A Randomized, Open-label, Phase 3 Trial of A+AVD Versus ABVD as Frontline Therapy in Patients With Advanced Classical Hodgkin Lymphoma
Phase: PHASE3
Conditions: Hodgkin Lymphoma
Sponsor: Takeda

This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

•
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: 
NCT Number: NCT01712490
Protocol Approve Date:  02 March 2015
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable information or 
company confidential information. 
Proprietary information, such as scales or coding systems, which are considered confidential
information under prior agreements with license holder.
A Randomized, Open-label, Phase 3 Trial of A+AVD Versus ABVD as Frontline 
Therapy in Patients With Advanced Classical Hodgkin Lymphoma

Brentuximab vedotin (ADCETRIS®)
Clinical Study Protocol C25003 Amendment 7, EudraCT:  2011-005450-60
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CLINICAL STUDY PROTOCOL C25003 AMENDMENT 7
Brentuximab vedotin
A Randomized, Open-label, Phase 3 Trial of A+AVD Versus ABVD as Frontline Therapy in 
Patients With Advanced Classical Hodgkin Lymphoma
Protocol Number:
C25003
Indication:
Treatment-naïve advanced Hodgkin lymphoma
Phase:
3
Sponsor:
Millennium Pharmaceuticals, Inc.
EudraCT Number:
2011-005450-60
Therapeutic Area:
Oncology
Protocol History
Original
29 March 2012
Amendment 1
14 May 2012
Amendment 2
01 June 2012
Amendment 3
13 July 2012
Amendment 4
03 August 2012
Amendment 5
06 February 2014
Amendment 6
27 May 2014
Amendment 7
02 March 2015
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street
Cambridge, MA  USA  02139
Telephone:  +1 (617) 679-7000
Approved by:
Note:  The electronic approval signatures may be found at the end of the document.
Signature
Date DD Month YYYY
Signature
Date DD Month YYYY
Signature
Date DD Month YYYY
Confidentiality Statement
The information contained herein is confidential and the proprietary property of Millennium 
Pharmaceuticals and any unauthorized use or disclosure of such information without the prior 
written authorization of Millennium Pharmaceuticals is expressly prohibited.
PPD
PPD
PPD
PPD
PPD
PPD

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Rationale for Amendment 7
Amendment 7 facilitates the enrollment of an additional 200 patients into the study to increase 
the likelihood of observing 260 modified progression-free survival (mPFS) events. The 
increased enrollment is predicated upon revised estimates of mPFS event rates for both treatment 
arms in the study. This amendment also contains minor revisions and updates to improve 
protocol clarity and compliance and align study conduct with the sponsor’s current guidelines 
and practices.  
Purposes for Amendment 7
The purposes of this amendment are to:

Increase study enrollment.
o
Increase the sample size by 200 patients to a total of approximately 1240 enrolled
patients, and increase the anticipated enrollment period.
o
Increase enrollment to 620 patients per treatment arm, and increase the estimated
number of sites to 250 study sites globally.
o
Delete reference to the percentage of the original sample size that was planned for
inclusion in the interim futility analysis.
o
Revise the projected length of enrollment and follow-up periods.

Revise the statistical assumptions of mPFS rates for both treatment arms in the study.
o
Align the timing of the interim overall survival analysis with that for the final mPFS
analysis.
o
Revise the timing for the final analysis of overall survival.

Institute minor modifications in protocol language to improve protocol clarity and
compliance, and align study conduct with the sponsor’s current guidelines and practices.
o
Clarify and align the posttreatment follow-up assessments for PFS disease status,
event-free survival, and overall survival.
o
Clarify the PK sampling time points for the 50-patient subset in both treatment arms by
correcting the study day stated in the protocol.
o
Update the contact information for product complaints and medication errors.
o
Add the Global Statistical Lead to the list of approvers for the amended protocol.

Correct typographical errors, punctuation, grammar, and formatting, as applicable.
For specific examples of changes in text and where the changes are located, see Section 15.14.

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PROTOCOL SUMMARY
Study Title:  A Randomized, Open-label, Phase 3 Trial of A+AVD Versus ABVD as Frontline 
Therapy in Patients With Advanced Classical Hodgkin Lymphoma
Number of Patients:  620 patients randomized to each treatment arm, for 1240 patients total
Study Objectives
Primary
To compare the modified progression-free survival (mPFS) obtained with brentuximab
vedotin (ADCETRIS®) plus AVD (doxorubicin [Adriamycin], vinblastine, and dacarbazine;
abbreviated A+AVD) versus that obtained with ABVD (doxorubicin (Adriamycin),
bleomycin, vinblastine, and dacarbazine) for the frontline treatment of advanced classical
Hodgkin lymphoma (HL)
Key Secondary
To determine if A+AVD improves overall survival (OS) versus that obtained with ABVD
Other Secondary
To determine if A+AVD improves complete remission (CR) rate versus that obtained with
ABVD
To determine the safety profile of A+AVD relative to that of ABVD
To determine the event-free survival (EFS) obtained with A+AVD and ABVD
To determine the disease-free survival (DFS) rate obtained with A+AVD and ABVD
To determine if A+AVD improves overall objective response rate (ORR, defined as CR +
partial response [PR]) versus that obtained with ABVD
To determine the duration of response (DOR) and duration of complete remission (DOCR)
obtained in the A+AVD and ABVD arms
To determine the rate of patients receiving irradiation for HL not in complete remission in the
A+AVD and ABVD arms
To determine the rate of patients in CR at the end of frontline therapy in the A+AVD and
ABVD arms
To determine the rate of Cycle 2 positron emission tomography (PET) negativity in patients
treated with A+AVD versus those treated with ABVD
To determine if A+AVD improves health-related quality of life (HRQOL) versus ABVD
To describe the pharmacokinetics (PK) of brentuximab vedotin, monomethyl auristatin E
(MMAE), and total antibody (TAb) in blood
To determine the immunogenicity of brentuximab vedotin
Exploratory
To investigate any differences in lung-specific patient reported outcomes (PROs) between the
treatment arms

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! To assess any impact of brentuximab vedotin dosing on serum concentrations of AVD
! To investigate any differences between the treatment arms in the rate of patients alive without
HL at 3 and 5 years (see Section 8.1.6.3 for definition)
! To assess changes in tumor biomarker expression before and after treatment
!
! To assess other PROs
! To assess medical resource utilization
! To assess fertility
Overview of Study Design:  
This open-label, randomized, 2-arm, multicenter, phase 3 study has the primary objective of 
comparing the mPFS obtained with A+AVD against that obtained with ABVD.  
! A+AVD:  Brentuximab vedotin 1.2 mg/kg, plus doxorubicin 25 mg/m2, vinblastine 6 mg/m2,
dacarbazine (DTIC) 375 mg/m2.
! ABVD:  Doxorubicin 25 mg/m2, bleomycin 10 units/m2, vinblastine 6 mg/m2, DTIC
375 mg/m2.
For this study, the definition of PFS has been modified to include the receipt of anticancer 
chemotherapy or radiotherapy for patients not in CR after the completion of frontline therapy as a 
progression event in addition to the customary events of disease progression or death due to any 
cause.  Computed tomography (CT) and PET scans for mPFS disease assessment will be read by a 
blinded independent review facility (IRF).
The study will enroll approximately 1240 patients; enrollment is anticipated to last 3 years.  All 
enrolled patients must have a histologically confirmed diagnosis of Stage III or IV classical HL that 
has not been previously treated with systemic chemotherapy or radiotherapy.  Patients will be 
stratified by region (Americas vs Europe vs Asia) and number of International Prognostic Factor 
Project (IPFP) risk factors (0-1 vs 2-3 vs 4-7).
Patients will be randomized 1:1 into 1 of 2 treatment arms, for a total of approximately 620 patients 
per arm.  A+AVD and ABVD will be administered intravenously on Days 1 and 15 of each 28-day 
cycle.  Brentuximab vedotin will be administered intravenously over 30 minutes at a dose of 
1.2 mg/kg; the brentuximab vedotin infusion is to be started within approximately 1 hour after 
completion of AVD therapy.  PET scan results at Cycle 2 Day 25 will be used to guide an optional 
switch to physician’s choice of alternative therapy for those patients with a Deauville score of 5.
Patients may receive up to 6 cycles of planned study therapy (A+AVD or ABVD). Radiotherapy is 
permitted for those patients in partial remission at conclusion of frontline therapy with a persistent 
PET-positive mass, however, receipt of such radiotherapy will be counted as an mPFS progression 
event for patients who are confirmed noncomplete responders per IRF.
An interim futility analysis will be conducted when the first approximately 348 patients have 
completed the regimen to which they were randomized (ie, received the planned study drug regimen 
with no more than 2 missed doses of A+AVD or ABVD) or have discontinued treatment prior to 
completion.  The study will use an independent data monitoring committee (IDMC); 
recommendation to terminate the study would be based on evaluation of the overall safety 
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information and efficacy data (CR rate per IRF for the A+AVD arm at least 5% lower than that of 
the ABVD arm, with trends toward inferior A+AVD efficacy for mPFS and other efficacy 
parameters).
The final analysis of the mPFS primary endpoint will be conducted when 260 mPFS events occur,
approximately 2 years after randomization of the last patient; an interim efficacy analysis of OS will 
also be conducted at that time.  The final analysis of OS will be conducted when 112 deaths occur, 
approximately 4 years after randomization of the last patient.
Study Population:
Treatment-naïve patients with HL and Ann Arbor Stage III or IV disease are eligible for the study.
Patients must have histologically confirmed classical HL according to the current World Health 
Organisation Classification (nodular sclerosis, mixed cellularity, lymphocyte rich, lymphocyte 
depleted, or classical Hodgkin lymphoma, NOS [not otherwise specified]).
Patients with any sensory or motor peripheral neuropathy are excluded, as are those with nodular 
lymphocyte predominant HL.
Duration of Study:  The study will last approximately 60 months to reach the final analysis of the 
mPFS endpoint (approximately 36 months of enrollment plus 24 months of additional follow-up 
after the last patient is randomized).  Patients will be followed for survival until death or the end of 
posttreatment follow-up (when 112 deaths occur, approximately 4 years from the date of the last 
patient randomized), whichever occurs first.  The total study duration is approximately 7 years.

Brentuximab vedotin (ADCETRIS®)
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STUDY OVERVIEW DIAGRAM

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SCHEDULE OF EVENTS
Screening
Enrollment
Cycle (C) Every 28 Days
EOT
PTFU a
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Day (D)
-28 to D1
Within 24
hours of 
first dose
D1
D2
D3
D 15
D1
D 15
D 25
D1
D2
D3
D 15
D1
D 15
D1
D 15
D1
D 15
30 ± 7 
days 
after last 
dose of  
frontline 
therapy
Every 3 
months 
for 36 
months 
and 
then 
every 6
months 
until 
study 
closure
Screening/ 
Baseline
Informed consent
X
Randomization
Inclusion/ exclusion
X
Demographics
X
Medical history
X
Tumor specimen 
Xb
IPFP
X
Safety 
Assessments
Height
X
Weight and BSA
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical exam
including focused 
lymphoma 
assessment 
X
Xc
X
X
X
X
X
X
X
Pregnancy test d
X
Xd
Vital signs e
X
Xe
Xe
X
X
X
X
X
X
X
X
X
X
X
ECOG 
performance status
X
X
X
X
X
X
X
Hematology and 
serum chemistry f
Xf
Xf
Xf
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
Quality of life 
(QOL) 
assessmentsg
X
Xg
X
X
X
X
X
X
Xg
Medical resource 
utilization
X
X
X
X
X
X
X
X

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Screening
Enrollment
Cycle (C) Every 28 Days
EOT
PTFU a
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Day (D)
-28 to D1
Within 24
hours of 
first dose
D1
D2
D3
D 15
D1
D 15
D 25
D1
D2
D3
D 15
D1
D 15
D1
D 15
D1
D 15
30 ± 7 
days 
after last 
dose of  
frontline 
therapy
Every 3 
months 
for 36 
months 
and 
then 
every 6
months 
until 
study 
closure
Monitoring of 
concomitant
medications and 
procedures
Concomitant medications and procedures will be recorded from signing the informed consent through 30 days after the last dose of Frontline 
Therapy
Adverse event 
reporting
Recorded from first dose of study drugs through 30 days after the last dose of Frontline Therapy
(Treatment-related adverse events must be followed until the sooner of resolution or study closure.  However, these AEs 
will only be recorded in the eCRF from first dose of study drugs through 30 days after the last dose of Frontline Therapy.)
All events related to peripheral neuropathy, regardless of seriousness, will be followed for all changes in severity until 
resolution to baseline or study closure, whichever occurs first, and recorded in the eCRF.  
Serious adverse 
eventsh
Serious adverse events will be collected from signing of the informed consent through 30 days after the last dose of Frontline Therapy
Disease Assessment
Tumor biopsyi
X
Xi
CT of chest, neck, 
abdomen, pelvisj
X
Xj
Xj
Xj
PETk
X
Xk
Xk
B symptom 
assessment
X
X
X
X
X
X
X
X
X
Survival/ disease 
status and 
anticancer
treatments for HL
Xl
Fertility 
Asses-
sment
Fertility 
assessmentm
Dates and outcomes of all pregnancies to be recorded from first dose of study drugs through end of study
Study 
Drug 
Admini
stra-
tion 
ABVD
or
A+AVDn
X
X
X
X
X
X
X
X
X
X
X
X

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Screening
Enrollment
Cycle (C) Every 28 Days
EOT
PTFU a
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Day (D)
-28 to D1
Within 24
hours of 
first dose
D1
D2
D3
D 15
D1
D 15
D 25
D1
D2
D3
D 15
D1
D 15
D1
D 15
D1
D 15
30 ± 7 
days 
after last 
dose of  
frontline 
therapy
Every 3 
months 
for 36 
months 
and 
then 
every 6
months 
until 
study 
closure
PK/PD
PK Sampleo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum biomarkers 
such as
 
X
X
X
X
X
X
X
Immunogenicityq
X
X
X
X
Germline DNAr
X
Abbreviations:  ATA=antitherapeutic antibodies; A+AVD=brentuximab vedotin (ADCETRIS®) plus doxorubicin, vinblastine and dacarbazine; ABVD=doxorubicin, 
bleomycin, vinblastine, and dacarbazine; BSA=body surface area; CT=computed tomography; CTACK=cutaneous T-cell-attracting chemokine; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOI=end of infusion; EOT=end of treatment; FDG=fluorodeoxyglucose; IL-6=interleukin-6;
IPFP=International Prognostic Factor Project; PD=pharmacodynamics; PET=positron emission tomography; PK=pharmacokinetics; PTFU=posttreatment follow-
up; TARC=thymus and activation-regulated chemokine.
Tests and procedures should be performed on schedule, but occasional changes are allowable (±3 days) for logistic reasons unless indicated otherwise.
a. All treated patients will be followed for progression-free survival disease status, event-free survival and overall survival every 12 weeks (±1 week) until 
36 months of PTFU and then every 6 months until study closure. For patients who have progressive disease, survival/disease status and information regarding 
the initiation of an alternative lymphoma treatment may be obtained by phone call.  Note: Radiological assessments are only required every 12 weeks (±1 week) 
until 12 months of PTFU and then every 6 months until study closure.  To assist with scheduling of visits, patients may begin to align the timing of their follow-up 
visits with the timing of the CT scans during PTFU, when applicable.
b. Tumor tissue collected at the time of original diagnosis or subsequent procedures (unstained slides or a formalin-fixed paraffin-embedded block) will be obtained 
after the patient has signed the informed consent form.  This will be used to assess biomarkers implicated in sensitivity or resistance to brentuximab vedotin or 
vinca alkyloids and taxanes (eg, p53, beta 3 tubulin, and ABCC transporters).  If archived tissue cannot be obtained, a biopsy should be performed at screening; 
refer to footnote “i.”
c. The Cycle 1 Day 1 physical examination is not required if the screening physical examination was conducted within 4 days before administration of the first dose  
CCI
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of study drug. A limited physical exam may be administered at the treating physician’s discretion.
d. A serum pregnancy test will be performed for women of childbearing potential during screening and again at Cycle 1, Day 1 (baseline).  A urine pregnancy test 
is required if the serum pregnancy test was not done within 4 days of the first dose of study drug.  The results must be negative within 4 days prior to the first
dose of brentuximab vedotin.  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. Vital signs should be measured at screening and within 1 hour prior to infusion of ABVD and AVD on Days 1 and 15 of each cycle and EOT.  All vital sign 
measurements include: systolic and diastolic blood pressure (sitting 3-5 minutes), heart rate and body temperature.  In Cycle 1 only (Days 1 and 15), vital signs 
should be recorded pre-dose and 1 hour post-dose (± 10 minutes).
f.
A blood sample for hematology and serum chemistry will be obtained at screening and predose at Days 1 and 15 of each cycle and EOT.
Hematology and chemistry blood samples for Cycle 1, Day 1 may be collected within 4 days prior to dosing to ensure patient eligibility on study Day 1.  In this 
situation it need not be repeated on Cycle 1, Day 1.
Hematology includes complete blood count (CBC) with differential consisting of the following:  hemoglobin, hematocrit, total white blood cell count (WBC), 
differential WBC count, absolute neutrophil count (ANC), and platelet count.  Machine counts are acceptable.  
Serum chemistry includes sodium, potassium, carbon dioxide, chloride, blood urea nitrogen (BUN), serum creatinine, bilirubin (total), alkaline phosphatase, 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), gamma glutamyl transferase, albumin, fasting glucose, 
urate, calcium, phosphate, and magnesium.  An Hb A1C measurement will be obtained at screening and at EOT.
g. All questionnaires should be completed on screening, Day 1 of every cycle (before any other study procedures are performed), 30 days after last dose of 
Frontline Therapy, and during posttreatment follow-up unless indicated otherwise (see table below).  If screening questionnaires were completed within 4 days 
before Cycle 1 Day 1, they do not need to be repeated on Cycle 1 Day 1.
Patient-reported outcomes will be evaluated using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, the FACIT-
Dyspnea 10 questionnaire, the EQ-5D questionnaire, and the Functional Assessment of Cancer Therapy—Neurotoxicity (FACT-Ntx; Abbreviated).
Patient Reported Outcomes
End of Collection Period
FACIT-Dyspnea 10 Item Short Form
Collected until EOT
FACT-Ntx Abbreviated
Collected until EOT
EuroQOL EQ-5D (Utility Measurement)
Collected until 3 years post last dose of frontline 
therapy or development of confirmed 
progressive disease (PD), whichever occurs first
EORTC QLQ-C30
Collected at all patient visits (as outlined in the 
SOE table), including visits during the PTFU, 
until the final visit by the patient
h. Includes serious pretreatment events.  Serious pretreatment events will be reported to Millennium Department of Pharmacovigilance & Risk Management or 
designee from the time of signing ICF up to first dose of study drug, but will not be recorded in the eCRF.

