximab Vedotin for 
Treatment-Associated Toxicity ......................................................................37
Table 8-1   
Overall Objective Response Rates and 95% Confidence Intervals (N = 60) .54
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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
5-HT3
5-hydroxytryptamine 3 serotonin receptor
ABVD
doxorubicin, bleomycin, vinblastine, dacarbazine
ADC
antibody drug conjugate
AE
adverse event
ALCL
anaplastic large cell lymphoma
alloSCT
allogeneic stem cell transplantation
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCT
autologous stem cell transplantation
AST
aspartate aminotransferase
ATA
antitherapeutic antibodies
BEACOPP
bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, 
prednisone
BM
bone marrow
BUN
blood urea nitrogen
CBC
complete blood count
CD30+
CD30-positive
Ceoi
concentration at the end of the infusion
CHF
congestive heart failure
CHL
classical Hodgkin lymphoma
CI
confidence interval
Cmax
single-dose maximum (peak) concentration  
CO2
carbon dioxide
CR
complete remission or complete response
CRO
contract research organization
CRu
complete response unconfirmed
CSF
colony-stimulating factor
CT
computed tomography
CTCL
cutaneous T-cell lymphoma
CYP
cytochrome P450
DLBCL
difuse large B-cell lymphoma
DNA
deoxyribonucleic acid
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Abbreviation
Term
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EMA
European Medicines Agency
EOT
end of treatment
EU
European Union
EVA
ethyl vinyl acetate
FDA
Food and Drug Administration
FDG
fluorodeoxyglucose
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GGT
gamma glutamyl transferase
GM-CSF
granulocyte macrophage-colony stimulating factor
HED
human equivalent dose(s)
HIV
human immunodeficiency virus
HL
Hodgkin lymphoma
HRS
Hodgkin-Reed-Sternberg
IB
Investigator’s Brochure
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMC
independent data monitoring committee
IEC
independent ethics committee
IgG1
immunoglobulin G1
IND
Investigational New Drug
IRB
institutional review board
IRF
independent review facility
IRR
infusion-related reaction
IST
investigator sponsored trial
ITT
intent-to-treat
IV
intravenous; intravenously
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Abbreviation
Term
IWG
International Working Group
IXRS® (IVRS/IWRS)
interactive voice response system and/or interactive web response system
JCV
John Cunningham virus
KS
Kaposi sarcoma
LDH
lactate dehydrogenase
LPHL
lymphocyte-predominant Hodgkin lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MMAE
monomethyl auristatin E
MRI
magnetic resonance imaging
MTCL
mature T cell lymphoma
MTD
maximum tolerated dose
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NOAEL
no observable adverse effect level
ORR
objective response rate
OS
overall survival
PCR
polymerase chain reaction
PD
progressive disease (disease progression)
PE
polyethylene
PET
positron-emission tomography 
PFS
progression-free survival
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
PR
partial remission or partial response
PT
preferred term
PVC
polyvinylchloride
sALCL
systemic anaplastic large cell lymphoma
SAE
serious adverse event
SAP
statistical analysis plan
SCT
stem cell transplantation
SPD
sum of the products of the largest diameters
SJS
Stevens-Johnson syndrome
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Abbreviation
Term
SOC
system organ class
TEAE
treatment-emergent adverse event
TLS
tumor lysis syndrome
ULN
upper limit of the normal range
USA
United States of America
USP
United States Pharmacopeia
WHO
World Health Organization
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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), some mature T cell lymphoma (MTCL) subtypes, including anaplastic 
large cell lymphoma (ALCL), Kaposi 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-positive (CD30) hematologic malignancies.  HL is among the most common of 
these CD30malignancies.
1.1.1   
Relapsed or Refractory Hodgkin Lymphoma
Hodgkin lymphoma is a malignancy involving the lymph nodes and lymphatic system.  The 
World Health Organization (WHO) divides HL into 2 main types:  classical HL (CHL), 
which accounts for 95% of reported cases and lymphocyte-predominant HL (LPHL), which 
accounts for 5% of reported cases.  CHL is histopathologically defined by the presence of 
malignant Hodgkin-Reed-Sternberg (HRS) cells in a background of inflammatory cells.  
CD30 is the characteristic surface antigen expressed on HRS cells.  
An estimated 11,777 new cases of HL were diagnosed in 2008 in the European Union (EU)
and approximately 2631 deaths were reported as a result of the disease.(7)  
Advances in the use of combined chemotherapy and radiotherapy over the past half century 
have dramatically improved outcomes for patients with HL. Common combination frontline 
therapies such as doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), or
bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and 
prednisone (BEACOPP), result in complete remission for more than 80% to 90% of treated 
patients.(8, 9) However, after frontline treatment with multimodality therapy, including 
combination chemotherapy and radiation, relapse can be observed in up to 35% of patients 
with advanced-stage disease. An additional 5% to 20% of patients are refractory to 
treatment in the frontline setting.(10, 11, 12)
Therapeutic options for patients with refractory or relapsed disease are very limited, offer 
only modest clinical benefit, and carry a high morbidity rate.(13, 14) For patients whose 
disease is either refractory to, or relapses shortly after frontline therapy, the chance of a 
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complete response (CR) with second-line therapy has historically been approximately 
20%.(15)  
Multiagent chemotherapy followed by autologous stem cell transplantation (ASCT) remains 
a widely advocated salvage therapy for patients after failure of frontline therapy.  However, 
more than half of these patients will eventually have disease relapse again or die of their 
disease, and others will be ineligible for transplantation because their disease does not 
respond to pre-ASCT salvage regimens.(8, 13, 14, 16, 17) Furthermore, while ASCT results in
improved disease-free survival in clinical studies, an improvement in overall survival (OS) 
has not yet been shown from this treatment modality.(15, 18) ASCT is also known to be 
associated with significant morbidity and mortality.(19) Importantly, experiencing a CR with 
systemic therapy before stem cell transplantation (SCT) is the most critical clinical factor for 
long-term survival after SCT.(20)
1.1.2   
Brentuximab Vedotin
Brentuximab vedotin (ADCETRIS®) is an ADC directed against the CD30 antigen.  It is 
composed of the anti-CD30 chimeric immunoglobulin G1 (IgG1) monoclonal antibody 
cAC10 and the potent antimicrotubule drug monomethyl auristatin E (MMAE) 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 the HRS cells of HL, ALCL cells, and tumor 
cells of other lymphoproliferative disorders.
Brentuximab vedotin received accelerated approval from the United States (US) Food and 
Drug Administration (FDA) as ADCETRIS® on 19 August 2011 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, and for the 
treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of 
at least 1 prior multiagent chemotherapy regimen.  Brentuximab vedotin also received 
conditional marketing authorization as ADCETRIS® in the EU by the European Medicines 
Agency (EMA) on 25 October 2012 for the treatment of adult patients with relapsed or 
refractory CD30HL following ASCT or following at least 2 prior therapies when ASCT or 
multiagent chemotherapy is not a treatment option, and for the treatment of adult patients 
with relapsed or refractory sALCL.  
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1.2   
Preclinical 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+ HL and ALCL cells with nanomolar 
concentrations producing 50% inhibition (IC50 values).  Antitumor activity has been 
demonstrated in xenograft models derived from human CD30+ 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.  Neutropenia was the most clinically 
significant toxicity in monkeys, 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 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
The accelerated approval of brentuximab vedotin in the USA and conditional approval in the 
EU was obtained on the basis of results from 6 completed phase 1 and phase 2 clinical 
studies, conducted in patients with CD30+ hematologic malignancies.  A total of 
357 patients received at least 1 dose of brentuximab vedotin in these 6 clinical studies, 
including 160 patients in the two pivotal phase 2 studies who received brentuximab vedotin 
1.8 mg/kg intravenously (IV) every 3 weeks.  The clinical data to date from 
sponsor-initiated studies support a favorable benefit-risk ratio for brentuximab vedotin in 
patients with relapsed or refractory classical HL.  
Fourteen clinical studies with brentuximab vedotin were ongoing as of January 2013, 
sponsored either by Millennium Pharmaceuticals Inc. (Millennium:  The Takeda Oncology 
Company) or Seattle Genetics Inc.  In addition, brentuximab vedotin has been administered 
to patients with HL in a completed single-patient Investigational New Drug (IND) program 
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in the USA, a Canadian Special Access Program, and a Named Patient Program in countries 
worldwide other than the USA and Canada.  Several investigator-sponsored trials (ISTs) are 
also in progress worldwide.  
Phase 1, Dose-Escalation Studies
In the first-in-humans study, Study SG035-0001, a total of 45 patients with 
CD30+ hematologic malignancies received brentuximab vedotin at doses of 0.1 to 
3.6 mg/kg IV every 3 weeks.  The most commonly reported treatment-emergent adverse 
events (TEAEs) were fatigue (36% of patients), pyrexia (33%), and diarrhea, nausea, 
peripheral neuropathy, and neutropenia (22% each).  Notable serious adverse events (SAEs) 
assessed by the investigator to be at least possibly related to study treatment included 
anaphylaxis, myocardial infarction, and peripheral neuropathy. The maximum tolerated 
dose (MTD) was determined to be 1.8 mg/kg administered IV every 3 weeks.  Forty-two of 
the 45 patients in the study had a primary diagnosis of HL.  The objective response rate 
(ORR) was 40%; 17 of 42 evaluable patients had an objective response, which included a 
CR for 9 patients and a partial remission (PR) for 6 patients with HL, according to the 
investigator assessment.  Similar results were obtained by independent review facility (IRF)
assessment.  
In the second phase 1, dose-escalation study, Study SG035-0002, 44 patients with 
CD30+ hematologic malignancies received brentuximab vedotin at doses of 0.4 to 
1.4 mg/kg IV weekly for 3 weeks of a 4-week cycle.  This weekly regimen was designed to 
enable combination use with gemcitabine.  However, efficacy with brentuximab vedotin 
monotherapy was considered to be sufficient, and no patient was enrolled in the planned 
brentuximab vedotin/gemcitabine combination treatment arm of the study.  In patients with 
relapsed or refractory HL who received brentuximab vedotin 1.2 mg/kg weekly for 3 weeks
of a 4-week cycle, the ORR (CR + PR) was 58% (95% confidence interval [CI], 27.7%; 
84.8%) and the CR rate was 25% (95% CI, 5.5%; 57.2%).  The most commonly reported
TEAEs were peripheral sensory neuropathy (66% of patients), fatigue (52%), nausea (50%),
diarrhea (32%), arthralgia (27%), pyrexia (25%), and decreased appetite, myalgia, and upper 
respiratory tract infection (23% each). Acute infusion-related reactions (IRRs) were 
reported for 6 patients and 2 patients (14%) who had an acute infusion reaction also had 
antitherapeutic antibodies (ATAs) at a postbaseline visit. Brentuximab vedotin was 
generally safe and well tolerated up to the MTD of 1.2 mg/kg.
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Phase 2 Studies
In Study SG035-0003, a pivotal phase 2, single-arm, open-label study in patients with
relapsed or refractory classical HL post-ASCT, brentuximab vedotin was administered IV at
a dose of 1.8 mg/kg every 3 weeks.  The median age of enrolled patients was 31 years 
(range, 15 to 77 years).  The median duration of treatment with brentuximab vedotin was 
27 weeks (range, 3 to 56 weeks), and the patients received a median of 9 cycles (range, 1 to 
16 cycles) of therapy.  Patients who had an objective response by IRF assessment received a 
median of 10 cycles of therapy per patient.  The primary endpoint of the study was ORR
(CR + PR), by an IRF assessment.  Key secondary endpoints included duration of response, 
OS, and progression-free survival (PFS).  The ORR, by IRF assessment was 75% (95% CI, 
64.9%; 82.6%); the CR rate was 34% (95% CI, 25.2%; 44.4%); 
 
