Clinical trial NCT01578499
Conditions: Primary Cutaneous Anaplastic Large Cell Lymphoma Mycosis Fungoides Cutaneous T-Cell Lymphoma
Keywords: Brentuximab vedotin ALCANZA
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2012-06-11; Completion date: 2018-07-06
Enrollment: 131 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine objective response rate (ORR), lasting at least 4 months (ORR4), with brentuximab vedotin in participants with cluster of differentiation antigen 30 positive (CD30+) cutaneous T-cell lymphoma \[mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL) \]compared to that achieved with therapy in the control arm.

Detailed description:
The drug being tested in this study is called brentuximab vedotin. Brentuximab vedotin is being tested to treat people who have CD30+ cutaneous T-cell lymphoma (mycosis fungoides and primary cutaneous anaplastic large cell lymphoma). This study will look at the overall response of people who took brentuximab vedotin compared to people who took methotrexate or bexarotene as standard care.

The study enrolled 131 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

* Methotrexate 5 to 50 mg or Bexarotene 300 mg/m\^2 (as per physician's choice)
* Brentuximab vedotin 1.8 mg/kg

This multicenter trial is being conducted worldwide. The overall time to participate in this study is approximately 6 years. Participants will make multiple visits to the clinic every 12 weeks for a minimum of 24 months after the end of treatment (EOT) visit, and then every 6 months until death, study closure, or 6 years after enrollment of the last participant.

Arms: arm 1: Brentuximab vedotin 1.8 mg/kg, intravenous over approximately 30 minutes, once on Day 1 of each 21-day cycle and may continue as monotherapy for up to a total of 16 cycles (48 weeks). arm 2: Methotrexate 5 to 50 mg, tablets, orally, once weekly (dose adjustment is guided by patient response and toxicity) or Bexarotene 300 mg/m\^2, tablets, orally, once daily with meals for up to 48 weeks.
Interventions: intervention 1: Brentuximab Vedotin intervention 2: Methotrexate intervention 3: Bexarotene
Intervention descriptions: intervention 1: Brentuximab vedotin intravenous injection. intervention 2: Methotrexate tablets. intervention 3: Bexarotene tablets.

Protocol documents:
Prot_001.pdf: 


•
Title: A Randomized, Open-Label, Phase 3 Trial of brentuximab vedotin (SGN-35) Versus 
Physician's Choice (Methotrexate or Bexarotene) in Patients With CD30-Positive Cutaneous T-
Cell Lymphoma
NCT Number: NCT01578499
Protocol Approve Date: 02 December 2014
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25001 Amendment 5, EudraCT:  2010-024215-14
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CLINICAL STUDY PROTOCOL C25001 AMENDMENT 5
Brentuximab vedotin (SGN-35)
A Randomized, Open-Label, Phase 3 Trial of brentuximab vedotin (SGN-35) Versus 
Physician's Choice (Methotrexate or Bexarotene) in Patients With CD30-Positive 
Cutaneous T-Cell Lymphoma
Protocol Number:
C25001
Indication:
CD30 Positive Cutaneous T-Cell Lymphoma
Phase:
3
Sponsor:
Millennium Pharmaceuticals, Inc.
EudraCT Number:
2010-024215-14
Therapeutic Area:
Oncology
Protocol History
Original
11 July 2011
Amendment 1
21 December 2011
Amendment 2
24 February 2012
Amendment 3
04 March 2013
Amendment 4
03 July 2013
Amendment 5
02 December 2014
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street
Cambridge, MA USA  02139
Telephone:  +1 (617) 679-7000
Approved by:
Note:  If this document was approved electronically, the electronic approval signatures may 
be found at the end of the document.
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


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Rationale for Amendment 5
Amendment 5 to the protocol includes updated safety information and revises the existing 
eligibility criteria regarding patients at risk for pancreatitis.  Acute pancreatitis has been 
reported with brentuximab vedotin in clinical trials and postmarketing experience.
Language has been added to the benefit and risk section of this amendment summarizing the 
potential risk of pancreatitis in this population of patients with cutaneous T-cell lymphoma 
(CTCL), a non-life threatening disease.  In addition, eligibility criteria have been updated to 
include the exclusion of patients with an elevated lipase value ≥3 the upper limit of 
normal (ULN) with an amylase level > ULN. Lipase and amylase have also been added to 
the chemistry lab panel.
As part of the screening requirements for this study, fludeoxyglucose positron emission 
tomography (FDG-PET) scans and computed tomography (CT) scans of the neck, chest, 
abdomen, and pelvis are performed at screening. Amendment 5 allows for FDG-PET scans 
that were taken within 8 weeks before signing the informed consent form (ICF) to be used as 
the screening FDG-PET, and CT scans taken within 4 weeks before signing the ICF to be 
used as the screening CT scan provided pre-specified conditions are met. This change is 
made in the interest of patient safety (to avoid unnecessary duplicate scans).
Purposes for Amendment 5
The purposes of this amendment are to:

Add safety language regarding the potential risk of pancreatitis

Add lipase values and amylase levels to pancreatitis exclusion criterion

Add lipase and amylase to the chemistry lab panel

Revise text regarding timing of FDG-PET and CT scans

Clarify text regarding follow-up for objective response

Clarify text regarding timing of clinical laboratory assessments

Revise timing for exclusion of oral retinoid therapy 

Add a statement regarding the scheduling of pregnancy tests

Revise the definition of relapse in the text to align with the definition in the response 
tables

Add relapse to the list of global response score (GRS) responses

Clarify text regarding the collection of pharmacokinetic parameters

Clarify text regarding the amount of blood to be collected for germline DNA 
assessments

Clarify text regarding the discontinuation of study drug

Revise text describing safety analysis

Revise text describing monitoring of adverse events

Revise text regarding the recording and reporting of adverse events and serious adverse 
events (SAEs) 


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
Replace references to PPD with Millennium Pharmacovigilance or designee

Update contact information for reporting SAEs

Correct errors in Background and Study Rationale text and in-text references 

Correct typographical errors, punctuation, grammar, and formatting
For specific examples of changes in text and where the changes are located, see 
Section 15.6.


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PROTOCOL SUMMARY
Study Title:  A Randomized, Open-Label, Phase 3 Trial of brentuximab vedotin (SGN-35) Versus 
Physician's Choice (Methotrexate or Bexarotene) in Patients With CD30-Positive Cutaneous T-Cell 
Lymphoma
Indication:  Patients with CD30-positive (CD30+) cutaneous T-cell lymphoma (CTCL) including 
those with primary cutaneous anaplastic large cell lymphoma (pcALCL) or mycosis fungoides (MF)
Study Objectives
Primary

To determine objective response rate (ORR), lasting at least 4 months, with brentuximab vedotin 
in patients with CD30+ MF or pcALCL compared to that achieved with therapy in the control 
arm
Key Secondary

To determine complete response (CR) rate with brentuximab vedotin compared to that achieved 
with therapy in the control arm

To determine progression-free survival (PFS) with brentuximab vedotin compared to that 
achieved with therapy in the control arm

To determine burden of symptoms during treatment with brentuximab vedotin compared to that 
achieved with therapy in the control arm
Other Secondary

To assess duration of response with brentuximab vedotin

To assess duration of skin response with brentuximab vedotin 

To determine event-free survival (EFS) with brentuximab vedotin compared to that achieved 
with therapy in the control arm

To describe the pharmacokinetics (PK) of brentuximab vedotin and monomethylauristatin E 
(MMAE) in blood

To determine the immunogenicity of brentuximab vedotin

To assess patient-reported quality of life outcomes

To assess the safety of brentuximab vedotin
Overview of Study Design: This is an open-label, randomized, multicenter study. All patients must 
have histologically-confirmed CD30+ MF or pcALCL by central pathology review. CD30 positivity 
is defined as ≥10% target lymphoid cells demonstrating membrane, cytoplasmic, and/or Golgi 
staining pattern for CD30 at any intensity above background staining as noted on the corresponding 
negative control.  (A minimum of 10% staining in at least 1 sample is required.)  Patients are to be 
stratified by diagnosis: primary cutaneous anaplastic large cell lymphoma (pcALCL) or mycosis 
fungoides (MF), and randomized to treatment with brentuximab vedotin monotherapy (Arm 1) up to 
16 cycles total (48 weeks), or methotrexate (MTX) or bexarotene per physician’s choice (Arm 2) up 
to a total of 48 weeks. 
Patients with documented partial response (PR) or CR at the completion of, and after Cycle 3, may 
continue to receive study drug for up to 16 cycles of treatment with brentuximab vedotin, or 
48 weeks of treatment with bexarotene or methotrexate; patients with stable disease (SD) may
continue therapy at the discretion of the investigator. Patients with progressive disease (PD) at any 
time during the study will be discontinued from study treatment (see Section 7.7). Patients with 
increasing mSWAT prior to assessment at the end of Cycle 3 will be allowed to continue therapy 
until the Cycle 3 assessment if, in the investigator's opinion, the findings are due to tumor flare rather 


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than disease progression.  
Objective response over the course of the study, per independent review facility (IRF), will be 
assessed by global response score (GRS), which consists of skin evaluation (modified severity 
weighted assessment tool [mSWAT]), nodal and visceral radiographic assessment, and detection of 
circulating Sézary cells (MF only).  Objective response will be evaluated at the end of Cycles 3, 6, 9, 
12, and 15, and at EOT. All treated patients without disease progression at EOT/ET will then be 
followed for objective response every 12 weeks for a minimum of 24 months, then every 6 months;
or until disease progression or study closure. 
All randomized patients will also be followed for survival every 12 weeks for a minimum of 
24 months after the EOT visit, and then every 6 months until patient withdrawal, death, or study 
closure.  
Safety will be evaluated by the incidence of treatment-emergent adverse events (TEAEs), severity 
and type of AEs, and by changes from baseline in the patient’s vital signs, ECOG performance 
status, and clinical laboratory results using the safety population.  
Statistical Analysis and Sample Size Determination:  The primary endpoint, the proportion of 
patients achieving an objective response that lasts at least 4 months, per IRF, will be analyzed using 
a Cochran-Mantel-Haenszel test stratified by baseline disease diagnosis (pcALCL or MF) based on 
ITT population.  The 95% confidence interval of the difference in ORR that lasts at least 4 months 
per IRF between the 2 treatments will be provided.
CR rate, progression-free survival, and changes in symptom domain per Skindex-29 assessment tool 
are designated as key secondary endpoints.  A fixed sequential testing procedure will be used to test 
between the primary endpoint and the key secondary endpoints; that is, the key secondary endpoints 
will be tested only if the primary endpoint is statistically significant.  To test the key secondary 
endpoints, a weighted Holm’s procedure will be used.
Approximately 124 patients (approximately 62 patients per treatment arm) will be randomized to the 
study, including a minimum of 30 patients (15 per treatment arm) with pcALCL.  The sample size 
was calculated based on providing 90% power to detect a 30% improvement in ORR, lasting at least 
4 months, in the brentuximab vedotin treatment group, assuming ORRs lasting at least 4 months for 
brentuximab vedotin treatment group and for the MTX or bexarotene alone treatment group are 70% 
and 40%, respectively.  This calculation is based on a two-sided 2 test with significance level of = 
0.05, and a 10% dropout rate using nQuery Advisor 7.0.
Study Population:  Male or female patients at least 18 years of age with a diagnosis of a CD30+ 
pcALCL who received at least 1 prior systemic therapy or prior radiation therapy, or CD30+ MF 
who received at least 1 prior systemic therapy for their disease.
Duration of Study:  Patients will be screened up to 28 days, receive study drug up to 48 weeks, and 
have follow-up assessments performed every 12 weeks for a minimum of 24 months after EOT, and 
then every 6 months until patient withdrawal, death, or study closure, for a total time on study of up 
to 5 years.  


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Study Overview Diagram
S
C
R
E
E
N
I
N
G
R
A
N
D
O
M
I
Z
A
T
I
O
N
Arm 1
SGN-35 q 21 days
Arm 2:
Methotrexate once weekly 
or
Bexarotene once daily
E
N
D
O
F
T
R
E
A
T
M
E
N
T
V
I
S
I
T
P
O
S
T
T
R
E
A
T
M
E
N
T
F
O
L
L
O
W
-
U
P
Within 28 days 
of 
randomization
30 days 
after last 
dose of 
study drug
Every 12 
weeks for a 
minimum of 
24 months 
and then 
every 6 
months until 
study closure


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Schedule of Events
Screeninga
Enrollment
Cycle 1
(21-Day Cycle)
Cycle 2
(21-Day 
Cycle)
Cycle 3-16
(21-Day Cycle)
EOT/ET
PTFUb
Cycle (C) Day (D)
Visit Window
-28 to D1
Within 72
hours of 
first dose
C1 
D1
C1 
D2 & 
4
C1 
D3 & 
5
C2 
D1
Cx 
D1
Cx 
D16-
21
30 days 
(±2 days)
after last 
dose
Minimum 
of 24
months
Baseline
Informed consent
X
Randomization to Study Treatment Arm
Arm 1 - brentuximab vedotin or Arm 2 - Methotrexate or Bexarotene
Inclusion/exclusion
X
Demographics
X
Medical history
X
Complete physical exam 
X
Height 
X
Weightc
X
X
X
X
X
Pregnancy testd
X
X
X
X
Archived tissuee
X
Safety 
Assessments
Vital signsf
X
Xf
X
X
X
Physical exam including focused 
lymphoma assessment
Xg
X
X
X
X
ECOG performance status
X
X
X
X
X
Hematology/serum chemistryh
X
X
X
X
Urinalysis
X
12-lead ECG
X
Xi
Immune reconstitution 
assessmentj
X
X
X
X
Disease 
Assessment
mSWAT and photographyk
X
X
X
X
X
X
X
Circulating Sézary cells
X
Xl
Xl
X
X
FDG-PETm
X
CTn
X
Xn
Xn
Xn
Quality of life assessmentso
X
X
X
X
X