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i. Patients who cannot provide at least 10 histological slides from their diagnostic biopsy will undergo a new tumor biopsy during screening, which may be obtained 
up to 14 days prior to the first dose of study drug.  Patients who have an archived tumor specimen/ histological slides as previously mentioned, will not need to 
undergo a biopsy at the time of screening.
Efforts should be made to obtain a tumor biopsy at the time of disease progression for patients in the A+AVD arm.  Additional on-study biopsies will be optional 
and may be used to test for other salient pharmacodynamic and genomic markers related to the 
j. Response to treatment and disease status assessments will be evaluated according to the Revised Response Criteria for Malignant Lymphomas (Cheson 2007) 
and confirmed by an independent review facility. MRI scans may be substituted for CT scans only if a patient 1) has a glomerular filtration rate of less than 
60 mL/min such that IV contrast presents a risk of renal failure, 2) develops anaphylaxis to IV contrast, or 3) becomes pregnant during posttreatment follow-up.  
If use of MRI is required, a consistent scanning modality must be maintained.
During the treatment phase CT scans will be performed at:
!
Screening
!
After Cycle 2: On C2D25 (∀1 day).  This corresponds to 10 days (∀1 day) after the 4th dose (after C2D15) of study drug administration
!
After last dose of frontline therapy (usually Cycle 6): between 3 and 7 weeks following last dose of frontline therapy.  In addition, patients who switch 
therapy prior to completion of frontline therapy must have a scan performed prior to the first dose of alternative treatment.
!
During the follow-up period: every 3 months for the first year and then every 6 months thereafter.  The CT scan time points are calculated from C1D1.
*The actual time points for CT scans during PTFU will be based on calendar days.
PTFU Scan Number
CT Scan Time Points (Calendar days)
Corresponding Year
1
Day 302 ∀7 days
Year 1
2
Day 393 ∀7 days
3
Day 484 ∀7 days
4
Day 575 ∀7 days
5
Day 757 ∀14 days
Year 2
6
Day 939 ∀14 days
7
Day 1121 ∀14 days
Year 3
8
Day 1303 ∀14 days
9
Day 1485 ∀14 days
Year 4
10
Day 1667 ∀14 days
11
Day 1849 ∀14 days
Year 5
12
Day 2031 ∀14 days
k. During the treatment phase PET scans will be performed at: 
!
Screening
!
After Cycle 2: On C2D25 (∀1 day). This corresponds to 10 days (∀1 day) after the 4th dose (after C2D15) of study drug administration
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
After last dose of frontline therapy (usually Cycle 6): between 3 and 7 weeks following last dose of frontline therapy.  In addition, patients who switch 
therapy prior to completion of randomized treatment must have a scan performed prior to the first dose of alternative treatment.
l.  Subjects will be followed for survival disease status every 3 months for 36 months and then every 6 months until death /study closure
m.  Fertility is being assessed as an exploratory endpoint independent of safety reporting.
n.   Brentuximab vedotin will be administered intravenously at a dose of 1.2 mg/kg within approximately 1 hour after completion of AVD therapy.  For patients 
whose frontline therapy is switched to physician’s choice, regimen details will be recorded.
o.   Pharmacokinetics will be assessed as indicated in the tables below.
Pharmacokinetic Sampling Time Points
Cycle
Study Day
Time
Window
Relative Time
Full A+AVD Arm
1-6
1
Predose
Within prior 4 hr
Start of brentuximab vedotin infusion
EOI (~30 min)
Within 1 hour post EOI
End of brentuximab vedotin infusion
15
Predose
Within prior 4 hr
Start of brentuximab vedotin infusion
EOI (~30 min)
Within 1 hour post EOI
End of brentuximab vedotin infusion
1 and 3, in 
addition
2
24 hr
±4 hr
Start of brentuximab vedotin infusion
3
48 hr
±4 hr
Start of brentuximab vedotin infusion
50 Patient Subset Arm:  In addition to the above time points, the below pharmacokinetic time points will be drawn from 
50 recruited patients from each treatment arm (total of 100 patients).
A.
PK Sampling Time Points for the 50-patient Subset of A+AVD Arm Group. 
1 and 3
1
2 min
±2 min
End of doxorubicin infusion
2 min
±2 min
End of vinblastine infusion
2 min
±2 min
End of dacarbazine infusion
1 hr
±5 min
End of brentuximab vedotin infusion
6 hr
±10 min
End of brentuximab vedotin infusion
8
168 hr
±24 hr
End of brentuximab vedotin infusion

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Pharmacokinetic Sampling Time Points
Cycle
Study Day
Time
Window
Relative Time
B.
Additional PK Sampling Time Points for the 50-patient Subset of ABVD Arm Group.  
1 and 3
1
Predose
Within prior 4 hr
Start of doxorubicin infusion
2 min
±2 min
End of doxorubicin infusion
2 min
±2 min
End of vinblastine infusion
2 min
±2 min
End of dacarbazine infusion
1 hr
±5 min
End of dacarbazine infusion
6 hr
±10 min
End of dacarbazine infusion
2
24 hr
±4 hr
End of dacarbazine infusion
8
168 hr
±24 hr
End of dacarbazine infusion
Abbreviations:  A+AVD = brentuximab vedotin (ADCETRIS®) plus doxorubicin, vinblastine, and dacarbazine; ABVD = doxorubicin, bleomycin, vinblastine, and 
dacarbazine; EOI = end of infusion; hr = hour; min = minutes.
*The 50 patients in each treatment arm from whom additional PK samples are drawn will be recruited from sites that agree to participate. In addition, 
approximately 20 patients in each 50-patient intensive-sampling group must be of Asian race.
p. Serum samples will be collected predose on Day 1 of each cycle, and at EOT in all patients to evaluate protein markers such as 
 
(circulating protein markers).
q. Immunogenicity samples will be collected for patients in the A+AVD arm only before dosing on Day 1 of Cycle 1, Cycle 2, and Cycle 6; or at termination if 
treatment is terminated before Cycle 6.
r. Optional germline DNA will be collected on Cycle 1 Day 1 predose for patients in the A+AVD arm only.
CCI

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TABLE OF CONTENTS
LIST OF TABLES.............................................................................................................17
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ..........................................17
1. BACKGROUND AND STUDY RATIONALE..............................................................21
1.1 Scientific Background ..............................................................................................21
1.1.1 Disease Under Treatment...................................................................................21
1.1.2 Study Drug ........................................................................................................21
1.2 Nonclinical Experience.............................................................................................22
1.3 Clinical Experience ..................................................................................................23
1.4 Study Rationale ........................................................................................................27
1.5 Potential Risks and Benefits .....................................................................................29
2. STUDY OBJECTIVES ..................................................................................................32
2.1 Primary Objective.....................................................................................................32
2.2 Secondary Objectives ...............................................................................................32
2.3 Exploratory Objectives .............................................................................................33
3. STUDY ENDPOINTS....................................................................................................34
3.1 Primary Endpoints....................................................................................................34
3.2 Secondary Endpoints................................................................................................34
3.3 Exploratory Endpoints..............................................................................................35
4. STUDY DESIGN...........................................................................................................36
4.1 Overview of Study Design........................................................................................36
4.2 Number of Patients...................................................................................................38
4.3 Duration of Study.....................................................................................................38
5. STUDY POPULATION.................................................................................................38
5.1 Inclusion Criteria......................................................................................................38
5.2 Exclusion Criteria.....................................................................................................40
6. STUDY DRUG..............................................................................................................42
6.1 ABVD Administration..............................................................................................43
6.2 A+AVD Administration ...........................................................................................43
6.3 Dose-Modification Guidelines..................................................................................44
6.3.1 Recommended Brentuximab Vedotin Dose Modifications for 
Treatment-Associated Toxicity....................................................................44
6.3.2 Reference Therapy Dose Modifications..............................................................45
6.3.3 Excluded Concomitant Medications and Procedures ..........................................45
6.4 Permitted Concomitant Medications and Procedures.................................................46
6.5 Precautions and Restrictions .....................................................................................46
6.6 Management of Clinical Events................................................................................48
6.7 Blinding and Unblinding ..........................................................................................49
6.8 Description of Investigational Agents.......................................................................49
6.9 Preparation, Reconstitution, and Dispensation ..........................................................50
6.10 Packaging and Labeling..........................................................................................50
6.11 Storage, Handling, and Accountability....................................................................50
7. STUDY CONDUCT ......................................................................................................51
7.1 Study Personnel and Organizations...........................................................................51
7.2 Arrangements for Recruitment of Patients ................................................................52

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7.3 Treatment Group Assignments .................................................................................52
7.4 Study Procedures......................................................................................................52
7.4.1 Informed Consent ..............................................................................................52
7.4.2 Patient Demographics ........................................................................................52
7.4.3 Medical History.................................................................................................52
7.4.4 Physical Examination.........................................................................................52
7.4.5 Patient Height, Weight, and Body Surface Area.................................................53
7.4.6 Vital Signs .........................................................................................................53
7.4.7 Pregnancy Test ..................................................................................................53
7.4.8 Concomitant Medications and Procedures..........................................................53
7.4.9 Adverse events...................................................................................................53
7.4.10 Enrollment .......................................................................................................54
7.4.11 Electrocardiograms ..........................................................................................54
7.4.12 Clinical Laboratory Evaluations.......................................................................54
7.4.13 Disease Assessment .........................................................................................55
7.4.14 Patient-Reported Outcomes..............................................................................56
7.4.15 Utility Measurement ........................................................................................56
7.4.16 Medical Resource Utilization Data Collection..................................................56
7.4.17 Cost Assessment ..............................................................................................57
7.4.18 Tumor Biopsies................................................................................................57
7.4.19 Pharmacokinetic Measurements.......................................................................57
7.4.20 Serum Biomarkers ...........................................................................................59
7.4.21 Immunogenicity Measurements........................................................................59
7.4.22 Germline DNA Polymorphism Assessment......................................................59
7.4.23 Fertility Assessment.........................................................................................60
7.5 Completion of Treatment..........................................................................................60
7.6 Completion of Study.................................................................................................60
7.7 Discontinuation of Treatment With Study Drug, and Patient Replacement................60
7.8 Withdrawal of Patients From Study..........................................................................62
7.9 Study Compliance ....................................................................................................62
7.10 Posttreatment Follow-up Assessments ....................................................................62
8. STATISTICAL AND QUANTITATIVE ANALYSES ..................................................63
8.1 Statistical Methods ...................................................................................................63
8.1.1 Determination of Sample Size............................................................................64
8.1.2 Randomization and Stratification .......................................................................64
8.1.3 Populations for Analysis ....................................................................................64
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data...........................65
8.1.5 Demographic and Baseline Characteristics.........................................................65
8.1.6 Efficacy Analysis...............................................................................................65
8.1.7 Analyses of Patient-Reported Outcomes and Health Economics.........................68
8.1.8 Pharmacokinetics/Pharmacodynamics/Biomarkers.............................................69
8.1.9 Safety Analysis ..................................................................................................70
8.1.10 Interim Analyses..............................................................................................72
9. STUDY COMMITTEES................................................................................................72
9.1 Data Safety Monitoring Board..................................................................................72
10. ADVERSE EVENTS ...................................................................................................73

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10.1 Definitions..............................................................................................................73
10.1.1 Pretreatment Event Definition..........................................................................73
10.1.2 Adverse Event Definition.................................................................................73
10.1.3 Serious Adverse Event Definition ....................................................................73
10.2 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events.................................................................................................74
10.3 Monitoring of Adverse Events and Period of Observation.......................................76
10.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events........77
11. ADMINISTRATIVE REQUIREMENTS .....................................................................78
11.1 Good Clinical Practice............................................................................................78
11.2 Data Quality Assurance ..........................................................................................78
11.3 Electronic Case Report Form Completion...............................................................78
11.4 Study Monitoring ...................................................................................................79
11.5 Ethical Considerations............................................................................................79
11.6 Patient Information and Informed Consent..............................................................79
11.7 Patient Confidentiality............................................................................................79
11.8 Investigator Compliance.........................................................................................80
11.9 On-site Audits ........................................................................................................80
11.10 Investigator and Site Responsibility for Drug Accountability................................80
11.11 Product Complaints and Medication Errors...........................................................80
11.12 Closure of the Study .............................................................................................81
11.13 Record Retention..................................................................................................82
12. USE OF INFORMATION............................................................................................82
13. INVESTIGATOR AGREEMENT................................................................................84
14. REFERENCES.............................................................................................................85
15. APPENDICES .............................................................................................................88
15.1 Ann Arbor Staging System for Hodgkin Lymphoma...............................................88
15.2 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status.........88
15.3 Cockcroft-Gault Equation.......................................................................................89
15.4 New York Heart Association Classification of Cardiac Disease ..............................89
15.5 International Prognostic Factors Scoring for Advanced Hodgkin Lymphoma..........89
15.6 Deauville Criteria for PET......................................................................................90
15.7 Body Surface Area Nomogram...............................................................................90
15.8 Amendment 1 Rationale and Purposes....................................................................91
15.9 Amendment 2 Rationale and Purposes....................................................................93
15.10 Amendment 3 Rationale and Purposes..................................................................94
15.11 Amendment 4 Rationale and Purposes..................................................................95
15.12 Amendment 5 Rationale and Purpose....................................................................96
15.13 Amendment 6 Rationale and Purpose....................................................................98
15.14 Amendment 7 Detailed Summary of Changes.......................................................99

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LIST OF TABLES
Table 6-1   
Recommended A+AVD Dose Modifications for Treatment-Associated 
Toxicity ......................................................................................................45
Table 7-1   
Pharmacokinetic Sampling Time Points ......................................................58
Table 8-1   
Completion of Frontline Therapy ................................................................66
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
A+AVD
brentuximab vedotin (ADCETRIS®) plus doxorubicin (Adriamycin), 
vinblastine, dacarbazine
ABVD
doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine
ADC
antibody-drug conjugate
AE
adverse event
ALCL
anaplastic large cell lymphoma
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
ARDS
acute respiratory distress syndrome
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
AVD
doxorubicin (Adriamycin), vinblastine, and dacarbazine
BEACOPP
bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, 
vincristine, procarbazine, and prednisone
BPT
bleomycin pulmonary toxicity
BSA
body surface area
BUN
blood urea nitrogen
CBC
complete blood count
CL
clearance
Cmax
maximum plasma concentration
CO2
carbon dioxide
CR
complete remission
CR(u)
unconfirmed complete response

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Abbreviation
Term
CT
computed tomography
CTACK
cutaneous T-cell-attracting chemokine
CYP
cytochrome P450
DLCO
carbon monoxide diffusion capacity
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DOCR
duration of complete remission
DOR
duration of response
DTIC
dacarbazine
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EORTC
European Organisation for Research and Treatment of Cancer
EOS
End of Study (visit)
EOT
End of Treatment (visit)
ESMO
European Society for Medical Oncology
EU
European Union
FDA
(United States) Food and Drug Administration
FDG
fluorodeoxyglucose
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GGT
gamma glutamyl transferase
GHSG
German Hodgkin Study Group
GI
gastrointestinal
GLP
Good Laboratory Practices
GM-CSF
granulocyte macrophage-colony stimulating factor
GMP
Good Manufacturing Practice
Hb
hemoglobin
Hct
hematocrit
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HNSTD
highest nonseverely toxic dose
HRQOL
health-related quality of life

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Abbreviation
Term
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
IL-6
interleukin-6
IPS
(Hasenclever) International Prognostic Score
IRB
institutional review board
IRF
independent review facility
ITT
intent-to-treat
IV
intravenous; intravenously
IXRS® (IVRS/IWRS)
interactive voice response system and/or interactive web response system
JCV
John Cunningham virus
LDH
lactate dehydrogenase
LFT
liver function test(s)
MedDRA
Medical Dictionary for Regulatory Activities
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
mPFS
modified progression-free survival
MRI
magnetic resonance imaging
MRU
medical resource utilization
MTD
maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NYHA
New York Heart Association
OS
overall survival
PCR
polymerase chain reaction
PD
progressive disease (disease progression)
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic(s)

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Abbreviation
Term
PML
progressive multifocal leukoencephalopathy
PN
peripheral neuropathy 
PR
partial response
PRO
patient-reported outcomes
QALY
quality-adjusted life year
QOL
quality of life
QTc
rate-corrected QT interval (millisec) of electrocardiograph
RBC
red blood cell
SAE
serious adverse event
SD
stable disease
SmPC
Summary of Product Characteristics
SPD
sum of the product of the (tumor) diameters
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life
TARC
thymus- and activation-regulated chemokine
TGD
tumor growth delay
TGI
tumor growth inhibition
Tmax
first time to maximum plasma concentration
UK
United Kingdom
ULN
upper limit of the normal range
US
United States
WBC
white blood cell
WHO
World Health Organization

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1.   
BACKGROUND AND STUDY RATIONALE
1.1   
Scientific Background
1.1.1   
Disease Under Treatment
Hodgkin lymphoma (HL), a neoplasm of lymphoid tissue, is histopathologically defined by 
the presence of malignant Hodgkin Reed-Sternberg (HRS) cells in a background of 
inflammatory cells.  The characteristic surface antigen expressed on HRS cells is CD30.  In 
2008 alone, it was estimated that approximately 8220 new cases of HL were diagnosed in 
the United States,(1) approximately 7709 new cases of HL were diagnosed in the 5 major EU 
countries (UK, France, Germany, Italy, and Spain),(2) and approximately 890 new cases of 
HL were diagnosed in Canada.(3)
Advanced HL, here defined as Ann Arbor Stage III or IV disease, is characterized by supra-
and sub-diaphragmatic or more widespread disease and is associated with diminished
survival.  Median overall survival (OS) in the more than 14,000-patient International 
Hodgkin Lymphoma Database(4) is approximately 9 years for patients with Stage IV disease
and approximately 18 years for patients with Stage III disease.  The Stage III and IV 
populations typically receive homogenous treatment modalities, providing fewer 
confounding factors for time-to-event endpoints.
1.1.2   
Study Drug
Brentuximab vedotin (ADCETRIS®, the first “A” of the experimental arm acronym) is an 
antibody-drug conjugate (ADC) composed of the anti-CD30 chimeric immunoglobulin G1 
(IgG1) monoclonal antibody cAC10 and the potent antimicrotubule drug monomethyl 
auristatin E connected by a protease-cleavable linker. cAC10 binds to the CD30 antigen, 
which has a very low expression on normal cells but is found on the HRS cells of HL, on 
anaplastic large cell lymphoma (ALCL) cells, and on tumor cells of other varied 
lymphoproliferative disorders.
Brentuximab vedotin in approved in the United States as ADCETRIS® for the treatment of 
patients with HL after failure of autologous stem cell transplant (ASCT) or after failure of at 
least 2 prior multi-agent chemotherapy regimens in patients who are not ASCT candidates 
and for the treatment of patients with systemic ALCL after failure of at least 1 prior 
multi-agent chemotherapy regimen.