; and the median duration of
response was 29.0 weeks (95% CI, 15.9, 52.1 weeks).  
Similarly, brentuximab vedotin administered IV at the dose of 1.8 mg/kg every 3 weeks in 
Study SG035-0004, a pivotal phase 2, single-arm, open-label study conducted in patients 
with relapsed or refractory sALCL induced clinically meaningful and durable objective 
responses (CR + PR) and a high rate of CRs, and had a manageable safety profile in patients 
with relapsed or refractory sALCL.  
1.3.1   
Patients With Relapsed or Refractory HL and No Prior Autologous Stem 
Cell Transplantation
Limited data are available on the efficacy and safety of brentuximab vedotin in 
transplant-naïve patients with relapsed or refractory classical HL.  However, a retrospective 
analysis was performed on data from 41 patients with relapsed or refractory HL who had not 
received a prior ASCT and received brentuximab vedotin 1.8 mg/kg every 3 weeks.  Fifteen 
of these patients were enrolled in phase 1, dose-escalation or clinical pharmacology studies.  
The analysis also included data from patients who participated in a Named Patient 
Program.(21, 22)
These patients had received a median of 3 prior chemotherapeutic regimens (range, 1 to 
7 regimens); 59% had Stage III or Stage IV disease at the time of study entry; and 25% of 
patients had an Eastern Cooperative Oncology Group (ECOG) performance score of ≥2.  
The results showed that these patients had clinically meaningful responses with an ORR of 
54% and a CR rate of 22%, according to the investigator assessment, after a median of 
5 cycles of brentuximab vedotin.  In addition, the safety profile of brentuximab vedotin 
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appeared to be similar for patients who had received a prior ASCT and those who had not 
received an ASCT.(23)  
1.4   
Study Rationale
Brentuximab vedotin has demonstrated a compelling level of antitumor activity in terms of 
ORR (CR + PR) and CR rates in several studies conducted in patients with relapsed or 
refractory HL. Meta analyses based on CR rate, an endpoint associated with long-term 
clinical benefit in patients with HL, suggest that brentuximab vedotin may be superior to 
other third-line options in patients with relapsed or refractory HL post-ASCT and is 
comparable with salvage regimens used in the pretransplantation setting.(24) The robust 
antitumor efficacy of brentuximab vedotin may translate into substantive rates of durable
remissions that do not appear to be observed with current therapies, without the severe or 
life-threatening toxicities that patients experience with those regimens.  
For the subset of patients with relapsed disease who may be sensitive to salvage 
chemotherapy, current second-line regimens followed by ASCT may represent a curative 
approach. However, data are limited on therapy outcomes for patients with primary 
refractory disease, those who fail to experience a CR with second-line treatments, or those 
who are otherwise either not suitable for or do not have access to an ASCT. 
The observed efficacy results for transplant-naïve patients with relapsed or refractory HL
represent meaningful activity of brentuximab vedotin in this patient population and provide 
the opportunity for a higher proportion of this subset of patients to receive potentially 
curative SCT.  While brentuximab vedotin has been approved for patients in this setting, the 
results from this study will further support the usefulness of this treatment option in this 
setting.
1.5   
Potential Risks and Benefits
Brentuximab vedotin monotherapy was granted accelerated approval in the USA and 
conditional marketing authorization in the EU on the basis of results from 6 completed 
clinical studies, including two pivotal phase 2 studies, which showed a high rate of durable 
responses for patients with CD30+ hematological malignancies including HL.  In the pivotal 
phase 2 study conducted in patients with HL, the ORR (CR + PR), by IRF assessment was 
75% (95% CI, 64.9%; 82.6%) post-ASCT with a median duration of response of 29.0 weeks 
(95% CI, 15.9, 52.1 weeks).
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Brentuximab vedotin is associated with peripheral neuropathy that is predominantly sensory.  
Peripheral motor neuropathy has also been reported.  The data suggest that the risk of 
peripheral neuropathy and, in particular, Grade 3 peripheral neuropathy is related to
cumulative exposure to brentuximab vedotin and the first onset of peripheral neuropathy 
tended to be reported at later cycles of brentuximab vedotin administration.  Most reports of 
peripheral neuropathy were Grade 1 or Grade 2.  Neuropathy was generally reversible with a 
median of approximately 16 weeks from onset to resolution or improvement of peripheral 
neuropathy symptoms.  Neuropathy associated with brentuximab vedotin was managed by 
dose delay and/or dose reduction to 1.2 mg/kg, which seemed to mitigate worsening of 
neuropathy.  No Grade 4 peripheral neuropathy was reported in the 6 completed studies that
supported the marketing authorization applications.  However, the administration of 
brentuximab vedotin should be discontinued for any patient who develops Grade 4 
peripheral neuropathy.  It is required that patients be monitored for symptoms of neuropathy, 
including hypoesthesia, hyperesthesia, paresthesia, a burning sensation, neuropathic pain, 
and weakness.  
IRRs, including anaphylaxis, have been reported with brentuximab vedotin.(25) Without 
routine prophylaxis, approximately 11% of patients in the 2 pivotal phase 2 studies 
conducted with brentuximab vedotin, Studies SG035-0003 and SG035-0004, experienced 
IRRs.  A similar incidence was reported for patients in the phase 1 studies.  Most IRRs were 
Grade 1 or Grade 2 and were reported within the first 2 cycles of therapy.  It is required that 
patients who are receiving brentuximab vedotin be monitored for IRRs.  The experience 
with IRRs related to the administration of brentuximab vedotin supports administration by 
appropriately trained personnel and without routine prophylaxis.  If an IRR occurs, the 
infusion should be interrupted, and the patient should receive appropriate medical 
management.  Infusion interruption for IRR treatment generally resulted in completion of 
the dose. The brentuximab vedotin infusion may be continued after interruption at a lower 
rate of administration.  Patients who experience a prior IRR should be premedicated 
according to institutional guidelines before the administration of subsequent infusions.  
Premedication may include acetaminophen, an antihistamine, and a corticosteroid.  If 
anaphylaxis occurs, the administration of brentuximab vedotin should be immediately and 
permanently discontinued and appropriate medical therapy administered.  
Clinically significant clinical laboratory abnormalities were reported as adverse events 
(AEs) in the 2 pivotal phase 2 studies, Studies SG035-0003 and SG035-0004, conducted in 
patients with relapsed or refractory HL and sALCL, respectively. Central laboratory data 
were collected before dose administration only in each treatment cycle.  Few patients in 
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these 2 studies had postbaseline worsening to Grade 3 or higher in clinical laboratory values.  
The most commonly reported clinical laboratory data for which new or worsening shifts to
Grade 3 or higher were reported were low neutrophil and low lymphocyte counts (11% each 
of patients), low platelet counts and high glucose levels (6% each), and low leukocyte
counts (5%).  Only 1 patient in the pivotal phase 2 studies had Grade 3 increased alanine 
aminotransferase (ALT) and Grade 3 increased aspartate aminotransferase (AST) levels.
Complete blood counts (CBCs) are measured before each dose of brentuximab vedotin, and 
more frequent monitoring of the CBC should be considered for patients with Grade 3 or 
Grade 4 neutropenia.  Severe, prolonged neutropenia of ≥1 week duration has been 
reported.  If Grade 3 or Grade 4 neutropenia develops, the clinical management of the 
patient can include dose delays, dose reductions, or the permanent discontinuation of study 
treatment.
Any treatment that can decrease immune function may increase the risk of infections.  
Patients should therefore be monitored for the development of infection during the treatment 
period and up through 30 days after the last dose of brentuximab vedotin is administered.  
Tumor lysis syndrome (TLS) has been reported in patients who received brentuximab 
vedotin.  The reported cases of TLS were not considered to be life threatening, and affected
patients continued to receive brentuximab vedotin after TLS was resolved.  Patients with 
rapidly proliferating tumor and high tumor burden are at risk of TLS and should be closely 
monitored.  If TLS is diagnosed, medically appropriate measures should be taken.
Stevens-Johnson syndrome (SJS) has been reported in patients who received brentuximab 
vedotin.  Patients were concurrently receiving other medications (naproxen and tramadol, 
respectively) that are known to cause SJS and may have contributed to the development of 
SJS. If SJS occurs, the administration of brentuximab vedotin must be discontinued and the 
appropriate medical therapy administered.
Progressive multifocal leukoencephalopathy (PML), including fatal PML, has been reported 
in patients who received brentuximab vedotin.  PML is a rare demyelinating disease of the 
brain that is caused by the John Cunningham virus (JCV).  PML is typically reported in 
immunocompromised patients and can be fatal.  Presenting features may include altered 
mental status, motor deficits such as hemiparesis or ataxia, visual disturbances, higher 
cortical dysfunction such as dysphasia or agnosia, and seizures.  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 
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disease are not typically associated with PML.  Peripheral neuropathy, which has been 
reported with brentuximab vedotin, is not commonly reported with PML.  If PML is 
suspected, a diagnostic evaluation should be performed (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.  
MMAE is primarily metabolized by cytochrome P450 (CYP)3A. Patients who are receiving 
strong CYP3A4 inhibitors concomitantly with brentuximab vedotin should be closely 
monitored for AEs.
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 after
administration of brentuximab vedotin.
Overall, considering the potential for therapeutic benefit of brentuximab vedotin in patients 
with relapsed or refractory classical HL and the frequently limited treatment options 
available to these patients with this life threatening disease, and the manageable safety 
profile of brentuximab vedotin, the benefit-risk assessment is considered to be favorable.
2.   
STUDY OBJECTIVES
2.1   
Primary Objective
The primary objective of the study is to assess the antitumor efficacy, as determined by the 
ORR of single-agent brentuximab vedotin 1.8 mg/kg administered intravenously (IV) every 
3 weeks, in patients with relapsed or refractory classical HL who are considered to be not 
suitable for SCT or multiagent chemotherapy.  
2.2   
Secondary Objectives
The secondary objectives are:

To determine the duration of tumor control, including the duration of response 
(DOR), PFS, and CR rate, by IRF assessment after treatment with brentuximab 
vedotin
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
To determine the proportion of patients who receive hematopoietic SCT, either 
ASCT or allogeneic stem cell transplantation (alloSCT) after treatment with 
brentuximab vedotin

To determine OS after treatment with brentuximab vedotin

To assess the safety and tolerability of brentuximab vedotin in this patient population

To assess the pharmacokinetics (PK) of brentuximab vedotin

To determine the immunogenicity of brentuximab vedotin
2.3   
Tertiary/Exploratory Objectives
3.   
STUDY ENDPOINTS
3.1   
Primary Endpoint
The primary endpoint of the study is ORR (CR + PR), by IRF assessment.(1)
3.2   
Secondary Endpoints
The secondary endpoints are:  

Duration of response, PFS, CR rate, and duration of CR, by IRF assessment 
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
Proportion of patients who receive SCT after treatment with brentuximab vedotin

OS

Incidence, severity, and relatedness of AEs; SAEs; and clinical laboratory 
abnormalities