Brentuximab vedotin (SGN-35)
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Screeninga
Enrollment
Cycle 1
(21-Day Cycle)
Cycle 2
(21-Day 
Cycle)
Cycle 3-16
(21-Day Cycle)
EOT/ET
PTFUb
Cycle (C) Day (D)
Visit Window
-28 to D1
Within 72
hours of 
first dose
C1 
D1
C1 
D2 & 
4
C1 
D3 & 
5
C2 
D1
Cx 
D1
Cx 
D16-
21
30 days 
(±2 days)
after last 
dose
Minimum 
of 24
months
Healthcare Utilization
X
X
X
X
X
X
Skin biopsyp (CD30 Expression)
X
Xp
Xp
Xp
Biopsies for disease assessmentq
X
Disease status/survivalr
X
X
X
Treatment
Brentuximab vedotin
administration
X
X
X
Methotrexate administrations
X
X
X
Bexarotene administrationt
Bexarotene is dosed once a day for the course of the study
Monitoring of concomitant 
medications and procedures
Recorded from screening through 30 days after the last dose of study drug.
Adverse event reportingu
Recorded from first dose of study drug through 30 days after the last dose of 
study drug.
Serious adverse events 
Serious adverse eventsv will be collected from signing of the informed consent form through 
30 days after the last dose of study drug
PK/PD
PK samplew
Xw
Xw
Xw
Xw
X
Immunogenicityy
X
X
X
Abbreviations: CT = computed tomography; CTACK = cutaneous T cell-attracting chemokine; ECG = electrocardiogram; ECOG = Eastern Cooperative 
Oncology Group; ET = early termination; EOT = end of treatment; FDG = fluorodeoxyglucose; MRI = magnetic resonance imaging; mSWAT = modified 
severity weighted assessment tool; 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 (± 2 days) for holidays, vacations, and other administrative 
reasons.  If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this time, the 
patient may continue the study only with the written permission of the project clinician.
a Screening must occur within 28 days prior to randomization.  
b All treated patients without disease progression at EOT/ET will be followed for objective response every 12 weeks (± 2 weeks) for a minimum of 24 
CCI
CCI


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Screeninga
Enrollment
Cycle 1
(21-Day Cycle)
Cycle 2
(21-Day 
Cycle)
Cycle 3-16
(21-Day Cycle)
EOT/ET
PTFUb
Cycle (C) Day (D)
Visit Window
-28 to D1
Within 72
hours of 
first dose
C1 
D1
C1 
D2 & 
4
C1 
D3 & 
5
C2 
D1
Cx 
D1
Cx 
D16-
21
30 days 
(±2 days)
after last 
dose
Minimum 
of 24
months
months after the EOT visit, and then every 6 months (± 1 month); or until progressive disease or study closure.  All randomized patients will also be 
followed for survival every 12 weeks (± 2 weeks) for a minimum of 24 months after the EOT visit, then every 6 months (± 1 month) until patient 
withdrawal, death, or study closure.
c Weight will be measured at screening, on Day 1 of each treatment cycle, and at EOT.  The brentuximab vedotin dose will be adjusted for patients who 
experience a ≥ 10% change in weight from baseline
d A serum beta-human chorionic gonadotropin (B-hCG) pregnancy test will be performed during screening only for patients of childbearing potential.  A 
urine pregnancy test will be performed before dosing on Day 1 of all cycles.  The results of any pregnancy test must be negative before dosing on Day 1 of 
all cycles.  Additional pregnancy testing may be performed during the study at the discretion of the investigator, upon request of the Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB), or if required by local regulations.
e If available and consistent with local regulations, tumor tissue collected at the time of original diagnosis (unstained slides or a paraffin-embedded block) 
will be obtained during screening after the patient has signed the informed consent form. The sample may be used in the evaluation of a diagnostic test to 
determine CD30 expression.
f
Perform vital signs measurement at screening, prior to dosing on Day 1 of each cycle, and at EOT. On Cycle 1, Day 1 only, also perform vital signs 
measurements at 1 hour (± 10 minutes) postdose for patients receiving brentuximab vedotin. Blood pressure should be determined with the patient in a 
seated position after the patient has been sitting quietly for 5 minutes.
g The Cycle 1, Day 1 physical examination is not required if the complete physical examination performed at screening was conducted within 4 days before 
randomization.  A limited physical exam may be administered at the treating physician’s discretion.
h A blood sample for hematology and serum chemistry will be obtained at screening, before dosing on Day 1 of all cycles, and at EOT.  For screening, labs 
must be performed within 4 days of randomization, and do not need to be repeated before dosing.  
Hematology panel includes complete blood count (CBC) with differential consisting of the following: hemoglobin, hematocrit, platelet count, leukocytes 
with differential, and neutrophils (absolute neutrophil count [ANC]). Machine counts are acceptable. 
Serum chemistry panel includes: sodium, potassium, carbon dioxide, chloride, blood urea nitrogen (BUN), creatinine, total bilirubin, alkaline phosphatase 
(ALP), aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), albumin, glucose, urate (uric acid), calcium, phosphate,
magnesium, GGT, amylase, and lipase. 
Hemoglobin A1C will be obtained at screening and on Day 1 of Cycles 1, 4, 7, 10, and 16.
Lipid panel (total cholesterol, HDL, LDL, triglycerides) and thyroid panel (TSH, free T4, free T3) should be obtained at screening and on Day 1 of Cycles 
1, 2, 3, 6, 9, 12, and 16.  
i
A 12-lead ECG will be obtained at screening and on Cycle 1, Day 1 (predose). ECG assessments are to be performed with the patient supine and rested for 
5 minutes and before any closely timed PK blood collection.
CCI


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Screeninga
Enrollment
Cycle 1
(21-Day Cycle)
Cycle 2
(21-Day 
Cycle)
Cycle 3-16
(21-Day Cycle)
EOT/ET
PTFUb
Cycle (C) Day (D)
Visit Window
-28 to D1
Within 72
hours of 
first dose
C1 
D1
C1 
D2 & 
4
C1 
D3 & 
5
C2 
D1
Cx 
D1
Cx 
D16-
21
30 days 
(±2 days)
after last 
dose
Minimum 
of 24
months
j
Lymphocytes counts, phenotypic T, B, and natural killer (NK) cell subsets (CD4+ T cells counts, CD8+ T cells counts, CD8/CD4 ratio, CD19+ B cells 
counts); NK cells (CD3−CD56 CD16+ vs CD3−CD56 CD16−).
k The mSWAT should follow guidelines from Olsen, et al, 2011, for analysis and response. Each of the designated index lesions (up to a total of 5) and 
lesions selected for biopsy will be serially photographed at screening; before dosing on Day 1 of Cycles 1, 2, and 3; at the end of every cycle beginning at 
Cycle 3 (Days 16-21 or before dosing on Day 1 of the subsequent cycle); within 30 days after the last dose of study drug; and at posttreatment follow-up 
visits. Full body global photographs including head, trunk, legs, front, back, and side, will be taken at the same time points indicated above. 
l
A blood sample for Sézary cell enumeration in patients with MF will be collected at screening; at the time of response assessments at the end of Cycles 3, 6, 
9, 12, and 15 (Days 16-21 or before dosing on Day 1 of the subsequent cycle); at EOT; and every 12 weeks (± 2 weeks) for a minimum of 24 months after 
the EOT visit, and then every 6 months (± 1 month); or until progressive disease or study closure.  If the screening sample was obtained within 4 days 
before randomization, it does not need to be repeated on Cycle 1, Day 1. The Sézary cell sample will be evaluated per independent pathology review and 
will not be used for dosing decisions; the slide should be prepared from the same vial of blood sent for CBC testing.  Investigators should ensure the result 
of a Sézary cell sample sent for local testing is available prior to dosing. 
m FDG-PET scans will be taken at screening.  No further FDG-PET scans will be required unless they are clinically indicated.  FDG-PET scans taken within 
8 weeks before signing the informed consent form (ICF) may be used as the screening FDG-PET scan.
n CT scans of the neck, chest, abdomen, and pelvis will be obtained at screening.  CT scans taken within 4 weeks before signing the ICF may be used for the
screening CT scan if all of the following conditions are met:
There is no nodal or visceral involvement noted
There is no clinically evident lymphadenopathy or splenogegaly by physical exam at the time of screening
The scan meets all quality criteria as outlined in the Imaging Manual
For patients without nodal or visceral involvement (as determined by baseline CT scans), CT scans will be performed:
During the cycle following the first skin response, ideally corresponding to the confirmation of the skin response, and 6 cycles (a minimum or 4 months) 
after that confirmed skin response
If there is a question of new or progressive disease in the LN/viscera 
For patients with baseline nodal/visceral disease, CT scans will be performed:
At the end of Cycles 3, 6, 9, 12, and 15 (Days 16-21 or on Day 1 of the subsequent cycle), and per the follow-up schedule until disease progression
If there is a question of new or progressive disease in the LN/viscera
At EOT if the previous CT scan was performed more than 8 weeks before EOT
o All questionnaires should be completed on Day 1 of Cycles 1, 2, 4, 6, 8, 10, 12, 14, and 16 before any other study procedures are performed, at EOT, and 
during posttreatment follow-up.  EQ-5D, FACT-G, and Skindex-29 questionnaires will be employed for health-related quality of life (HRQoL) assessment 
from the patient’s perspective.  Questionnaires may be collected by phone or by mail for patients not required to return to clinic for posttreatment follow-


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Screeninga
Enrollment
Cycle 1
(21-Day Cycle)
Cycle 2
(21-Day 
Cycle)
Cycle 3-16
(21-Day Cycle)
EOT/ET
PTFUb
Cycle (C) Day (D)
Visit Window
-28 to D1
Within 72
hours of 
first dose
C1 
D1
C1 
D2 & 
4
C1 
D3 & 
5
C2 
D1
Cx 
D1
Cx 
D16-
21
30 days 
(±2 days)
after last 
dose
Minimum 
of 24
months
up.  
p Skin biopsies with a minimum of 2-mm diameter (at least 2 samples from separate lesions for patients with MF, and at least 1 sample for patients with 
pcALCL) will be obtained at screening (within 28 days prior to randomization) to confirm tumor specific CD30+ expression and again at the end of 
Cycle 3, and at the time of disease progression (EOT or during the posttreatment follow-up period). If possible, repeat skin biopsies should be taken from 
the same lesions as the samples obtained at screening. At the time of PD, an effort should be made to take an additional sample from a new lesion. In the 
event that a patient is rescreened, repeat skin biopsies should be discussed with the sponsor, project clinician, or designee.
q If applicable, biopsies for response assessment may be needed as outlined in Section 7 (refer to the following tables):
Bone marrow: Refer to Table 7-5
Lymph node: Refer to Table 7-3
Skin: Refer to Table 7-2
Viscera: Refer to Table 7-4
r
Response to treatment (CR, PR, SD, PD, relapse) will be monitored on a continual basis.  For all treated patients, GRS will be assessed at the end of Cycles 
3, 6, 9, 12, and 15 (Days 16-21 or before dosing on Day 1 of the subsequent cycle), at EOT; and then every 12 weeks for a minimum of 24 months, and 
then every 6 months; or until disease progression or study closure.  All randomized patients will also be followed for survival every 12 weeks for a 
minimum of 24 months after the EOT visit, then every 6 months until patient withdrawal, death, or study closure. Additional unscheduled GRS 
determinations may occur following a change in response in skin or at the time of a CT scan.  Information may be collected by phone for patients with 
progressive disease.
s Methotrexate will be administered once weekly as an oral dose.
t
Patients taking bexarotene will receive fenofibrate for a total of 7 days before the start of bexarotene dosing.
u 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.
v Including serious pretreatment events; see Section 10.1.1 and Section 10.3 of the study protocol.
w Patients randomized to brentuximab vedotin will be assigned to Group A or Group B at the time of randomization for PK sampling.  PK blood samples will 
be obtained at the following times:
All brentuximab vedotin-treated patients:
Cycles 1, 3, 5, 7, 9, 11, 13, and 15 
Day 1:  within 4 hours before the start of the brentuximab vedotin infusion and 30 minutes (± 25 minutes) after the end of the brentuximab vedotin infusion 
End of Treatment Visit
Group A (consisting of half the brentuximab vedotin-treated patients):


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Screeninga
Enrollment
Cycle 1
(21-Day Cycle)
Cycle 2
(21-Day 
Cycle)
Cycle 3-16
(21-Day Cycle)
EOT/ET
PTFUb
Cycle (C) Day (D)
Visit Window
-28 to D1
Within 72
hours of 
first dose
C1 
D1
C1 
D2 & 
4
C1 
D3 & 
5
C2 
D1
Cx 
D1
Cx 
D16-
21
30 days 
(±2 days)
after last 
dose
Minimum 
of 24
months
Cycles 1 and 3 
Day 1:  within 4 hours before the start of the brentuximab vedotin infusion and 30 minutes (± 25 minutes) after the end of the brentuximab vedotin infusion 
Day 2:  24 hours (± 4 hours) from the start of the Day 1 dose infusion 
Day 4:  72 hours (± 4 hours) from the start of the Day 1 dose infusion
Group B (consisting of half the brentuximab vedotin-treated patients):
Cycles 1 and 3 
Day 1:  within 4 hours before the start of the brentuximab vedotin infusion and 30 minutes (± 25 minutes) after the end of the brentuximab vedotin infusion  
Day 3:  48 hours (± 4 hours) from the start of the Day 1 dose infusion 
Day 5:  96 hours (± 4 hours) from the start of the Day 1 dose infusion
x
y Immunogenicity samples in patients receiving brentuximab vedotin will be collected before dosing on Day 1 of Cycles 1, 3, 5, 7, 9, 11, 13, and 15 and at 
EOT.
z
CCI
CCI