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1.2   
Nonclinical Experience
Brentuximab vedotin has the potential to target and selectively deliver a potent cytotoxic to 
tumor cells. It induces cell death of both HL and ALCL cell lines in vitro with 
subnanomolar concentrations producing 50% inhibition (IC50) and has demonstrated 
antitumor activity in xenograft models of the same tumors.
Multiple-dose brentuximab vedotin toxicity studies have been performed in monkeys and 
rats.  In both species, hypocellularity of the bone marrow and lymphoid depletion of the 
thymus were observed.  In addition, lesions were seen in the kidneys, liver, and spleen in 
monkeys and in the liver and testes in rats.  Reversibility of toxicity was demonstrated for all 
of the findings with the exception of the testicular changes in rats.  At the recovery sacrifice 
4 weeks following the last dose of brentuximab vedotin, testicular changes (diffuse 
seminiferous tubule degeneration) were still evident.  The no observed adverse effect level
for brentuximab vedotin was defined at 1.0 mg/kg in monkeys and 0.5 mg/kg in rats.  
Human equivalent doses are 0.32 and 0.08 mg/kg, respectively.
In the L540cy tumor model,(5) administration of doxorubicin (Adriamycin), bleomycin, 
vinblastine, and dacarbazine (ABVD) plus brentuximab vedotin in tumor-bearing mice 
demonstrated significantly increased antitumor activity as compared to the mice treated with 
ABVD or brentuximab vedotin alone, suggesting a synergistic effect.(6)  ABVD and 
brentuximab vedotin-treated animals demonstrated 0/8 and 4/9 durable responses, 
respectively, while the combination of brentuximab vedotin and ABVD resulted in 9/9 
durable tumor regressions in all experimental animals. In addition, combination therapy was 
associated with a statistically significant tumor growth delay (TGD) relative to each 
treatment arm alone (combination vs brentuximab vedotin: P <0.0101, combination versus 
ABVD: P <0.0001). Improved efficacy in high tumor burden models suggests that 
combining brentuximab vedotin with ABVD may be associated with greater efficacy.
Similarly, when treatment was initiated when tumors reached 300 mm3 volume, the 
combination of brentuximab vedotin with ABVD significantly increased the TGD, resulting 
in durable responses in 5 of 10 animals. The delay in tumor growth induced by the 
combination treatment was highly significant relative to each individual treatment arm alone 
(combination versus brentuximab vedotin: P <0.05, combination versus ABVD: P <0.001).
Doxorubicin, vinblastine, and bleomycin had little if any single-agent antitumor activity in 
L540cy xenograft models and did not significantly improve antitumor activity of 
brentuximab vedotin when used in combination with the single-agent chemotherapy drugs 

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(data on file, Seattle Genetics).  Specifically, vinblastine had neither a synergistic nor an 
antagonistic effect when used in combination with brentuximab vedotin. Although 
vinblastine and auristatins are cell-cycle specific agents belonging to the vinca alkaloid 
family, they have slightly different mechanisms of action due to their interactions with 
different microtubule-associated proteins.(7)
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 safety and efficacy of brentuximab vedotin has been evaluated in more than 
450 patients with HL, sALCL, and other CD30+ hematologic malignancies in 11 clinical 
studies.  Clinical data have been collected from 2 completed phase 1 dose-escalation studies
(SG035-0001 and SG035-0002), a pivotal phase 2 study in relapsed or refractory HL after 
ASCT (SG035-0003), a pivotal phase 2 study in relapsed or refractory systemic ALCL 
(sALCL) (SG035-0004), and a phase 1, drug-drug interaction study (SGN35-008A).  
Preliminary and final analyses of safety data indicate that brentuximab vedotin has a 
manageable safety profile in the studied populations.
In Study SG035-0001, a total of 45 patients with CD30+ hematologic malignancies (42 with 
HL, 2 with sALCL, 1 with angioimmunoblastic T-cell lymphoma) were treated with 
brentuximab vedotin at doses of 0.1 to 3.6 mg/kg administered intravenously (IV) every 
3 weeks. The primary objectives of the study were to establish a maximum tolerated dose 
(MTD) of brentuximab vedotin and to assess the associated toxicity profile. The most 
common adverse events (AEs) were fatigue (36% of patients), pyrexia (33%), diarrhea, 
nausea, peripheral neuropathy, and neutropenia (22% each). Notable serious adverse events 
(SAEs) considered at least possibly related to treatment included anaphylaxis, myocardial 
infarction, and peripheral neuropathy. Numerous responses, including complete remissions
(CRs), were observed.  The MTD was determined to be 1.8 mg/kg administered IV over 
30 minutes every 3 weeks.
In Study SG035-0002, a total of 44 patients with CD30-positive hematologic malignancies 
(including 38 with HL) were treated with brentuximab vedotin at doses of 0.4 to 1.4 mg/kg 
administered IV weekly for 3 of 4 weeks. The primary objectives explored in this study 
were to establish the safety profile and MTD of weekly brentuximab vedotin monotherapy 
in patients with relapsed/refractory CD30+ hematologic malignancies. Although this 
weekly regimen was designed to enable combination use with gemcitabine, efficacy with 

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brentuximab vedotin monotherapy was deemed sufficient and the planned brentuximab 
vedotin/gemcitabine combination was not pursued.  The most common AEs 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). Treatment discontinuations due to AEs were observed in 30% of 
patients. The most frequent AE that led to dose modification or delay was peripheral 
sensory neuropathy. Acute infusion reaction AEs occurred in a total of 6 patients. Overall, 
these acute infusion reaction AEs were reported as less than Grade 2 and resolved. Overall, 
2 patients (14%) who had an acute infusion reaction also had antitherapeutic antibodies at 
any postbaseline visit.
In Study SG035-0003, a phase 2, single-arm, open-label study in patients with relapsed or 
refractory HL after ASCT, and Study SG035-0004, a phase 2 study conducted in patients 
with relapsed or refractory sALCL, brentuximab vedotin was administered at a dose of 
1.8 mg/kg every 3 weeks. One hundred two patients with relapsed and refractory HL and 
58 patients with relapsed and refractory sALCL were exposed for a median duration of 
approximately 27 weeks (9 cycles) and 20 weeks (6 cycles), respectively. Most patients 
(89%) in the 2 phase 2 studies were between the ages of 18 and 65 years. The primary 
endpoint of both studies was overall response rate (ORR) as assessed by an independent 
review facility (IRF). Key secondary endpoints included duration of response, CR rate per 
IRF, OS, and progression-free survival (PFS). The key efficacy results in HL (SG035-0003) 
include ORR per IRF (75% [95% confidence interval (CI): 64.9-82.6%]), CR rate per IRF 
(34% [95% CI: 25.2 44.6%]), B symptom resolution rate (77%), and duration of response 
(DOR; 6.7 months). Of interest, for those patients achieving a CR, the median DOR was 
20.5 months. Key efficacy endpoints in sALCL (SG035-0004) include ORR per IRF (88% 
[95% CI: 74.6-93.9%]), CR rate per IRF (53% [95% CI: 39.6-66.7%]), and B symptom 
resolution rate (82%).
Treatment-emergent AEs (TEAEs) occurring in ≥20% of patients in the phase 2 studies were 
peripheral sensory neuropathy (44%), fatigue (42%), nausea (41%), diarrhea (34%), pyrexia 
(31%), upper respiratory tract infection (28%), neutropenia (21%), and vomiting (20%).
These events were primarily mild to moderate and reversible. Approximately half of 
patients had treatment-emergent peripheral neuropathy, predominantly sensory neuropathy, 
with an onset and severity pattern consistent with a cumulative effect. Dose delay and 
subsequent reduction to 1.2 mg/kg was generally effective in managing peripheral 
neuropathy. Grade 3 and 4 neutropenia occurred in 13% and 7% of patients, respectively; 
these events were typically of short duration and well managed by brief dose delays with 

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growth factor support in some cases. Infusion-related reactions occurred in approximately 
10% of patients and were typically managed by dose interruption. Infusion-related reaction 
prophylaxis in subsequent treatment cycles was instituted at the discretion of the 
investigator. The clinical laboratory parameters for which the most patients had new or 
worsening shifts to ≥Grade 3 were low neutrophils (11%), lymphocytes (11%), platelets 
(6%), leukocytes (5%), and high glucose (6%). Only 1 patient in the phase 2 studies had 
Grade 3 alanine aminotransferase (ALT) and Grade 3 aspartate aminotransferase (AST).
In the phase 2 studies, 31% of patients had an SAE, 28% had a Grade 3 or higher SAE, and 
15% had an SAE that was determined by the investigator to be related to brentuximab 
vedotin. The most common SAE preferred terms (2%) were abdominal pain, disease 
progression (recurrent sALCL), pulmonary embolism, and septic shock. A higher 
proportion of patients with sALCL experienced SAEs, including deaths within 30 days of 
last dose, relative to patients with HL, likely due to the older age and more aggressive nature 
of the malignancy in this patient population.
A total of 9 deaths were reported within the safety evaluation period (within 30 days of the 
last dose of brentuximab vedotin) in 357 patients across the six phase 1 and phase 2 studies 
for which data are available. Two patient deaths (0.6%) were considered related to study 
treatment. One patient in Study SG035-0001 who received 3.6 mg/kg in phase 1 died due to 
febrile neutropenia and presumed septic shock. A second treatment-related death in 
Study SGN35-008A was attributed to pancytopenia, cytomegalovirus (CMV) infection, and 
intracranial hemorrhage. The remaining on-study deaths were primarily related to disease 
progression in patients with sALCL.
Brentuximab vedotin has been shown to induce durable remissions in patients with HL both 
pre- and post-ASCT, and in patients with relapsed or refractory sALCL.  PFS results 
comparing PFS after brentuximab vedotin with PFS from prior systemic therapy indicate 
that PFS is significantly prolonged with brentuximab vedotin for both HL and sALCL. A 
substantial number of patients with HL and sALCL and B symptoms at baseline saw these 
symptoms resolve during treatment with brentuximab vedotin.  In addition, the large 
majority of patients with sALCL presenting with cutaneous lesions at baseline experienced 
resolution of these symptoms after receiving brentuximab vedotin.
Study SGN35-009 is a phase 1, 2-arm, open-label, multicenter study to evaluate the safety of 
brentuximab vedotin when administered in combination with standard therapy (ABVD) or a 
modified standard (doxorubicin [Adriamycin], vinblastine, dacarbazine [AVD]).  To date, 

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patients have received doses of 0.6, 0.9, or 1.2 mg/kg brentuximab vedotin with standard 
doses of ABVD or 1.2 mg/kg brentuximab vedotin with AVD, depending upon cohort 
assignment.  The combination regimens are administered on Days 1 and 15 of each 28-day 
cycle for up to 6 cycles of therapy.  Each regimen evaluated a dose-limiting toxicity (DLT) 
period, defined as any Cycle 1 toxicity requiring a delay of ≥7 days in standard ABVD or 
AVD therapy.  No DLTs were observed.  Enrollment of an expansion cohort further testing 
1.2 mg/kg brentuximab vedotin plus AVD is now complete and treatment of enrolled 
patients is ongoing within this cohort.
Of the 51 patients enrolled in Study SGN35-009, the mean age was 34.8 (range 18-59); 47% 
of patients had Stage IV disease at diagnosis, and 25% had a Hasenclever Hodgkin’s 
Prognosis Score (IPS) ≥4.  A recent review of interim safety data as of 07 February 2012 for 
all 51 enrolled patients included data from 25 patients in the brentuximab vedotin plus 
ABVD cohorts and 26 patients in the brentuximab vedotin plus AVD cohorts.  The most 
commonly reported TEAEs were nausea, neutropenia, peripheral sensory neuropathy, 
fatigue, vomiting, constipation, alopecia, pyrexia, bone pain, decreased appetite, diarrhea, 
and insomnia, each reported in 25% or more patients.  Peripheral neuropathy events have 
been reported in 25 patients (49%); 1 patient had Grade 3 peripheral motor and sensory 
neuropathy, but no other patient’s peripheral neuropathy event exceeded Grade 2.  In the 
brentuximab vedotin plus ABVD cohorts, Grade ≥3 events included neutropenia (n=20, 
80%), febrile neutropenia (n=5), pulmonary toxicity (n=5), anemia (n=4), dyspnea (n=3), 
pulmonary embolism (n=3), syncope (n=3), and anorectal cellulitis, cough, fatigue, 
hypokalemia, hyponatremia, leukopenia, pericardial effusion, rash, and respiratory failure 
(n=1 each).  In the brentuximab vedotin plus AVD cohorts, Grade ≥3 events included 
neutropenia (n=17, 65%), anemia (n=3), febrile neutropenia (n=2), and decreased appetite, 
dyspnea, elevated ALT, fatigue, leukopenia, peripheral sensory and motor neuropathy, 
Pneumocystis jiroveci pneumonia, SIADH, syncope, and tooth abscess (n=1 each).
Interim efficacy data as of 07 February 2012 demonstrate that all patients who completed 
frontline therapy on study for whom response assessment results are available achieved a 
CR at the end of treatment, including 18 patients from the ABVD cohorts and 6 patients 
from the AVD cohorts.  Additionally, an exploratory analysis of interim fluorodeoxyglucose 
(FDG) positron emission tomography (PET) results after 2 cycles of therapy was performed 
by independent radiology review using the Deauville criteria.(8)  Of 37 patients, 36 (97%) 
had a negative interim PET after Cycle 2 by central review, including 22 of 22 (100%) 
negative in the ABVD cohorts and 14 of 15 (93%) negative in the AVD cohorts.

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Further details on these studies are provided in the IB.
1.4   
Study Rationale
Advances in the use of combined chemotherapy and radiotherapy over the past half century 
have dramatically improved outcomes for patients with HL. The most commonly used
frontline therapies, ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and 
BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, 
procarbazine, and prednisone), result in CRs in 72% to 90% of patients.(9, 10, 11) However, 
following frontline treatment with multimodality therapy, including combination 
chemotherapy and radiation, relapse is observed in up to 35% of advanced-stage cases. 
Also, 10% to 20% of patients are refractory to frontline treatment.(12, 13, 14)
The high CR rate and ORR obtained with brentuximab vedotin in 2 single-arm, phase 2 
studies in relapsed or refractory HL (SG035-0003) and relapsed or refractory sALCL 
(SG035-0004) suggest that its addition to frontline therapy may enhance efficacy in newly 
diagnosed HL.
Of the 4 agents in ABVD, bleomycin is the agent most associated with unpredictable, 
life-threatening toxicity and is thought to have the lowest single-agent activity.(15) Standard 
practice in patients who develop bleomycin pulmonary toxicity (BPT) is to continue 
frontline therapy with AVD while omitting bleomycin. Retrospective analyses of the 
Cancer and Leukemia Group B (CALGB) 8251 and 8952 studies have shown no difference 
in response or relapse rates for patients who had bleomycin discontinued at any point in their 
frontline therapy.(16) Furthermore, noninfectious pulmonary toxicity was observed in some 
patients treated with brentuximab vedotin in combination with bleomycin within the ABVD 
cohorts of Study SGN35-009.  The incidence of pulmonary toxicity in the brentuximab 
vedotin plus ABVD cohorts of the trial was approximately 44% (11 of 25 patients), 
compared with an incidence of 10% to 25% most commonly reported in the literature for
bleomycin-based regimens.(17, 18, 19)  Patients presented with cough and dyspnea.  Interstitial 
infiltration and/or inflammation were observed on radiographs and computed tomography
(CT) scans of the chest.  Six patients had a Grade 3 or higher event (3 with Grade 3, 2 with 
Grade 4, and 1 with Grade 5).  It was determined that concomitant administration of 
brentuximab vedotin and bleomycin is contraindicated due to pulmonary toxicity.  Of note, 
Study SGN35-009 patients who experienced pulmonary toxicity with brentuximab vedotin 
plus ABVD were permitted to discontinue bleomycin but resume therapy with brentuximab 
vedotin plus AVD.  Due to the proven antitumor activity and tolerability with single-agent 

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treatment, evaluation of brentuximab vedotin as a replacement for bleomycin in the AVD 
combination regimen is hypothesized to provide an improvement in PFS over the standard 
ABVD regimen, and eliminate the risk of bleomycin-associated pulmonary toxicity.
In ongoing Study SGN35-009, brentuximab vedotin is administered in combination with 
ABVD (doxorubicin 25 mg/m2, bleomycin 10 units/m2, vinblastine 6 mg/m2, dacarbazine 
[DTIC] 375 mg/m2) or in combination with AVD (doxorubicin 25 mg/m2, vinblastine 
6 mg/m2, DTIC 375 mg/m2) in 28-day cycles, with brentuximab vedotin administered on 
Days 1 and 15 of each cycle for up to 6 cycles of therapy.  Brentuximab vedotin was 
administered in combination with ABVD at doses of 0.6, 0.9, and 1.2 mg/kg (N=25) and 
was administered in combination with AVD at 1.2 mg/kg in dose cohorts of 6 or more 
patients (N=26). No DLTs were observed in any of the cohorts. Brentuximab vedotin 
monotherapy has previously been shown to be reasonably well tolerated in a phase 1 study 
and a phase 2 pivotal trial at 1.8 mg/kg in every-3-week dosing.  Because the 
pharmacokinetics (PK) of brentuximab vedotin are linear, PK modeling has shown that the 
administration of 1.2 mg/kg IV every 2 weeks or 1.8 mg/kg IV every 3 weeks should result 
in similar exposures (area under the plasma concentration versus time curve [AUC]). 
Therefore, given the tolerability and the expected PK profiles, it was determined that an 
appropriate dose level of brentuximab vedotin is 1.2 mg/kg delivered IV every 2 weeks and 
the recommended combination for further clinical development in phase 3 is with AVD 
(hereafter called A+AVD).  Furthermore, additional PK samples will be taken in the current 
study to allow further understanding of the PK of brentuximab vedotin and AVD when 
coadministered in frontline HL setting.
Regarding patients’ duration of therapy, functional imaging has recently changed how 
physicians determine the number of cycles of chemotherapy that patients with newly 
diagnosed HL receive. Prior to the widespread use of PET scanning, many patients with 
advanced stage HL appeared to have partial responses due to residual masses visible upon 
CT. This large category of partial responses or “complete responses, unconfirmed” (CRu) is 
now mostly eliminated with the use of PET scanning, which has shown that at least 75% of 
such patients assessed by CT actually have a CR when PET scanning is added,(20) and such 
patients with PET-negative residual masses have the same prognosis as patients with no 
residual mass.(21)  As there is no known benefit to continued chemotherapy for HL after 
achievement of CR, most patients will be assessable after 6 cycles and the very large 
majority will have reached a CR. For those patients with a PET-positive residual mass after 
6 cycles of chemotherapy, most clinicians would prefer to switch to radiation, thus also 
concluding frontline chemotherapy after 6 cycles. Therefore, information obtained by 

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functional imaging typically obviates the need for a flexible number of cycles (6-8), and 
European Society for Medical Oncology (ESMO) and other guidelines are in the process of 
being updated to reflect this evolving information.  Six cycles was thus selected as the 
duration of frontline therapy in this study.
Notably, this trial does not prospectively plan for patients, even those with bulky disease, to 
receive radiation therapy.  It instead follows the model recently presented by Engert et al as 
used in the German Hodgkin Study Group (GHSG) HD15 trial.(21) In that study, patients in 
partial response (PR) with a persistent mass measuring 2.5 cm or more upon completion of 
frontline chemotherapy were assessed by PET.  Only patients who were positive on 
centrally-reviewed PET scan received additional radiotherapy with 30Gy, yet these data 
show that frontline therapy was successful.  Although the GHSG HD15 study investigated 
3 various BEACOPP regimens, this approach to radiotherapy has also been recommended
for use with ABVD(22) and seems to strike an appropriate compromise between therapeutic 
benefit and reducing the risk of later malignancy secondary to radiation exposure.
1.5   
Potential Risks and Benefits
As detailed in Section 1.3, brentuximab vedotin monotherapy has demonstrated therapeutic 
activity in CD30+ hematological malignancies.
Brentuximab vedotin treatment causes a peripheral neuropathy that is predominantly 
sensory.  Cases of peripheral motor neuropathy have also been reported.  Brentuximab 
vedotin-induced peripheral neuropathy is typically cumulative and generally reversible. In 
the SG035-0003 and SG035-0004 clinical studies, 54% of patients experienced neuropathy
of any grade.  Of these patients, 49% had complete resolution, 31% had partial 
improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% 
had residual neuropathy at the time of their last evaluation. Monitoring patients for 
symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a 
burning sensation, neuropathic pain or weakness is required. Patients experiencing new or 
worsening peripheral neuropathy may require brentuximab vedotin dose modifications, 
including a dose delay (see Table 6-1).
Infusion-related reactions, including anaphylaxis, have occurred with brentuximab 
vedotin.(23)  Monitoring of patients during infusion is required. If anaphylaxis occurs, the 
administration of brentuximab vedotin should be immediately and permanently discontinued
and appropriate medical therapy administered. If an infusion-related reaction occurs, the 
infusion should be interrupted and appropriate medical management instituted. Patients who 