PK for brentuximab vedotin, MMAE, and total antibody

The presence of ATAs to brentuximab vedotin
3.3   
Tertiary/Exploratory Endpoints 
4.   
STUDY DESIGN 
4.1   
Overview of Study Design
This phase 4, single-arm, multicenter study is designed to evaluate the efficacy and safety of 
brentuximab vedotin in adult patients 18 years or older with histologically confirmed 
CD30+ relapsed or refractory classical HL who have not received a prior ASCT and are 
considered to be not suitable for SCT or multiagent chemotherapy at the time of study entry.  
Patients who are considered to be not suitable for SCT or multiagent chemotherapy include 
those who experience disease progression within 90 days of the earliest date of complete 
remission (CR) or complete remission unconfirmed (CRu) after the end of treatment with 
multiagent chemotherapeutic regimens and/or radiotherapy, or experience disease 
progression during frontline multiagent chemotherapy or alternatively, experience disease 
relapse after treatment with at least 2 chemotherapeutic regimens, including any salvage 
treatments.
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Brentuximab vedotin will be administered as a single, outpatient, 1.8-mg/kg IV infusion on 
Day 1 of each 3-week cycle.  Patients with a CR, a PR, or stable disease should receive a 
minimum of 8 cycles, and all patients will be given the opportunity to complete a maximum 
of 16 cycles (see Section 15.1).  Dedicated computed tomography (CT) scans (spiral 
preferred) of chest, neck, abdomen, and pelvis will be performed at baseline (screening) and 
Cycles 2, 4, 7, 10, 13, and 16; and fluorodeoxyglucose (FDG) positron-emission 
tomography (PET) scans will be done at baseline and at Cycles 4 and 7.  No additional PET 
scans are required during the treatment period after Cycle 7 unless they are clinically 
indicated.  A PET scan should be done at the end of treatment only for those patients who 
discontinue study treatment without a postbaseline PET assessment.
Measures of anticancer activity will be assessed by an IRF according to the International 
Working Group (IWG) Revised Response Criteria for Malignant Lymphoma.(1)  Patients 
who experience disease progression at any time will discontinue the study drug.  These 
patients will continue to be followed for OS.  Patients with an objective response, either a 
CR or a PR, and are eligible for an SCT may discontinue receiving brentuximab vedotin and 
proceed to an SCT.  These patients should receive at least 4 cycles of brentuximab vedotin 
before proceeding to SCT.  
Safety assessments will include the incidence and severity of AEs and changes in clinical 
laboratory values, vital signs measurements, and physical examination findings.  Toxicity 
will be evaluated according to National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) version 4.03, effective 14 June 2010.(26)  
Clinical laboratory samples will be obtained before dose administration on Study Day 1 of 
each 3-week cycle at Cycle 2 through Cycle 16.  Cycle 1, Day 1 samples may be collected 
within 4 days before dose administration to ensure patient eligibility on Day 1.  Physical 
examination, including vital signs measurements, weight, ECOG performance status score, 
and 
will be performed on Day 1 of each treatment cycle.  In 
addition, samples for PK, immunogenicity, 
 
 will be collected on Day 1 of each treatment cycle.  
 
 
  
A bone marrow biopsy is required only for those patients with previous known bone marrow 
involvement or suspected infiltration suspicious of bone marrow involvement.  In addition, a 
bone marrow biopsy is required to confirm a CR in patients who have bone marrow 
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involvement or suspected infiltration suspicious of bone marrow involvement at baseline.  
The follow-up bone marrow biopsy specimen must be obtained within 2 weeks of 
documentation of a CR.  Once the bone marrow specimen is negative, no further bone 
marrow evaluations are required.  
Serum concentrations of brentuximab vedotin, ATA, and free drug (MMAE) will be 
measured.  
 
.  A possible dose response for any such effects and the presence of ATAs may be 
subsequently examined.  
.
Patients may continue to receive the study treatment for a maximum of 16 cycles or until 
disease progression or unacceptable toxicity.  Patients will have an end-of-treatment (EOT)
visit 30 days (± 7 days) after receiving their last dose of study drug.  
Patients who discontinue study treatment with a CR, a PR, or stable disease will have CT 
scans performed for assessment of PFS every 3 months for 18 months after EOT or until the 
sooner of disease progression, death, or study closure.  For patients who complete the 
18-month PFS follow-up assessment period with a CR, a PR, or stable disease, a CT scan 
will be performed during the OS follow-up period at the time of disease progression, and the 
results will be sent to the IRF.  Posttreatment follow-up assessments for OS will be 
performed every 3 months for 18 months after the EOT; thereafter, assessment for OS will 
continue every 6 months until the sooner of death, study closure, or 5 years after enrollment 
of the last patient.  
4.2   
Number of Patients
At least 60 patients with relapsed or refractory classical HL who are considered to be not 
suitable for SCT or multiagent chemotherapy will be enrolled in this study at approximately 
20 investigative sites in Europe and potentially other regions of the world.  Patients who are 
enrolled in the interactive voice response system (IVRS) or interactive web response system 
(IWRS) (known as IXRS®) will be considered to be enrolled in the study.  Enrolled patients 
who do not receive the study drug for any reason will not be replaced.  
4.3   
Duration of Study
Study enrollment is expected to take approximately 15 months.  Patients will complete a 
Screening period of up to 28 days and may receive a maximum of 16 cycles of brentuximab 
vedotin.  Patients will be followed for 30 days (7 days) after administration of the last dose 
of brentuximab vedotin to permit the detection of any delayed treatment-related AEs.  For 
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patients who discontinue the study treatment with a CR, a PR, or stable disease, 
posttreatment follow-up assessments for PFS will be performed every 3 months for 
18 months after the EOT or until the sooner of disease progression, death, or study closure.  
For patients who complete the 18-month PFS follow-up assessment period with a CR, a PR, 
or stable disease, a CT scan will be performed during the OS follow-up period at the time of 
disease progression, and the results will be sent to the IRF.  Posttreatment follow-up 
assessments for OS will be performed every 3 months for 18 months after the EOT; 
thereafter, assessment for OS will continue every 6 months until the sooner of death, study 
closure, or 5 years after enrollment of the last patient.  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. Male or female patients 18 years or older.
2. A diagnosis of relapsed or refractory classical HL, confirmed by biopsy if clinically 
feasible on the basis of local pathology review.
3. A history of at least 1 prior systemic chemotherapeutic regimen. 
4. Not suitable for SCT or multiagent chemotherapy, according to 1 of the following 
criteria:

Disease progression within 90 days of the earliest date of complete remission 
(CR) or complete remission unconfirmed (CRu) after the end of treatment 
with multiagent chemotherapeutic regimens and/or radiotherapy

Progressive disease during frontline multiagent chemotherapy

Disease relapse after treatment with at least 2 chemotherapeutic regimens, 
including any salvage treatments
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5. Bidimensional measurable disease, of at least 1.5 cm, as documented by radiographic 
technique (spiral CT scan preferred), per IWG Revised Response Criteria for 
Malignant Lymphoma.(1)
6. At least 1 of the following as evidence of relapsed or refractory classical HL:

Histologically documented CD30+ CHL 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 HL- related symptoms 
such as pruritus and B symptoms such as fever, night sweats, or 10% 
weight loss, after infectious causes have been excluded.
7. Patients must have completed any prior immunotherapy (eg, rituximab) or 
radioisotopic therapy at least 12 weeks before the first dose of brentuximab vedotin 
in the absence of clear disease progression.
8. Patient has recovered to Grade 1 or lower toxicity related to radiotherapy, 
immunotherapy, and chemotherapy unless evidence of toxicity is due to underlying 
HL.  If toxicity is related to underlying HL, Grade 2 or lower toxicity is acceptable.
9. ECOG performance status score of 0 or 1 (refer to Section 15.2).
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10. 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, postovulation methods] and withdrawal are not acceptable 
methods of contraception.)
11. 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, postovulation 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. Suitable venous access for the study-required blood sampling, including PK and 
serum biomarker sampling.
14. Clinical laboratory values as specified within 4 days before the first dose of study 
drug, unless due to the presence of underlying disease involvement, then recovery to 
less than or equal to Grade 2 toxicity: 

Absolute neutrophil count ≥1000/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.

Total serum bilirubin must be 1.5 the upper limit of normal range (ULN)
or 3 ULN for patients with an indirect hyperbilirubinemia due to 
Gilbert’s disease or documented hepatic involvement with lymphoma.

ALT or AST must be ≤2.5 ULN.  AST and ALT may be elevated up to 
5 times the ULN if their elevation can be reasonably ascribed to the presence 
of metastatic disease in the liver.

Serum creatinine must be ≤1.5 ULN. 
5.2   
Exclusion Criteria
Patients who meet any of the following exclusion criteria are not to be enrolled in the study:
1. Previous treatment with brentuximab vedotin.
2. Previously received an ASCT or alloSCT.
3. Female patients who are lactating and breastfeeding or have a positive serum or urine 
pregnancy test during the Screening period or a positive serum or urine pregnancy 
test on Day 1 before first dose of study drug.
4. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol.
5. Treatment with any investigational products within 4 weeks before the first dose of 
study drug.
6. Any of the following cardiovascular conditions or values within 6 months before the 
first dose of study drug:  

New York Heart Association Class III or IV heart failure (refer to 
Section 15.3)

Myocardial infarction within 6 months before the first dose of study drug
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
Evidence of current uncontrolled cardiovascular conditions, including 
clinically relevant cardiac arrhythmias, congestive heart failure (CHF), 
angina, or electrocardiographic evidence of acute ischemia or active 
conduction system abnormalities
7. History of another primary malignancy that has not been in remission for at least 
3 years. (The following are exempt from the 3-year limit: nonmelanoma skin 
cancer, curatively treated localized prostate cancer, and cervical carcinoma in situ on 
biopsy or a squamous intraepithelial lesion on PAP smear.)
8. Any active uncontrolled systemic viral, bacterial, or fungal infection.
9. Any antimicrobial, antiviral, or antifungal therapy within 1 week prior to the first 
dose of brentuximab vedotin (routine prophylaxis is acceptable).
10. Known cerebral/meningeal disease, including signs or symptoms suggestive of PML, 
or any history of PML.
11. Known human immunodeficiency virus (HIV).
12. Known hepatitis B surface antigen positive, or known or suspected active hepatitis C 
infection.
13. Grade 2 or higher peripheral neuropathy.  
14. Current therapy with other systemic antineoplastic or investigational agents.
15. Therapy with corticosteroids at higher than or equal to 20 mg/day of prednisone 
equivalent within 1 week before administration of the first dose of brentuximab 
vedotin.
16. Patients with a known hypersensitivity to recombinant proteins, murine proteins, or 
any excipient contained in the drug formulation.
17. Patients with dementia or an altered mental state that would preclude the 
understanding and rendering of informed consent.
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6.   
STUDY DRUG
6.1   
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented 
prior to 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 over 
approximately 30 minutes.  Patients who have a CR, a PR, or stable disease should receive a
minimum 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 an approximate 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.
Dose administration is determined on the basis of the patient’s weight, according to 
institutional guidelines; however, doses will be adjusted for patients who experience a 
≥10% change in weight from baseline.  The patient’s actual body weight will be used 
except for those patients who weigh more than 100 kg.  For patients who weigh more than 
100 kg, the dose will be calculated on the basis of 100 kg.  Brentuximab vedotin dose should 
be rounded to the nearest whole number of milligrams.
Additional information on the administration of brentuximab vedotin 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 describes the recommended dose modifications for brentuximab vedotin for 
treatment-associated toxicity.
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Table 6-1   
Dose Modification Guidelines for Brentuximab Vedotin for 
Treatment-Associated Toxicity
Nonhematologic
(Excluding Neuropathy)
Hematologic
Peripheral Neuropathy
Grade 1
Continue at same dose.
Continue at same dose.
Continue at same dose.
Grade 2
Continue at same dose.
Continue at same dose.
For Grade 2 neuropathy, withhold 
dose until toxicity is ≤Grade 1 or 
baseline, then resume treatment at 
the 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.a
Withhold dose until toxicity 
is ≤Grade 2, or has returned 
to baseline, then resume 
treatment at the same dose 
level.b  Consider growth 
factor support (G-CSF or 
GM-CSF) for treatment of 
neutropenia and prophylaxis 
in subsequent cycles.
Withhold dose until toxicity 
returns to Grade 1 or baseline, 
then restart treatment at a reduced 
dose of 1.2 mg/kg every 3 weeks.
Grade 4
Withhold dose until 
toxicity is ≤Grade 1 or 
has returned to baseline, 
then reduce dose to 
1.2 mg/kg and resume 
treatment, or discontinue 
at the discretion of the 
investigator after 
discussion with the 
sponsor.a
Withhold dose until toxicity 
is ≤Grade 2, then resume 
treatment at the same dose.  
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.
Toxicity grading based on NCICTCAE version 4.03.
a Patients who develop clinically insignificant Grade 3 or Grade 4 electrolyte laboratory abnormalities may 
continue study treatment without interruption.
b Patients who develop clinically insignificant Grade 3 or Grade 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 instructions on the criteria to determine the requirement for a 
dose interruption.  
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6.2.3   
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
The cycle length for treatment with brentuximab vedotin will be 3 weeks.  For a new cycle 
of treatment to begin, all drug-related toxicity must have resolved, according to the 
guidelines presented in Table 6-1.  
If the patient fails to meet the criteria for treatment at the scheduled time for the next cycle 
of treatment, initiation of the next cycle should be delayed for 1 week.  At the end of that 
time, the patient should be re-evaluated to determine whether the criteria for treatment 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 drug-associated toxicity experienced during 
the current cycle.  Delays of longer than 3 weeks for drug-related toxicities require 
discontinuation of study treatment, unless the sponsor agrees that the benefit-risk assessment 
supports continued treatment with the study drug.
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 (as previously described in Table 6-1) and after the sponsor and investigator 
review the available data for that patient.
After a dose has been reduced for a patient because of drug-related toxicity, the dose should 
generally not be increased for that patient to the previous dose at which the toxicity 
occurred.  However, an intrapatient re-escalation to the previous dose may be permitted at 
the discretion of the investigator and only after discussion with the sponsor.
6.2.5   
Criteria for Discontinuation of Brentuximab Vedotin
Criteria for discontinuation of the study drug are provided in Section 7.7.  Please refer to 
Table 6-1 for further information regarding dose requirements for patients who discontinue 
the study drug due to toxicity.
Patients will attend the EOT visit 30 days (± 7 days) after receiving their last dose of the 
study drug.  At the time of discontinuation of the study drug, 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).  
If the sponsor and/or the investigator should discover conditions arising during the study that 
indicate that the study should be stopped, an appropriate schedule for termination will be 
instituted.
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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 the treatment period of this study.