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TABLE OF CONTENTS
LIST OF TABLES.............................................................................................................16
LIST OF FIGURES............................................................................................................16
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:  Cutaneous T-cell Lymphoma...................................21
1.1.2 Disease Treatment and Staging ..........................................................................22
1.1.3 Study Drug ........................................................................................................24
1.2 Preclinical Experience ..............................................................................................25
1.3 Clinical Experience ..................................................................................................25
1.4 Study Rationale ........................................................................................................28
1.4.1 Treatment Options in CTCL...............................................................................28
1.4.2 Choice of Comparator........................................................................................29
1.4.3 Summary of Study Rationale..............................................................................30
1.5 Potential Risks and Benefits .....................................................................................31
2. STUDY OBJECTIVES ..................................................................................................34
2.1 Primary Objectives ...................................................................................................34
2.2 Secondary Objectives ...............................................................................................35
2.3 Exploratory Objectives.............................................................................................35
3. STUDY ENDPOINTS....................................................................................................36
3.1 Primary Endpoint .....................................................................................................36
3.2 Secondary Endpoints................................................................................................36
3.3 Exploratory Endpoints..............................................................................................37
4. STUDY DESIGN...........................................................................................................37
4.1 Overview of Study Design........................................................................................37
4.2 Number of Patients...................................................................................................40
4.3 Duration of Study.....................................................................................................40
5. STUDY POPULATION.................................................................................................41
5.1 Inclusion Criteria......................................................................................................41
5.2 Exclusion Criteria.....................................................................................................43
6. STUDY DRUG..............................................................................................................45
6.1 Brentuximab vedotin Administration........................................................................45
6.2 Reference/Control Therapy.......................................................................................46
6.2.1 Methotrexate......................................................................................................46
6.2.2 Bexarotene.........................................................................................................48
6.3 Dose Escalation Rules ..............................................................................................50
6.4 Dose-Modification Guidelines..................................................................................51
6.4.1 Criteria for Beginning or Delaying a Subsequent Treatment Cycle.....................51
6.4.2 Criteria for Dose Reduction ...............................................................................51
6.4.3 Discontinuation of Study Drug Due to Toxicity .................................................53
6.5 Excluded Concomitant Medications and Procedures.................................................53
6.6 Permitted Concomitant Medications and Procedures.................................................54
6.7 Precautions and Restrictions .....................................................................................54


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6.8 Management of Clinical Events................................................................................55
6.8.1 Nausea and/or Vomiting ....................................................................................55
6.8.2 Diarrhea.............................................................................................................55
6.8.3 Management of Infusion-Related Reactions.......................................................55
6.8.4 Management of Peripheral Neuropathy..............................................................56
6.8.5 Management of Progressive Multifocal Leukoencephalopathy...........................56
6.9 Blinding and Unblinding ..........................................................................................57
6.10 Description of Investigational Agents .....................................................................57
6.11 Preparation, Reconstitution, and Dispensation ........................................................57
6.12 Packaging and Labeling..........................................................................................58
6.13 Storage, Handling, and Accountability....................................................................58
7. STUDY CONDUCT ......................................................................................................60
7.1 Study Personnel and Organizations...........................................................................60
7.2 Arrangements for Recruitment of Patients ................................................................60
7.3 Treatment Group Assignments .................................................................................61
7.4 Study Procedures......................................................................................................61
7.4.1 Informed Consent ..............................................................................................61
7.4.2 Patient Demographics ........................................................................................61
7.4.3 Medical History.................................................................................................61
7.4.4 Physical Examination.........................................................................................61
7.4.5 Patient Height ....................................................................................................62
7.4.6 Patient Weight ...................................................................................................62
7.4.7 Vital Signs .........................................................................................................62
7.4.8 Pregnancy Test ..................................................................................................62
7.4.9 Skin Biopsy .......................................................................................................62
7.4.10 Archived Tissue...............................................................................................62
7.4.11 Concomitant Medications and Procedures........................................................63
7.4.12 Adverse Events................................................................................................63
7.4.13 Enrollment .......................................................................................................63
7.4.14 ECG.................................................................................................................63
7.4.15 Clinical Laboratory Evaluations.......................................................................63
7.4.16 Disease Assessment .........................................................................................65
7.4.17 Response Assessments.....................................................................................65
7.4.18 Pharmacokinetic Measurements.......................................................................73
7.4.19 Immunogenicity Measurements........................................................................74
7.4.20 Pharmacodynamic Measurements ....................................................................75
7.4.21 Tumor Biopsy for Baseline CD30 Expression and Biomarker 
Measurements.............................................................................................75
7.4.22 Germline DNA Polymorphism Assessment......................................................76
7.4.23 Utility Measurement ........................................................................................76
7.4.24 Healthcare Utilization Data Collection.............................................................76
7.4.25 Cost Assessment ..............................................................................................76
7.5 Completion of Treatment..........................................................................................76
7.6 Completion of Study.................................................................................................77
7.7 Discontinuation of Treatment With Study Drug, and Patient Replacement................77
7.8 Withdrawal of Patients From Study..........................................................................78


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7.9 Study Compliance ....................................................................................................79
8. STATISTICAL AND QUANTITATIVE ANALYSES ..................................................79
8.1 Statistical Methods ...................................................................................................79
8.1.1 Determination of Sample Size............................................................................79
8.1.2 Randomization and Stratification .......................................................................79
8.1.3 Populations for Analysis ....................................................................................80
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data...........................81
8.1.5 Demographic and Baseline Characteristics.........................................................81
8.1.6 Efficacy Analysis...............................................................................................81
8.1.7 Analyses of Patient-Reported Outcomes and Health Economics.........................83
8.1.8 Pharmacokinetics/Pharmacodynamics/Biomarkers.............................................83
8.1.9 Safety Analysis ..................................................................................................84
9. STUDY COMMITTEES................................................................................................85
9.1 Independent Data Monitoring Committee.................................................................85
10. ADVERSE EVENTS ...................................................................................................86
10.1 Definitions..............................................................................................................86
10.1.1 Pretreatment Event Definition..........................................................................86
10.1.2 Adverse Event Definition.................................................................................86
10.1.3 Serious Adverse Event Definition ....................................................................86
10.2 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events.................................................................................................87
10.3 Monitoring of Adverse Events and Period of Observation.......................................89
10.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events........89
11. ADMINISTRATIVE REQUIREMENTS .....................................................................90
11.1 Good Clinical Practice............................................................................................90
11.2 Data Quality Assurance ..........................................................................................90
11.3 Electronic Case Report Form Completion...............................................................90
11.4 Study Monitoring ...................................................................................................91
11.5 Ethical Considerations............................................................................................91
11.6 Patient Information and Informed Consent..............................................................91
11.7 Patient Confidentiality............................................................................................91
11.8 Investigator Compliance.........................................................................................92
11.9 On-site Audits ........................................................................................................92
11.10 Investigator and Site Responsibility for Drug Accountability................................92
11.11 Product Complaints and Medication Errors...........................................................92
11.12 Closure of the Study .............................................................................................93
11.13 Record Retention..................................................................................................94
12. USE OF INFORMATION............................................................................................94
13. INVESTIGATOR AGREEMENT................................................................................96
14. REFERENCES.............................................................................................................97
15. APPENDICES ...........................................................................................................104
15.1 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status.......104
15.2 Body Surface Area Nomograms ...........................................................................104
15.3 New York Heart Association Classification of Cardiac Disease ............................105
15.4 Tumor-Node-Metastasis-Blood Classification and Clinical Staging System for 
Mycosis Fungoides .........................................................................................105


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15.5 Amendment 4 Rationale and Purposes..................................................................107
15.6 Amendment 5 Detailed Summary of Changes.......................................................108
LIST OF TABLES
Table 6-1   
Methotrexate Dose Modifications for Hyperbilirubinemia...........................46
Table 6-2   
Methotrexate-Associated Toxicities ............................................................47
Table 6-3   
Recommended brentuximab vedotin Dose Modifications for Treatment-
Associated Toxicity Excluding Neuropathy.................................................52
Table 6-4   
Recommended brentuximab vedotin Dose Modifications for Treatment-
Emergent or Worsening Peripheral Sensory or Motor Neuropathy...............53
Table 7-1   
Modified Severity Weighted Assessment Tool............................................66
Table 7-2   
Response in Skin.........................................................................................68
Table 7-3   
Response in Lymph Nodesa.........................................................................69
Table 7-4   
Response in Viscera ....................................................................................69
Table 7-5   
Response in Blood ......................................................................................71
Table 7-6   
Global Response Score................................................................................72
Table 7-7   
Pharmacokinetic Sampling Time Points ......................................................74
LIST OF FIGURES
Figure 6-1   
Bexarotene Risk Mitigation.........................................................................50
Figure 7-1   
mSWAT % Total Body Surface Area (TBSA) for 12 Main Body Areas......67


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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
ADC
antibody-drug conjugate
AE
adverse event
ALCL
anaplastic large cell lymphoma
ALK
anaplastic lymphoma kinase
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
ATA
antitherapeutic antibodies
BSA
body surface area
BUN
blood urea nitrogen
pcALCL
primary cutaneous anaplastic large cell lymphoma
CBC
complete blood count
CD30+
CD30-positive
Cmax
maximum plasma concentration
CNS
central nervous system
CO2
carbon dioxide
CR
complete response
CT
computed tomography
CTCL
cutaneous T-cell lymphoma
CTACK
cutaneous T cell-attracting chemokine
DME
drug metabolizing enzymes
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EFS
event-free survival
ELISA
enzyme-linked immunosorbent assay
EORTC
European Organisation for Research and Treatment of Cancer
EOS
End of Study (visit)


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Abbreviation
Term
EOT
End of Treatment (visit)
EU
European Union
EVA
ethyl vinyl acetate
FDA
United States Food and Drug Administration
FDG
Fludeoxyglucose
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GGT
Gamma-glutamyl transpeptidase
GI
Gastrointestinal
GLP
Good Laboratory Practices
GM-CSF
granulocyte macrophage-colony stimulating factor
GMP
Good Manufacturing Practice
GRS
global response score
Hb
Hemoglobin
Hct
Hematocrit
HDAC
histone deacetylase
HDACi
histone deacetylase inhibitor
HDL
high-density lipoprotein
HED
human equivalent dose
hERG
human ether-à-go-go related gene
HIV
human immunodeficiency virus
HL
Hodgkin lymphoma
HRQoLHU
health-related quality of lifehealthcare utilization
HU
healthcare utilization
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
IRB
Institutional Review Board
IRF
independent review facility
ISCL
International Society for Cutaneous Lymphoma
ITT
intent-to-treat


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Abbreviation
Term
IV
intravenous; intravenously
IVRS
interactive voice response system
IWRS
interactive web response system
JCV
John Cunningham virus
LDH
lactic dehydrogenase
LDL
low density lipoprotein
LyP
lymphomatoid papulosis
MF
mycosis fungoides
MMAE
monomethylauristatin E
MedDRA
Medical Dictionary for Regulatory Activities
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MRI
magnetic resonance imaging
mSWAT
modified severity weighted assessment tool
MTD
maximum tolerated dose
MTX
methotrexate
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NOAEL
no observed adverse effect level
NYHA
New York Heart Association
ORR
objective response rate
ORR4
objective response rate lasting at least 4 months
pcALCL
primary cutaneous anaplastic large cell lymphoma
PD
progressive disease (disease progression)
PE
polyethylene 
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
PO
per os; by mouth (orally)
PP
per protocol
PR
partial response
PRO
patient-reported outcome
PUVA
psoralen with ultraviolet light A
PVC
polyvinyl chloride


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Abbreviation
Term
RBC
red blood cell
RR
response rate
SAE
serious adverse event
sALCL
systemic anaplastic large cell lymphoma
SD
stable disease
SDT
skin-directed therapy
SmPC
Summary of Product Characteristics
SS
Sézary Syndrome
SWAT
severity weighted assessment tool
TARC
thymus and activation regulated chemokin
TEAE
treatment-emergent adverse event
tMF
transformation mycosis fungoides 
TNMB
Tumor-Node-Metastasis-Blood
TNM
Tumor-Node-Metastasis
TSEBT
total skin electron beam therapy
ULN
upper limit of the normal range
US
United States
UVA
ultraviolet light A
UVB
ultraviolet light B
WBC
white blood cell
WHO
World Health Organization
CCI


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1.   
BACKGROUND AND STUDY RATIONALE
1.1   
Scientific Background
1.1.1   
Disease Under Treatment: Cutaneous T-cell Lymphoma
Cutaneous T-cell lymphoma (CTCL) is the most common cutaneous lymphoma, accounting
for 72% of cases.  From 1973 to 2002, reported CTCL incidence rates in the United States 
(US) have steadily increased.  The incidence rate of CTCL from 1998 through 2002 was 
9.6 per million person-years, up from 2.8 per million person-years in 1973 through 1977.  
CTCL incidence increases with age; it is quite low in those under 20 years (0.3 per million 
person-years) and it peaks in the 70- to 79–year age group (24.6 per million person-years).  
Cutaneous T-cell lymphoma also has notable racial and ethnic incidence differences, with 
much higher rates among blacks than among whites.(1, 2, 3)
CTCL is characterized by clonal expansions of mature, post-thymic T cells that infiltrate the 
skin.  The current World Health Organization (WHO) classification includes 7 major 
subtypes:  mycosis fungoides (MF), Sézary syndrome (SS), primary cutaneous CD30-
positive (CD30+) lymphoproliferative disorders (comprising primary cutaneous anaplastic 
large cell lymphoma [pcALCL] and Lymphomatoid papulosis [LyP]), subcutaneous 
panniculitis-like T-cell lymphoma, primary cutaneous γδ T-cell lymphoma, primary 
cutaneous aggressive epidermotropic CD8+cytotoxic T-cell lymphoma, and primary 
cutaneous small/medium CD4+ T-cell lymphoma.
Brentuximab vedotin is an anti-CD30 targeted antibody-drug conjugate (ADC). Two major 
CD30-expressing CTCL subtypes have been selected for this study: MF and pcALCL.(4)
1.1.1.1   
Mycosis Fungoides 
Mycosis fungoides, the most common form of CTCL, accounts for approximately 44% of all 
cutaneous lymphomas.  An indolent disease with a protracted course, it occurs most often in 
middle-aged to elderly adults, with a male (66%) predominance.  The 10-year disease-
specific survival for patients who have progressed to the tumor stage is approximately 42%; 
this drops to 20% with histologically proven lymph-node involvement.(5) The skin lesions of 
MF tend to be on the trunk and include erythematous patches, thickened plaques, nodular 
tumors, and generalized erythroderma.  Patches and plaques may persist for years and 
eventually spread and progress to tumors; dissemination to lymph nodes and visceral organs 
is a late manifestation.  