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have experienced a prior infusion-related reaction should be premedicated according to 
institutional guidelines for subsequent infusions. Premedication may include 
acetaminophen, an antihistamine and a corticosteroid.
Clinically significant laboratory abnormalities were to be reported as adverse events per the 
phase 2 study protocols. Central laboratory data were collected only predose for each 
treatment cycle. Few patients overall had postbaseline worsening to Grade 3 or higher in 
clinical laboratory values. The clinical laboratory parameters for which the most patients 
had new or worsening shifts to Grade 3 were low neutrophils (11%), lymphocytes (11%), 
platelets (6%), leukocytes (5%), and high glucose (6%). Only 1 patient in the phase 2 
studies had Grade 3 ALT and AST.
Any treatment that can decrease immune function may contribute to malignancy and 
infections; patients are to be monitored for these events during the treatment period and up 
to and including 30 days after the last dose of frontline therapy.
Complete blood counts should be monitored prior to each dose of brentuximab vedotin and 
more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia. 
Prolonged (≥1 week) severe neutropenia can occur. If Grade 3 or 4 neutropenia develops, 
manage by dose delays, reductions, or discontinuations (see Table 6-1).
Tumor lysis syndrome may occur.  Patients with rapidly proliferating tumor and high tumor 
burden are at risk of tumor lysis syndrome and should be closely monitored.  If tumor lysis 
syndrome occurs, take medically appropriate measures.
Stevens-Johnson syndrome has been reported with brentuximab vedotin.  If Stevens-Johnson 
syndrome occurs, brentuximab vedotin must be discontinued and the appropriate medical 
therapy administered.
Progressive multifocal leukoencephalopathy (PML) has been reported with brentuximab 
vedotin use.  PML is a rare demyelinating disease of the brain that is caused by the John 
Cunningham virus (JCV).  It typically occurs in immunocompromised individuals and can 
be fatal.  Presenting features may include altered mental status, motor deficits such as 
hemiparesis or ataxia, visual disturbances, or higher cortical dysfunction such as dysphasia 
or agnosia.  Seizures have also been reported in patients with PML (approximately 20%).  
The onset of neurological deficits may occur over weeks to months.  Cognitive decline 
without accompanying deficits in motor or sensory function is uncommon.  Optic nerve 
involvement, fever, and spinal cord disease are not typically associated with PML.  In 

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addition, peripheral neuropathy, which has been reported with brentuximab vedotin 
treatment, is not commonly reported with PML.  If PML is suspected, a diagnostic work-up 
should be performed, as described in Section 6.6.
Acute pancreatitis has been reported in patients treated with brentuximab vedotin and has 
contributed to fatal outcomes in some cases.  Onset typically occurred after 1 to 2 doses of 
brentuximab vedotin.  Early symptoms included severe abdominal pain, nausea, and 
vomiting.  The majority of pancreatitis cases were complicated by other possible 
contributory factors, including cholelithiasis and alternate etiologies (eg, pancreatic 
lymphoma progression, displacement of bile duct stent, etc.).  
Approximately 1% of patients treated with brentuximab vedotin in the investigational or 
commercial setting have had an AE that was suggestive of a hepatobiliary disorder.  The 
majority of events occurred after 1 to 2 treatment cycles and they were characterized by 
asymptomatic mild to moderate transient elevations in ALT and AST.  Elevated liver 
enzymes were observed upon rechallenge for some patients.  
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.  Additional analysis is planned to more fully characterize the 
pharmacokinetics in these patient populations.
Monomethyl auristatin E (MMAE) is primarily metabolized by CYP3A.  Coadministration 
of brentuximab vedotin with ketoconazole, a potent CYP3A4 inhibitor, increased exposure 
to MMAE by approximately 34%. Patients who are receiving strong CYP3A4 inhibitors 
concomitantly with brentuximab vedotin should be closely monitored for adverse reactions. 
Coadministration of brentuximab vedotin with rifampin, a potent CYP3A4 inducer, reduced 
exposure to MMAE by approximately 46%.
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 triggered by the 
administration of study medication.

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2.   
STUDY OBJECTIVES
2.1   
Primary Objective

To compare the modified progression-free survival (mPFS) obtained with 
brentuximab vedotin (ADCETRIS®) plus AVD (abbreviated A+AVD) versus that
obtained with ABVD for the frontline treatment of advanced classical HL
2.2   
Secondary Objectives
The key secondary objective is

To determine if A+AVD improves OS versus that obtained with ABVD
Other secondary objectives are:

To determine if A+AVD improves CR rate versus that obtained with ABVD

To determine the safety profile of A+AVD relative to that of ABVD

To determine the event-free survival (EFS) obtained with A+AVD and ABVD

To determine the disease-free survival (DFS) rate obtained with A+AVD and ABVD

To determine if A+AVD improves overall ORR (defined as CR + PR) versus that 
obtained with ABVD

To determine the DOR and duration of complete remission (DOCR) obtained in the
A+AVD and ABVD arms

To determine the rate of patients receiving irradiation for HL not in CR in the 
A+AVD and ABVD arms

To determine the rate of patients in CR at the end of frontline therapy in the A+AVD
and ABVD arms

To determine the rate of Cycle 2 PET negativity in patients treated with A+AVD
versus those treated with ABVD

To determine if A+AVD improves health-related quality of life (HRQOL) versus 
ABVD

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!
To describe the PK of brentuximab vedotin, MMAE, and total antibody (TAb) in 
blood
!
To determine the immunogenicity of brentuximab vedotin
2.3   
Exploratory Objectives
The exploratory objectives are:
!
To investigate any differences in lung-specific patient-reported outcomes (PROs) 
between the treatment arms
!
To assess any impact of brentuximab vedotin dosing on serum concentrations of 
AVD
!
To investigate any differences between the treatment arms in the rate of patients 
alive without HL at 3 and 5 years (see Section 8.1.6.3 for definition)
!
To assess changes in tumor biomarker expression before and after treatment
!
 
 
!
To assess other PROs
!
To assess medical resource utilization
!
To assess fertility
CCI

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3.   
STUDY ENDPOINTS
3.1   
Primary Endpoints
The primary endpoint is

Modified PFS per IRF assessment using the Revised Response Criteria for Malignant 
Lymphoma
3.2   
Secondary Endpoints
The key secondary endpoint is

OS
Other secondary endpoints are:

Rate of CR as best overall response achieved at the end of randomized regimen 
(A+AVD or ABVD) per IRF assessment using the Revised Response Criteria for 
Malignant Lymphoma

AEs, SAEs, assessments of clinical laboratory values, and vital sign measurements

EFS

DFS

ORR

DOR per IRF

DOCR per IRF

The rate of patients not in CR that received irradiation

CR rate per IRF at the end of frontline therapy

The rate of Cycle 2 PET negativity 

PRO per European Organization for Research and Treatment of Cancer (EORTC)
QLQ-C30

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!
PK parameters for brentuximab vedotin, MMAE, and TAb
!
The presence of antitherapeutic antibodies (ATA) to brentuximab vedotin
3.3   
Exploratory Endpoints
The exploratory endpoints are:
!
PRO per FACIT-Dyspnea 10
!
Serum concentrations of AVD in a subset of ABVD- and A+AVD-treated patients, 
respectively
!
Percent of patients alive without HL at 3 and 5 years
!
Percent of patients switching therapy post Cycle 2 pre-End of Treatment (EOT)
!
 
 
!
 
 
!
PRO per FACT-Ntx (Abbreviated)
!
Patient-reported health utility values per EQ-5D
!
Utilization of medical resources
!
Incidence of pregnancy (patients or partners of patients) in each treatment arm at 
time of study closure
CCI
C
C
I
CCI

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4.   
STUDY DESIGN 
4.1   
Overview of Study Design
This open-label, randomized, 2-arm, multicenter, phase 3 study has the primary objective of 
comparing the mPFS obtained with A+AVD against that obtained with ABVD. For this 
study, the definition of PFS has been modified to include the receipt of anticancer 
chemotherapy or radiotherapy for patients not in CR after the completion of frontline 
therapy as a progression event in addition to the customary events of disease progression or 
death due to any cause (a definition of completion of frontline therapy is provided in 
Table 8-1).
The study will enroll approximately 1240 patients; enrollment is anticipated to last 3 years.  
All enrolled patients must have a histologically-confirmed diagnosis of Stage III or IV 
classical HL that has not been previously treated with systemic chemotherapy or 
radiotherapy.  Patients will be stratified by region (Americas vs Europe vs Asia) and number 
of International Prognostic Factor Project (IPFP) risk factors (0-1 vs 2-3 vs 4-7).  (IPFP risk 
factors are listed in Section 15.5.)
Patients will be randomized 1:1 into 1 of 2 treatment arms, for a total of approximately 
620 patients per arm:

A+AVD:  Brentuximab vedotin 1.2 mg/kg plus doxorubicin 25 mg/m2, 
vinblastine 6 mg/m2, dacarbazine (DTIC) 375 mg/m2.

ABVD:  Doxorubicin 25 mg/m2, bleomycin 10 units/m2, vinblastine 6 mg/m2, 
dacarbazine (DTIC) 375 mg/m2.
A+AVD and ABVD will be administered intravenously on Days 1 and 15 of each 28-day 
cycle.  Brentuximab vedotin will be administered intravenously over 30 minutes at a dose of 
1.2 mg/kg; the brentuximab vedotin infusion is to be started within approximately 1 hour
after completion of AVD therapy.  Patients may receive up to 6 cycles of therapy (A+AVD
or ABVD).
Response to treatment and disease status assessments will be evaluated according to the 
Revised Response Criteria for Malignant Lymphoma(25) by an IRF that will be blinded to 
patients’ treatment.  Tumor measurements will be assessed (CT and PET scans) at screening, 
after completion of Cycle 2 (Cycle 2 Day 25 1 day), and at 3 to 7 weeks after the last dose 
of frontline therapy.  CT scans only will be used for the disease assessment follow-up, 

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performed every 3 months during the first year of posttreatment disease follow-up, then 
every 6 months until study closure (5 years after the last patient is enrolled).  If, for any 
reason other than death or documented disease progression, a patient discontinues 
randomization therapy (A+AVD or ABVD) after Cycle 2 Day 25 but before completion of 
randomization therapy, every effort must be made to obtain PET and CT scans prior to 
initiation of subsequent therapy for HL.  Responses and relapses will be assessed by an IRF.  
Evaluations will be performed until progressive disease (PD) is documented, receipt of 
second-line anticancer therapy for HL (including chemotherapy or radiation), death occurs, 
or the end of study. Patients will be followed for survival until death or for a minimum of 
5 years after enrollment of the last patient.
Deauville scoring (see Section 15.6) per IRF will be used to evaluate the results of patients’ 
Cycle 2 Day 25 PET/CT.  Patients whose disease earns a Deauville score of 4 or less will 
continue study drug treatment according to their randomized arm (ABVD or A+AVD).
Patients whose PET-positive disease earns a score of 5 may, at the investigator’s discretion, 
receive an alternative regimen (physician’s choice) for the remainder of planned frontline 
therapy. Patients with a Deauville score of 5 who, at investigator’s discretion, are taken off 
study drug will be continue to be followed for response assessment; switching therapy prior 
to completion of frontline therapy will not be considered an mPFS progression event.  Of 
further note, any switch in therapy prior to completion of frontline therapy will not be 
considered an mPFS event.
An interim futility analysis will be conducted when the first approximately 348 patients have 
completed the regimen to which they were randomized (ie, received the planned study drug 
regimen with no more than 2 missed doses of A+AVD or ABVD) or have discontinued 
treatment prior to completion.  The final analysis of the mPFS primary endpoint will be 
conducted when 260 mPFS events occur; an interim analysis of OS will also be conducted at 
that time.  The final analysis of OS will be conducted when 112 deaths occur, approximately 
4 years after randomization of the last patient.
Safety will be evaluated according to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) version 4.03, effective 14 June 2010,(26) and by 
measuring changes from baseline in the patient’s vital signs, ECOG performance status, 
electrocardiogram (ECG), and clinical laboratory results.  Safety data will be periodically 
reviewed by an independent data monitoring committee (IDMC) per the IDMC charter.

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Patient-reported outcomes will be evaluated using the EORTC QLQ-C30, the 
FACIT-Dyspnea 10 questionnaire, the EQ-5D questionnaire, and the abbreviated Functional 
Assessment of Cancer Therapy—Neurotoxicity (FACT-Ntx; Abbreviated).
Relationships between plasma levels of brentuximab vedotin, soluble CD30, and CD30 
expression on lymphoma cells will be assessed.  A possible dose response for any such 
effects as well as the presence of ATAs may be subsequently examined.
Patients may discontinue therapy at any time.  Patients will attend the EOT visit 30 (7) 
days after completion of their last dose of frontline therapy.
4.2   
Number of Patients
Approximately 1240 patients (approximately 620 patients per treatment arm) will be 
randomized in this study from approximately 250 study centers globally.
4.3   
Duration of Study
Patients will be screened within 4 weeks of randomization, receive a maximum of six 
28-day cycles of A +AVD or ABVD treatment (approximately 6 months), and will have 
follow-up disease assessments performed until study closure for a minimum of 5 years.
It is expected that the study will last approximately 60 months to reach the final analysis of 
the mPFS endpoint (approximately 36 months of enrollment plus 24 months of additional 
follow-up after the last patient is randomized). Patients will be followed for survival until 
death or the end of posttreatment follow-up (when 112 deaths occur, approximately 4 years 
from the date of the last patient randomized), whichever occurs first.  The total study 
duration is approximately 7 years.
5.   
STUDY POPULATION
Eligible patients with treatment-naïve advanced classical HL will be randomized to receive 
either A +AVD or ABVD.
5.1   
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be randomized to treatment:
1. Male or female patients 18 years or older.

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2. Treatment-naïve, HL patients with Ann Arbor Stage III or IV disease (refer to 
Section 15.1).
3. Patients must have histologically confirmed classical HL according to the current 
World Health Organisation Classification (nodular sclerosis, mixed cellularity, 
lymphocyte rich, lymphocyte depleted, or classical Hodgkin lymphoma, NOS [not 
otherwise specified]).
4. ECOG performance status ≤2 (refer to Section 15.2).
5. Patients must have bidimensional measurable disease as documented by radiographic 
technique (spiral CT preferred) per the International Working Group Revised 
Criteria for Response Assessment for Malignant Lymphoma (Cheson 2007).(25)
6. Female patients who:

Are postmenopausal for at least 1 year before the screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed consent 
through 6 months after the last dose of study drug, 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.)
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.)

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7. 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.
8. Suitable venous access for the study-required blood sampling, including PK 
sampling.
9. Clinical laboratory values as specified below within 7 days before the first dose of
study drug:

Absolute neutrophil count ≥1,500/μL unless there is known HL marrow 
involvement

Platelet count ≥75,000/μL unless there is known HL marrow involvement

Total bilirubin must be 1.5 the upper limit of normal (ULN) unless the 
elevation is known to be due to Gilbert syndrome.

ALT or AST must be 3 the upper limit of the normal range.  AST and ALT 
may be elevated up to 5 times the ULN if their elevation can be reasonably 
ascribed to the presence of HL in liver.

Serum creatinine must be 2.0 mg/dL and/or creatinine clearance or calculated 
creatinine clearance 40 mL/minute (refer to Section 15.3).

Hemoglobin must be 8 g/dL.
5.2   
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be randomized to 
treatment.
1. Nodular lymphocyte predominant Hodgkin lymphoma
2. Female patients who are both lactating and breastfeeding or who have a positive 
serum pregnancy test during the screening period or a positive pregnancy test on 
Day 1 before first dose of study drug
3. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol

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4. Known cerebral or meningeal disease (HL or any other etiology), including signs or 
symptoms of PML
5. Symptomatic neurologic disease compromising normal activities of daily living or 
requiring medications
6. Any sensory or motor peripheral neuropathy
7. Any active systemic viral, bacterial, or fungal infection requiring systemic antibiotics 
within 2 weeks prior to first study drug dose
8. Prior immunosuppressive chemotherapy, therapeutic radiation, or any 
immunotherapy (eg, immunoglobulin replacement, other monoclonal antibody 
therapies) within 12 weeks of first study drug dose
9. Known hypersensitivity to recombinant proteins, murine proteins, or to any excipient 
contained in the drug formulation of brentuximab vedotin or any component of 
ABVD
10. Known human immunodeficiency virus (HIV) positive
11. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C 
infection
12. Diagnosed or treated for another malignancy within 3 years before the first dose or 
previously diagnosed with another malignancy and have any evidence of residual 
disease.  Patients with nonmelanoma skin cancer or carcinoma in situ of any type are 
not excluded if they have undergone complete resection.
13. Any of the following cardiovascular conditions or values within 6 months before the 
first dose of study drug: 

A left-ventricular ejection fraction <50%

Myocardial infarction within 2 years of randomization

New York Heart Association (NYHA) Class III or IV heart failure (see 
Section 15.4).

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
Evidence of current uncontrolled cardiovascular conditions, including cardiac 
arrhythmias, congestive heart failure (CHF), angina, or electrocardiographic 
evidence of acute ischemia or active conduction system abnormalities
6.   
STUDY DRUG
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).  The components of 
ABVD used in this study will be supplied by the study site and will be billed to patients 
and/or their third-party payer (insurance) and/or the sponsor according to local regulations
unless otherwise arranged between the study site and sponsor.  Brentuximab vedotin will be 
supplied by the study sponsor.
Treatment for advanced HL has improved over the past 30 years with combination 
chemotherapy regimens.  The current anthracycline-containing regimen of doxorubicin, 
bleomycin, vinblastine, and dacarbazine (ABVD) has been proven superior to alkylating 
agent regimens and results in a long-term cure rate of approximately 70% in patients with 
advanced disease.  Although combination regimens have successfully been expanded to up 
to 8 chemotherapeutic agents in attempts to increase overall response, these additional 
agents have also produced increased toxicity.  ABVD thus remains the standard of care in
many regions.  
However, of the four agents in ABVD, bleomycin is the agent most associated with 
unpredictable, life-threatening toxicity, and is thought to have the lowest single-agent 
activity.(15) Standard practice in patients who develop BPT is to continue frontline therapy 
with AVD while omitting bleomycin. Retrospective analyses of CALGB 8251 and 8952 
have shown no difference in response or relapse rates for patients who had bleomycin 
discontinued at any point in their frontline therapy.(16)  Due to the proven antitumor activity 
and manageable safety profile of brentuximab vedotin monotherapy, substituting 
brentuximab vedotin for bleomycin (A+AVD) is hypothesized to provide a PFS 
improvement over the standard ABVD regimen and eliminate the risk of BPT.

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6.1   
ABVD Administration
ABVD consists of doxorubicin 25 mg/m2, bleomycin 10 units/m2, vinblastine 6 mg/m2, and 
dacarbazine (DTIC) 375 mg/m2.