Concurrent participation in another clinical study with medical intervention. 
6.4   
Permitted Concomitant Medications and Procedures
The following medications and procedures are allowed during the study:

The use of topical, inhalational, and ophthalmic steroids is permitted.  
Corticosteroids are permitted as part of a premedication regimen or for the treatment 
of HL-related symptoms, according to institutional standards or to manage potential 
hypersensitivity.  

The use of hormonal therapy, provided that a stable dose was being administered for 
at least 1 month before study enrollment.  No restrictions are placed on the use of 
hormonal contraceptives.

The use of platelet and/or red blood cell supportive growth factors or transfusions 
when applicable.

The use of colony-stimulating factors (CSFs) for the treatment of neutropenia, 
according to institutional practice.

Medications for IRRs, such as epinephrine, antihistamines, and corticosteroids; these 
medications should be available for immediate use.

Palliative radiation or surgery if other sites of measurable disease remain.
6.5   
Precautions and Restrictions 
Use of CYP3A Inhibitors
MMAE is primarily metabolized by CYP3A.  Patients who are receiving strong CYP3A
inhibitors concomitantly with brentuximab vedotin should be closely monitored for adverse 
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reactions.  Please refer to the Study Manual for a list of examples of strong CYP3A
inhibitors.
Infusion-related Reactions
An IRR 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 after each infusion of brentuximab vedotin.  
During this observation period, the IV line should remain open for at least 1 hour to allow 
for the IV administration of drugs if necessary.  All supportive measures consistent with 
optimal patient care will be given throughout the study according to institutional standards.  
Medications for IRRs, such as epinephrine and antihistamines, should be available for 
immediate use.  However, premedication should not be routinely administered before
administration of the first dose of brentuximab vedotin.
Patients who experience a Grade 1 or Grade 2 IRR may receive subsequent brentuximab 
vedotin infusions with premedication consisting of acetaminophen, 650 mg orally, and 
diphenhydramine, 25 to 50 mg orally or 10 to 25 mg IV or according to institutional 
standards, administered 30 to 60 minutes before each 30-minute brentuximab vedotin 
infusion.
Patients who experience a Grade 3 or Grade 4 IRR may potentially receive additional 
treatment with brentuximab vedotin at the discretion of the investigator only after discussion 
with the sponsor.  If anaphylaxis occurs, the administration of brentuximab vedotin should 
be immediately and permanently discontinued and appropriate medical therapy should be 
administered to the affected patient.  
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 and male patients should use effective 
methods of contraception through defined periods during and after study treatment as 
specified.
Female patients must meet 1 of the following: 

Postmenopausal for at least 1 year before the screening visit, or
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
Surgically sterile, or

If they are of childbearing potential, agree to practice 2 effective methods of 
contraception from the time of signing of the informed consent 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, 
postovulation methods for the female partner] and withdrawal are not acceptable 
methods of contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:

Practice effective barrier contraception during the entire study treatment period and 
through 6 months after the last dose of 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, 
postovulation 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 antiemetics, their use is not 
prohibited in the management of a patient who develops nausea and/or vomiting.  As in the 
prophylactic setting, 5-hydroxytryptamine 3 (5-HT3) serotonin receptor antagonists and 
corticosteroids should be used for treatment first in the management of patients with these 
side effects.
Diarrhea
Prophylactic antidiarrheals will not be used in this study; however, patients will be 
instructed to take antidiarrheal medication(s) at the physician’s discretion until they are 
diarrhea free for at least 12 hours.  Fluid intake should be maintained to avoid dehydration.
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Peripheral Neuropathy
Patients will be monitored closely for peripheral neuropathy throughout the study.  Grade 2 
or higher peripheral neuropathy may result in a dose modification for brentuximab vedotin, 
according to the guidelines previously described (Table 6-1).
Suspected Progressive Multifocal Leukoencephalopathy
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 approximately 20% of patients with PML.  
The onset of neurological deficits may occur over weeks to months.  Refer to the IB for 
further details.
If PML is suspected, stop administration of brentuximab vedotin 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 a focal lesion or multifocal lesions, mainly of the white matter, which are 
typically nonenhancing and do not have mass effect.

Polymerase chain reaction (PCR) analysis:  JCV deoxyribonucleic acid (DNA)
detectable in cerebrospinal fluid or there is evidence of JCV in a brain biopsy.

Neurology consultation.
Treatment with brentuximab vedotin must be permanently discontinued for patients with a 
confirmed diagnosis of PML.
Anaphylaxis
If anaphylaxis occurs, the administration of brentuximab vedotin should be immediately and 
permanently discontinued and appropriate medical therapy should be administered to the 
affected patient.
6.7   
Blinding and Unblinding
Blinding is not applicable in this single-arm study.  
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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, United States Pharmacopeia (USP) or an 
equivalent standard, yields 11 mL of brentuximab vedotin solution (5 mg/mL).
6.9   
Preparation, Reconstitution, and Dispensation of Brentuximab Vedotin
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 dose solutions are to be discarded 
using appropriate institutional drug disposal procedures according to the guidelines in the 
Study Manual.
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 appropriate amount of reconstituted study 
treatment will be withdrawn from the vial(s) and diluted in an infusion bag containing a 
minimum volume of 100 mL.
No incompatibilities are known between brentuximab vedotin 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.  The reconstituted and diluted drug product should be inspected 
visually for any particulate matter and discoloration before it is administered to the patient.  
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.
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Refer to the Directions for Use/Pharmacy Manual for more specific instructions on 
reconstitution and use.
6.10   
Packaging and Labeling
Brentuximab vials will be packaged as single-use cartons.  Each carton will contain 1 vial of 
the investigational product and the vial and carton will be labeled to meet country-specific 
regulatory requirements.
6.11   
Storage, Handling, and Accountability
Brentuximab vedotin must be refrigerated at 2C to 8C in a secure location (eg, locked 
room) that is accessible to the pharmacist, the investigator, or a duly designated person only.
Brentuximab vedotin does not contain preservatives; therefore, opened and reconstituted 
vials of brentuximab vedotin must be used within 24 hours of reconstitution when they are 
stored under refrigeration at 2C to 8C.  Reconstituted brentuximab vedotin should not be 
stored at room temperature.  It is recommended that brentuximab vedotin 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 study 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 Millennium project clinician for this study, the central 
laboratory and any additional clinical laboratories, the coordinating investigator for each 
member state/country, the IRF, the IXRS (IVRS/IWRS) 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 
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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 a single-arm study with no reference therapy.  Treatment group assignments are not 
applicable. An IXRS (IVRS/IWRS) system will be used to enroll patients in 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.
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, 
according to country and 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).  
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7.4.6   
Patient Weight
Weight will be measured at times specified in the Schedule of Events.  The actual dose of
brentuximab vedotin is determined on the basis of the patients’ weight, according to 
institutional guidelines; however, doses will be adjusted for patients who experience a 10% 
change from baseline in body weight (Section 6.1).
7.4.7   
Vital Signs 
Vital signs measurements will be assessed at times specified in the Schedule of Events and 
include seated (after 3 to 5 minutes in this position) measurements of diastolic and systolic 
blood pressure, heart rate, and oral temperature.
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 score will be assessed at times specified in the Schedule of 
Events.  See Section 15.2 for a description of the ECOG scale for performance status.
7.4.10   
Tumor Specimen Measurements
If available, tumor tissue collected from the time of the most recent diagnostic biopsy of the 
original diagnosis or subsequent procedures for relapsed or refractory disease (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 at least 
10 histological slides will not need to undergo a biopsy procedure at the time of screening.  
Patients who cannot provide archived tissue or at least 10 histological slides from their most 
recent biopsy will undergo a new tumor biopsy during screening.  This sample will be used 
to confirm the diagnosis of classical HL and CD30 expression by central laboratory review.  
Central laboratory results for classical HL diagnosis are not required before administration 
of the first dose of study drug.  Refer to the Schedule of Events for details regarding tumor 
tissue collection.
7.4.11   
Electrocardiograms
A 12-lead electrocardiogram (ECG) will be administered at the time of screening, as 
specified in the Schedule of Events.
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7.4.12   
Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures that the patient completes will 
be recorded in the eCRF as specified in the Schedule of Events.  Refer to Section 6.3 for a 
list of excluded concomitant medications procedures and Section 6.4 for a list of permitted 
concomitant medications and procedures 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 he or she is enrolled in the IXRS
(IVRS/IWRS).  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 administration of the study drug may be made by using local laboratory results.  If local 
clinical laboratory values are used for either eligibility or study dose administration
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:  
Clinical Chemistry and Hematology
Blood samples for analysis of the following clinical chemistry and hematological parameters 
and urine samples for urinalysis will be obtained as specified in the Schedule of Events.
Hematology

Hemoglobin

Hematocrit

Platelet (count)