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Although the clinical course of MF is usually indolent, occasionally, individuals with MF 
develop a morphologic transformation (tMF) from small- to intermediate-sized cerebriform 
cells to a large cell variant.  Large cells in excess of 25% of the total lymphoid infiltrate 
typically characterize large-cell transformation and incidence of such transformation 
reportedly ranges between 8% and 55%.(6, 7)  Approximately 30% to 50% of tMF cases 
express CD30 by large cells, with a positivity of more than 75% in approximately 15% of 
tMF cases.(5) Edinger et al showed that in 47 nontransformed MF biopsies, at least rare 
dermal CD30-positive cells were present in all cases. More than 25% CD30-positive 
lymphoid cells were present in the epidermis and dermis in 12 (25%) and 2 (4%) cases, 
respectively, indicating that CD30 staining can be prominent in MF without 
transformation.(8)
1.1.1.2   
Primary Cutaneous Anaplastic Large Cell Lymphoma
The incidence of primary cutaneous ALCL (pcALCL) peaks in the 6th decade. The disease-
specific survival rate for pcALCL patients at 5 years is 85% to 90%.(9, 10)  pcALCL usually 
presents in adults as solitary or localized nodules that may undergo partial necrosis and 
resolution, but it does not spontaneously regress.  It has a 5-year OS of approximately 90%.  
The tumor cells involve the dermis extensively, may infiltrate subcutaneous tissue, and have 
little epidermotropism.  In contrast to nodal ALCL, primary cutaneous forms of ALCL lack 
epithelial membrane antigen and express the cutaneous lymphocyte antigen (HECA-452). 
Anaplastic lymphoma kinase [ALK-1 (p80)] and t(2;5) translocation are usually absent in 
pcALCL. If these are present, one needs to be highly suspicious of the lesions being a 
cutaneous manifestation of underlying systemic ALCL.(11)
1.1.2   
Disease Treatment and Staging
1.1.2.1   
Mycosis Fungoides Treatment and Staging
Mycosis fungoides survival is dependent on stage, and patients with limited patch and 
plaque disease have survival equal to age-matched controls.  MF is staged based on clinical 
features of skin involvement and degree of infiltration of the lymph nodes and viscera.  The 
most common staging system for MF is based on a tumor (T)-node (N)-metastasis (M)-
blood (B) classification (Section 15.4).  Staging is based on modified American Joint 
Committee on Cancer (AJCC) criteria according to the International Society for Cutaneous 
Lymphomas (ISCL)/European Organisation for Research and Treatment of Cancer 
(EORTC) Tumor-Node-Metastasis-Blood (TNMB) classification.(12)


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Disease stage dictates prognosis and choice of treatment in MF.(13)  Early-stage patients with 
mycosis fungoides often respond to skin-directed therapies (SDTs) alone.  For patients with 
extensive/refractory skin disease or more advanced-stage disease, biologic systemic 
therapies (often combined with SDTs) are utilized initially, and chemotherapies are reserved 
for later.  Because of the chronic and recurrent nature of CTCL, patients frequently require 
repeat treatment courses and maintenance regimens for disease control.
Phototherapy, including broadband ultraviolet B (280–320 nm wavelength), narrowband 
UVB (311 nm wavelength, NBUVB), and photochemotherapy (psoralen and ultraviolet A 
[PUVA]) are useful for whole-body SDT for CTCL.  However, with advancing disease 
stage, response rates decrease and recurrent disease becomes all but certain.(14)  Responses to 
SDT have been described in treatment resistant stage IA to IIB mycosis fungoides, but 38% 
to 50% of patients experience recurrence.  It is less effective in tumor stage mycosis 
fungoides or folliculotropic mycosis fungoides due to lesion depth.(15, 16, 17, 18)
Total skin electron beam therapy (TSEBT) is effective for extensive plaque, tumor, or 
erythrodermic disease.  A recent retrospective review of 18 cases of advanced refractory 
CTCL (stage IIB–IV) treated with palliative TSEBT demonstrated a CR in 50% and a 
limited response in 39%.  Twenty-four percent of patients exhibited progression-free 
survival.  Four patients (22%) had a median continuing remission of 6 months (range 2-14 
months). The overall 1-year survival was 48%, and most patients relapsed within 1 year 
after completing treatment.(19)
Histone deacetylase inhibitors (HDACi) vorinostat and romidepsin have been used in 
patients with relapsed and refractory CTCL, with objective response rates (ORR) of 24% to 
30 %, and 34%, respectively.(20, 21) HDACi are a novel class of compounds that inhibit the 
enzyme HDAC, and thus inhibit the deacetylation of histone proteins associated with DNA 
and nonhistone proteins. Chemotherapy agents with notable activity in patients with
relapsed and refractory disease include gemcitabine and liposomal doxorubicin. These 
agents have moderate to high response rates (70% and 88%, respectively); however, 
response durations are short.(22, 23) Both methotrexate and bexarotene are approved by the 
FDA and remain widely used treatments for CTCL across the diagnoses.
1.1.2.2   
pcALCL Treatment and Staging
Similar to MF, the ISCL/EORTC proposal for non-MF CTCL uses the Tumor-Node-
Metastasis (TNM) nomenclature for classification.(24)


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Because it is implicit in the definition of cutaneous lymphomas other than MF that 
extracutaneous disease (lymph node or visceral) is absent, all patients are N0 and M0 at 
presentation. However, to permit application of the staging system at the time of relapse (as 
a relapse-stage designation) or disease progression, the N-M-classification is defined as in 
Kim, et al 2007.(24)
The most common therapies for solitary or localized pcALCL are surgical excision and 
radiotherapy.  Response rates for these therapies are high (90%–100%); relapsed rates range 
from 41% to 43%.  Chemotherapy is used primarily for multifocal pcALCL or relapsed
disease.  High response rates have been reported with multiagent chemotherapy but the 
majority of patients relapse, with median remission rates of 6 weeks to 4 months.(11)
1.1.3   
Study Drug
Brentuximab vedotin is an antibody-drug conjugate (ADC) consisting of the antibody 
cAC10 chemically conjugated to monomethylauristatin E (MMAE), a synthetic analog of 
the naturally occurring cytotoxic agent, dolastatin10.  cAC10 binds to a number of CD30+
cancer cell lines including Hodgkin lymphoma (HL), anaplastic large cell lymphoma 
(ALCL), and other varied lymphoproliferative disorders.
The cAC10 antibody itself (SGN-30) was previously evaluated as a target for 
immunotherapy in pcALCL, LyP, and tMF.  In 2009, Duvic M, et al,(25) reported the results 
of a phase 2 study of SGN-30 in pcALCL.  The overall ORR (complete response [CR] + 
partial response [PR]) was 70% (16 of 23 patients):  10 patients achieved a CR and another 
6 patients achieved a PR.  Overall, disease control rate of SGN-30, as assessed by achieving 
a response to therapy or stable disease (CR + PR + stable disease), was shown by 87% of 
patients during the study, including all patients (14 of 14) with pcALCL or LyP and 
6 of 9 patients (67%) with transformation mycosis fungoides (tMF) or with multiple clinical 
diagnoses (lymphoma and related lymphoproliferative disorders).  Fifteen of 23 patients 
(65%) experienced at least 1 adverse event during the study, most of which were mild or 
moderate.(25)
Although cAC10, the unconjugated anti-CD30 antibody, was not further developed, 
brentuximab vedotin uses cAC10 as the targeting mechanism for delivering its cytotoxic 
MMAE payload and therefore may be equally, if not more effective, in CD30+ CTCL based 
upon its mechanism of action.


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1.2   
Preclinical 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 concentration producing 50% inhibition (IC50) values 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
(NOAEL) for brentuximab vedotin was defined at 1.0 mg/kg in monkeys and 0.5 mg/kg in
rats.  Human equivalent doses (HED) are 0.32 and 0.08 mg/kg respectively.
Detailed information regarding the nonclinical pharmacology and toxicology of brentuximab 
vedotin may be found in the Investigator’s Brochure (IB).
1.3   
Clinical Experience
The safety and efficacy of brentuximab vedotin have been evaluated in more than 
300 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 sALCL (SG035-
0004), and a phase 1 drug-drug interaction study (SG035-008A). Preliminary and final 
analyses of safety data indicate that brentuximab vedotin has a tolerable and manageable 
safety profile in the studied populations. 
In Study SG035-0001, a total of 45 patients with CD30-positive hematologic malignancies 
(42 with HL, 2 with sALCL, 1 with angioimmunoblastic T-cell lymphoma) were treated 
with brentuximab vedotin at dose levels of 0.1 to 3.6 mg/kg administered intravenously 
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 were fatigue (36%), pyrexia (33%), diarrhea, nausea, peripheral 
neuropathy, and neutropenia (22% each).  Notable serious adverse events considered at least 


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possibly related to treatment included anaphylaxis, myocardial infarction, and peripheral 
neuropathy.  
In Study SG035-0002, 44 patients with CD30-positive hematologic malignancies (38 with 
HL, 5 with sALCL, and 1 with peripheral T-cell lymphoma) were treated with brentuximab 
vedotin at dose levels of 0.4 to 1.4 mg/kg administered intravenously 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 brentuximab vedotin monotherapy was 
deemed sufficient and the planned brentuximab vedotin/gemcitabine combination was not 
pursued.  The most common adverse events were peripheral sensory neuropathy (66%); 
fatigue (52%); nausea (50%); diarrhea (32%); arthralgia (27%); pyrexia (25%); and 
decreased appetite, myalgia, and upper respiratory tract infection (23% each).  Treatment 
discontinuations due to adverse events (AEs) were observed in 30% of patients.  The most 
frequent AE that led to dose modification or delay was peripheral sensory neuropathy.  
In SG035-0003, a phase 2, single-arm, open-label study in patients with relapsed or 
refractory HL post ASCT, and SG035-0004, a phase 2 trial conducted in patients with 
relapsed or refractory sALCL, brentuximab vedotin was administered at a dose of 1.8 mg/kg 
every 3 weeks.  One-hundred two patients with relapsed and refractory HL and 58 patients 
with relapsed and refractory sALCL were exposed for a median duration of approximately 
27weeks (9 cycles) and 20 weeks (6 cycles), respectively.  Most patients (89%) in the two 
phase 2 studies were between the ages of 18 and 65 years.  The primary endpoint of both 
studies was ORR as assessed by an independent radiographic facility.  Key secondary 
endpoints included duration of response, OS, and PFS.  The key efficacy results in HL 
(SG035-0003) include ORR per IRF (75% [95% CI:  64.9%-82.6%]), CR rate (34% [95% 
CI:  25.2%-44.6%]), B symptom resolution rate (77%), and duration of response (DOR, 
29 weeks).  Key efficacy points in sALCL (SG035-0004) include ORR (86% [95% CI:  
74.6%-93.9%]), CR rate (53% [95% CI:  39.6%-66.7%]), and B symptom resolution rate 
(82%).
Treatment-emergent AEs occurring in ≥20% of patients in phase 2 were peripheral sensory 
neuropathy (44%), fatigue (42%), nausea (41%), diarrhea (34%), pyrexia (31%), upper 
respiratory tract infection (28%), neutropenia (21%), and vomiting (20%).  These events 
were primarily mild to moderate in severity and reversible.  Approximately half of patients 
had treatment-emergent peripheral neuropathy, predominantly sensory neuropathy, with an 


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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 growth factor support 
in some cases.  
Infusion-related reactions (IRRs) were reported for 17 patients (11%) in the phase 2 
population (Studies SG035-0003 and SG035-0004), and were reported in similar proportions 
of HL and ALCL patients.  The preferred terms reported most frequently were chills in 6 
(4%) patients, nausea in 5 (3%) patients, dyspnoea and pruritus in 4 patients each (3%), and 
cough in 3 (2%) patients. All IRRs in the phase 2 population (Studies SG035-0003 and 
SG035-0004) were Grade 1 or 2 in severity. No serious IRRs, nor any events of anaphylaxis,
were reported in the phase 2 population. All but 1 patient had their first IRR within Cycle 3 
(9 patients in Cycle 1; 6 patients in Cycle 2; and 1 patient in Cycle 3); 1 patient had a first 
IRR in Cycle 15. Of the 17 patients with IRRs reported by the investigator, 7 patients 
received no IRR prophylaxis and had no further IRRs reported, while 10 received IRR 
prophylaxis. Of the 10 patients who received IRR prophylaxis, no additional IRRs were 
reported for 8 of these patients. Incidences of IRRs were also observed in the phase 1 
studies. Most IRRs occurred within the first 2 cycles. Most IRRs in the phase 1 studies were 
Grade 1 or 2. Grade 3 IRRs occurred in 2 patients (both in phase 1 dose-escalation safety 
studies). Two SAEs of anaphylaxis occurred, both in phase 1 safety (SG035-0001) and 
clinical pharmacology (SGN35-007) studies. One of these 2 cases of anaphylaxis resulted in 
treatment discontinuation. The other patient continued treatment with IRR prophylaxis and a 
longer infusion time.
The clinical laboratory parameters for which the most patients had new or worsening shifts 
to Grade 3 were low neutrophils (11%), lymphocytes (11%), platelets (6%), leukocytes 
(5%), and high glucose (6%).  Only 1 patient in the phase 2 studies had Grade 3 ALT and 
aspartate aminotransferase (AST).
In the phase 2 studies, 31% of patients had a serious adverse event (SAE), 28% had an SAE 
of Grade 3 or higher, and 15% had an SAE that was determined by the investigator to be 
related to brentuximab vedotin.  The most common SAEs, reported in ≥ 2% of patients,
were abdominal pain, disease progression (recurrent sALCL), pulmonary embolism, and 
septic shock.  A higher proportion of sALCL patients experienced SAEs, including deaths 
within 30 days of last dose, relative to HL patients, likely due to the older age and more 
aggressive nature of the malignancy in this patient population.