A: Doxorubicin: 25 mg/m2 will be administered by IV infusion on Days 1 and 15 of 
each 28-day cycle

B: Bleomycin: 10 units/m2 will be administered by IV infusion on Days 1 and 15 of 
each 28-day cycle

V: Vinblastine: 6 mg/m2 will be administered by IV infusion on Days 1 and 15 of 
each 28-day cycle

D: Dacarbazine (DTIC): 375 mg/m2 will be administered by IV infusion on Days 1 
and 15 of each 28-day cycle
ABVD is to be administered in the stated order, per institutional guidelines.  If an 
investigator needs to choose a different order of administration of the study drugs, 
this must first be discussed with the CRO and/or the Millennium project clinician.  
The order of administration must not be changed for the 50-patient subset in each 
treatment arm from whom additional PK samples are to be obtained (see 
Section 7.4.19).  
6.2   
A+AVD Administration
A+AVD consists of brentuximab vedotin (ADCETRIS®) 1.2 mg/kg plus 
doxorubicin 25 mg/m2, vinblastine 6 mg/m2, and dacarbazine (DTIC) 375 mg/m2.

A: Doxorubicin: 25 mg/m2 will be administered by IV infusion on Days 1 and 15 of 
each 28-day cycle

V: Vinblastine: 6 mg/m2 will be administered by IV infusion on Days 1 and 15 of 
each 28-day cycle

D: Dacarbazine (DTIC): 375 mg/m2 will be administered by IV infusion on Days 1 
and 15 of each 28-day cycle
AVD is to be administered first, in the stated order, per institutional guidelines.  If an 
investigator needs to choose a different order of administration of the study drugs, this must 

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first be discussed with the CRO and/or the Millennium project clinician.  The order of 
administration must not be changed for the 50-patient subset in each treatment arm from 
whom additional PK samples are obtained (see Section 7.4.19).  
Brentuximab vedotin is to be administered after AVD:

A: brentuximab vedotin (ADCETRIS): 1.2 mg/kg will be administered by IV 
infusion over approximately 30 minutes on Days 1 and 15 of each 28-day cycle; the 
infusion is to start approximately 1 hour after the conclusion of the dacarbazine
administration.
In the absence of infusion toxicities, the infusion rate for all patients must be 
calculated in order to achieve a 30-minute (approximate) brentuximab vedotin 
infusion period.
Brentuximab vedotin must not be administered as an IV push or bolus. It must be 
administered through a dedicated IV line and cannot be mixed with other 
medications.
The dose of brentuximab vedotin is 1.2 mg/kg. Dosing is based on patients’ weight 
according to the institutional standard; however, doses will be adjusted for patients 
who experience a ≥10% change in weight from baseline. Actual weight will be used 
except for patients weighing greater than 100 kg; dose will be calculated based on 
100 kg for these individuals. The dose will be rounded to the nearest whole number 
of milligrams.
Further brentuximab vedotin administration information can be found in the 
Pharmacy Binder.
No routine pre- or post-medications are required for A+AVD therapy.
6.3   
Dose-Modification Guidelines
6.3.1   
Recommended Brentuximab Vedotin Dose Modifications for 
Treatment-Associated Toxicity
Table 6-1 details the recommended brentuximab vedotin dose modifications to be enacted in 
the event of treatment-associated toxicity.  Please also refer to Section 6.3.2 for criteria 
pertinent to ABVD and AVD dose modifications.

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Table 6-1   
Recommended A+AVD Dose Modifications for Treatment-Associated 
Toxicity
Toxicity
≤Grade 2
≥Grade 3
Nonhematologic 
(excluding 
neuropathy)
Continue at same dose level.
Hold A+AVD dosing until toxicity has 
resolved to ≤Grade 2 or has returned to 
baseline.a
Hematologic
Continue at same dose level.
For neutropenia, manage with growth factors 
(granulocyte colony stimulating factor
[G-CSF] or granulocyte-macrophage colony 
stimulating factor [GM-CSF]) per 
institutional guidelines.
For thrombocytopenia, consider platelet 
transfusion and/or proceed according to 
institutional guidelines.
For anemia, manage per institutional 
guidelines.
Peripheral 
neuropathy
Grade 1
Continue at same 
dose level.
Grade 2
Reduce dose to 
0.9 mg/kg and 
resume treatment; if 
already at 0.9 mg/kg, 
continue dosing at 
that level.
Grade 3
Withhold 
brentuximab vedotin 
until toxicity is 
≤Grade 2, then 
reduce dose to 
0.9 mg/kg and 
resume treatment.  If 
already at 
0.9 mg/kg, consult 
with sponsor
(AVD may be 
continued or held 
concurrently at 
physician’s 
discretion.)
Grade 4
Discontinue 
brentuximab vedotin
a Patients who develop clinically insignificant Grade 3 or 4 electrolyte laboratory abnormalities may continue 
study treatment without interruption.
6.3.2   
Reference Therapy Dose Modifications
ABVD or AVD treatment should be modified or discontinued per applicable label/Summary 
of Product Characteristics (SmPC) instructions.
6.3.3   
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study:

Any investigational agent other than brentuximab vedotin.

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
Any frontline anticancer treatment for remission induction other than ABVD or 
AVD (unless on the basis of a Cycle 2 Day 25 PET Deauville score of 5 as noted in 
Section 6.4).

The concomitant use of brentuximab vedotin and bleomycin has resulted in increased 
pulmonary toxicity versus bleomycin alone.  Coadministration of brentuximab 
vedotin and bleomycin is contraindicated.
6.4   
Permitted Concomitant Medications and Procedures
The following medications and procedures are allowed during the study:

For patients with a Deauville score of 5 upon Cycle 2 Day 25 PET scanning, 
physician’s choice of alternative therapy is permitted, but not required, for the 
remainder of frontline treatment.

Radiotherapy based on end-of-frontline therapy PET scanning:  Patients in PR upon 
completion of frontline chemotherapy with PET-positive disease may receive 
radiotherapy.

The use of topical, inhalational and ophthalmic steroids is permitted.  Corticosteroids 
are permitted as part of a chemotherapy premedication regimen or for the treatment 
of HL per institutional standards.

Patients may receive concomitant hormonal therapy provided they have been on a 
stable dosage for at least 1 month prior to enrollment.  No restrictions are placed 
upon the use of birth control.

The use of platelet and/or red blood cell supportive growth factors or transfusions 
when applicable is allowed.

The use of colony stimulating factors for the treatment of neutropenia per 
institutional practice is permitted during therapy.
6.5   
Precautions and Restrictions
Infusion-Related Reactions
All infusions should be administered at a site properly equipped and staffed for anaphylaxis 
should it occur.  Medications for treatment of hypersensitivity reactions, such as 

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epinephrine, antihistamines, and steroids, should be available for immediate use in the event 
of a reaction during administration and also during the observation period following the first
brentuximab vedotin infusion.  
Pregnancy
It is not known what effects brentuximab vedotin has on human pregnancy or development 
of the embryo or fetus, and ABVD is known to have deleterious effects on pregnancy.  
Therefore, female patients participating in this study should avoid becoming pregnant, and 
male patients should avoid impregnating a female partner.  Nonsterilized female patients of 
reproductive age group and male patients should use effective methods of contraception 
through defined periods during and after study treatment as specified below.
Female patients must meet 1 of the following: 

Postmenopausal for at least 1 year before the screening visit, or

Surgically sterile, or

If they are of childbearing potential, agree to practice 2 effective methods of 
contraception from the time of signing of the informed consent form 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] 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.)

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6.6   
Management of Clinical Events
Nausea and/or Vomiting
Although this study will not require prophylactic antiemetics, there is no prohibition against 
their use.  
Diarrhea
Prophylactic antidiarrheals will not be used in this protocol; however, patients will be 
instructed to take antidiarrheal medication(s) at physician’s discretion until they are 
diarrhea-free for at least 12 hours.  Fluid intake should be maintained to avoid dehydration.
Infusion-Related Reactions
Infusion-related reactions may occur during the infusion of brentuximab vedotin.  The 
infusion should be administered at a site properly equipped and staffed to manage an 
infusion-related reaction, including anaphylaxis should it occur.  The patient should be 
observed for approximately 60 minutes following the first infusion of brentuximab vedotin.  
During this observation period, the IV line should remain open for at least 1 hour to allow 
administration of IV drugs if necessary.  All supportive measures consistent with optimal 
patient care will be given throughout the study according to institution standards.  
Medications for infusion-related reactions, such as epinephrine and antihistamines should be 
available for immediate use.
Patients who experience a Grade 1 or 2 infusion-related reaction may receive subsequent 
brentuximab vedotin infusions with premedication consisting of acetaminophen (650 mg 
orally) and diphenhydramine (25-50 mg orally or 10-25 mg IV) or according to institutional 
standards, administered 30 to 60 minutes prior to each 30-minute brentuximab vedotin 
infusion.
Peripheral Neuropathy
AEs of peripheral neuropathy will be monitored closely throughout the study.  These events 
may include, but are not limited to peripheral sensory neuropathy, peripheral motor 
neuropathy, paresthesia, hypoesthesia, polyneuropathy, muscular weakness, and 
demyelinating polyneuropathy.  Such events, regardless of seriousness, will be followed for 
all changes in severity until the sooner of resolution to baseline or study closure, and 
recorded in the eCRF.  Events that are higher than Grade 1 will result in brentuximab 
vedotin dose modification as shown in Table 6-1.  

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Suspected Progressive Multifocal Leukoencephalopathy (PML)
Signs and symptoms of PML may include altered mental status; motor deficits, such as 
hemiparesis or ataxia; visual disturbances; or higher cortical dysfunction, such as dysphasia 
or agnosia. Seizures have also been reported in patients with PML (approximately 20%). 
The onset of neurological deficits may occur over weeks to months.  See the IB for further 
details.
If PML is suspected, hold further brentuximab vedotin dosing and undertake a diagnostic 
workup that may include (but is not limited to):

Neurologic examinations, as warranted.

Brain magnetic resonance imaging (MRI):  Features suggestive of PML include 
presence of unifocal or multifocal lesions, mainly of the white matter, which are 
typically nonenhancing and do not have mass effect.

Polymerase chain reaction (PCR) analysis:  JCV DNA detectable in cerebrospinal 
fluid or there is evidence of JCV in a brain biopsy.

Neurology consultation.
If PML is confirmed, permanently discontinue treatment with brentuximab vedotin.
6.7   
Blinding and Unblinding
This is an open-label study; investigators and patients will know the individual treatment 
assignments.  However, aggregate efficacy data will be blinded to the sponsor’s study team, 
investigators, and patients throughout the study conduct.  The IRF will be blinded to 
treatment assignments.
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).

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6.9   
Preparation, Reconstitution, and Dispensation
Brentuximab vedotin is an anticancer drug, and as with other potentially toxic compounds, 
caution should be exercised when handling brentuximab vedotin.
Recommended safety measures for handling and preparation include masks, protective 
clothing, gloves, and vertical laminar airflow safety cabinets.
Study treatment vials are single-use containers.  Any partially used vials or diluted dosing 
solutions are to be discarded using appropriate institutional drug disposal procedures.
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 according to the instructions provided in the Pharmacy 
Manual.  Refer to the Pharmacy Manual for more specific instructions on drug preparation.  
6.10   
Packaging and Labeling
Vials of study treatment will be packaged in cardboard kits.  Each kit will contain 1 vial of 
investigational product.  Vials and kits will be labeled to meet country-specific regulatory 
requirements.
6.11   
Storage, Handling, and Accountability
Brentuximab vedotin
Vials containing study treatment must be refrigerated at 2oC to 8oC in a secure location 
(eg, locked room) accessible only to the pharmacist, the investigator, or a duly designated 
person.
Study treatment does not contain preservatives; therefore, opened and reconstituted vials of 
study treatment must be used within 24 hours when stored under refrigeration at 2oC to 8oC.  
Reconstituted study treatment should not be stored at room temperature.  It is recommended 
that study treatment vials and solutions be protected from direct sunlight until the time of 
use.  Reconstituted vials must not be shaken.

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Drug accountability instructions are provided in the Pharmacy Binder.
Bleomycin
Bleomycin may be sourced locally by the clinical sites when 1) arrangements have been 
made and agreed to by Millennium and the clinical sites and 2) local and regional 
regulations are met.
Please refer to the appropriate package insert for information regarding the proper storage 
and handling of bleomycin.
Bleomycin must be kept in an appropriate, limited-access, secure place until it is dispensed 
to study enrollees, returned to the sponsor, or forwarded to the sponsor’s designee for 
destruction.
The investigator must maintain 100% accountability for all bleomycin received from the 
study sponsor and dispensed during his or her entire participation in the study.  Drug 
accountability instructions can be found in the Pharmacy Binder. Drug supplies will be 
counted and reconciled at the site before being returned.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately.
7.   
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, good clinical practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines.
7.1   
Study Personnel and Organizations
The contact information for the Millennium project clinician for this study, the central 
laboratory and any additional clinical laboratories, the coordinating investigator for each 
member state/country, the independent radiologic review facility, the interactive voice 
response system (IVRS) / interactive web response system (IWRS) provider, known as 
IXRS®, 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.

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7.2   
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians.  If advertisements become 
part of the recruitment strategy, they will be reviewed by the institutional review board 
(IRB)/independent ethics committee (IEC).  It is not envisioned that prisoners (or other 
populations that might be subject to coercion or exploitation) will be enrolled into this study.
7.3   
Treatment Group Assignments
Patients will be randomized to receive either A+AVD or ABVD.  Patients will be stratified 
by region (Americas vs Europe vs Asia), and number of IPFP risk factors (0-1 vs 2-3 vs 
4-7).
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.
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 7.4.8.
7.4.4   
Physical Examination
A physical examination will be completed per standard of care at the times specified in the 
Schedule of Events.

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7.4.5   
Patient Height, Weight, and Body Surface Area
Height will be measured only during screening (within 28 days before the first dose of study 
drug).  Weight and body surface area (BSA) will be determined to support dosing at the 
times specified in the Schedule of Events (see Section 15.7).
7.4.6   
Vital Signs
Vital sign measurements include seated (after 3-5 minutes in this position) measurements of 
diastolic and systolic blood pressure, heart rate, and body temperature.
7.4.7   
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at screening
and at Cycle 1 Day 1.  The results from this test must be available and negative before the 
first dose of study drug is administered.  If Cycle 1 Day 1 serum pregnancy results will not 
be available before dosing, a urine pregnancy test must be performed.  Pregnancy tests may 
also be repeated during the study if requested by an IEC/IRB or if required by local 
regulations.  
7.4.8   
Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will 
recorded in the electronic case report form (eCRF) from date of informed consent through 
30 days after completion of frontline therapy.  See Section 6.3.3 and Section 6.4 for a list of 
medications and therapies that are prohibited and/or allowed during the study.
7.4.9   
Adverse events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as 
specified in the Schedule of Events.  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. Refer to Section 10 for 
details regarding definitions, documentation, and reporting of pretreatment events, AEs, and 
SAEs.
The occurrence of PML, malignancies other than classical HL, and changes in severity of 
events related to peripheral neuropathy will be recorded as described in Section 10.

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7.4.10   
Enrollment
A patient is considered to be enrolled in the study when randomized to a treatment arm.
Procedures for completion of the enrollment information are described in the Study Manual.
7.4.11   
Electrocardiograms
A 12-lead ECG will be administered at the time points specified in the Schedule of Events.
7.4.12   
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed centrally.  Decisions regarding eligibility 
for this study may be made using local laboratory determinations.  For dosing decisions, 
local hematology and chemistry laboratory results may be used.
Handling and shipment of clinical laboratory samples will be outlined in the Study Manual.
Clinical laboratory evaluations will be performed as outlined below.
Clinical Chemistry and Hematology
Blood samples for analysis of the following clinical chemistry and hematological parameters 
will be obtained as specified in the Schedule of Events.
Hematology

Hemoglobin

Hematocrit

Platelet (count)

Leukocytes with Differential

Neutrophils (absolute neutrophil count [ANC])

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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)

AST

ALT

Glucose

Sodium

Potassium

Calcium

Chloride

Carbon dioxide 
(CO2)

Magnesium
Other

Hemoglobin A1C
7.4.13   
Disease Assessment
Response to treatment and disease status assessments will be evaluated according to the 
Revised Response Criteria for Malignant Lymphomas.(25)  These disease assessments will be 
performed by investigators and a blinded IRF at times specified in the Schedule of Events.  
In addition, patients’ disease status following Cycle 2 and at EOT will be assessed per IRF 
by PET scan using the Deauville criteria (Section 15.6); an IRF assessment using the 
Deauville criteria will also be made if an unscheduled PET scan is obtained.  Investigator 
assessments using the Deauville criteria are not required.
If, for any reason other than death or documented disease progression, a patient discontinues 
randomization therapy (A+AVD or ABVD ) after Cycle 2 Day 25 but before completion of 
randomization therapy, every effort must be made to obtain PET and CT scans prior to 
initiation of subsequent therapy for HL.
MRI scans may be substituted for CT scans only if a patient 1) has a glomerular filtration 
rate of less than 60 mL/min such that IV contrast presents a risk of renal failure, 2) develops 
anaphylaxis to IV contrast, or 3) becomes pregnant during posttreatment follow-up.  If use 
of MRI is required, a consistent scanning modality must be maintained.  Further detail may 
be found in the Imaging Manual.

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All subsequent anticancer therapies will be recorded, regardless if they are initiated before 
or after progressive disease.  For patients whose frontline therapy is switched to physician’s 
choice, regimen details will be recorded.  Subsequent anticancer therapy during the 
posttreatment follow-up is discussed in Section 7.10.
B symptom assessments, including fever, night sweats, and weight loss, will be evaluated at 
the time points indicated in the Schedule of Events.
Bone marrow assessments are not required for this study.  However, if bone marrow 
biopsies are obtained at baseline or during the course of the study, the results of each bone 
marrow assessment should be recorded.  Similarly, if cytology results of any kind are 
obtained (eg, from malignant ascites) they should be recorded.
7.4.14   
Patient-Reported Outcomes
Questionnaires (FACIT-Dyspnea 10-item short form, FACT-Ntx; Abbreviated, EORTC 
QLQ-C30) will be administered as specified in the Schedule of Events and must be 
completed before study drug is administered. For patients who discontinue study drug, the 
scheduled collection of patient-reported outcomes (PRO) data should continue until the 
patient discontinues scheduled study visits.
7.4.15  
Utility Measurement
The EuroQOL EQ-5D is a 5-item questionnaire with a “thermometer” visual analog scale 
ranging from 0 (worst imaginable health state) to 100 (best imaginable health state) that will 
be administered as specified in the Schedule of Events.  The utility measurement should be 
collected until the sooner of development of confirmed PD or 3 years after the last dose of 
frontline therapy.
7.4.16   
Medical Resource Utilization Data Collection
All medical care encounters will be collected for all patients until study closure.  Each time 
an AE or unscheduled physician visit occurs, medical resource utilization (MRU) data will 
be captured.  Examples of data to be collected are number of medical care encounters, such 
as hospital admissions or major diagnostic procedures.