Leukocytes with differential

Neutrophils (absolute neutrophil count [ANC])
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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 
IWG criteria for patients with lymphoma.(1)  Disease assessments will be performed as 
specified in the Schedule of Events.  Records of disease assessments will be provided to the 
IRF for central review.
A CT scan, spiral preferred (chest, neck, abdomen, and pelvis), with contrast as appropriate, 
and 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 by 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 for patients who have a glomerular filtration rate 
of 60 mL/min and the IV contrast, therefore, presents a risk of renal failure; patients who 
develop anaphylaxis to IV contrast; or patients who become pregnant during posttreatment 
follow-up. If use of MRI is required, a consistent scanning modality must be maintained. 
Further details may be found in the Imaging Manual.
 will be 
performed at the time points indicated in the Schedule of Events.  A bone marrow biopsy 
may also be obtained for bone marrow assessment as specified in the Schedule of Events.  A 
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bone marrow biopsy is required only for those patients with previous known bone marrow 
involvement or suspected infiltration suspicious of bone marrow involvement.  
7.4.17   
Pharmacokinetic Measurements
PK measurements will be taken for MMAE, ADC, and total antibody.  PK values to be 
estimated may include the maximum plasma concentration (Cmax) for MMAE, and 
concentration at the end of infusion (Ceoi) for brentuximab vedotin.  Population PK
methodologies may be used to determine PK parameters and covariates in this population.
All sampling times are relative to the end of the brentuximab vedotin infusion.  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.
7.4.18   
Serum Biomarkers
7.4.19   
Immunogenicity
Blood for serum samples will be collected as specified in the Schedule of Events to evaluate 
ATAs and neutralizing ATAs as a safety assessment.  On the days of dose administration, 
the blood samples for ATA and neutralizing ATA assessment must be collected before the 
dose is administered.  Neutralizing ATA assessment will be performed for ATA-positive 
samples only.  Details regarding the preparation, handling, and shipping of samples are 
provided in the Study Manual.
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7.4.21   
Cost Assessment
The cost of treatment will be assessed through the collection of health care utilization data.  
Valuation of the costs will be undertaken separately.
7.5   
Completion of Treatment
Patients will be considered to have completed study treatment if they complete 16 cycles of 
brentuximab vedotin.
7.6   
Completion of Study
Patients will be considered to have completed the study if they complete 16 cycles of 
treatment with brentuximab vedotin and complete the EOT visit.  
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 the study closes.  Study closure will occur when 50% of patients 
have had an OS event or 5 years after the last patient is enrolled in the study, whichever 
occurs first.  The total study duration is anticipated to be approximately 6 to 7 years.  Refer 
to Section 7.10 for a 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 the maximum number of cycles of brentuximab vedotin, as described in 
the protocol

Progressive disease

Initiation of hematopoietic stem cell transplantation

Withdrawal of informed consent by the subject.
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The reason for withdrawal from the study should be documented in the eCRF.  Patients who 
discontinue the 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

Symptomatic deterioration 

Study terminated by sponsor

Withdrawal by patient

Lost to follow-up

Other
Once study drug has been discontinued, all study procedures outlined for the EOT visit will 
be completed as specified in the Schedule of Events.  The primary reason for study drug 
discontinuation will be recorded on the eCRF.  Some patients may discontinue the 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.  Patients who experience disease progression will continue to be 
followed for OS.  
Enrolled patients who do not receive the study drug for any reason will not be replaced.  
Patient enrollment will continue until at least 60 patients with relapsed or refractory HL who 
are considered to be not suitable for SCT or multiagent chemotherapy are available for 
analysis of the primary study endpoint, ORR (CR + PR).  
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
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
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 discontinue study treatment with a CR, a PR, or stable disease will continue to 
be followed for PFS and will have CT scans performed every 3 months for 18 months after 
the EOT or until the sooner of disease progression, death, or study closure.  For patients who 
complete the 18-month PFS follow-up assessment period with a CR, a PR, or stable disease, 
a CT scan will be performed during the OS follow-up period at the time of disease 
progression, and the results will be sent to the IRF.  Posttreatment follow-up assessments for 
OS will be performed every 3 months for 18 months after the EOT; thereafter, assessment 
for OS will continue every 6 months until the sooner of death, study closure, or 5 years after 
enrollment of the last patient.  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 (Progression-Free Survival and Overall 
Survival)
Posttreatment follow-up for all patients consists of a physical examination, CT scan, 
collection of OS/PFS status, and anticancer treatment for HL as specified in the Schedule of 
Events.
Patients who discontinue study treatment with a CR, a PR, or stable disease will have CT 
scans done every 3 months for 18 months after the EOT or until the sooner of disease 
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progression, death, or study closure.  For patients who complete the 18-month PFS 
follow-up assessment period with a CR, a PR, or stable disease, a CT scan will be performed 
during the OS follow-up period at the time of disease progression, and the results will be 
sent to the IRF.  Posttreatment follow-up assessments for OS will be performed every 
3 months for 18 months after the EOT; thereafter, assessment for OS will continue every 
6 months until the sooner of death, study closure, or 5 years after enrollment of the last 
patient.  See the Schedule of Events for appropriate assessments during follow-up. 
NOTE:  Related SAEs must be reported to the Millennium Department of 
Pharmacovigilance or designee.  This includes deaths that the investigator considers to be 
related to study drug that occur during the posttreatment follow-up period. 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.  For continuous variables, 
descriptive statistics will be used including number (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 in subsequent sections; 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
At least 60 patients with relapsed or refractory classical HL who are considered to be not 
suitable for SCT or multiagent chemotherapy will be enrolled in this study.  With a sample 
size of 60 patients and different ORRs, the two-sided 95% CIs will vary.  An example is 
shown (Table 8-1).  
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Table 8-1   
Overall Objective Response Rates and 95% Confidence Intervals 
(N = 60)
Response Rate, %
Number of Responders (CR or PR)
95% CI, %
20
12
(11, 32)
30
18
(19, 43)
40
24
(27, 53)
50
30
(37, 63)
60
36
(47, 72)
Abbreviations:  CI = confidence interval; CR = complete remission; PR = partial remission.
8.1.2   
Randomization and Stratification
Randomization and stratification are not applicable to this single-arm study.
8.1.3   
Populations for Analysis
The populations used for analysis will include the following:
Intent-to-Treat (ITT):  The ITT analysis population includes all patients enrolled in the 
study.  The ITT analysis population will be used for analysis of the primary efficacy 
endpoint.  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 analysis 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, 
and for patient demographics and baseline disease characteristics.  
Pharmacokinetic:  Patients with sufficient dosing and PK concentration-time data to 
reliably estimate PK parameters will be used for the PK analysis.
Biomarker:  Patients with sufficient dosing and sufficient blood samples for analysis of 
serum biomarkers will be included in the biomarker analysis population.
Additional details of analyses and analysis sets of patients may be defined in the SAP.
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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% CI will be presented for selected efficacy endpoints.  The standard survival 
analysis techniques of the Kaplan-Meier method will be utilized for time-to-event endpoints 
including duration of response, duration of response in the subset of patients with a CR, PFS
by IRF assessment, 
  
The primary efficacy analysis will use the ITT population.  Secondary and additional 
efficacy endpoints will also be analyzed using the ITT population.  
Detailed methodology will be provided in the SAP.
8.1.6.1   
Primary Efficacy Analysis
The primary efficacy endpoint is the overall ORR (CR + PR), by IRF assessment, in patients 
with relapsed or refractory classical HL who are considered to be not suitable for SCT or 
multiagent chemotherapy.  
The ORR by IRF assessment, and its two-sided 95% exact CI will be calculated by using the 
F distribution method.(27)  This endpoint may also be tabulated by covariates such as sex, age
(≤60 years and 60 years), race, categorized weight (≤100 kg and > 100 kg), prior 
treatment, and ECOG performance status score.  The maximum percent reduction in the sum 
of the products of the 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 for the per-protocol population.  
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The ORR (CR + PR), according to the investigator assessment and its two-sided 95% exact 
CI, will also be calculated.  
8.1.6.2   
Secondary Efficacy Analyses
The CR rate by IRF assessment will be derived and its two-sided 95% exact CI will be 
calculated by using the F distribution method.(27)  
Duration of response by IRF assessment, duration of response in the subset of patients with 
a CR, PFS by IRF assessment, and OS will be estimated by using the Kaplan-Meier 
methodology, and Kaplan-Meier plots will be provided.  The median duration of response
by IRF assessment, duration of response by IRF assessment in the subset of patients with a 
CR, PFS by IRF assessment, and OS and their two-sided 95% CI by Brookmeyer and 
Crowley(28) will be calculated.  These endpoints may also be summarized by covariates such 
as sex, age, race, categorized weight, prior treatment, and ECOG performance status score, 
etc.  
Descriptive statistics will be used to present the percentage of patients receiving SCT after
treatment with brentuximab vedotin.  
These efficacy endpoints, according to the investigator assessment will be similarly 
analyzed.
8.1.6.3   
Additional Efficacy Analyses
Analysis of Other Efficacy Endpoints
PFS from the most recent prior treatment versus PFS as determined by the investigator from
the current study will be presented by a Kaplan-Meier plot.  
will be analyzed in the 
same manner.
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8.1.8   
Pharmacokinetics/Biomarkers
Pharmacokinetic Analysis
The PK of MMAE and total antibody (free antibody and ADC) will be derived from serum 
or plasma concentrations versus time data for all patients who met study inclusion criteria, 
received the study drug, and had evaluable and adequate PK data.  The reporting of PK
parameters will be determined on the basis of final parameter analysis on the available data.
Immunogenicity
All patients who receive at least 1 dose of brentuximab vedotin will be evaluated for ATA 
development.  A list/table of ATA status will be provided.  ATA 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.
8.1.9   
Safety Analysis
The safety population will be used for all safety analyses.  
8.1.9.1   
Adverse Events
Safety will be evaluated by the incidence of AEs, treatment-emergent AEs, severity and type 
of AEs, the summary of ECOG performance status score, and by changes from baseline in 
the patient’s vital signs, weight, and clinical laboratory results.  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), 
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severity, and relationship to study drug.  The relationship to study drug 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 for
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.
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 scores will be summarized.  
All medications taken by patients during the study will be recorded.  Concomitant 
medications will be summarized by the WHO Drug Dictionary substance name.  A listing of
all concomitant taken by patients 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 at screening will be provided for each patient.
8.1.10   
Interim Analysis
No formal interim analysis is planned for this study.  
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9.   
STUDY COMMITTEES 
9.1   
Data Safety Monitoring Board
An independent data monitoring committee (IDMC) will not be required for this single-arm
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.
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.
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
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 
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 14 June 2010.(26)  Clarification should be made 
between a serious AE (SAE) and an AE that is considered severe in intensity (Grade 3 or 
Grade 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 Grade 4) does not necessarily need to be 
considered serious.  For example, a white blood cell count of 1000/µL to less than 2000/L
is considered Grade 3 (severe) but may not be considered serious.  Seriousness (not 
intensity) serves as a guide for defining regulatory reporting obligations.
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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 
Millennium 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 Millennium, 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 
Millennium.  SAE report information must be consistent with the data provided on the 
eCRF.
SAE and Pregnancy Reporting Contact Information
please refer to Section 15.4
Planned hospital admissions or surgical procedures for an illness or disease that existed
before the patient was enrolled in the study are not to be considered to be AEs unless the 
condition deteriorated in an unexpected manner during the study (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 14 June 2010.(26)  The criteria are provided in the Study 
Manual.
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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, will be monitored throughout the study as follows:  

AEs will be reported from the time of administration of the first dose of the study 
drug through 30 days after administration of the last dose of study drug and recorded 
in the eCRFs.  All events relating to peripheral neuropathy, regardless of seriousness, 
will be followed for all changes in severity until the resolution to baseline or study 
closure, whichever occurs first, and recorded in the eCRF.  

SAEs that occur pretreatment will be reported to the Millennium Department of 
Pharmacovigilance or designee from the time of the signing of the ICF up to the time 
of administration of the first dose of study drug, but will not be recorded in the 
eCRF.