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A total of 9 deaths were reported within the safety evaluation period (within 30 days of the 
last dose of brentuximab vedotin) in 357 patients across the 6 phase 1 and phase 2 studies 
for which data are available.  Two patient deaths (0.6%) were considered related to study 
treatment.  One patient in study SG035-0001 who received 3.6 mg/kg in phase 1 died due to 
febrile neutropenia and presumed septic shock.  A second treatment-related death in study 
SG035-008A was attributed to pancytopenia, cytomegalovirus (CMV) infection, and 
intracranial hemorrhage.  The remaining on-study deaths were primarily related to disease 
progression in sALCL patients.
Brentuximab vedotin has been shown to induce durable remissions in patients with HL both 
pre- and post-ASCT, and in patients with relapsed or refractory sALCL.  Progression-free 
survival results comparing PFS with brentuximab vedotin to PFS from prior systemic 
therapy indicate that PFS is significantly prolonged with brentuximab vedotin for both HL 
and sALCL.  A substantial number of HL and sALCL patients with B symptoms at baseline 
saw these symptoms resolve during treatment with brentuximab vedotin.  In addition, the 
large majority of sALCL patients presenting with cutaneous lesions at baseline experienced 
resolution of these symptoms after receiving brentuximab vedotin.
Further details on clinical studies with brentuximab vedotin are provided in the brentuximab 
vedotin IB.
1.4   
Study Rationale
1.4.1   
Treatment Options in CTCL
There is no universally accepted single standard of care across first, second, and advanced 
lines of treatment of CTCL.  Single-agent therapy has been used, including retinoids, 
interferons, HDAC inhibitors, and chemotherapy; these therapies include methotrexate, 
bexarotene, glucocorticoids, cyclophosphamide, cisplatin, etoposide, bleomycin, 
doxorubicin, vincristine, and vinblastine.(26)  Single-agent therapy can yield complete 
response rates up to 30%, but remissions are generally of short duration.  Chemotherapy 
combined with other agents may induce remissions of pcALCL.  More potent chemotherapy 
is complicated by immune deficiency, and infectious complications.  Both methotrexate and 
bexarotene are approved by the FDA and are widely used treatments for CTCL across the 
diagnoses.(27)
Denileukin diftitox (ONTAK®) is a recombinant fusion protein combining human IL-2 with 
the membrane translocation and catalytic domain of diphtheria toxin.  It targets and induces 


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apoptosis of IL-2 receptor-bearing cells.  FDA approved denileukin diftitox for CTCL in 
1999, denileukin diftitox was initially reported to have a 30% ORR with one-third of 
responders experiencing CR.  Two recent follow-up studies(28, 29, 30, 31) describe complete 
responders with exceptionally durable responses of at least 5 and 9 years.  Patients 
experiencing a PR to denileukin diftitox may receive further combination therapy with IFN, 
oral bexarotene, and chemotherapy or phototherapy.  
Histone deacetylase inhibitors (HDACi) are a novel class of compounds that inhibit the 
enzyme HDAC, and thus inhibit the deacetylation of histone proteins associated with DNA 
and nonhistone proteins.  Vorinostat is the first FDA-approved, oral HDACi for refractory 
CTCL.  Vorinostat has not yet received EMA approval for CTCL.  In two phase 2 trials, 
vorinostat 400 mg daily was found to be well tolerated and effective with an ORR of 24% to 
30% among highly refractory patients.  Responses were observed at all disease stages, 
including those diagnosed with Sézary syndrome and large cell transformation.  
Improvement in pruritus, a major clinical symptom, was noted as well.(20, 32, 33)
A second HDACi, romidepsin, is an intravenously administered bicyclic peptide that inhibits 
classes I and II HDACs with activity in not only CTCL, but also peripheral T-cell 
lymphoma (PTCL).  A single-arm, open-label, multicenter, pivotal, phase 2 study of 
romidepsin for the treatment of refractory CTCL (stages IB–IVA) was recently completed. 
After 6 cycles of treatment, a response rate (RR) of 34% was observed in 96 evaluable 
patients (including 6 clinical CRs), and pruritus improved in 43%. Median time to response 
was 2 months. Romidepsin was granted approval by the FDA for treatment of patients with 
CTCL.(21)
Chemotherapy is reserved for relapsed and refractory disease and yields moderate to high
response rates; however, response durations are short. Agents with notable activity include 
gemcitabine and liposomal doxorubicin. In a phase 2 study, gemcitabine showed a response 
rate of 53% and a CR rate of 22%. In a retrospective analysis of pegylated liposomal 
doxorubicin, the response rate was 88% (30 out of 34 patients) and approximately 43% had 
CR.(22, 34, 35)
1.4.2  
Choice of Comparator
1.4.2.1   
Bexarotene
Bexarotene (Targretin®) is approved in the United States and European Union for the 
treatment of patients who are refractory to at least 1 prior systemic therapy for cutaneous T-


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cell lymphoma.  In clinical trials, bexarotene was administered for up to 97 weeks.  In 
patients with advanced CTCL, 49% of patients achieved an objective response (complete 
and partial responses) to treatment with any dose of bexarotene.  Patient response rates were 
45% at a dose of 300 mg/m2/day PO and 55% at doses > 300 mg/m2/day PO.  Responses 
were seen in patients with erythrodermic CTCL (mycosis fungoides) and Sézary syndrome.  
Median time to best response was 180 days and these responses were durable for a median 
of 299 days at bexarotene doses of 300 mg/m2/day PO.  Median time to response was shorter 
and the duration of response was longer with doses > 300 mg/m2/day PO but the incidence 
of side effects increased substantially at the higher doses.(36)
1.4.2.2   
Methotrexate
Methotrexate (MTX, amethopterin) is a folate antimetabolite.  It is an analog of aminopterin, 
which is also derived from folic acid, and is approved for the treatment of patients with 
CTCL.  Methotrexate is a standard of care in early and advanced CTCL.  Although low-dose 
methotrexate has been used to treat mycosis fungoides for many years, documentation is 
very limited.  In a retrospective study of 69 patients with patch/plaque and tumor stage 
mycosis fungoides patients were observed for up to 201 months.  The greatest number of 
patients (60) had patch/plaque stage T2 disease (≥10% skin involved).  Of these, 7 (12%) 
achieved complete remission and 13 (22%) achieved partial remission for a total response 
rate of 20 of 60 (33%).  The median time to treatment failure was 15 months.  Only 1 
of 7 patients with tumor stage disease responded.  Adverse events resulted in treatment 
failure in 6 (9%) of the total cohort of 69 patients.(37, 38)
1.4.3   
Summary of Study Rationale
CTCL is a rare tumor that presents an unmet need; most therapies are associated with 
response rates of 30% to 49%.  Though chemotherapy regimens tend to have higher 
response rates, the duration of response is often short lived.  More effective therapeutic 
options, with improved toxicity profiles, are needed.  The CTCL disease subtypes chosen for 
inclusion in this study constitute the majority of CD30-positive CTCL.(4) CD30 expression 
is a diagnostic criteria in lymphamatoid papulosis and primary cutaneous anaplastic 
lymphoma, and CD30 expression is reported in MF.  Selected diseases have a similar 
clinical course of disease: they are indolent and incurable.  They share a common treatment 
goal: reduction in tumor burden (CR and PR) and symptomatic relief.  The treatment 
modalities are similar.  In addition the number and types of prior systemic therapies is
generally not considered to influence sensitivity to subsequent therapy, and patient can be 
retreated with the same agents.


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Although a number of treatments have shown efficacy in the symptomatic management of 
CTCL, response durations are short and many patients with advanced disease rapidly 
become refractory to therapy, presumably because of drug resistance.  Other intensive 
lymphoma salvage regimens likewise have demonstrated responses, albeit with significant 
immunosuppression-related toxicity.
Brentuximab vedotin is a novel ADC directed against the CD30 surface antigen expressed 
on hematologic malignancies including some types of CTCL.  Preclinical studies of 
brentuximab vedotin demonstrated antitumor activity in both in vitro and in vivo models.  
Currently brentuximab vedotin as monotherapy in relapsed/ refractory patients with CD30+ 
systemic ALCL and Hodgkin lymphoma has been studied in two phase 1 studies and 
2 pivotal phase 2 studies, for a total of more than 300 patients who have completed 
brentuximab vedotin therapy.
Building on these data as well as the robust results of a phase 2 study of the cAC10 antibody 
component alone in CD30+ CTCL, we propose a study designed to investigate if 
brentuximab vedotin, a novel targeted antibody-drug conjugate agent, could increase 
efficacy in patients with CD30+ MF or pcALCL.
1.5   
Potential Risks and Benefits
Brentuximab vedotin had been shown to be therapeutically active in CD30+ hematological 
malignancies.  A phase 1, single-arm, open-label, dose escalation study of brentuximab 
vedotin was conducted in patients with CD30+ hematologic malignancies (SG035-0001).  
Brentuximab vedotin was generally well tolerated at doses of up to 1.8 mg/kg in this study 
and induced multiple objective responses in these heavily pretreated patients.  Complete and 
partial responses were achieved by 10 patients treated at the 1.2-, 1.8-, or 2.7-mg/kg dose 
level with the following diagnoses:  HL (8 of 20 patients; 3 CR, 5 PR) and systemic ALCL 
(2 CR in 2 patients).  In addition, clinical benefit (defined as CR, PR, or SD) was achieved 
in 86% of patients treated at 1.2, 1.8, and 2.7 mg/kg.
Study SG035-0003, a phase 2 trial of brentuximab vedotin evaluated 1.8 mg/kg 
administered intravenously every 3 weeks in a relatively homogeneous population of 
102 adult HL patients whose lymphoma had relapsed or was refractory to multiple-agent, 
high-dose chemotherapy and autologous SCT.  A 75% ORR (representing the predefined 
primary endpoint of the trial) with a durability of 6.7 months was observed.  A substantial 
proportion (34%) of all treated patients obtained a complete remission as manifested by no 
evidence of lymphoma by clinical, laboratory, or radiographic measures.  Observed CRs 


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were durable, with the median duration not reached and a lower 95% confidence interval 
bound of 8.8 months.  Achievement of CR in lymphoma is highly correlated with prolonged 
survival after a subsequent alloSCT, and this potentially curative treatment option was 
enabled in a meaningful fraction of HL patients treated in the pivotal study.
In a preplanned analysis of PFS per investigator assessment in which each patient served as 
his or her own control, PFS with brentuximab vedotin was nearly twice that of the most 
recently delivered treatment.  Analysis of transplant ineligible patients in phase 1 studies 
demonstrated clinical benefit in the pretransplant setting.
Study SG035-0004, a phase 2 study of brentuximab vedotin 1.8 mg/kg administered 
intravenously every 3 weeks in 58 patients 12 years of age or older with sALCL, an ORR of 
86% was observed and 53% of patients obtained a CR as manifested by no evidence of 
lymphoma by clinical, laboratory, or radiographic measures.  The ability to attain a second 
CR or achieve a first CR after the failure of frontline therapy enables an improved 
opportunity for SCT, an exploratory yet potentially curative treatment.
The recommended dose of brentuximab vedotin is 1.8 mg/kg administered intravenously 
every 3 weeks for a minimum of 8 treatment cycles for those patients who achieve stable 
disease or better; there is clinical experience with treating patients through 16 cycles.  At 
this dose and schedule, the most common adverse events observed were peripheral sensory 
neuropathy, fatigue, nausea, diarrhea, pyrexia, upper respiratory tract infection, neutropenia, 
and vomiting.  These events were primarily mild to moderate in severity.  
The most notable adverse event associated with brentuximab vedotin was peripheral 
neuropathy, which tended to increase in severity with longer duration of therapy, consistent 
with what is observed with other antimicrotubule agents such as vinca alkyloids or taxanes.  
The majority of peripheral neuropathy events were Grade 1 to 2 and were manageable by 
dose delay and reduction.  Further information on the management of peripheral neuropathy 
events is provided in Table 6-3.
Severe and prolonged (≥1 week) neutropenia can occur with brentuximab vedotin, which 
may increase the risk of patients developing serious infections.  The median duration of 
Grade 3 or 4 neutropenia was limited (1 week); 2% of patients had Grade 4 neutropenia that 
lasted ≥7 days.  Less than half of the patients in the phase 2 population with Grade 3 or 4 
neutropenia had temporally associated infections, and the majority of temporally associated 
infections were Grade 1 or 2.  Complete blood counts should be monitored prior to 


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administration of each dose of brentuximab vedotin.  Events of Grade 3 or 4 neutropenia 
should be managed according to best medical practice.
Infusion-related reactions are possible with brentuximab vedotin, especially related to the 
development of clinically significant titers of antitherapeutic antibodies (ATA). 
Premedication prior to the infusion of brentuximab vedotin will not be required in Cycle 1, 
but is allowed in subsequent cycles, if indicated. Patients must be monitored for the 
possibility of an acute reaction during brentuximab vedotin administration.(39)
Progressive multifocal leukoencephalopathy (PML) has been reported with brentuximab 
vedotin use.  PML is a rare demyelinating disease of the brain that is caused by the John 
Cunningham virus (JCV). It typically occurs in immunocompromised individuals and can 
be fatal. Presenting features may include altered mental status, motor deficits such as 
hemiparesis or ataxia, visual disturbances, or higher cortical dysfunction such as dysphasia 
or agnosia. Seizures have also been reported in PML patients (approximately 20%). The 
onset of neurological deficits may occur over weeks to months.(40)  Cognitive decline 
without accompanying deficits in motor or sensory function is uncommon.  Optic nerve 
involvement, fever, and spinal cord disease are not typically associated with PML. In 
addition, peripheral neuropathy, which has been reported with brentuximab vedotin 
treatment, is not commonly reported with PML. If PML is suspected, a diagnostic work-up 
should be performed, as described in Section 6.8.5.
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.  Some of the pancreatitis cases were complicated by other possible contributory 
factors, including cholelithiasis and alternate etiologies (eg, pancreatic lymphoma 
progression, displacement of bile duct stent, etc).
Concomitant use of brentuximab vedotin and bleomycin is contraindicated due to pulmonary 
toxicity. In a clinical trial that studied brentuximab vedotin with bleomycin as part of a
combination regimen, the rate of noninfectious pulmonary toxicity was higher than the 
historical incidence reported with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine).
Patients typically reported cough and dyspnea. Interstitial infiltration and/or inflammation 
were observed on radiographs and computed tomographic imaging of the chest. Most 
patients responded to corticosteroids.