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7.4.17   
Cost Assessment
The cost of treatment in each arm of the study will be assessed through the collection of 
MRU in each arm in terms of medical resource utilization frequency.  Valuation of the costs 
will be undertaken separately.
7.4.18   
Tumor Biopsies
Banked formalin-fixed paraffin-embedded tumor tissue or a minimum of 10 unstained slides 
of the tumor tissue (ie, tumor tissue obtained at the time of the patient’s original diagnosis 
and/or at the time of subsequent procedures conducted as part of the patient’s standard care) 
will be collected at screening to assess biomarkers implicated in sensitivity or resistance to 
brentuximab vedotin or vinca alkyloids and taxanes (eg, p53, beta 3 tubulin, and ABCC 
transporters).  The tumor pathology block will be returned to the original site by the sponsor
or designee if requested.  If the pathology block is not provided, submission of 10 unstained 
slides will be accepted.  See the Laboratory Manual for details. Patients who cannot provide 
at least 10 histological slides from their diagnostic biopsy will undergo a new tumor biopsy 
during screening (may be obtained up to 14 days prior to the first dose of study drug).
Efforts should be made to take an additional biopsy when patients randomized to the 
A+AVD treatment arm have disease relapse.  These samples are to be tested for the 
expression of CD30 and other potential markers of tumor resistance.
7.4.19   
Pharmacokinetic Measurements
PK measurements will be made in all brentuximab vedotin-treated patients and a subset of 
patients in the ABVD arm.  PK parameters to be estimated may include the maximum 
concentration for MMAE (maximum plasma concentration [Cmax]) and concentration at the 
end of infusion for brentuximab vedotin (Ceoi). Concentrations will be measured and PK 
parameters also estimated for the intact brentuximab vedotin ADC and TAb.  Population PK
methodologies will be used to determine PK parameters and covariates in this population.  
Efficacy parameters will be related to brentuximab vedotin exposure in the patients.
The incidence of ATA to brentuximab vedotin will also be assessed (see Section 7.4.21).
The Schedule of Events presents the sample collection time points.  Refer to the Laboratory
Manual for information on collection, processing, storage, and shipment of samples.
ATA samples will be taken only at predose Cycle 1, Cycle 2, and Cycle 6 or at termination 
if treatment is terminated before Cycle 6 (see Section 7.4.21).

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Table 7-1   
Pharmacokinetic Sampling Time Points
Cycle
Study Day
Time
Window
Relative Time
Full A+AVD Arm
1-6
1
Predose
Within prior 4 hr
Start of brentuximab vedotin
infusion
EOI
(~30 min)
Within 1 hour 
post EOI
End of brentuximab vedotin 
infusion
15
Predose
Within prior 4 hr
Start of brentuximab vedotin
infusion
EOI
(~30 min)
Within 1 hour 
post EOI
End of brentuximab vedotin 
infusion
1 and 3, in 
addition
2
24 hr
±4 hr
Start of brentuximab vedotin
infusion
3
48 hr
±4 hr
Start of brentuximab vedotin
infusion
Additional Sampling for 50-Patient Subset of A+AVD Arm
1 and 3
1
2 min
±2 min
End of doxorubicin infusion
2 min
±2 min
End of vinblastine infusion
2 min
±2 min
End of dacarbazine infusion
1 hr
±5 min
End of brentuximab vedotin 
infusion
6 hr
±10 min
End of brentuximab vedotin
infusion
8
168 hr
±24 hr
End of brentuximab vedotin
infusion
Additional Sampling for 50-Patient Subset of ABVD Arm
1 and 3
1
Predose
Within prior 4 hr
Start of doxorubicin infusion
2 min
±2 min
End of doxorubicin infusion
2 min
±2 min
End of vinblastine infusion
2 min
±2 min
End of dacarbazine infusion
1 hr
±5 min
End of dacarbazine infusion
6 hr
±10 min
End of dacarbazine infusion
2
24 hr
±4 hr
End of dacarbazine infusion
8
168 hr
±24 hr
End of dacarbazine infusion
Abbreviations:  A+AVD=brentuximab vedotin (ADCETRIS®) plus doxorubicin, vinblastine, and 
dacarbazine; ABVD=doxorubicin, bleomycin, vinblastine, and dacarbazine; EOI=end of 
infusion; hr=hour; min=minutes.
The 50 patients in each treatment arm from whom additional PK samples are obtained will 
be recruited from sites that agree to participate. Further, approximately 20 patients in each 
50-patient intensive-sampling group must be Asian.

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7.4.20   
Serum Biomarkers
Blood for serum samples will be collected as specified in the Schedule of Events to measure 
circulating biomarkers such as soluble CD30 (sCD30), thymus- and activation-regulated 
chemokine (TARC), cutaneous T-cell-attracting chemokine (CTACK), and interleukin-6 
(IL-6).  Previous research has demonstrated a relationship between circulating sCD30 
concentration and overall tumor burden.(27)  A decrease in sCD30 may reflect a decrease in 
overall tumor burden.  The Reed-Sternberg cells characteristic of classical HL produce high 
concentrations of TARC that correlate with increased T-cell infiltration of tumor tissue.(28)  
Further, previous phase 2 clinical studies of brentuximab vedotin showed 
 
 
 
 
.
Biomarkers such as sCD30, TARC, and IL-6 may be measured on Day 1 of all cycles and at 
the EOT visit.  Baseline values and changes in these markers may be compared to efficacy. 
In addition, the possible impact of sCD30 concentrations on PK will be explored.
The timing of the blood samples may be changed and/or the number of samples reduced if 
emerging data indicate that changes to the sampling scheme are needed to better characterize 
the effects of brentuximab vedotin.  Details regarding the preparation, handling, and 
shipping of samples are provided in the Study Manual.
7.4.21   
Immunogenicity Measurements
Blood for serum samples will be collected as specified in the Schedule of Events to evaluate 
antitherapeutic antibody (ATA) and neutralizing ATA as a PK and safety assessment.  On 
dosing days, the blood samples for ATA and neutralizing ATA assessment must be collected 
before dosing.  Neutralizing ATA assessment will be performed only for ATA-positive 
samples.  Immunogenicity parameters will be assayed only for patients who receive at least 
1 brentuximab vedotin dose.
7.4.22   
Germline DNA Polymorphism Assessment
For patients on the A+AVD arm only, an optional blood sample will be collected on Day 1 
of Cycle 1, before dosing, to examine genotyping variations in the germ line genes of the 
disease pathway, drug mechanism, and drug clearance proteins, such as CD30, tubulin, 
Fcneo, and Fcγ receptors.
CCI

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7.4.23   
Fertility Assessment
The incidence of pregnancy in each treatment arm will be assessed at the time of study 
closure.  Any pregnancy occurring in patients or their partners from the date of first dose 
until the date of study closure should be reported.
7.5   
Completion of Treatment
Patients will be considered to have completed study treatment if they:

Complete frontline treatment (see Table 8-1), or

Experience PD or die prior to completion of frontline treatment
7.6   
Completion of Study
Patients will be considered to have completed the study if they meet both of the following 
criteria:

Complete 6 cycles of frontline treatment

Have 5 years of follow-up or have died
Regardless of the duration of treatment, all patients will remain on study for follow-up 
following the last dose of study treatment until they withdraw consent for further follow-up, 
are lost to follow-up, have been followed for 5 years from randomization, or until study 
closure.  The study is expected to close approximately 7 years after the first patient starts 
study treatment. Posttreatment follow-up is further described in Section 7.10.
For patients who do not complete 6 treatment cycles, please see the Schedule of Events for 
details of follow-up assessments.
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 6 cycles of A+AVD or ABVD

Investigator deems it is in the patient’s best interest to discontinue
The primary reason for study treatment withdrawal must be documented.

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Patients who discontinue from study treatment will remain on study for follow-up unless 
they withdraw consent for the follow-up phase of the study.  All randomized patients will be 
followed until study closure (see Section 7.6).
Patients who are randomized to a treatment arm but do not receive study drug for any reason 
will not be replaced.
Treatment with study drug may also be discontinued for any of the following reasons: 

AE

Protocol violation

PD

Unsatisfactory therapeutic response

Study terminated by sponsor

Withdrawal by subject

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.
Note that some patients may discontinue study drug for reasons other than PD before 
completing the full treatment course (eg, after Cycle 2 based on a Deauville score of 5); 
these patients will remain in the study for posttreatment assessments as outlined in the 
Schedule of Events until disease progression occurs.

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7.8   
Withdrawal of Patients From Study
A patient may be discontinued from the study (during treatment cycle or follow-up) for any 
of the following reasons: 

Lost to follow-up

Study terminated by sponsor

Withdrawal by 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.
Millennium or their designee must be notified in writing if a patient is withdrawn from study 
treatment or from the study.  The reason(s) for withdrawal must be documented in the 
patient’s medical records.  The investigators will make every reasonable effort to keep each 
patient on the study until all planned treatments and assessments have been performed.  If a 
patient withdraws from study treatment, every attempt should be made to follow the patient 
until death or administrative study closure.  Final treatment assessments will be performed 
before any other therapeutic intervention if possible.  Additionally, any planned alternative 
treatments should be documented on the patient’s medical records and CRF.
7.9   
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision 
of the investigator or identified subinvestigator(s).  The appropriate study personnel will 
maintain records of study drug receipt and dispensing.
7.10   
Posttreatment Follow-up Assessments
Posttreatment follow-up for all patients consists of a physical exam, B symptom assessment, 
selected QOL assessments as specified in the Schedule of Events, medical resource 
utilization, CT scan, and collection of survival/disease status and anticancer treatment for 
HL.  Information regarding new primary malignancies will be recorded.  All assessments 
except CT scans are to be performed every 3 months until 36 months after the EOT and then 

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every 6 months until the first of disease progression or study closure.  CT scans are required 
every 12 weeks (±1 week) until 12 months of PTFU and then every 6 months (±2 weeks) 
until study closure.  For patients who have PD, survival/disease status and information 
regarding the initiation of an alternative lymphoma treatment may be obtained by phone 
call.  To support fertility assessment, any pregnancy occurring in patients or their partners 
from the date of first dose until the date of study closure should be reported.
Patients who stop treatment for any reason other than PD will continue to have mPFS 
follow-up visits until the occurrence of PD; the patient withdraws consent for further 
follow-up; or, the start of another anticancer therapy for patients not in CR after completion 
of frontline therapy.  
Patients will be followed for survival until 5 years from the date of the last patient 
randomized, or death, whichever occurs first.  Survivor information may be collected by 
methods that include, but are not limited to, telephone, e-mail, mail, or retrieved from online 
or other databases (eg, social security indexes). In addition, the start of another anticancer
therapy will be collected.
See the Schedule of Events for appropriate assessments during follow-up.
NOTE: Related SAEs must be reported to the Millennium Department of 
Pharmacovigilance & Risk Management or designee. This includes deaths that the 
investigator considers related to study drug that occur during the posttreatment follow-up. 
Refer to Section 10 for details regarding definitions, documentation, and reporting of SAEs.
8.   
STATISTICAL AND QUANTITATIVE ANALYSES
8.1   
Statistical Methods
In general, summary tabulations will be presented by treatment arm and will display the 
number of observations, mean, standard deviation, median, minimum, and maximum for 
continuous variables, and the number and percent per category for categorical data.  The 
Kaplan-Meier survival curves and 25th, 50th (median), and 75th percentiles will be provided 
along with their 2-sided 95% CIs for time-to-event data.

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The statistical methods are outlined below; analysis details will be provided in the statistical 
analysis plan (SAP).  The SAP will be written by Millennium and will be finalized prior to 
the formal interim analysis.
Deviations from the statistical analyses outlined in this protocol will be indicated in the 
SAP; any further modifications will be noted in the final clinical study report.
8.1.1   
Determination of Sample Size
The primary endpoint of the study is mPFS, and the study is powered on the following 
assumption: a 2-year mPFS of 81% for patients in the A+AVD treatment group versus 73% 
for patients in the ABVD treatment group (HR=0.67; assuming a decrease in the PFS event 
rate after 2 years). A total of 260 mPFS events will provide 90% power to detect a hazard 
ratio of 0.67 at a 1-sided significance level of 0.025 using a log-rank test.  Approximately 
1240 patients will be randomized to achieve (with 95% probability) 260 mPFS events in 
approximately 60 months, assuming 36 months of accrual, a 5% annual dropout rate, and 
24 months of mPFS follow-up after last patient in.  
8.1.2   
Randomization and Stratification
The randomization scheme will be generated by Millennium.  Prior to dosing, a 
randomization number will be assigned to each patient.  The randomization schedule also 
includes the study specific identifiers (company name, protocol name, and protocol number) 
and the date and time the schedule was generated.
Patients will be randomized in an overall ratio 1:1 to A+AVD or ABVD. Patients will be 
stratified by region (Americas vs Europe vs Asia) and number of IPFP risk factors (0-1 vs 
2-3 vs 4-7).
8.1.3   
Populations for Analysis
The populations used for analysis will include the following:

Safety population:  patients who receive at least 1 dose of study drug will be used for 
all safety analyses.  All patients in the safety population will be analyzed according 
to the actual treatment received.

Intent-to-Treat (ITT) population: all patients randomized to treatment.  All patients 
in the ITT population will be analyzed according to the treatment they were 
randomized to receive and not according to what they actually received, if different.

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
Per-Protocol (PP) population: a subset of ITT patients who do not have a major 
protocol violation as determined by the project clinician.  All decisions to exclude 
patients from the PP population will be made prior to database lock.

Response-Evaluable population: all patients with diagnosis as confirmed by an 
independent pathology review facility, with measurable disease at baseline, who 
receive at least 1 dose of study drug, and have at least 1 postbaseline response 
assessment.

PK population:  patients with sufficient dosing and PK data to reliably estimate PK 
parameters as determined by a clinical pharmacologist.  The PK population will be 
used for PK analyses.

Pharmacodynamics population:  patients with sufficient dosing and sufficient 
pharmacodynamics data to reliably measure pharmacodynamics parameters will be 
used for pharmacodynamics analyses.
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
Demographic and baseline characteristics will be summarized, including gender, age, race, 
weight, height, BSA, primary diagnosis, and other parameters as appropriate.  No inferential 
statistics will be carried out.
8.1.6   
Efficacy Analysis
All efficacy evaluations will be conducted using the ITT population unless otherwise 
specified.
8.1.6.1   
Analysis of Primary Efficacy Endpoint
Modified PFS per IRF will be used for the primary efficacy analysis.

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Modified Progression-Free Survival
As PET-negative CR is the expected therapeutic outcome in frontline HL, the definition of 
PFS has been modified to reflect current standards of care.  Modified PFS per IRF will be 
analyzed based on the ITT population using a stratified log-rank test. Modified PFS is 
defined as the time from the date of randomization to the date of the first of (1) 
documentation of PD; (2) death due to any cause; (3) for patients who are confirmed 
noncomplete responders per IRF, receipt of anticancer chemotherapy or radiotherapy for HL 
after completion of frontline therapy, as defined in Table 8-1; these patients’ mPFS event 
date will be the date of the first PET scan post completion of frontline therapy demonstrating 
the absence of a CR, defined as a Deauville score of 3.
Table 8-1
Completion of Frontline Therapy
Treatment History
Completion of Frontline Therapy
Did not switch therapy
Upon receipt of planned study drug regimen with no more than 2 missed
doses of A+AVD or ABVDa
Switched therapy before 
completion of A+AVD or ABVD
Upon conclusion of 1 alternative anticancer regimenb for HL subsequent 
to A+AVD or ABVD discontinuation
a A “missed dose” refers to administration of the full study regimen of either A+AVD or ABVD.  Patients 
may miss individual agents within the A+AVD or ABVD regimen (such as patients who discontinue 
bleomycin for pulmonary toxicity) without this counting as a missed dose.  
b Receipt of chemotherapy OR radiation.
Patients without a documented mPFS event at the time of analysis (defined as PD/relapse, 
subsequent anticancer therapy for residual disease after completion of planned frontline 
therapy for HL, or death) will be censored at the date of last response assessment.  Detailed 
handling rules for missing assessments and censoring for the analysis of mPFS will be 
described in Section 5.8.1.2 of the SAP.
Modified PFS will be tested at a 1-sided 0.025 level at the final analysis.
In addition, a stratified Cox regression model will be used to estimate the hazard ratio and 
the 95% CI for the treatment effect. The Kaplan-Meier survival curves, 25th, 50th (median), 
and 75th percentiles (if estimable), along with their 2-sided 95% CIs, will also be presented 
for each treatment arm.
Sensitivity analyses for mPFS per IRF will be performed using the PP population. Modified 
PFS per IRF using different censoring approaches will be also analyzed in the ITT 
population. Details of different censoring approaches and further sensitivity analyses of 

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mPFS will be included in the SAP. Modified PFS per investigator will also be analyzed 
similarly using the ITT population.
8.1.6.2   
Analyses of Secondary Efficacy Endpoints
Overall survival is designated as a key secondary endpoint.  It will be tested at 1-sided 0.025 
level when the test of mPFS is statistically significant at the final analysis.
Overall Survival
OS is defined as the time from the date of randomization to the date of death.  Patients 
without documented death at the time of analysis will be censored at the date last known to 
be alive.
Two formal analyses will be performed for OS.  An OS interim analysis will be performed 
at the time of the final mPFS analysis, and the final analysis of OS will be performed when 
112 deaths have occurred, assuming 5-year OS rates for the A+AVD and ABVD arms are 
91% and 88%, respectively (HR=0.75).  Overall type I error will be controlled using the 
O’Brien-Fleming method with a Lan-DeMets alpha-spending function.
Stratified log-rank testing will be used to compare OS between the 2 treatment arms.  The 
hazard ratios along with the 95% CIs will be estimated using a stratified Cox regression 
model.  The Kaplan-Meier method will be used to estimate the distribution of the OS 
endpoint for each treatment.  Median survival times (if estimable), along with the 2-sided 
95% CIs will be presented.  Analysis of OS will be performed based on the ITT population.
Other Secondary Efficacy Endpoints
CR per IRF will be analyzed based on the ITT population.  CR rate per IRF is defined as the 
proportion of patients who achieve CR at the end of treatment with randomized regimen 
(A+AVD or ABVD) as determined by an IRF.  CR rates between the 2 treatment arms will 
be compared using a stratified Cochran-Mantel-Haenszel (CMH) test.  A logistic regression 
model will be used to estimate the treatment effect in terms of odds ratio.  The odds ratio 
and its associated 95% CIs will be presented.  Sensitivity analyses for CR per IRF will be 
performed using the response-evaluable population.  CR rate per investigator will also be 
analyzed similarly using the ITT population.
Comparison of the ORR between the 2 treatment groups will be conducted using the 
stratified Cochran-Mantel-Haenszel test.  The 95% CI of the difference of the response rates 

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between the 2 treatments will also be provided.  ORR per IRF will be analyzed based on the 
ITT population.
Similar analyses will be conducted to compare the rate of patients that received 
consolidating irradiation between the 2 treatment arms.
CR rate at the end of frontline therapy will be assessed similarly to CR rate at the end of 
treatment with randomized regimen.
DOR in subjects with confirmed response is the time between first documentation of 
response and disease progression. DOCR in subjects with confirmed CR is the time 
between first documentation of CR and disease progression.  DOR and DOCR per IRF will 
be analyzed based on the ITT population.
EFS is defined as the time from randomization until any cause of treatment failure:  disease 
progression, premature discontinuation of treatment for any reason, or death due to any 
cause, whichever occurs first.  Analyses of EFS will be performed based on the ITT 
population.
DFS is defined as the time from CR to disease progression or to death from lymphoma or 
acute toxicity from treatment.  Analyses of DFS will be performed based on the subset of the 
ITT population achieving a CR.
The same analyses will be applied to these time-to-event endpoints as those described for 
OS above.
8.1.6.3   
Exploratory Endpoints
Alive without HL rate at 3 years and 5 years is defined as the proportion of patients who are 
alive without classical Hodgkin lymphoma at 3 years or 5 years after the patient’s 
randomization date.
Alive without lymphoma rates between the 2 treatment arms will be compared using a 
stratified Cochran-Mantel-Haenszel (CMH) test.
8.1.7   
Analyses of Patient-Reported Outcomes and Health Economics
Analyses of PROs and health economics will be performed using the ITT population.