Related and unrelated SAEs will be reported to the Millennium Department of 
Pharmacovigilance or designee from administration of 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 Millennium
Department of Pharmacovigilance or designee.  SAEs should be monitored until they 
are resolved or are clearly determined to be due to a patient’s stable or chronic 
condition or intercurrent illness(es).
10.4   
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study, she must inform the investigator immediately and permanently discontinue study 
drug.  The sponsor must also be contacted immediately by faxing a completed Pregnancy 
Form to the Millennium 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 Millennium Department of Pharmacovigilance or 
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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, 
web-based electronic data capture (EDC) application.  Millennium 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 
Millennium 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.
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Millennium, 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 Millennium 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.   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.
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11.8  
Investigator Compliance
The investigator will conduct the clinical study in compliance with the protocol provided by 
Millennium 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 Millennium. 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.  Millennium, 
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 Millennium, or a designee, if 
circumstances 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 Millennium 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 study 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 Millennium, or a designee (or disposal of 
the drug, if approved by Millennium) will be maintained by the clinical site.  Millennium 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 and Medication Errors
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 
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should be maintained in accordance with the label instructions pending further guidance 
from a Millennium Quality representative.
A medication error is a preventable event that involves an identifiable patient and that leads 
to inappropriate medication use, which may result in patient harm.  While overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not.  
Individuals who identify a potential medication error situation should immediately contact 
MedComm Solutions (see below) and report the event.
For Product Complaints and Medication Errors,
call MedComm Solutions at
1-510-740-1273 (international number)
1-866-835-2233 (for US sites)
Product complaints and medication errors in and of themselves are not AEs.  If a product 
complaint or medication error results in an SAE, an SAE form should be completed and sent 
to PPD (refer to Section 10.2).
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 study 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 Millennium, there is sufficient reasonable cause.  
Written notification documenting the reason for study termination will be provided to the 
investigator or Millennium 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
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
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 Millennium once the site’s participation in the study has concluded.
Within 15 days of premature closure, Millennium 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 
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 
Millennium notified.  
12.   
USE OF INFORMATION
All information regarding brentuximab vedotin supplied by Millennium 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 
Millennium.  It is understood that there is an obligation to provide Millennium 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 Millennium, the hospital 
or institution and/or investigator may publish or disclose the clinical study results pursuant 
to the terms contained in the applicable Clinical Trial Agreement.
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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 Millennium 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 Millennium.
A prepublication manuscript or abstract is to be provided to Millennium a minimum of 
30 days before the intended submission date of the manuscript or abstract to a publisher.  
Within 30 days after receipt by Millennium of the notification, Millennium shall inform the
study centers whether it has objections to the publication for reasons including, but not
limited to, those defined as follows:

If patentable subject matter is disclosed, the publication shall be delayed for a period 
not to exceed 90 days from Millennium’s receipt of the proposed publication to 
allow time for the filing of patent applications covering patentable subject matter. 

If confidential information is contained in any proposed publication or public 
disclosure, such confidential information will be removed at Millennium’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 Millennium.
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13.   
INVESTIGATOR AGREEMENT
I have read Protocol C25007:  A Single-arm Study of Brentuximab Vedotin in Patients With 
Relapsed or Refractory Hodgkin Lymphoma Who Are Not Suitable for Stem Cell 
Transplantation or Multiagent Chemotherapy.  
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.   
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American Journal of Clinical Oncology 1982;5(6):649-55.
30.
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   
Response Definitions for Clinical Studies
Response
Definition
Nodal Masses
Spleen, Liver
Bone Marrow
CR
Disappearance of 
all evidence of 
disease
a. FDG-avid or PET 
positive prior to therapy; 
mass of any size
permitted if PET negative
b. Variably FDG-avid or 
PET negative; regression 
to normal size on CT.
Not palpable, 
nodules 
disappeared. 
Infiltrate cleared on 
repeat biopsy; if 
indeterminate by 
morphology, 
immunohistochemistry 
should be negative
PR
Regression of 
measurable 
disease and no 
new sites
≥50% decrease in SPD 
of up to 6 largest 
dominant masses; no 
increase in size of other 
nodes
a. FDG-avid or PET 
positive prior to therapy; 
1 or more PET positive at 
previously involved site
b. Variably FDG-avid or 
PET negative; regression 
on CT.
≥50% decrease in 
SPD of nodules 
(for single nodule 
in greatest 
transverse 
diameter); no 
increase in size of 
liver or spleen.
Irrelevant if positive 
prior to therapy; cell 
type should be 
specified
Stable 
disease or 
SD
Failure to attain 
CR/PR or PD
FDG-avid or PET 
positive prior to therapy; 
PET positive at prior sites 
of disease and no new 
sites on CT or PET
Variably FDG-avid or 
PET negative; no change 
in size of previous lesions 
on CT.  
--
--
Relapsed 
disease or 
PD
Any new lesion 
or increase by 
≥50% of 
previously 
involved sites 
from nadir
Appearance of a new 
lesion(s) 1.5 cm in any 
axis, ≥50% increase in 
SPD of more than 1 node, 
or ≥50% increase in 
longest diameter of a 
previously identifed node 
1 cm in short axis
Lesions PET positive if 
FDG-avid lymphoma or 
PET positive prior to 
therapy.
≥50% increase 
from nadir in the 
SPD of any 
previous lesions.
New or recurrent 
involvement.
Source:  Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised response 
criteria for malignant lymphoma. J Clin Oncol 2007;25(5):579-86.(1)  
Abbreviations:  CR = complete remission; CT = computed tomography; FDG = fluorodeoxyglucose; 
PD = progressive disease; PET = positron emission tomography; PR = partial remission; SPD = sum of 
the product of diameters; SD = stable disease.  
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15.2   
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.(29)
15.3   
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.(30)
15.4   
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)
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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)
3. Listen for tone/chime and menu; enter five digit WP access code listed beside 
applicable Worldwide access number in the following table.
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
China
Colombia
Cook Islands
Costa Rica
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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
Honduras
Hong Kong
Hungary
Iceland
India
Indonesia
Iran
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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
Nicaragua
Norway
Pakistan
Panama
Paraguay
Peru
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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
Trinidad & Tobago
Turkey
Turks & Caicos
Ukraine
United Arab Emirates
United Kingdom
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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 in table)
3. Listen for tone/chime and menu; enter five digit WP access code listed beside 
applicable worldwide access number provided in the table.
4. Note: Some fax machines may require pushing the “pause” or “add digit” or “star” 
button either 2 or 3
American Samoa 
Anguilla 
Antigua 
Argentina 
Aruba
Austria
Australia
Bahamas
Bahrain
Bangladesh
Barbados
Belarus
Belgium
Brazil
British Virgin Islands
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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
Ghana
Greece
Grenada
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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
Monaco
Montserrat
Morocco
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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
St. Vincent
Sweden
Switzerland
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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
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ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A Single-arm Study of Brentuximab Vedotin in Patients With Relapsed or Refractory
Hodgkin Lymphoma and Not Suitable for Stem Cell Transplantation or Multiagent
Chemotherapy
Clinical Approval
12-Jul-2013 14:17
Clinical Approval
15-Jul-2013 21:06
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f Use
PPD

SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Single-arm Study of Brentuximab Vedotin in Patients With Relapsed or Refractory 
Hodgkin Lymphoma Who Are Not Suitable for Stem Cell Transplantation or Multiagent 
Chemotherapy
NCT Number: NCT01990534
SAP Approve Date: 22 February 2016
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