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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 directed towards blocking 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 study medication.  Additional information 
on risk minimization and assessment strategies to be used in this study is provided in 
Section 6.8.
Preliminary population PK analyses of the effects of brentuximab vedotin on renal and 
hepatic function suggest that no dose adjustments are necessary for patients with renal or 
hepatic impairment.  Additional analysis is planned to more fully characterize the 
pharmacokinetics in this patient population.
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.  Female patients of childbearing potential are advised to use 
adequate and effective contraception during brentuximab vedotin treatment and for a 30-day 
period thereafter.  Male patients are advised to use adequate and effective contraception 
during treatment with brentuximab vedotin and for 6-months thereafter.
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
and the applicable regulatory requirements (including International Conference on 
Harmonisation [ICH] guidelines).
2.   
STUDY OBJECTIVES
2.1   
Primary Objectives
The primary objective is:

To determine ORR, lasting at least 4 months, with brentuximab vedotin in patients 
with CD30+ MF or pcALCL compared to that achieved with therapy in the control 
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2.2   
Secondary Objectives
The key secondary objectives are:
∀
To determine complete response (CR) rate with brentuximab vedotin compared to 
that achieved with therapy in the control arm
∀
To determine progression-free survival (PFS) with brentuximab vedotin compared to 
that achieved with therapy in the control arm
∀
To determine burden of symptoms during treatment with brentuximab vedotin 
compared to that achieved with therapy in the control arm
Other secondary objectives include:
∀
To assess duration of response with brentuximab vedotin
∀
To assess duration of skin response with brentuximab vedotin 
∀
To determine event-free survival (EFS) with brentuximab vedotin compared to that 
achieved with therapy in the control arm
∀
To describe the PK of brentuximab vedotin and monomethylauristatin E (MMAE) in 
blood
∀
To determine the immunogenicity of brentuximab vedotin
∀
To assess patient-reported quality of life outcomes
∀
To assess the safety of brentuximab vedotin
2.3   
Exploratory Objectives
The exploratory objectives include:
CCI


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3.   
STUDY ENDPOINTS
3.1   
Primary Endpoint
∀
Proportion of patients achieving an objective response that lasts at least 4 months, as 
determined by an independent review of global response score consisting of skin 
evaluations (modified severity weighted assessment tool [mSWAT] assessment),
nodal and visceral radiographic assessment, and detection of circulating Sézary cells.
3.2   
Secondary Endpoints
The key secondary endpoints are:
∀
Proportion of patients achieving CR
∀
Progression-free survival
∀
Changes in symptom domain per Skindex-29 questionnaire
Other secondary endpoints include:
∀
Adverse events (AEs) according to National Cancer Institute (NCI) Cancer Therapy 
Evaluation Program (CTEP) Common Terminology Criteria for AEs version 4.03, 
serious adverse events (SAEs), assessments of clinical laboratory values
∀
Duration of response
∀
Duration of response in skin
CCI


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∀
Event-free survival
∀
Blood concentrations of brentuximab vedotin and MMAE
∀
Immunogenicity assessment
∀
Quality of life assessments per Skindex-29 and FACT-G questionnaire
3.3   
Exploratory Endpoints
The exploratory endpoints include:
4.   
STUDY DESIGN 
4.1   
Overview of Study Design
This is an open-label, randomized, multicenter study. All patients must have a diagnosis of 
MF or pcALCL and histologically-confirmed CD30+ disease by central laboratory 
assessment and pathology review. Patients are to be stratified by diagnosis:  pcALCL or 
MF. Patients will enter 1 of 2 treatment arms:
∀
Arm 1: brentuximab vedotin monotherapy
Brentuximab vedotin (1.8 mg/kg) will be administered intravenously over 
approximately 30 minutes once every 21 days and may continue as monotherapy for 
up to a total of 16 cycles (48 weeks).
CCI


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
Arm 2: methotrexate (MTX) or bexarotene per physician’s choice, up to a total of 
48 weeks treatment.
Methotrexate will be administered orally (5 to 50 mg) once weekly.  Dose 
adjustment is guided by patient response and toxicity.  
OR
Bexarotene will be administered orally (300 mg/m2 recommended total dose per 
guidelines in Figure 6-1) once daily with meals.
Investigators are advised to consider a patient’s prior treatment with reference therapy. It is 
recommended that patients who were last treated with methotrexate be treated with 
bexarotene, and patients who last received bexarotene be treated with methotrexate.
Objective response, lasting at least 4 months (ORR4), per independent review facility (IRF),
will be assessed by global response score (GRS), which consists of skin evaluation 
(mSWAT assessment), nodal and visceral radiographic assessment, and detection of 
circulating Sézary cells (MF only).  Objective response will be evaluated at the end of 
Cycles 3, 6, 9, 12, and 15, and at end of treatment (EOT).  All treated patients without 
disease progression at EOT/ET will then be followed for objective response every 12 weeks
for a minimum of 24 months, and then every 6 months; or until disease progression or study
closure.  CR or PR per GRS will be confirmed by sustained response in skin per mSWAT
assessment at the subsequent cycle. Additional unscheduled GRS determinations may occur 
following a change in response in skin or at the time of a CT scan.
All randomized patients will also be followed for survival every 12 weeks for a minimum of
24 months after the EOT visit, and then every 6 months until patient withdrawal, death, or 
study closure.  Safety will be evaluated by the incidence of treatment-emergent adverse 
events (TEAEs), severity and type of AEs, and by changes from baseline in the patient’s 
vital signs, ECOG performance status, and clinical laboratory results using the safety 
population.  
Patients with documented PR or CR at the end of Cycle 3 and at any disease assessment 
thereafter, may continue treatment with study drug for up to 16 cycles with brentuximab 
vedotin or 48 weeks with bexarotene or methotrexate; patients with stable disease may
continue therapy at the discretion of the investigator. Patients with progressive disease at 
any time during the study will be discontinued from study treatment (Section 7.7). Patients 
with increasing mSWAT prior to assessment at the end of Cycle 3 will be allowed to 


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continue therapy until the Cycle 3 assessment if, in the investigator's opinion, the findings 
are due to tumor flare rather than disease progression.
Disease progression will be assessed using the response criteria included in Olsen et al, 
2011, and Kempf et al, 2011(11, 41). As described in Section 7.4.16, efficacy will be assessed 
per IRF, using a global response score, which consists of skin evaluation (modified severity 
weighted assessment tool [mSWAT] assessment), nodal and visceral radiographic 
assessment, and detection of circulating Sézary cells.  
FDG-PET scans and CT scans of the neck, chest, abdomen, and pelvis will be performed at 
screening.  FDG-PET scans taken within 8 weeks before signing the informed consent form 
(ICF) may be used as the screening FDG-PET.  FDG-PET scans will not be taken after 
screening unless clinically indicated.  CT scans taken within 4 weeks before signing the ICF 
may be used as the screening CT scan if all of the following conditions are met: 

There is no nodal or visceral disease involvement noted

There is no clinically evident lymphadenopathy or splenomegaly by physical exam at 
the time of screening 

The scan meets all quality criteria as outlined in the Imaging Manual  
For patients without nodal or visceral involvement as determined by baseline CT scans, CT 
scans will be performed during the cycle following the first skin response, ideally 
corresponding to the confirmation of the skin response, and 6 cycles (a minimum of 
4 months) after that confirmed skin response.  Repeat CT scans will be performed if there is 
a question of new or progressive disease in the lymph node or viscera. For patients with 
baseline nodal/visceral disease, CT scans will be performed at the end of Cycles 3, 6, 9, 12, 
and 15 (Days 16-21 or before dosing on Day 1 of the subsequent cycle), and per the follow-
up schedule until disease progression, or if there is a question of new or progressive disease 
in the lymph node or viscera.  CT scans will be performed at EOT for all patients with 
baseline nodal/visceral disease if the previous scan was performed more than 8 weeks before 
EOT.
All CT scans will be taken with IV contrast (unless contraindicated) and they will be of 
diagnostic quality.  Specific disease sites that cannot be adequately imaged by CT may be 
documented by MRI.  In addition, lymphoma response and progression will be assessed by 
an independent review facility (IRF).  


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Toxicity will be evaluated according to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), version 4.03, effective date 14 June 2010.(42)
AEs will be assessed, and laboratory values and vital signs will be obtained to evaluate the 
safety and tolerability of brentuximab vedotin.
4.2   
Number of Patients
Approximately 124 patients (approximately 62 per treatment arm) will be enrolled in this 
study from approximately 50 study centers globally. A minimum of 30 patients (15 per 
treatment arm) with pcALCL will be enrolled.  Enrollment is defined as randomization to a 
treatment arm.  Patients will be stratified by diagnosis in each treatment arm (pcALCL or 
MF). 
4.3   
Duration of Study
Patients who achieve a response (CR or PR) may receive brentuximab vedotin up to 
16 cycles (48 weeks) or reference therapy for up to 48 weeks.  Patients with stable disease 
may continue therapy (maximum 16 cycles brentuximab vedotin or 48 weeks reference 
therapy) at the discretion of the investigator.  For all patients who complete either 48 weeks 
of dosing in the control arm or 16 cycles of brentuximab vedotin, an attempt to discontinue 
therapy should be made following EOT. For patients who complete 48 weeks of reference 
therapy, initiation of subsequent standard-of-care therapy should be discussed with the study 
sponsor. For patients who complete 16 cycles of brentuximab vedotin, access to
brentuximab vedotin may be permitted in accordance with local regulatory requirements and 
at the joint discretion of the sponsor and investigator.  
To permit the detection of any delayed treatment-related AEs, patients will be followed for 
30 days after the last dose of study medication.  Posttreatment assessments of disease 
response will be conducted every 12 weeks for a minimum of 24 months after EOT, and
then every 6 months; or until progressive disease or study closure.  All randomized patients 
will also be followed for survival every 12 weeks for a minimum of 24 months after the 
CCI
CCI


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EOT visit, then every 6 months until patient withdrawal, death, or study closure.  
Information may be collected by phone for patients with progressive disease.
The final analyses for the clinical study report will be performed 10 months after the last 
patient is enrolled (ie, approximately 34 months from the start of study).  The updated 
analyses on the efficacy endpoints will be conducted after all patients enrolled in the study 
have had the opportunity to complete 16 cycles of treatment with brentuximab vedotin or 
48 weeks of treatment with reference therapy and 24 months of posttreatment follow up, and 
will be included in an addendum to the clinical study report.
The total study duration will be approximately 5 years, including an anticipated enrollment 
duration of 24 months.  
5.   
STUDY POPULATION
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 with diagnosis of MF or pcALCL.
2. Histologically-confirmed CD30+ disease by central laboratory assessment and 
pathology review. Tissue from at least 2 lesion biopsies for MF and 1 lesion biopsy 
for pcALCL performed at screening must be available for confirmation of CD30 
positivity, defined as ≥10% target lymphoid cells demonstrating membrane, 
cytoplasmic, and/or Golgi staining pattern for CD30 at any intensity above 
background staining as noted on the corresponding negative control. (A minimum of 
10% staining in at least 1 sample is required.  Percent positivity should be 
determined using percent neoplastic cells staining first. If neoplastic cells cannot be 
easily distinguished from non-neoplastic, then percent positivity should be 
determined using percent total lymphocytes staining.)
3. Patients with pcALCL who have received prior radiation therapy or at least 1 prior 
systemic therapy; patients with MF who have received at least 1 prior systemic 
therapy.
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (refer to 
Section 15.1).