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8.1.7.1   
Patient-Reported Outcomes Analysis
PRO assessments based on the QLQ-C30 will be analyzed to determine if treatments affect 
PRO scores. Analyses of PRO scores including global health status will be performed using 
longitudinal models. All subscales and individual item scores will be tabulated. Descriptive 
summaries of observed data will be provided at each scheduled assessment time point. PRO
assessments based on FACIT Dyspnea 10 and FACT-Ntx Abbreviated; will be analyzed 
using the same methods as QLQ-C30.
Initially, the manuals for scoring and handling missing data published for QLQ-C30, FACIT 
Dyspnea 10, and FACT-Ntx Abbreviated; will be used. Further investigation of missing 
patterns and details of imputation will be discussed in SAP.
8.1.7.2   
Health Economics Analysis Using Medical Resource Utilization and Utility
EQ-5D-3L scores will be summarized in descriptive statistics for treatment groups.
MRU data will be summarized in descriptive statistics for hospitalization (length of stay, 
inpatient, outpatient, and reason), number of missing days from work or other activities by 
patient, and care-giver, by treatment group.
8.1.8   
Pharmacokinetics/Pharmacodynamics/Biomarkers
Pharmacokinetic Analysis
The PK of the antibody-drug conjugate (brentuximab vedotin), total antibody, and 
unconjugated drug (MMAE) will be based on serum or plasma samples collected from 
patients who meet study inclusion criteria, received study drug, and provided evaluable PK 
data.  Population PK parameters will be calculated with an appropriate method based on a 
validated PK analysis program.  Exploratory safety-PK, efficacy-PK, and if possible, 
PK-pharmacodynamic relationships will be determined.
Descriptive statistics (eg, number of patients, mean, standard deviation, median, minimum, 
and maximum) will be used to summarize concentrations of analyte for brentuximab 
vedotin-treated patients.
The pharmacokinetics of doxorubicin, vinblastine, and dacarbazine will be compared 
between the treatment arms.  Descriptive statistics (eg, number of patients, mean, standard 
deviation, median, minimum, and maximum) will be used to summarize concentrations of 

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analyte.  Geometric mean ratios of the AUC will be calculated for each AVD component 
(doxorubicin, vinblastine, and dacarbazine).
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.
Relationships between ATA development and safety and efficacy will be explored.
Biomarkers
Absolute and change from baseline value of circulating biomarkers will be summarized by 
time point using descriptive statistics, as applicable.  Descriptive statistics (eg, number of 
patients, mean, standard deviation, median, minimum, maximum) will also be provided to 
summarize disease markers 
), tissue levels of potential 
resistance markers (s
, and qualitative and semiquantitative measures of markers (
 
 
), and change from baseline values of these markers, as 
applicable.  The association between these and clinical response or safety endpoints might 
be explored.  These analyses will be detailed in the SAP.
8.1.9   
Safety Analysis
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes 
from baseline in the patient’s vital signs, weight, and clinical laboratory results using the 
safety population.  Exposure to frontline therapy and reasons for discontinuation will be 
tabulated.
Treatment-emergent AEs that occur after administration of the first dose of study drug and 
through 30 days after the last dose of frontline therapy will be tabulated.
AEs will be tabulated according to the Medical Dictionary for Regulatory Activities 
(MedDRA) and will include the following categories:
CCI
CCI
CCI

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
Treatment-emergent AEs

Drug-related treatment-emergent AEs

Grade 3 or higher treatment-emergent AEs

Grade 3 or higher drug-related treatment-emergent AEs

The most commonly reported treatment-emergent AEs (ie, those events reported by 
10% of all patients)

SAEs
A listing of treatment-emergent AEs resulting in frontline therapy discontinuation will be 
provided.
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.
Descriptive statistics for the actual values (and/or the changes from baseline) of vital signs 
and weight over time will be tabulated by scheduled time point.
Shift tables for laboratory parameters will be generated based on changes in NCI CTCAE 
grade from baseline to the worst postbaseline value.  Graphical displays of key safety 
parameters, such as scatter plots of baseline versus worst postbaseline values, may be used 
to understand the safety profile of patients’ frontline therapies.
All concomitant medications collected from screening through the study period will be 
classified to preferred terms according to the World Health Organization (WHO) drug 
dictionary.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities 
and to further define the safety profile of patients’ frontline therapies.

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Electrocardiogram Analysis
Investigators’ assessments of ECG monitoring (normal, abnormal and clinically significant, 
or abnormal and not clinically significant), including unscheduled or retested measurements, 
will be presented in a listing.
8.1.10   
Interim Analyses
Two formal interim analyses (IAs) are planned for this study.
The first IA to be performed is a futility analysis.  CR rate will be analyzed when the first 
approximately 348 patients have completed the regimen to which they were randomized (ie, 
received the planned study drug regimen with no more than 2 missed doses of A+AVD or 
ABVD) or have discontinued treatment prior to completion.
Recommendation by the IDMC whether to terminate the study based on this IA will be 
determined upon evaluation of the overall safety information and efficacy data, specifically 
if the CR rate per IRF for the A+AVD arm is at least 5% lower than that of the ABVD arm,
and trends in mPFS and other efficacy endpoints suggest inferior efficacy in the A+AVD
arm.
Enrollment will continue during the first IA.
An IA for OS is also planned to occur at the time of the final mPFS analysis.  Overall type I 
error for OS will be controlled using the O’Brien-Fleming method with a Lan-DeMets 
alpha-spending function.
9.   
STUDY COMMITTEES
9.1   
Data Safety Monitoring Board
An IDMC will review safety and efficacy data at the interim analysis. The IDMC will 
provide a recommendation regarding study continuation based on the safety and efficacy
parameters.  In the event that the study is terminated early based on an IDMC 
recommendation, Millennium will notify the appropriate regulatory authorities.
Additionally, the IDMC will periodically review safety data per the IDMC charter. The first 
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(8 weeks) of treatment or discontinued prior to completing 2 cycles of treatment. 
Subsequently, IDMC safety reviews will be performed periodically per the IDMC charter.
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.

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).

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
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 v4.03, 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 4), because 
the terms serious and severe are NOT synonymous. The general term severe is often used to 
describe the intensity (severity) of a specific event; the event itself, however, may be of 
relatively minor medical significance (such as a Grade 3 headache). This is NOT the same 
as serious, which is based on patient/event outcome or action criteria described above, and is 
usually associated with events that pose a threat to a patient’s life or ability to function. A 
severe AE (Grade 3 or 4) does not necessarily need to be considered serious. For example, a 
white blood cell count of 1000/mm3 to less than 2000 is considered Grade 3 (severe) but 
may not be considered serious.  Seriousness (not intensity) serves as a guide for defining 
regulatory reporting obligations.
10.2   
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events
All AEs spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination, or other diagnostic 

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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 & Risk Management or designee (contact 
information provided below).  This should be done by faxing the SAE Form within 24 hours
after becoming aware of the event. All SAEs and serious pretreatment events (which 
include all deaths) must be reported whether or not considered causally related to the study 
drug or study procedures. 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 or designee.  SAE report information must be consistent with the data 
provided on the eCRF.
SAE Reporting Contact Information
US and Canada
Toll-Free Fax #: 
E-mail:
All Other Countries (Rest of World)
Fax #: 
E-mail:
Planned hospital admissions or surgical procedures for an illness or disease that existed 
before the patient was enrolled in the trial are not to be considered AEs unless the condition
deteriorated in an unexpected manner during the trial (eg, surgery was performed earlier or 
later than planned).
For both serious and nonserious AEs, the investigator must determine both the intensity of 
the event and the relationship of the event to study drug administration.  For serious 
pretreatment events, the investigator must determine both the intensity of the event and the 
relationship of the event to study procedures.
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Intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE v4.03, effective 14 June 2010.(26)  The criteria are provided in the Study 
Manual.
Relationship to study drug administration will be determined by the investigator responding 
yes or no to this question:  Is there a reasonable possibility that the AE is associated with the 
study drug?
Sponsor Responsibilities
The IB will be used as the resource for determining expectedness of SAEs for brentuximab 
vedotin.  
Millennium will ensure that all relevant information regarding suspected, unexpected serious 
adverse reactions (SUSARs) that are fatal or life threatening is recorded and reported as 
soon as possible to the competent authorities in all the member states concerned, and to the 
IEC, and in any case no later than 7 days after knowledge by Millennium of such a case.  
The relevant follow-up information will subsequently be communicated within an additional 
8 days or as required by country regulations.  
All other SUSARs will be reported as required to the competent authorities and IEC as soon 
as possible but within a maximum of 15 days after Millennium becomes aware of the event.
10.3   
Monitoring of Adverse Events and Period of Observation
AEs, both nonserious and serious (which include all deaths), will be monitored throughout 
the study as follows:

AEs will be reported from first dose of frontline therapy through 30 days after
administration of the last dose of frontline therapy and recorded in the eCRFs. A 
diagnosis of a malignancy other than classical HL that occurs at any time prior to 
study closure must be recorded in the eCRF regardless of causality.  Additionally,
events of malignancy occurring more than 30 days post the last dose of frontline 
therapy that are deemed serious and related to study drug must be reported to 
Millennium Department of Pharmacovigilance & Risk Management or designee on 
an SAE form.  All events relating to peripheral neuropathy, regardless of seriousness, 
will be followed for all changes in severity until resolution to baseline or study 
closure, whichever occurs first, and recorded in the eCRF.

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
Treatment-related AEs will be reported from first dose of frontline therapy through 
30 days after administration of the last dose of frontline therapy and recorded in the 
eCRFs.  Treatment-related AEs must be monitored for resolution through event 
resolution or study closure.  

Serious pretreatment events will be reported to Millennium Department of 
Pharmacovigilance & Risk Management or designee from the time of the signing of 
the ICF up to first dose of frontline therapy, but will not be recorded in the eCRF.

Related and unrelated SAEs will be reported to Millennium Department of 
Pharmacovigilance & Risk Management or designee from the first dose of frontline 
therapy through 30 days after administration of the last dose of frontline therapy and 
recorded in the eCRF.  All SAEs should be monitored until they are resolved or are 
clearly determined to be due to a patient’s stable or chronic condition or intercurrent 
illness(es). Any SAE that occurs between 30 days post last dose of frontline therapy 
and study closure that the investigator considers related to study drug must be 
reported to the Millennium Department of Pharmacovigilance & Risk Management
or designee.  In addition, events of PML must be reported on an SAE form, 
regardless of treatment arm or causal relationship, from the first dose of study drug 
through death or termination of the study by the sponsor.
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 & Risk Management or 
designee.  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 & Risk 
Management or designee.  Every effort should be made to follow the pregnancy for the final 
pregnancy outcome.
Pregnancy follow-up will continue throughout the posttreatment follow-up period until 
study closure.

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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.
11.5   
Ethical Considerations
The study will be conducted in accordance with applicable regulatory requirement(s) and 
will adhere to GCP standards.  The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the patients.  The study will 
be conducted only at sites where IRB/IEC approval has been obtained.  The protocol, IB, 
ICF, advertisements (if applicable), written information given to the patients (including 
diary cards), safety updates, annual progress reports, and any revisions to these documents 
will be provided to the IRB/IEC by the investigator or the sponsor, as allowed by local 
regulations.
11.6   
Patient Information and Informed Consent
After the study has been fully explained, written informed consent will be obtained from 
either the patient or his/her guardian or legal representative before study participation.  The 
method of obtaining and documenting the informed consent and the contents of the consent 
must comply with the ICH-GCP and all applicable regulatory requirements.
11.7   
Patient Confidentiality
To maintain patient privacy, all eCRFs, study drug accountability records, study reports, and 
communications will identify the patient by initials where permitted and/or by the assigned 
patient number.  The patient’s confidentiality will be maintained and will not be made 
publicly available to the extent permitted by the applicable laws and regulations.

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11.8  
Investigator Compliance
The investigator will conduct the trial 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 investigational medicinal product at the trial site is the responsibility of 
the investigator.  Drug accountability records indicating the drug’s delivery date to the site, 
inventory at the site, use by each patient, and amount returned to 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 
 
 (formerly 
) (see below) and report the 
PPD
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event.  Whenever possible, the associated product 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 
(see below) and report the event.
For Product Complaints or Medication Errors,
call 
at
; Option 1 (toll free)
or 
(non-toll free)
Product complaints and medication errors in and of themselves are not AEs.  If a product 
complaint results in an SAE, an SAE form should be completed and sent to 
(refer 
to Section 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 trial results will be 
submitted to the competent authorities and IECs in all member states involved in the study.
Study participation by individual sites or the entire study may be prematurely terminated if,
in the opinion of the investigator or 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
PPD
PPD
PPD
PPD
PPD

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
Insufficient, incomplete, and/or unevaluable data

Determination of efficacy based on interim analysis

Plans to modify, suspend or discontinue the development of the study drug
Should the study be closed prematurely, the site will no longer be able to access the EDC 
application, will not have a right to use the EDC application, and will cease using the 
password or access materials once their participation in the study has concluded.  In the 
event that any access devices for the EDC application have been provided, these will be 
returned to 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.

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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 trial results pursuant to 
the terms contained in the applicable Clinical Trial Agreement.
It is anticipated that the results of this study will be presented at scientific meetings and/or 
published in a peer-reviewed scientific or medical journal.  A Publications Group 
comprising 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 below:

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 C25003 Amendment 7:  A Randomized, Open-label, Phase 3 Trial of 
A+AVD Versus ABVD as Frontline Therapy in Patients With Advanced Classical Hodgkin 
Lymphoma.
I agree to conduct the study as detailed herein and in compliance with International 
Conference on Harmonisation Guidelines for Good Clinical Practice and applicable 
regulatory requirements and to inform all who assist me in the conduct of this study of their 
responsibilities and obligations.
Principal investigator printed name
Principal investigator signature
Date
Investigational site or name of institution and 
location (printed)

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14.   
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24.
Sarr MG, Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, et al. The 
new revised classification of acute pancreatitis 2012. Surgical Clinics of North 
America 2013;93(3):549-62.
25.
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. 
Revised response criteria for malignant lymphoma. Journal of Clinical Oncology 
2007;25(5):579-86.
26.
U.S. Department of Health and Human Services, National Institutes of Health 
National Cancer Institute. Common Terminology Criteria for Adverse Events 
(CTCAE). Version 4.03. 14 June 2010.
27.
Falini B, Pileri S, Pizzolo G, Durkop H, Flenghi L, Stirpe F, et al. CD30 (Ki-1) 
molecule: a new cytokine receptor of the tumor necrosis factor receptor superfamily 
as a tool for diagnosis and immunotherapy. Blood 1995;85(1):1-14.
28.
van den Berg A, Visser L, Poppema S. High expression of the CC chemokine TARC 
in Reed-Sternberg cells. A possible explanation for the characteristic T-cell 
infiltratein Hodgkin's lymphoma. Am J Pathol 1999;154(6):1685-91.
29.
Fauci A, Braunwauld E, Kasper D, Hauser S, Longo D, Jameson J, et al. Ann Arbor 
Staging System for Hodgkin’s Disease. In: Harrison’s Principles of Internal 
Medicine, 17th edition, Manual of Medicine. New York, NY: McGraw-Hill; 2009.
30.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. 
American Journal of Clinical Oncology 1982;5(6):649-55.
31.
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.
32.
Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin's disease. 
International Prognostic Factors Project on Advanced Hodgkin's Disease. New 
England Journal of Medicine 1998;339(21):1506-14.
33.
Meignan M, Gallamini A, Haioun C, Polliack A. Report on the Second International 
Workshop on interim positron emission tomography in lymphoma held in Menton, 
France, 8-9 April 2010. Leukemia & Lymphoma 2010;51(12):2171-80.
34.
Mosteller RD. Simplified calculation of body-surface area. New England Journal of 
Medicine 1987;317(17):1098.

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15.   
APPENDICES
15.1   
Ann Arbor Staging System for Hodgkin Lymphoma
Stage
Definition
I
Involvement of a single lymph node region or lymphoid structure (eg, spleen, thymus, 
Waldeyer’s ring)
II
Involvement of 2 or more lymph node regions on the same side of the diaphragm (the 
mediastinum is a single site; hilar lymph nodes should be considered "lateralized" and, 
when involved on both sides, constitute Stage II disease)
III
Involvement of lymph node regions or lymphoid structures on both sides of the 
diaphragm
III1
Subdiaphragmatic involvement limited to spleen, splenic hilar nodes, celiac nodes, or 
portal nodes
III2
Subdiaphragmatic involvement includes paraaortic, iliac, or mesenteric nodes plus 
structures in III1
IV
Involvement of extranodal site(s) beyond that designated as "E"
More than 1 extranodal deposit at any location
Any involvement of liver or bone marrow
A
No symptoms
B
Unexplained weight loss of >10% of the body weight during the 6 months before staging 
investigation
Unexplained, persistent, or recurrent fever with temperatures >38ºC during the previous 
month
Recurrent drenching night sweats during the previous month
E
Localized, solitary involvement of extralymphatic tissue, excluding liver and bone 
marrow
Source: Harrison’s Manual of Medicine, 17th Edition.(29)
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.(30)

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15.3   
Cockcroft-Gault Equation
For male patients:  
Creatinine Clearance=[(140-age) (body weight in kg) / (72 × serum creatinine in mg/dL)]
For female patients:
Creatinine Clearance=[(140-age) (body weight in kg) / (72 × serum creatinine in 
mg/dL)] × 0.85
15.4   
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.(31)
15.5   
International Prognostic Factors Scoring for Advanced Hodgkin Lymphoma
One Point To Be Assigned for Each Prognostic Factor:
Serum albumin <4 g/dL
Hemoglobin <10.5 g/dL
Male sex
Stage IV disease
Age ≥45 years
White cell count ≥15,000 mm3
Lymphocyte count <600 mm3 or <8% of white-cell count
Source:  A Prognostic Score for Advanced Hodgkin’s Disease.  Hasenclever D and Diehl V for the 
International Prognostic Factors Project on Advanced Hodgkin’s Disease. NEJM 339; 1998: 1506-15.(32)

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15.6   
Deauville Criteria for PET
Score
1
no uptake
2*
uptake mediastinum
3*
uptake >mediastinum but liver
4
Uptake moderately increased compared to the liver at any site.
5
Uptake markedly increased compared to the liver at any site or/and new sites of disease.
Source:  Report on the Second International Workshop on interim positron emission tomography in lymphoma 
held in Menton, France, 8-9 April 2010.  Meignan M, Gallamini A, Haioun C, Polliack A.  Leuk Lymphoma
51; 2010:2171-80.(33)
* If mediastinal blood pool activity is equal or greater than liver then the uptake within the lesion should be 
compared with liver (lesion uptake less than liver=score 2; lesion uptake equal to liver=score 3).
15.7   
Body Surface Area Nomogram
Body surface area should be calculated according to institutional guidelines, preferably by
using the Mosteller formula standard nomogram.
The Mosteller Formula
BSA (m²)=( [Height(cm) Weight(kg) ]/ 3600 )½
eg, BSA=SQRT( [cm*kg]/3600 )
or in inches and pounds: BSA (m²)=( [Height(in) Weight(lbs) ]/ 3131)½
Adapted from: Mosteller RD.  Simplified calculation of body-surface area.  N Engl J Med 
1987;317(17):1098.(34)

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15.8   
Amendment 1 Rationale and Purposes
Rationale for Amendment 1
This amendment reduces subjectivity in the assessment of the study’s modified 
progression-free survival (mPFS) primary endpoint and clarifies the sourcing of bleomycin, 
corrects the posttreatment follow-up disease assessment scanning schedule, and clarifies the 
sampling schema for serum chemistry, PK, urinalysis, fasting A1C Hb, immunogenicity,
and germline DNA.
Purposes for Amendment 1
The purposes of this amendment are to:

Change the mPFS event date for patients who receive subsequent anticancer 
chemotherapy in the absence of disease progression.  The mPFS event will be recorded 
as occurring on the date of the first positron emission tomography (PET) scan post
completion of frontline therapy demonstrating the absence of a complete remission 
(CR), defined as a Deauville score of 3.