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Brentuximab vedotin (SGN-35)
Statistical Analysis Plan, Study C25007
2
TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.........................................4
1. INTRODUCTION............................................................................................................6
1.1 Study Design..............................................................................................................6
1.2 Study Objectives ........................................................................................................7
1.2.1 Primary Objectives ..............................................................................................7
1.2.2 Secondary Objectives...........................................................................................7
1.2.3 Tertiary/Exploratory Objectives ...........................................................................7
2. POPULATIONS FOR ANALYSIS..................................................................................8
2.1 Intent-to-Treat Population...........................................................................................8
2.2 Per-Protocol Population..............................................................................................8
2.3 Safety Population .......................................................................................................8
2.4 Pharmacokinetics Population......................................................................................9
2.5 Biomarker Population.................................................................................................9
3. HYPOTHESES AND DECISION RULES.......................................................................9
4. INTERIM ANALYSIS.....................................................................................................9
5. STATISTICAL METHODOLOGY .................................................................................9
5.1 Sample Size Justification............................................................................................9
5.2 Randomization and Stratification..............................................................................10
5.3 Unblinding ...............................................................................................................10
5.4 Data Handling ..........................................................................................................10
5.4.1 Methods for Handling Missing Data...................................................................10
5.4.2 Definition of Baseline Values ............................................................................10
5.4.3 Windowing of Visits..........................................................................................11
5.4.4 Justification of Pooling ......................................................................................11
5.4.5 Withdrawals, Dropouts, Loss to Follow-up ........................................................11
5.5 Patient Disposition ...................................................................................................11
5.6 Demographics and Baseline Disease Characteristics.................................................11
5.6.1 Demographics....................................................................................................11
5.6.2 Medical History.................................................................................................12
5.7 Treatments and Medications .....................................................................................12
5.7.1 Concomitant Medications ..................................................................................12
5.7.2 Study Treatments...............................................................................................12
5.8 Efficacy Analyses.....................................................................................................14
5.8.1 Primary Efficacy Endpoint.................................................................................14
5.8.2 Secondary Efficacy Endpoints ...........................................................................14
5.8.3 Other Efficacy Endpoints...................................................................................17
5.9 Pharmacokinetic, Pharmacodynamic, and Biomarker Analysis .................................18
5.9.1 Pharmacokinetic Analyses .................................................................................18
5.9.2 Immunogenicity Analysis ..................................................................................18
5.9.3 Biomarker Analysis ...........................................................................................18
5.10
........................................................................19
5.11 Safety Analyses ......................................................................................................19
5.11.1 Adverse Events................................................................................................19
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.6
.......7
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5.8
5.5
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5.11.2 Laboratory Data...............................................................................................21
5.11.3 Electrocardiogram............................................................................................22
5.11.4 Vital Signs .......................................................................................................22
5.11.5 Other Safety Assessments ................................................................................22
6. CHANGES TO PLANNED ANALYSES FROM PROTOCOL .....................................23
7. PROGRAMMING CONSIDERATIONS .......................................................................23
7.1 Statistical Software...................................................................................................23
7.2 Rules and Definitions ...............................................................................................23
8. REFERENCES...............................................................................................................23
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Statistical Analysis Plan, Study C25007
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List of Abbreviations and Definitions of Terms
Abbreviation
Term
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCT
autologous stem cell transplantation
AST
aspartate aminotransferase
ATA
antitherapeutic antibodies
BMI 
body mass index
BUN
blood urea nitrogen
CO2
carbon dioxide
CSR
clinical study report
CT
computed tomography
DOR
duration of response 
DOCR
duration of response in the subset of patients achieving complete remission
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EOT
end of treatment
GGT
gamma-glutamyl transpeptidase
HL
Hodgkin lymphoma
HLT
High Level Term
IRF
independent review facility
ITT
intent-to-treat
IV
intravenous; intravenously
IVRS
interactive voice response system
IWG
International Working Group
IWRS
interactive web response system
LDH
lactic dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
MMAE
monomethylauristatin E 
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
ORR
objective response rate
OS
overall survival
PD
progressive disease (disease progression)
PFS
progression-free survival
Property of Takeda: For non-com
rcial use only and subject to the applicable Terms of Use
subset of 
bset o
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report form
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Statistical Analysis Plan, Study C25007
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Abbreviation
Term
PK
pharmacokinetic(s)
PP
per protocol
PR
partial response
PT
Preferred Term
SAE
serious adverse event
SAP
statistical analysis plan 
SCT
stem cell transplantation
SD
stable disease
SOC
System Organ Class
SPD
sum of the products of the largest diameters
TEAE
treatment-emergent adverse event
WHO
World Health Organization
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CCI
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Statistical Analysis Plan, Study C25007
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1.
INTRODUCTION
In general, the purpose of the Statistical Analysis Plan (SAP) is to provide a framework that 
addresses the protocol objectives in a statistically rigorous fashion, with minimized bias or 
analytical deficiencies. Specifically, this plan has the following purpose:
To prospectively (a priori) outline the types of analyses and data presentations that addresses 
the study objectives outlined in the protocol, and to explain in detail how the data will be 
handled and analyzed, adhering to commonly accepted standards and practices of 
biostatistical analysis in the pharmaceutical industry.
1.1
Study Design
This phase 4, single-arm, multicenter study is designed to evaluate the efficacy and safety of 
brentuximab vedotin in adult patients 18 years or older with histologically confirmed 
CD30+ relapsed or refractory classical Hodgkin Lymphoma (HL) who have not received a 
prior stem cell transplantation (SCT) and are considered to be not suitable for SCT or 
multiagent chemotherapy at the time of study entry.
Brentuximab vedotin will be administered as a single, outpatient, 1.8-mg/kg intravenous 
(IV) infusion 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 complete remission,
partial remission and stable disease (SD). Overall response will be assessed by independent 
review facility (IRF) according to the International Working Group (IWG) Revised 
Response Criteria for Malignant Lymphoma [1]. Patients who experience disease 
progression at any time will discontinue the study drug, and will continue to be followed for 
overall survival (OS).
Patients may continue on study treatment until disease progression or unacceptable toxicity.
Patients will have an End of Treatment (EOT) assessment 30 ± 7 days after receiving their 
final dose of study drug. Patients who discontinue study treatment with SD or better will 
have computed tomography (CT) scans done every 3 months for 18 months from EOT or 
until the sooner of disease progression, death, or study closure. For patients who complete 
the 18-month progression-free survival (PFS) follow-up assessment period with a complete 
response (CR), a partial response (PR), or SD, a CT scan will be performed during the OS 
follow-up period at the time of disease progression, and the results will be sent to the IRF. 
Post-treatment follow-up assessments for OS will be performed every 3 months for 18 
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Brentuximab vedotin (SGN-35)
Statistical Analysis Plan, Study C25007
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months after the EOT; thereafter, assessment for OS will continue every 6 months until the 
sooner of death, study closure, or 5 years after enrollment of the last patient.
1.2
Study Objectives
1.2.1
Primary Objectives
The primary objective is:
!
To assess the antitumor efficacy, as determined by the objective response rate (ORR) 
of single-agent brentuximab vedotin 1.8 mg/kg administered IV every 3 weeks, in 
patients with relapsed or refractory classical HL who are considered to be not 
suitable for SCT or multiagent chemotherapy.
1.2.2
Secondary Objectives
The secondary objectives include:
!
To determine the duration of tumor control, including duration of response (DOR), 
PFS, and CR rate, by IRF assessment after treatment with brentuximab vedotin
!
To determine the proportion of patients who receive hematopoietic SCT,  either 
autologous stem cell transplantation (ASCT) or allogeneic stem cell transplantation 
(alloSCT) after treatment with brentuximab vedotin 
!
To determine OS after treatment with brentuximab vedotin
!
To assess the safety and tolerability of brentuximab vedotin in this patient population
!
To assess the pharmacokinetics (PK) of brentuximab vedotin
!
To determine the immunogenicity of brentuximab vedotin
1.2.3
Tertiary/Exploratory Objectives
Property 
eda: For non-commercial use only and subject to the applicable Terms of Use
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Brentuximab vedotin (SGN-35)
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2.
POPULATIONS FOR ANALYSIS
2.1
Intent-to-Treat Population
The Intent-to-Treat (ITT) analysis population includes all patients enrolled in the study. 
A patient is considered to be enrolled in the study when enrolled in the interactive voice 
response system (IVRS) or in the interactive Web response system (IWRS). Procedures for 
completion of the enrollment information are described in the Study Manual.
The ITT analysis population will be used for the primary efficacy analysis. Secondary and 
additional efficacy endpoints will also be analyzed using this population.
2.2
Per-Protocol Population
The Per-Protocol (PP) 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 analysis of the primary efficacy 
endpoint. 
2.3
Safety Population
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.
Property of Takeda: For non-commercial use only and subject to the ap
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Statistical Analysis Plan, Study C25007
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2.4
Pharmacokinetics Population
Patients who receive at least 1 dose of brentuximab vedotinand have PK concentration data 
available will be included in the PK analysis population.
PK analysis will be performed using PK population.
2.5
Biomarker Population
Patients who receive at least 1 dose of brentuximab vedotin and have biomarker data 
available will be included in the Biomarker analysis population. 
Biomarker analysis will be performed using Biomarker population.
3.
HYPOTHESES AND DECISION RULES
Not applicable.
4.
INTERIM ANALYSIS
No formal interim analysis is planned for this study.
5.
STATISTICAL METHODOLOGY
Statistical analyses will be primarily descriptive and graphical. For continuous variables, 
descriptive statistics will be used including number (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.
5.1
Sample Size Justification
At least 60 patients with relapsed or refractory classical HL who are considered to be not 
suitable for SCT or multiagent chemotherapy will be enrolled in this study. With a sample 
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Brentuximab vedotin (SGN-35)
Statistical Analysis Plan, Study C25007
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size of 60 patients and different ORRs, the two-sided 95% CIs will vary. An example is 
shown (Table 5.a).
Table 5.a
Overall Objective Response Rates and 95% Confidence 
Intervals (N=60)
Response Rate, %
Number of Responders (CR or PR)
95% CI, %
20
12
(11, 32)
30
18
(19, 43)
40
24
(27, 53)
50
30
(37, 63)
60
36
(47, 72)
Abbreviations: CI=confidence interval; CR=complete response; PR=partial response. 
5.2
Randomization and Stratification 
This is an open-label, single-arm study. Randomization and stratification are not applicable 
to this study.
5.3
Unblinding
This is an open-label, single-arm study; investigators and patients will know their individual 
treatment assignment. Unblinding is not applicable to this study.
5.4
Data Handling
5.4.1
Methods for Handling Missing Data
All available efficacy and safety data will be included in data listings and tabulations. The 
relevance of missing sample data will be assessed. Data that are potentially spurious or 
erroneous will be examined according to standard data management operating procedures.
In general, missing data will be treated as missing, and no data imputation will be applied 
unless otherwise specified.
5.4.2
Definition of Baseline Values
Unless otherwise specified, the baseline value is defined as the value collected at the time 
closest to, but before, the start of study drug administration. 
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5.4.3
Windowing of Visits
All data will be categorized based on the scheduled visit at which they were collected. 
These visit designators are predefined values that appear as part of the visit tab in the 
electronic case report form (eCRF). 
5.4.4
Justification of Pooling
All data from all sites will be pooled. Study center or treatment-by-center interaction will 
not be included in any statistical analysis due to the rarity of the disease and potentially 
limited number of patients at each center.
5.4.5
Withdrawals, Dropouts, Loss to Follow-up
Enrolled patients who do not receive study drug for any reason will not be replaced. Patient 
enrollment will continue until at least 60 patients with relapsed or refractory HL who are 
considered to be not suitable for SCT or multiagent chemotherapy are available for analysis 
of the primary study endpoint, ORR (CR + PR).
5.5
Patient Disposition
Patient disposition will be summarized. The disposition of patients includes the number and 
percentage of patients for each analysis population (ITT population, PP population, safety 
population, PK population, and biomarker population) in the study. 
The number and percentage of patients who completed the study treatment will be 
summarized. The primary reason for treatment and study discontinuation will also be 
summarized in this table. 
A listing will be presented of data concerning patient disposition.
5.6
Demographics and Baseline Disease Characteristics
5.6.1
Demographics
Demographic, baseline characteristics and prior therapies will be summarized using 
descriptive statistics for safety population. 
Demographics to be evaluated will include age at informed consent, sex, ethnicity, race, 
baseline height, weight, and body mass index (BMI). 
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The formulation for BMI is:
BMI = weight/height2,
where weight is in kilograms (kg) and height in meters (m).
Baseline characteristics and prior therapies to be evaluated will include disease type, Eastern 
Cooperative Oncology Group (ECOG) performance status, time from initial HL diagnosis to 
first dose of brentuximab vedotin, the sum of the products of the largest diameters (SPD) of 
the nodes or nodal masses being followed for response assessment per IRF,
 
 or the evidence of bone marrow involvement, Ann
Arbor Stage at initial diagnosis, and other parameters as appropriate.
No inferential statistics will be generated.
A listing of demographic data will be provided.
5.6.2
Medical History
No table or listing is planned to be produced for general medical history in this study.
5.7
Treatments and Medications
5.7.1
Concomitant Medications
Concomitant medications will be coded by generic term using the World Health 
Organization (WHO) Drug Dictionary. The number and percentage of patients taking 
concomitant medications from signing informed consent form through 30 days after the last 
dose of study drug will be tabulated using WHO drug generic term. A listing of all 
concomitant mediations taken by patients will be provided.
Concomitant procedures will not be coded.
5.7.2
Study Treatments
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 
of 8 cycles and, all patients will be given the opportunity to complete a maximum of up to 
16 cycles of brentuximab vedotin. Patients with an objective response, either a CR or a PR, 
and who are eligible for an SCT may discontinue receiving brentuximab vedotin and 
proceed to an SCT. These patients should receive at least 4 cycles of brentuximab vedotin 
before proceeding to SCT.
Property of Takeda: For non-commercial use only and subject to the applic
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Brentuximab vedotin (SGN-35)
Statistical Analysis Plan, Study C25007
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Brentuximab vedotin should be administered through a dedicated IV line and cannot be 
mixed with other medications. Details on the dosing of study drug can be found in the 
protocol and Pharmacy Manual.
5.7.2.1
Extent of Exposure
The exposure to study drug will be characterized by duration of treatment, total amount of 
dose taken in mg, total number of doses taken, number of treated cycles, and average dose 
per cycle in mg. Dose intensity and relative dose intensity (%) will be derived and 
summarized.
A treatment cycle is defined as a 3-week period, during which the patient received any 
amount of brentuximab vedotin (scheduled for a single dose on Day 1 of the 3-week cycle).
The duration of treatment is defined as time from the first study dose to 3 weeks after the 
last study dose: Duration of Treatment = last dose date + 3 weeks – first dose date. If death 
occurs less than 3 weeks after the last study dose, duration of treatment is defined as (date of 
death – first dose date +1 day). If discontinuation of the study drug occurs less than  3 weeks
after the last study dose due to reasons including but not limited to progressive disease (PD), 
initiating SCT, etc, duration of treatment is defined as (date of EOT – first dose date +1
day). The amount of dose taken in mg for each cycle will be calculated as:
prepared dose in mg × (actual volume / prepared volume).
Dose intensity (mg/week) will be calculated as:
actual total dose administered (mg)/(3 × number of treated cycles).
Relative dose intensity (%) will be calculated as:
100% × (Total dose administered (mg) / Total dose expected (mg)).
where the dose expected for each cycle is the standard lose level (1.8 mg/kg) × the body 
weight used for the dosing calculation.
All extent-of-exposure data will be summarized as continuous variables for brentuximab 
vedotin in the safety population.
The number and percentage of patients whose dose was ever modified will be summarized 
for each type of modification by cycle and overall.
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5.8
Efficacy Analyses
All efficacy analysis will use the ITT population unless otherwise specified.
5.8.1
Primary Efficacy Endpoint
The primary endpoint of this study is ORR per IRF in SCT-naïve patients with relapsed or 
refractory classical HL who are considered to be not suitable for SCT or multiagent 
chemotherapy. 
ORR is defined as the proportion of patients with CR or PR according to the International 
Working Group (IWG) Revised Response Criteria for Malignant Lymphoma (Cheson 2007). 
ORR per IRF is based upon the response assessment from an independent review facility. 
5.8.1.1
Primary Efficacy Analysis
The ORR per IRF and its two-sided 95% exact confidence interval will be calculated. The 
primary analysis will be performed using the ITT population. The same analysis will be 
performed using the per-protocol population.
The maximum percent reduction in the SPD of the nodes or nodal masses being followed for 
response assessment per IRF will be graphically displayed.
The ORR per investigator and its two-sided 95% exact confidence interval will also be 
calculated. The concordance of objective responses between assessments by IRF and 
investigator will be tabulated.
As exploratory analyses, subgroup analyses will be conducted for ORR using sex, age (<65 
years, ≥65 years), race, categorized weight (≤ 100 kg, > 100 kg), number of prior cancer-
related treatments (1, >1), ECOG performance status score at baseline (0,1), 
 