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5. Female patients who:
Are postmenopausal for at least 1 year before the screening visit, OR
Are surgically sterile, OR
If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed consent 
through 30 days after the last dose of study drug, OR
Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods] and withdrawal are not acceptable 
methods of contraception.)
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] and withdrawal are not acceptable 
methods of contraception.)
6. Voluntary written consent must be given before performance of any study-related 
procedure not part of standard medical care, with the understanding that consent may 
be withdrawn by the patient at any time without prejudice to future medical care.
7. Suitable venous access for the study-required blood sampling, including PK 
sampling.
8. Clinical laboratory values as specified below within 4 days before randomization
(laboratory values may be performed locally.):
Total bilirubin must be 1.5 the upper limit of normal (ULN).
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) must be 
3 the upper limit of the normal range.  AST and ALT may be elevated up to 


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5 times the ULN if their elevation can be reasonably ascribed to the presence of 
metastatic disease in liver.
Creatinine clearance or calculated creatinine clearance 40 mL/minute.
9. Patients must have radiographically or clinically measurable or evaluable disease
10. A 3-week washout period is required from previous treatments (with the exception 
of a 12-week washout for antibody-directed or immunoglobulin-based immune 
therapy, or other monoclonal antibody therapies), unless it is not in the best interest 
of the patient in the opinion of the investigator. Individual cases should be discussed 
with the project clinician before enrollment.
11. Recovered (ie, Grade 1 toxicity) from the reversible effects of prior antineoplastic 
therapy.
5.2   
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not eligible for participation:
1. A concurrent diagnosis of systemic ALCL, or other non Hodgkin lymphoma
(excluding lymphomatoid papulosis [LyP]).
2. A concurrent diagnosis of Sézary syndrome or B2 disease.
3. Any of the following cardiovascular conditions or values within 6 months before the 
first dose of study drug: 
Myocardial infarction within 6 months of enrollment.
New York Heart Association (NYHA) Class III or IV heart failure (see Section 
15.2).  
Evidence of current uncontrolled cardiovascular conditions, including cardiac 
arrhythmias, congestive heart failure (CHF), angina, or electrocardiographic 
evidence of acute ischemia or clinically significant conduction system 
abnormalities.  
4. History of another primary malignancy not in remission for at least 3 years.  The 
following are exempt from the 3-year limit: completely resected in situ carcinoma, 


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such as nonmelanoma skin cancer and cervical carcinoma in situ on biopsy or a 
squamous intraepithelial lesion on Pap smear.
5. Known active cerebral/meningeal disease, including signs or symptoms of 
progressive multifocal leukoencephalopathy (PML).
6. Known HIV infection.
7. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C 
infection.
8. Any severe active systemic viral, bacterial, or fungal infection within 1 week prior to 
first study drug dose requiring systemic antimicrobial therapy. (Oral antibiotics for 
prophylaxis are allowed.)
9. Receiving antibody-directed or immunoglobulin-based immune therapy (eg, 
immunoglobulin replacement, other monoclonal antibody therapies) within 12 weeks
of first study drug dose.
10. Corticosteroid therapy for the treatment of CTCL within 3 weeks of first dose of 
study drug.
11. Known hypersensitivity to recombinant proteins, murine proteins, or any excipient 
contained in the drug formulation.
12. Female patients who are lactating and breastfeeding or have a positive serum 
pregnancy test during the Screening period or a positive urine pregnancy test on Day 
1 of any cycle.
13. Treatment with radiotherapy or other skin-directed therapy or any investigational 
products within 3 weeks before the first dose of study drug.
14. Progressed on prior therapy with both bexarotene and methotrexate.
15. Oral retinoid therapy for any indication within 3 weeks of the first dose of study 
drug.  
16. Systemic therapy with Vitamin A in doses of greater than 15,000 IU (5,000 mcg) per 
day (equivalent to approximately 3 times RDA) within 3 weeks before the first dose 
of study drug.


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17. History of pancreatitis or significant risk factors for developing pancreatitis (eg, prior 
pancreatitis, uncontrolled hyperlipidemia, excessive alcohol consumption, 
uncontrolled diabetes mellitus, biliary tract disease, and medications known to 
increase triglyceride levels or to be associated with pancreatic toxicity), or elevated 
lipase value ≥3 ULN with an amylase level > ULN at screening.  
18. Any other condition that, in the opinion of the investigator or project clinician, would 
interfere with a patient’s ability to receive or complete the study.
19. Previous receipt of brentuximab vedotin.
6.   
STUDY DRUG
Patients will be randomized in a 1:1 ratio to receive study treatment with either Arm 1: 
brentuximab vedotin, or Arm 2: bexarotene or methotrexate (for bexarotene-treated 
patients, study treatment will include pretherapy with fenofibrate, per Section 6.2.2). 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).
6.1   
Brentuximab vedotin Administration
Study treatment will be administered by IV infusion given over approximately 30 minutes
on Day 1 of each 21-day cycle.  In the absence of infusion toxicities, the infusion rate for all 
patients must be calculated in order to achieve a 30-minute (approximate) infusion period.  
Brentuximab vedotin must not be administered as an IV push or bolus.  Study treatment will 
be administered through a dedicated IV line and cannot be mixed with other medications.
The dose of brentuximab vedotin is 1.8 mg/kg.  Dosing is based on patients’ weight 
according to the institutional standard; however, doses will be adjusted for patients who 
experience a ≥ 10% change in weight from baseline.  Actual weight will be used except for 
patients weighing greater than 100 kg; dose will be calculated based on 100 kg for these 
individuals.  The dose will be rounded to the nearest whole number of milligrams.
Further brentuximab vedotin administration information can be found in the Pharmacy 
Manual.


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6.2   
Reference/Control Therapy
6.2.1   
Methotrexate
Methotrexate will be given once weekly as a single dose of 5 to 50 mg orally.  Dosages may 
be gradually adjusted to achieve optimal clinical response but must not exceed 50 mg/week.  
Once optimal clinical response is achieved, the methotrexate dosage should be decreased to 
the lowest effective dose.  For patients deriving benefit, methotrexate dosing should be 
continued up to 48 weeks.  For further dose modification guidelines, refer to the 
methotrexate product label.  
Further Guidelines for Methotrexate Use
Methotrexate cytotoxicity is highly dependent on the absolute drug concentration and the 
duration of drug exposure.  MTX is actively transported across cell membranes.  At serum 
methotrexate concentrations exceeding 0.1 μmol/mL, passive diffusion becomes a major 
means of intracellular transport of MTX.  The drug is widely distributed throughout the 
body with the highest concentration in the kidney, liver, spleen, gallbladder, and skin.  After 
oral administration, approximately 60% of a 30-mg/m2 dose is rapidly absorbed from the GI 
tract, with peak blood levels at 1 hour.  Even at low doses absorption may be very erratic, 
varying between 23% and 95%.  MTX is excreted primarily by the kidneys via glomerular 
filtration and active secretion into the proximal tubules.  Renal clearance usually equals or 
exceeds creatinine clearance.  Small amounts are excreted in the feces.  
Methotrexate Toxicity
When MTX toxicity occurs, the dosage should be modified.

A 50% dose reduction of MTX is indicated when severe mouth ulcerations occur.
Dose modifications for hyperbilirubinemia are described in Table 6-1.
Table 6-1   
Methotrexate Dose Modifications for Hyperbilirubinemia
Severity
Methotrexate Action
Total bilirubin > 1.5 - ≤3 mg/dL with 
an abnormal direct bilirubin
Reduce MTX to 50% of previous dose
Total bilirubin > 3 - ≤5 mg/dL
Reduce MTX to 25% of previous dose
Total bilirubin > 5 mg/dL
Discontinue MTX


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Reported MTX-associated toxicities, categorized by frequency and onset time relative to 
MTX dosing, are presented in Table 6-2.
Table 6-2   
Methotrexate-Associated Toxicities
Common (> 10%)
Occasional (1%-10%)
Rare (< 1%)
Immediate: Within 
1-2 days of receiving 
drug
Transaminase elevations
Nausea, vomiting, 
anorexia
Anaphylaxis, chills, 
fever, dizziness, malaise, 
drowsiness, blurred 
vision, acral erythema, 
urticaria, pruritus, toxic 
epidermal necrolysis, 
Stevens-Johnson 
Syndrome, tumor lysis 
syndrome, seizures, 
photosensitivity
Prompt: Within 
2-3 weeks, prior to the 
next course
Myelosuppression, 
stomatitis, gingivitis, 
photosensitivity, fatigue
Alopecia, folliculitis, 
acne, renal toxicity 
(ATN, increased 
creatinine/BUN, 
hematuria), enteritis, GI 
ulceration and bleeding, 
acute neurotoxicity 
(headache, drowsiness, 
aphasia, paresis, blurred 
vision, transient 
blindness, dysarthria, 
hemiparesis, decreased 
reflexes) diarrhea, 
conjunctivitis
Delayed: Any time 
later during therapy, 
excluding the above 
conditions
Learning disability
Pneumonitis, pulmonary 
fibrosis, hepatic fibrosis, 
osteonecrosis, 
leukoencephalopathy, 
pericarditis, pericardial 
effusions, 
hyperpigmentation of the 
nails
Late: Any time after 
the completion of 
therapy
Progressive CNS 
deterioration
Unknown Frequency 
and Timing
Methotrexate crosses the placenta.  Fetal toxicities and teratogenic effects of 
methotrexate have been noted in humans.  The toxicities include: congenital 
defects, chromosomal abnormalities, severe newborn myelosuppression, low 
birth weight, abortion, and fetal death.  Methotrexate is excreted into breast milk 
in low concentrations


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6.2.2   
Bexarotene
The risks of bexarotene therapy should be considered by the investigator when selecting an 
appropriate Arm B treatment. The recommended total dose of bexarotene capsules is 
300 mg/m2/day. The Mosteller formula or the Dubois and Dubois formula should be used 
for all body surface area (BSA) determinations for each patient, and are provided in Section 
15.2. Dosage should be rounded to the nearest 75 mg. Bexarotene capsules should be taken 
as a single oral daily dose with a meal. The dose of bexarotene may be reduced to 
200 mg/m2/day PO then to 100 mg/m2/day PO, or temporarily suspended, if clinical toxicity 
occurs. When toxicity is controlled, doses may be restarted and carefully increased. 
Bexarotene capsules should be continued as long as the patient is deriving benefit, up to 
48 weeks. For further dose modification guidelines, refer to the bexarotene product label.
Further Guidelines for Bexarotene Use
Hypertriglyceridemia of all grades has been recorded in 79% of patients who took 
bexarotene in a study in early-stage CTCL; hypercholesterolemia occurred in 48% of 
patients; and hypothyroidism in 40%.  Similarly, in a study in advanced-stage CTCL, the 
incidence of hyperlipidemia of all grades (primarily hypertriglyceridemia) with bexarotene 
was 82%, hypercholesterolemia was 30%, and hypothyroidism was 29%.  Before initiating 
bexarotene therapy, a patient history should be taken to identify those with familial 
hypertriglyceridemia, uncorrected hypothyroidism, an individual or family history of 
myocardial infarction or cardiovascular events, or a history of diabetes.  A minority of 
patients with familial hypertriglyceridemia cannot tolerate bexarotene and should be 
considered for alternative therapy.  A substantial proportion of patients will have pathology 
related to cardiovascular atherosclerosis or a history of cardiovascular disease and have 
hypertriglyceridemia that will need to be treated before bexarotene therapy.  In addition, 
those with coronary heart disease are likely to have active atherosclerotic plaques that 
should be stabilized with low-dose statin therapy (eg, 10 mg daily) 3 days before beginning 
bexarotene.  Diabetes can also contribute to the development of coronary heart disease and 
should be controlled.  These groups of at-risk patients are identified by elevated plasma lipid 
levels and should be monitored particularly closely during treatment, with measurement of 
fasting lipid levels at weekly intervals for as long as necessary until it becomes apparent that 
these are stabilized reliably at the levels recommended.
Prior to dosing with bexarotene, attempts should be made to obtain triglyceride levels that 
meet the normalized lipid levels per the United States Prescribing Information (USPI) 


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guidelines.  Baseline free T4, TSH and fasting levels of triglycerides, LDL-cholesterol, and 
HDL-cholesterol should be obtained in all patients being considered for bexarotene 
treatment and, if elevated, these should be normalized before the therapy is initiated.  
Ideally, normalization of lipid levels should be achieved through lifestyle changes: adopting 
a healthy diet low in calories, sugar, saturated fat, and alcohol, and high in fiber and 
unsaturated fat, along with increased exercise, and weight loss in obese patients.  However, 
achieving compliance with lifestyle changes is difficult and, particularly in a patient with 
rapidly progressing CTCL, the physician may wish to begin bexarotene therapy as soon as 
possible.  Many patients will therefore require therapy with lipid-lowering agents, such as a 
fibrate or high-dose omega-3 fatty acids for high triglycerides, a statin to normalize high 
LDL-cholesterol.(43)
All patients (with normal or normalized triglyceride levels) who are to be given bexarotene 
should receive 7 days of pretherapy with fenofibrate 145 to 200 mg daily (the dose should 
be reduced to 100 mg or even 50 mg daily if creatinine is > 1.5 mg dL-1/0·133 µmol L-1, or 
in nephrotic syndrome).  The fibrate gemfibrozil is not recommended for administration 
with oral bexarotene, as it results in higher plasma levels of bexarotene and an elevation of 
triglycerides.  Fibrates are contraindicated in patients with liver and kidney failure and in 
pregnancy, and they potentiate the action of warfarin.  They are also associated with a 
number of reversible adverse effects, including increased liver transaminases and muscular
creatine kinase, which may lead to muscle pain.  Should these events occur, fibrate treatment 
should be discontinued.
Most patients do not require a statin at this stage, as the increase in triglycerides with 
bexarotene therapy is generally more problematic than the increase in LDL-cholesterol 
level.  In addition, patients should be advised on dietary and lifestyle changes that may help 
to reduce the need for lipid-lowering drugs during treatment.
Bexarotene therapy results in a dose-related reduction in thyroid hormone levels through an 
initial, rapid suppression of TSH gene expression, which leads to central hypothyroidism.  
This effect is reversible within several days of cessation of therapy.  While measurement of 
TSH levels can provide a useful tool to assess patient compliance, it is essential to monitor 
free T4 and to keep this hormone within the normal range.  At the recommended dose of 
300 mg/m2 daily, most patients experience a decrease in free T4 concentration to ≥ 25% 
below the normal range, and TSH decreases to the low-normal or even subnormal levels.  In 
anticipation of this, low-dose thyroxine (levothyroxine 0.05 mg daily) should be initiated 
along with the bexarotene.  Correcting hypothyroidism with hormone replacement during 


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bexarotene therapy will ease hypertriglyceridemia by increasing lipid clearance and can 
stabilize triglyceride levels.  In addition, patients feel less fatigued if thyroxine is 
supplemented.  Based on measurements of free T4, fasting cholesterol, and triglycerides at 
Days 7, 14, 28, 35, and 49 after initiation of bexarotene therapy, the doses of thyroxine and 
lipid-lowering therapy should be adjusted as necessary with the target of achieving normal 
levels of T4 5-12 µg dL-1 (64-154 nmol L-1), triglycerides ≤ 200 mg dL-1 (2.2 mmol L-1), 
LDL-cholesterol ≤ 160 mg dL-1 (4·2 mmol L-1), and HDL-cholesterol ≥ 50 mg dL-1 (1·3 
mmol L-1).  As patients on bexarotene may metabolize T4 more rapidly, the final daily dose 
of thyroxine required to keep free T4 within the normal range may be as high as 0.20 to 0.25 
mg daily, depending on the patient's age and weight.  Monitoring of lipids and free T4 
should continue subsequently every 1 to 2 months during treatment.  If the bexarotene dose 
is modified at any time, the doses of thyroxine and antilipid therapy will need to be adjusted 
accordingly.(36, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59)
Figure 6-1   
Bexarotene Risk Mitigation
Abbreviations:  HDL = high-density lipoprotein; LDL = low-density lipoprotein.
Suggested approach to minimize adverse events with bexarotene in patients with cutaneous T-cell lymphoma 
with normal (or normalized) free thyroxine (T4), fasting triglyceride and cholesterol levels at start of 
therapy.(43)
6.3   
Dose Escalation Rules
No dose escalation of brentuximab vedotin (Arm 1) is permitted in this study.  However, in 
Arm 2 (control arm), the dose of methotrexate or bexarotene may be escalated per treating 
physician as detailed in the methotrexate or bexarotene product label.