Specify that Deauville scoring must be performed for the End of Treatment (EOT) PET 
scan and any unscheduled PET scan to support objective determination of mPFS.

Clarify that sensitivity analyses around the mPFS endpoint and censoring rules will be 
described in the Statistical Analysis Plan (SAP).

Align Section 8.1, Statistical Methods, with Sections 2 (objectives) and 3 (endpoints) 
with regard to key secondary versus other secondary objectives and endpoints.

Simplify the bleomycin Storage, Handling, and Accountability rules and permit local 
sourcing of bleomycin as agreed by the site and sponsor if applicable regulations are 
met.

Delete bilirubin subtypes from the Schedule of Events to align with Section 7.4, Study 
Procedures.

Add Day 15 PK sampling in the Schedule of Events as already specified in Section 7.4, 
Study Procedures.

Delete urinalysis from the Schedule of Events to align with Section 7.4, Study 
Procedures.

Remove the option for patients with stable disease to have patient-reported outcomes
(PRO) collection via phone from the Schedule of Events to align with Section 7.10.

Reflect collection of a fasting Day 15 A1C Hb in the footnote accompanying the 
Schedule of Events table as specified in the table body.

Remove immunogenicity sampling at screening and restrict immunogenicity sampling 
at all other time points to patients in the A+AVD arm, only.

Restrict germline DNA sampling only to patients in the A+AVD arm.

Restrict post-progression tumor biopsies only to patients in the A+AVD arm in the 
Schedule of Events to align with Section 7.4.18.

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
Correct calendar days of posttreatment follow-up computed tomography (CT) 
scanning.

Align pregnancy testing in Section 7.4.7 with the Schedule of Events.

Clarify collection of and populations for PK sampling.

Remove requirement for baseline biomarker sampling.

Correct typographical errors, punctuation, grammar, and formatting.

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15.9   
Amendment 2 Rationale and Purposes
Rationale for Amendment 2
This amendment seeks to clarify the modified progression-free survival (mPFS) censoring 
rules, clarify the content and timing of disease and other assessments, and to further align 
the biostatistical analysis methods section with the existing “other secondary” objectives and 
endpoints.
Purposes for Amendment 2
The purposes of this amendment are to:

Refer the reader to the Statistical Analysis Plan (SAP) for censoring rules for the mPFS 
primary endpoint in the event of missing information

Describe the biostatistical analysis of complete remission (CR) rate at the end of 
frontline therapy

Specify that B symptoms will be assessed

Clarify that concomitant procedure data will be collected

Clarify that the “concomitant treatments” recorded during long-term follow-up are 
anticancer treatments for Hodgkin lymphoma

Clarify language describing the frequency of posttreatment follow-up assessments, 
including radiological assessments

Specify that MRI may be substituted for CT in select circumstances

Correct typographical errors, punctuation, grammar, and formatting

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15.10   Amendment 3 Rationale and Purposes
Rationale for Amendment 3
This amendment seeks to improve the accuracy of the Cycle 2 positron emission 
tomography (PET)/computed tomography (CT) scan.  The timing of the Cycle 2 PET/CT 
scan was originally scheduled for Cycle 2 Day 20 (±2 days).  The scheduled assessment 
time has been revised to Cycle 2 Day 25 (±1 day) to allow for additional recovery time 
following the second Cycle 2 dose to decrease the likelihood of a false-positive result related 
to posttreatment inflammation.
Purposes for Amendment 3
The purposes of this amendment are to:

Change the scheduled timing of the Cycle 2 PET/CT scan to Day 25 (±1 day)

Correct typographical errors, punctuation, grammar, and formatting

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15.11   Amendment 4 Rationale and Purposes
Rationale for Amendment 4
This amendment seeks to align sites’ choice to administer radiotherapy to noncomplete 
responders at the conclusion of frontline therapy with current clinical practice.  It also 
reduces variation in dose calculations by specifying a single formula for body surface area 
(BSA) and simplifies blood pressure measurements for ease and increased compliance.  It 
clarifies multiple types of data recording to reduce potential reporting errors and improve the 
resulting understanding of the studied treatments’ safety and efficacy profiles.  Last, it aligns 
certain protocol language with the sponsor’s other clinical protocols investigating 
brentuximab vedotin for greater consistency and ease of use.
Purposes for Amendment 4
The purposes of this amendment are to:

Allow sites’ determination of positron emission tomography (PET) positivity to guide 
additional radiotherapy for noncomplete responders at the conclusion of frontline 
therapy, allow radiation to be given for patients with PET-positive residual masses of 
any size instead of only those with masses of 2.5 cm or larger, and allow sites to select 
radiation doses as medically appropriate.

Specify Mosteller’s nomogram for calculating BSA

Require only seated measurements of blood pressure

Align progressive multifocal leukoencephalopathy (PML) descriptive text across the 
sponsor’s clinical protocols

Clarify that sites need not perform Deauville assessments of PET scans, which will be 
performed by an independent review facility

Specifically describe the recording of data regarding the incidence PML or 
malignancies other than classical Hodgkin lymphoma (HL), data regarding a switch in 
frontline therapy, and data regarding unscheduled bone marrow or cytology results

Remove specific limits on blood sampling volumes for serum biomarkers, 
immunogenicity, and germline DNA to accommodate small variations among sampling 
kits

Remove patient decision as a reason for discontinuing study drug as it is already a 
reason for study withdrawal

Clarify that, unless otherwise specified, only those serious adverse events that occur 
during long term follow-up that are considered related to study drug (instead of 
“frontline therapy”) will be reported.

Further clarify that pregnancy data will be collected until study closure

Correct typographical errors, punctuation, grammar, and formatting.

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15.12   Amendment 5 Rationale and Purpose
Rationale for Amendment 5
Amendment 5 seeks to eliminate a potential bias in favor of the experimental treatment arm 
by providing symmetry across the 2 treatment arms in the definition of completion of 
frontline therapy, which might affect the modified progression-free survival (mPFS) primary 
endpoint of the study.  The amendment also contains minor updates to enhance patient 
safety, improve protocol clarity and compliance, and align study conduct with the sponsor’s 
current guidelines and practices.  
Purposes for Amendment 5
The purposes of this amendment are to:

Provide symmetry across the 2 treatment arms in the definition of completion of 
frontline therapy:
o
Standardize the definition of a missed dose across the 2 treatment arms to permit 
investigators, who are best able to determine the adequacy of the delivered regimen 
and the need to make adjustments for treatment-related toxicity, to omit individual 
agents from the randomized treatment regimen without this counting as a missed 
dose.  

Enhance patient safety:
o
Add acute pancreatitis and hepatotoxicity to the discussion of potential risks 
associated with brentuximab vedotin.  
o
Require consultation with the contract research organization (CRO) and/or 
sponsor’s project clinician as prerequisite for changing the order of administration 
of the study drugs and specify that the order of administration must not be changed 
for the subset of patients from whom additional pharmacokinetic (PK) samples are 
to be obtained.
o
Permit the prophylactic use of antiemetics during the treatment period of the study.  
o
Allow for the use of alternate methods other than the Mosteller formula standard 
nomogram for the calculation of body surface area (BSA) to ensure that sites using 
electronic chemotherapy order entry systems are able to comply with the protocol.  
Electronic chemotherapy order entry systems enhance patient safety by eliminating 
the potential for manual calculation errors, and should be supported where 
available.  

Institute minor modifications in study procedures to enhance clarity and/or 
facilitate greater compliance with the protocol:
o
Clarify that the abbreviated version of Functional Assessment of Cancer 
Therapy-Neurotoxicity (FACT-Ntx Abbreviated) is being used in the study.
o
Revise the anticipated number of study sites globally.  
o
Clarify the exclusion criterion pertaining to pulmonary diffusion capacity.  
o
Clarify the procedure for supply of study drugs.
o
Clarify the guidelines for reconstitution and disposal of brentuximab vedotin.

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o
Clarify the accountability requirements for bleomycin. 
o
Remove the requirement for body temperature to be measured orally.
o
Align the pregnancy testing guideline with that in the Schedule of Events. 
o
Clarify the guidelines for preparation of unstained slides of tumor tissue to be used 
for assessment of biomarkers to reflect current practice at some diagnostic 
facilities.
o
Clarify posttreatment follow-up assessments for patients who do not complete 
6 treatment cycles.
o
Clarify the guideline for posttreatment follow-up assessments for mPFS. 
o
Stipulate fasting for patients before measurement of blood glucose concentrations; 
remove the requirement for the patient to fast before measurement of hemoglobin 
A1C (Hb A1C) concentrations and revise the timing of these measurements to 
optimize the clinical value of these measurements.
o
Specify that posttreatment patient-reported outcomes (PRO) assessments will not 
be performed by telephone.
o
Clarify the timing between screening and administration of first dose of study 
drugs.  
o
Clarify that a computed tomography (CT) scan must be performed when patients 
start an alternate therapy before completion of the randomized treatment regimen 
(either A+AVD or ABVD).

Align study conduct with the sponsor’s current guidelines and practices:
o
Modify contraception language.  
o
Define peripheral neuropathy (PN) and PN-related adverse events (AEs) and align
the monitoring guidelines for these AEs across the brentuximab vedotin clinical 
development program.
o
Update the reporting period for serious adverse events (SAEs) to Millennium from 
1 working day to 24 hours. 
o
Update SAE reporting language to meet regulatory requirements in the European 
Union (EU) Directive, 2001/20/EC Article 17 parts (a) and (b).  
o
Clarify the monitoring and reporting guidelines for treatment-related AEs.
o
Update text pertaining to product complaints and medication errors for commercial 
products.
o
Revise and update the Serious Adverse Event and Pregnancy Contact Information.

Correct typographical errors, punctuation, grammar, and formatting.
For specific examples of changes in text and where the changes are located, see 
Section 15.13.

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15.13   Amendment 6 Rationale and Purpose
Rationale for Amendment 6
Amendment 6 removes the exclusion criterion pertaining to pulmonary diffusion capacity on 
the basis of input from study investigators and the study’s Steering Committee to better 
align with standard practice in the treatment of patients with advanced classical Hodgkin 
lymphoma (HL) and increase the generalizability of the study.  Pulmonary carbon monoxide 
diffusion capacity (DLCO) does not accurately reflect pulmonary reserve, particularly in 
patients with advanced HL who may have mediastinal and/or pulmonary involvement.  
Patients who have been excluded from this study on the basis of DLCO have generally been 
treated with ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine), 
indicating that the exclusion criterion does not reflect current standard practice.  
The amendment also contains revised and updated serious adverse event (SAE) reporting 
contact information.  
Purposes for Amendment 6
The purposes of this amendment are to:

Remove the exclusion criterion pertaining to pulmonary diffusion capacity

Revise and update the SAE Reporting Contact Information to reflect the change in the 
sponsor’s vendor

Correct typographical errors, punctuation, grammar, and formatting
For specific examples of changes in text and where the changes are located, see 
Section 15.14.

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15.14   Amendment 7 Detailed Summary of Changes
THE PRIMARY SECTIONS OF THE PROTOCOL AFFECTED BY THE CHANGES IN 
AMENDMENT 7 ARE INDICATED.  THE CORRESPONDING TEXT HAS BEEN 
REVISED THROUGHOUT THE PROTOCOL.
Purpose:  Increase study enrollment.
o
Increase the sample size by 200 patients to a total of approximately 1240 enrolled 
patients, and increase the anticipated enrollment period.
The primary change occurs in Section 4.1, Overview of Study Design:
Formerly 
read:  
The study will enroll approximately 1040 patients; enrollment is anticipated to 
last 2 years.  
Now 
reads:  
The study will enroll approximately 1240 patients; enrollment is anticipated to 
last 3 years.  
Sections that also contain this change are:

Section 4.2, Number of Patients

Section 8.1.1, Determination of Sample Size

Protocol Summary
o
Increase enrollment to 620 patients per treatment arm, and increase the estimated 
number of sites to 250 study sites globally.
The primary change occurs in Section 4.2, Number of Patients:
Formerly 
read:  
Approximately 1040 patients (approximately 520 patients per treatment arm) 
will be randomized in this study from approximately 200 study centers 
globally, including centers in North America, Europe, and Asia.
Now 
reads:  
Approximately 1240 patients (approximately 620 patients per treatment arm) 
will be randomized in this study from approximately 250 study centers 
globally.
Sections that also contain this change are:

Section 4.1, Overview of Study Design

Protocol Summary

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o
Delete reference to the percentage of the original sample size that was planned for 
inclusion in the interim futility analysis.
The primary change occurs in Section 4.1, Overview of Study Design:
Deleted 
text:
An interim futility analysis will be conducted when the first approximately 
348 patients (1/3 of overall sample size of 1040 patients) have completed the 
regimen to which they were randomized (ie, received the planned study drug 
regimen with no more than 2 missed doses of A+AVD or ABVD) or have 
discontinued treatment prior to completion.
Section 8.1.10, Interim Analyses also contains this change.
o
Revise the projected length of enrollment and follow-up periods.
The primary change occurs in Section 4.3, Duration of Study:  
Formerly 
read:  
It is expected that the study will last approximately 60 months to reach the 
final analysis of the mPFS endpoint (approximately 24 months of enrollment 
plus 36 months of additional follow-up after the last patient is randomized).  
Now 
reads:  
It is expected that the study will last approximately 60 months to reach the 
final analysis of the mPFS endpoint (approximately 36 months of enrollment 
plus 24 months of additional follow-up after the last patient is randomized).  
Sections that also contain this change are:

Section 8.1.1, Determination of Sample Size

Protocol Summary
Purpose:  Revise the statistical assumptions of mPFS rates for both treatment arms in the 
study.
The change occurs in Section 8.1.1, Determination of Sample Size:  
Formerly 
read:
The primary endpoint of the study is mPFS, and the study is powered on the 
following assumption: a 3-year mPFS of 82.5% for patients in the A+AVD
treatment group versus 75% for patients in the ABVD treatment group 
(HR=0.67 assuming exponential distribution).  A total of 260 mPFS events
will provide 90% power to detect a hazard ratio (HR) of 0.67 at a 1-sided 
significance level of 0.025.  Approximately 1040 patients will be randomized 
to achieve 260 mPFS events in about 60 months, assuming 24 months of 
accrual, a 5% annual dropout rate, and 36 months of mPFS follow-up after 
last patient in.

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Now 
reads:  
The primary endpoint of the study is mPFS, and the study is powered on the 
following assumption:  a 2-year mPFS of 81% for patients in the A+AVD 
treatment group versus 73% for patients in the ABVD treatment group 
(HR=0.67; assuming a decrease in the PFS event rate after 2 years). A
total of 260 mPFS events will provide 90% power to detect a hazard ratio of 
0.67 at a 1-sided significance level of 0.025 using a log-rank test.  
Approximately 1240 patients will be randomized to achieve (with 95%
probability) 260 mPFS events in approximately 60 months, assuming 
36 months of accrual, a 5% annual dropout rate, and 24 months of mPFS 
follow-up after last patient in.  
o
Align the timing of the interim overall survival analysis with that for the final 
mPFS analysis.
The primary change occurs in Section 8.1.6.2, Analyses of Secondary Efficacy Endpoints:  
Deleted 
text:  
An OS interim analysis will be performed at the time of the final mPFS 
analysis (approximately 3 years after the last patient is enrolled), and the final 
analysis of OS will be performed when 112 deaths have occurred, assuming 
5-year OS rates for the A+AVD and ABVD arms are 91% and 88%, 
respectively (HR=0.75).  
Section 8.1.10, Interim Analyses also contains this change.
o
Revise the timing for the final analysis of overall survival.
The primary change occurs in Section 4.1, Overview of Study Design:  
Formerly 
read:
The final analysis of OS will be conducted when 112 deaths occur, 
approximately 5 years after randomization of the last patient.
Now 
reads:
The final analysis of OS will be conducted when 112 deaths occur, 
approximately 4 years after randomization of the last patient.
Sections that also contain this change are: 

Section 4.3, Duration of Study

Protocol Summary
Purpose:  Institute minor modifications in protocol language to improve protocol clarity 
and compliance, and align study conduct with the sponsor’s current guidelines and 
practices.
o
Clarify and align the posttreatment follow-up assessments for PFS disease status, 
event-free survival, and overall survival.
The change occurs in the Schedule of Events, footnotes a and j:

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Added 
text:  
a.  Note: Radiological assessments are only required every 12 weeks 
(± 1 week) until 12 months of PTFU and then every 6 months until study 
closure.  To assist with scheduling of visits, patients may begin to align the
timing of their follow-up visits with the timing of CT scans during PTFU, 
when applicable.
…
j.  Response to treatment and disease assessments…
…
!
During the follow-up period: every 3 months for the first year and then 
every 6 months thereafter. The CT scan time points are calculated
from C1D1.
o
Clarify the PK sampling time points for the 50-patient subset in both treatment 
arms by correcting the study day stated in the protocol.
The primary change occurs in Section 7.4.19, Pharmacokinetic Measurements; Table 7-1.  
Formerly 
read:
Cycle 
Study Day
Time
Window
Relative Time
7
168 hr
± 24 hr
End of brentuximab vedotin infusion
Now 
reads:  
Cycle 
Study Day
Time
Window
Relative Time
8
168 hr
± 24 hr
End of brentuximab vedotin infusion
or 
End of dacarbazine infusion
The Schedule of Events also contains this change.  
o
Update the contact information for product complaints and medication errors.
The change occurs in Section 11.11, Product Complaints and Medication Errors:  
Formerly 
read:  
Individuals who identify a potential product complaint situation should 
immediately contact 
 (see below) and report the event.  
…
Individuals who identify a potential medication error situation should 
immediately contact 
(see below) and report the event.
For Product Complaints or Medication Errors,
call 
at
(US and International)
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Brentuximab vedotin (ADCETRIS®)
Clinical Study Protocol C25003 Amendment 7, EudraCT:  2011-005450-60
Confidential
103
Now 
reads: 
Individuals who identify a potential product complaint situation should 
immediately contact 
(formerly
) (see below) and report the event.  
…
Individuals who identify a potential medication error situation should 
immediately contact 
(see below) and report the event.
For Product Complaints or Medication Errors,
call
at
 Option 1 (toll free)
or
 (non-toll free)
o
Add the Global Statistical Lead to the list of approvers for the amended protocol.
The change occurs on the Title Page:
Added 
text:  
Signature
Date
Purpose:  Correct typographical errors, punctuation, grammar, and formatting, as 
applicable.
These changes are not listed individually.
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