 and other variables as appropriate. The subgroup analyses will 
be conducted for IRF assessment and investigator assessment.
5.8.2
Secondary Efficacy Endpoints
Complete remission rate is defined as the proportion of patients with CR according to the 
International Working Group (IWG) Revised Response Criteria for Malignant Lymphoma 
(Cheson 2007). CR per IRF is based upon the response assessment from an independent 
review facility. 
Property of Takeda
 non-commercial use only and subject to the applicable Terms of Use
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Duration of response (DOR) is defined as the time between initial response and documented 
tumor progression. DOR per IRF is based upon the radiological assessment of measured 
lesions from an independent review facility. DOR will only be calculated for the subgroup 
of patients with CR or PR. DOR will also be analyzed in the subset of patients achieving 
CR.
Progression-free survival is defined as the time from start of study treatment to first 
documentation of objective tumor progression or to death due to any cause, whichever 
comes first. PFS per IRF is based upon the radiological assessment from an independent 
review facility.
Overall survival is defined as the time from start of study treatment to date of death due to 
any cause. In the absence of confirmation of death, survival time will be censored at the last 
date the patient is known to be alive, including study closure. Patients lacking data beyond 
the day of first dose for patients who have at least 1 dose of study drug, or inform consent 
for patients who are enrolled but not dosed, will have their survival time censored at 1 day.
Another secondary efficacy endpoint is the proportion of patients receiving hematopoietic 
stem cell transplantation (SCT, either autologous or allogeneic) after brentuximab vedotin 
therapy.
5.8.2.1
Handling of Censoring for Analysis of Progression-Free Survival
Disease assessment data (PFS and response) should be collected according to the intended 
schedule of assessment, and the date of PD/response should be assigned based on the time of 
the first documentation of PD/response regardless of violations, discontinuation of study 
treatment, or initiation of a new subsequent anti-cancer therapy. 
Patients who discontinue the study treatment with a CR, a PR, or SD will have CT scans 
performed for assessment of PFS every 3 months for 18 months after the patient’s EOT or 
until the sooner of disease progression (PD), death, or study closure.
For PFS, patients will be censored on the date of the last disease assessment documenting 
absence of PD for patients who are lost to follow-up, withdraw consent, start the 
subsequently new anti-cancer therapy other than stem cell transplant, or discontinue 
treatment due to undocumented PD after the last adequate disease assessment. Patients 
lacking an evaluation of tumor response after their first dose will have their event time 
censored at 1 day.
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Brentuximab vedotin (SGN-35)
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If PD is documented between scheduled visits, then the date of the documented PD is the 
date of progression. 
5.8.2.2
Secondary Efficacy Analysis
CR per IRF will be derived and its two-sided 95% exact confidence interval will be 
calculated. 
DOR per IRF, DOR per IRF in the subset of patients achieving CR (DOCR), PFS per IRF,
and overall survival will be estimated using Kaplan-Meier methodology and Kaplan-Meier 
plots will be provided. If estimable, the 25th percentile, median, and 75th percentile DOR per 
IRF, DOCR per IRF, PFS per IRF, OS and their two-sided 95% CI will be calculated, along 
with the minimum and maximum values. The median follow-up based on the reverse 
Kaplan-Meier will be provided. The censoring rules for these endpoints will be similar to 
PFS. These endpoints may also be summarized by subgroups as appropriate The subgroup 
analyses for ORR will be applied to PFS and OS. The investigator assessment of CR, DOR, 
DOCR and PFS will be analyzed in the same manner.
PFS from the most recent prior treatment before the initiation of the study drug versus PFS 
from the current study treatment will be presented via Kaplan-Meier and water-fall plot. The 
investigator assessment will be used for this analysis.
The primary analysis for PFS will use the censoring rules defined in Section 5.8.2.1. To 
evaluate the robustness of treatment effects, the following sensitivity analyses are also 
planned for PFS.

Patients who start the subsequently new anti-cancer therapy other than stem cell 
transplantation before PD will not be censored, nor be treated progressed at the date 
of the last disease assessment, until documented disease progression. Patients will be 
treated as progressed at the date of documented disease progression.

Patients who start new alternative anti-cancer therapy before PD will be treated as 
progressed at the date of the last disease assessment.
To investigate the patient characteristics, PFS will be also presented by the baseline bone 
marrow involvement using Kaplan-Meier plot.
To evaluate the relationship between PFS/OS and best response, the Kaplan-Meier plots will 
be displayed for PFS by IRF, PFS by investigator and OS, by best response. 
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Brentuximab vedotin (SGN-35)
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In addition, descriptive statistics will be used to present percent of patients receiving stem 
cell transplantationtation (SCT) following treatment with brentuximab vedotin.
5.8.3
Other Efficacy Endpoints 
5.8.3.1
Other Efficacy Analysis
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5.9
Pharmacokinetic, Pharmacodynamic, and Biomarker Analysis
5.9.1
Pharmacokinetic Analyses
The PK of the antibody drug-conjugate (brentuximab vedotin), total antibody, and 
unconjugated drug (MMAE) will be derived from serum or plasma concentration versus 
time data for all patients who met study inclusion criteria for the PK population ( received 
study drug, and provided evaluable analyte concentration data). Summary statistics of each 
analyte concentration-time data will be performed. Concentrations of analytes obtained in 
this study may be combined with those of other studies and be used in population PK 
analysis. Output of such data may or may not be available at the time of writing the clinical 
study report (CSR) for this study. Such data may be used in the summary of clinical 
pharmacology section of regulatory submission that includes information from this study.
5.9.2
Immunogenicity Analysis
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. Confirmed 
ATA positive response will be separated into transient (1 or 2 post baseline confirmed ATA 
positive responses) and persistent (more than tow post baseline confirmed ATA positive 
responses). The confirmed ATA positive sample titers will be separated into high, moderate 
and low titers. The relationship between immunogenicity and efficacy and/or safety will be 
explored, including the efficacy and/or safety end points by ATA status, such as best 
response, PFS, and infusion-related treatment - emergent adverse event
Immunogenicity analysis will be performed using safety population.
5.9.3
Biomarker Analysis
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5.11
Safety Analyses
Safety evaluations will be based on the incidence of treatment- emergent adverse events 
(TEAEs), severity and type of TEAE), and clinically significant changes, or abnormalities in 
the subject’s physical examination, vital signs, weight and clinical laboratory results. 
Exposure to study drug and reasons for discontinuation will be tabulated. Total dose, 
duration of treatment and dose modifications will be summarized.
These analyses will be performed using the safety population.
5.11.1
Adverse Events
5.11.1.1
Adverse Events
Overall summary of TEAEs will be presented. TEAEs will be tabulated by primary System 
Organ Class (SOC), High Level Term (HLT), and Preferred Term (PT). All AEs will be 
listed for each patient. 
A TEAE is defined as any AE that occurs after administration of the first dose of study drug 
and up through 30 days after the last dose of study drug. If the date of onset/stop is missing, 
the following rules will be used for the imputation.
Property of Takeda: For non-commercial use only and subject t
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For missing or partial AE onset dates: They will be estimated using following rules:
Non-
missing 
Missing
Estimated
Month and 
Year
Day
Day of first dose date of STUDY DRUG, if month and year of onset date are 
the same as month and year of date of first dose.
The last day of the month, if the month and year of onset date are before the 
month and year of date of first dose of STUDY DRUG.
The first day of the month, if the month and year of onset date are after the 
month and year of date of first dose of STUDY DRUG.
Year
Day and 
Month
Day and month of first dose date of STUDY DRUG, if the year of onset date 
is the same as the year of date of first dose of STUDY DRUG.
December 31st, if the year of onset date is prior to the year of date of first 
dose of STUDY DRUG.
January 1st, if the year of onset date is after the year of date of first dose of 
STUDY DRUG.
Day, Month 
and Year
Date of first dose of STUDY DRUG
For missing or partial AE stop dates: If only day missing, use 15th of the month; if month 
and day are missing, use June 30th. For a record with start date and partial stop date, if 
estimated stop date is before the start date, the stop date will not be estimated (i.e. leave 
estimated stop date missing).
If AE stop date is not missing and AE stop date < estimated onset date, let estimated onset 
date = AE stop date. 
All dates presented in listings are recorded dates without imputation.
AEs will be tabulated according to the most recent version (Version 17.0or higher) of the 
Medical Dictionary for Regulatory Activities (MedDRA) by SOC, HLT, and PT and will 
include the following categories: 

TEAEs

Study drug-related TEAEs

Grade 3 or higher TEAEs

Grade 3 or higher drug-related TEAEs

AEs of peripheral neuropathy identified by the broad search MedDRA SMQ 
“Peripheral neuropathy”
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The most commonly reported TEAEs (i.e., those events reported by 5% of all patients) 
will be tabulated by PT. TEAEs leading to study drug dose modification will be summarized 
in the same manner.
TEAEs will be also summarized by SOC, HLT, PT and intensity.
Infusion-related TEAEs will be summarized by PT.
5.11.1.2
Serious Adverse Events
The number and percentage of subjects experiencing at least 1 treatment-emergent serious 
adverse event (SAE) including study drug-related SAEs, will be summarized by MedDRA 
primary SOC, HLT, and PT.
In addition, a by-subject listing of the SAEs will be presented (the subject listing will 
contain all SAEs regardless of treatment-emergent status).
5.11.1.3
Deaths
A by-subject listing of the deaths will be presented. All deaths occurring on-study and 
during follow-up will be displayed (regardless of treatment-emergent status). On-study death 
is defined as a death that occurs between the first dose of study drug and 30 days after the 
last dose of study drug.
5.11.1.4
Adverse Events Resulting in Discontinuation of Study Drug
TEAEs leading to study drug discontinuation will be tabulated by SOC and PT. 
A by-subject listing of AEs resulting in discontinuation of study drug will be presented. 
5.11.2
Laboratory Data
For the purposes of summarization in both the tables and listings, all laboratory values will 
be converted to standardized units. If a lab value is reported using a nonnumeric qualifier 
(e.g., less than (<) a certain value, or greater than (>) a certain value), the given numeric 
value will be used in the summary statistics, ignoring the nonnumeric qualifier. 
If a subject has repeated laboratory values for a given time point, the value from the last 
evaluation will be used.
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The parameters to be analyzed are as follows:

Hematology: hemoglobin, hematocrit, platelet count, leukocytes with differential, 
and neutrophils (absolute neutrophil count [ANC]), 

Serum chemistry: blood urea nitrogen (BUN), creatinine, bilirubin (total), urate, 
lactate dehydrogenase (LDH), phosphate, gamma-glutamyl-transferase (GGT), 
albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), glucose, sodium, potassium, calcium, chloride, carbon 
dioxide (CO2), and magnesium
Descriptive statistics for the actual values of clinical laboratory parameters (hematology and 
serum chemistry) will be presented at baseline and over time. Mean laboratory values over 
time will be plotted for key laboratory parameters. 
Summary statistics for change from baseline of clinical laboratory parameters will also be 
presented.
Shift tables for laboratory parameters will be generated based on changes in National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade from 
baseline to the worst post-baseline value.
The data from central laboratory will be used for the analysis.
5.11.3
Electrocardiogram
A listing of electrocardiogram (ECG) results will be provided for each patient by visit.
5.11.4
Vital Signs
The actual values of vital sign parameters, including seated (after 3-5 minutes in this 
position) measurements of diastolic and systolic blood pressure, heart rate, and body 
temperature, when available, will be summarized over time. 
5.11.5
Other Safety Assessments
5.11.5.1
ECOG Performance Status
ECOG status will be summarized. 
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5.11.5.2
Concomitant Medications
All medications taken during the study will be recorded. Concomitant medications will be 
summarized by the WHO generic term.
6.
CHANGES TO PLANNED ANALYSES FROM PROTOCOL
Not applicable
7.
PROGRAMMING CONSIDERATIONS
7.1
Statistical Software 
SAS version 9.1 (or higher) will be used for all analyses. 
7.2
Rules and Definitions
Subject populations are defined in Section 2.
Baseline values are defined in Section 5.4.2.
Treatment-emergent AEs are defined in Section 5.11.1.1.
8.
REFERENCES
1.
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. 
Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25(5):579-86.
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