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6.4   
Dose-Modification Guidelines
Dose modifications specific to peripheral neuropathy for patients receiving brentuximab 
vedotin are described in Table 6-4 in Section 6.4.2, Criteria for Dose Reduction.  
6.4.1   
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
Treatment with brentuximab vedotin or reference therapy will use a cycle length of 21 days.  
For a new cycle of treatment to begin, the patient must meet the following criteria:

ANC must be ≥ 1,000/mm3

All other study drug-related toxicity must have resolved per the guidelines provided 
in Table 6-3 and Table 6-4.
If the patient fails to meet the criteria for retreatment cited previously, initiation of the next 
cycle of treatment should be delayed up to 1 week.  At the end of that time, the patient 
should be re-evaluated to determine whether the criteria for retreatment have been met.  The 
start of the next cycle may be delayed for up to 3 weeks if additional time is required for the 
patient to recover from study treatment-associated toxicity experienced during the current
cycle.  Delays of greater than 3 weeks are prohibited without approval of the sponsor.
6.4.2   
Criteria for Dose Reduction
Brentuximab vedotin
Intrapatient dose reduction to 1.2 mg/kg brentuximab vedotin will be allowed depending on 
the type and severity of toxicity.  Please refer to Table 6-3 and Table 6-4 for further 
information.
When a dose reduction of brentuximab vedotin is required, no re-escalation of dose will be 
permitted.
Reference Therapy
Please refer to Section 6.2 for drug-specific dose reduction guidelines for methotrexate and 
bexarotene, respectively.


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Table 6-3   
Recommended brentuximab vedotin Dose Modifications for 
Treatment-Associated Toxicity Excluding Neuropathy
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Non-
hematologic
(excluding 
neuropathy)
Continue at 
same dose 
level.  
Continue at same dose 
level.
Withhold dose until 
toxicity is ≤ Grade 1 
or has returned to 
baseline, then resume 
treatment at the same 
dose levela.
Withhold dose until 
toxicity is ≤ Grade 1 or 
has returned to baseline, 
then reduce dose to 1.2 
mg/kg and resume 
treatment, or 
discontinue at the 
discretion of the 
investigator after 
discussion with the 
sponsor.a
Hematologic 
Continue at 
same dose 
level.  
Continue at same dose 
level.  
Withhold dose until 
toxicity is ≤ Grade 2,
or has returned to 
baseline, then resume 
treatment at the same 
dose level b. Consider 
growth factor support 
(G-CSF or GM-CSF) 
for treatment of 
neutropenia and 
prophylaxis in 
subsequent cycles. 
Withhold dose until 
toxicity is ≤ Grade 2,
then resume treatment at 
the same dose level. 
Consider growth factor 
support (G-CSF or GM-
CSF) for treatment of 
neutropenia and 
prophylaxis in 
subsequent cycles. For 
the second occurrence 
of Grade 4 toxicity (if 
neutropenia, while 
receiving growth factor 
support), withhold dose 
until toxicity is ≤ Grade 
2, then reduce the dose 
to 1.2 mg/kg and 
resume treatment after 
discussion with the 
sponsor.b
Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v. 4.03
a Patients who develop Grade 3 or 4 electrolyte laboratory abnormalities may continue study treatment 
without interruption. Brentuximab vedotin will be held for clinically meaningful Grade 3 or 4 electrolyte 
abnormalities. 
b Patients who develop Grade 3 or 4 lymphopenia may continue study treatment without interruption.


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Table 6-4   
Recommended brentuximab vedotin Dose Modifications for 
Treatment-Emergent or Worsening Peripheral Sensory or Motor 
Neuropathy
Severity of Peripheral Sensory or Motor 
Neuropathy (Signs and Symptoms [abbreviated 
description of CTCAE])
Modification of Dose and Schedule
Grade 1 (Asymptomatic; clinical or diagnostic 
observations only; intervention not indicated; 
paresthesia and/or loss of deep tendon reflexes)
Continue with the same dose and schedule
Grade 2 (Moderate symptoms; limiting instrumental 
activities of daily living)
Grade 3 ( Severe symptoms; limiting self care activities 
of daily living)
Withhold dose until toxicity returns to ≤ Grade 1 
or baseline, then restart treatment at a reduced 
dose of 1.2 mg/kg every 3 weeks
Grade 4 (life-threatening consequences; urgent 
intervention indicated)
Discontinue treatment
Grade 5 (Death)
Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v. 4.03; see neuropathy; peripheral motor neuropathy; peripheral sensory neuropathy.
6.4.3   
Discontinuation of Study Drug Due to Toxicity
Brentuximab vedotin
Please refer to Table 6-3 and Table 6-4 for further information.
Reference Therapy
Methotrexate or bexarotene should be discontinued per institutional standards or local 
product label, as applicable.
6.5   
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study:

Any investigational agent other than brentuximab vedotin, including agents that are 
commercially available for indications other than CTCL (including bleomycin, 
where use is contraindicated due to pulmonary toxicity)

Any antineoplastic treatment with activity against CTCL other than study drug

Any phototherapy including psoralen with ultraviolet light A (PUVA)


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
Any immunotherapy (eg, immunoglobulin replacement, any other monoclonal 
antibody therapy)

Radiation therapy (note that, in general, the requirement for local radiation therapy 
indicates disease progression)

Systemic or topical corticosteroids for the treatment of CTCL
6.6   
Permitted Concomitant Medications and Procedures
Patients may receive concomitant hormonal therapy provided they have been on a stable 
dosage for at least 1 month prior to enrollment.  The use of platelet and/or red blood cell 
supportive growth factors or transfusions when applicable is allowed.  The use of colony 
stimulating factors for the treatment of neutropenia per institutional practice is permitted 
during therapy.  The use of systemic, topical, or inhaled corticosteroids during the study for 
reasons other than CTCL should be reviewed by the investigator and project clinician.  The 
use of corticosteroids for the management of complications from infusion reactions and/or 
anaphylaxis is permitted.
6.7   
Precautions and Restrictions 
It is not known what effects brentuximab vedotin has on human pregnancy or development 
of the embryo or fetus.  Therefore, female patients participating in this study should avoid 
becoming pregnant, and male patients should avoid impregnating a female partner.  
Nonsterilized female 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 30 days
after the last dose of study drug, or


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
Practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-
ovulation methods] and withdrawal are not acceptable methods of contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy) 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

Practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-
ovulation methods] and withdrawal are not acceptable methods of contraception.)
6.8   
Management of Clinical Events
6.8.1   
Nausea and/or Vomiting
Although this study will not initially employ prophylactic anti-emetics, there is no 
prohibition against their use in the management of a patient who develops nausea and/or 
vomiting.  As in the prophylactic setting, 5-HT3 receptor antagonists should be tried first.
6.8.2   
Diarrhea
Prophylactic antidiarrheals (eg, loperamide) are not recommended in this protocol; however, 
patients may be instructed to take antidiarrheal medications at physician’s discretion until 
they are diarrhea-free for at least 12 hours.  Fluid intake should be maintained to avoid 
dehydration.
6.8.3   
Management of Infusion-Related Reactions
Infusion-related reactions may occur during the infusion of brentuximab vedotin.  The 
infusion should be administered at a site properly equipped and staffed to manage 
anaphylaxis should it occur.  The patient should be observed closely during and for 
60 minutes following the infusion of brentuximab vedotin.  During this observation period, 
the IV line should remain open for at least 1 hour to allow administration of IV drugs if 
necessary.  All supportive measures consistent with optimal patient care will be given 
throughout the study according to institution standards.  Medications for infusion-related 
reactions, such as epinephrine and antihistamines should be available for immediate use.


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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 (approximate)
brentuximab vedotin infusion.  The planned use of steroids as premedication is prohibited.
If anaphylaxis occurs, brentuximab vedotin administration should be immediately and 
permanently discontinued.
6.8.4  
Management of Peripheral Neuropathy
Adverse events 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, pareaesthesia, hypoaesthesia, polyneuropathy, muscular weakness, and 
demyelinating polyneuropathy.  Such events, 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. Events that are greater than Grade 1 in severity will result in 
dose interruption, reduction, or discontinuation. Guidelines for brentuximab vedotin dose 
modification in the event of peripheral neuropathy are shown in Table 6-4.
6.8.5   
Management of Progressive Multifocal Leukoencephalopathy
Signs and symptoms of progressive multifocal leukoencephalopathy (PML) may include 
altered mental status; motor deficits, such as hemiparesis or ataxia; visual disturbances; or 
higher cortical dysfunction, such as dysphasia or agnosia. See the Investigator’s Brochure
for further details.  
If PML is suspected, hold further brentuximab vedotin dosing and undertake a diagnostic 
work-up that may include (but is not limited to): 

Neurologic examinations, as warranted

Brain MRI: features suggestive of PML include presence of unifocal or multifocal 
lesions, mainly of the white matter, which are typically nonenhancing and do not 
have mass effect

Polymerase chain reaction analysis: John Cunningham virus (JCV) DNA detectable 
in cerebrospinal fluid or there is evidence of JCV in a brain biopsy 


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
Neurology consultation
If PML is confirmed, treatment with brentuximab vedotin should be discontinued 
permanently.
6.9   
Blinding and Unblinding
This is an open-label study; investigators and patients will know the individual treatment 
assignments.  However, aggregate efficacy results by treatment group will be blinded to the 
study team, investigators, patients, and IRF, throughout the study conduct.
6.10   
Description of Investigational Agents
Brentuximab vedotin for Injection is a sterile, preservative-free, white to off-white 
lyophilized cake for reconstitution for IV administration.  Brentuximab vedotin for Injection 
is supplied in single-use, Type 1 borosilicate glass vials with FluroTec®-coated butyl rubber 
stoppers and aluminum seals.  Each vial of the product contains brentuximab vedotin, 
trehalose, sodium citrate, and polysorbate 80.  The lyophilized product, after reconstitution 
with 10.5 mL sterile Water for Injection, USP, yields 11 mL of brentuximab vedotin
solution (5 mg/mL).
6.11   
Preparation, Reconstitution, and Dispensation
Recommended safety measures for handling and preparation include masks, protective 
clothing, gloves, and vertical laminar airflow safety cabinets.
Study treatment vials are single-use containers.  Any partially used vials or diluted dosing 
solutions are to be discarded using appropriate institutional drug disposal procedures
according to the guidelines in the Study Manual.  
The required volume of 5 mg/mL reconstituted brentuximab vedotin solution needed must 
be calculated and withdrawn from the vials.  The reconstituted solution should be added 
immediately to an infusion bag containing a minimum volume of 100 mL.  The dose for 
patients weighing greater than 100 kg should be calculated based on a weight of 100 kg.  
Study treatment must be reconstituted with the appropriate amount of Sterile Water for 
Injection, USP (see 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.  


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There are no known incompatibilities between study treatment and polyvinyl chloride 
(PVC), ethyl vinyl acetate (EVA), polyolefin, or polyethylene (PE) bags.  The bag should be 
gently inverted to mix the solution.  The bag must not be shaken; excess agitation may 
cause aggregate formation.  Prior to administration, the reconstituted and diluted drug 
product should be inspected visually for any particulate matter and discoloration.  
The formulation contains no preservative and is intended for single use only; infusion 
solutions should be prepared and transferred using aseptic technique in a biosafety hood.  
Refer to the Pharmacy Manual for more specific instructions on reconstitution and use.
6.12   
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.  
6.13   
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.  
Drug accountability instructions are provided in the Pharmacy Manual.  
Reference Therapy
Please refer to the methotrexate package insert for information regarding the proper storage 
and handling of methotrexate.
Please refer to the bexarotene package insert for information regarding the proper storage 
and handling of bexarotene.


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Report all investigational product events, including complaints and issues, using the 
Investigational Product Complaints and reporting information listed in Section 11.11 in the 
protocol.
The drug supply 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.  Drug supplies will be counted and reconciled at the site before being 
returned.
The investigator must maintain 100% accountability for all study medication received and 
dispensed during his or her entire participation in the study.  Proper drug accountability
includes, but is not limited to:

Continuously monitoring expiration dates if retest date is provided to the investigator

Frequently verifying that actual inventory matches documented inventory

Verifying that the drug accountability log is completed for the drug lot used to 
prepare each dose

Verifying that all containers used are documented accurately on the log

Verifying that required fields are completed accurately and legibly
If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately.
The investigator must maintain a current inventory (drug accountability log) of all study 
medication delivered to the site, inventory at the site, and patients’ use records.  This log 
must accurately reflect the drug accountability of the study medication at all times.  The 
following information will be recorded at a minimum: protocol number and title, name of 
the investigator, site identifier and number, description of the study medication, expiry 
and/or retest date, date and amount dispensed, and the date and amount returned to the site 
by the patient, including the initials of the person dispensing and receiving the study 
medication.  The log should include all required information as a separate entry for each 
patient to whom study medication is dispensed.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its 
designee will perform clinical study material accountability and reconciliation before 


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clinical study materials are returned to the sponsor or its designee for destruction.  The 
investigator will retain the original documentation regarding clinical study material 
accountability, return, and/or destruction, and copies will be sent to the sponsor.
The investigator will be notified of any expiry date or retest date extension of clinical study 
material during the study conduct.  On expiry date notification from the sponsor or designee, 
the site must complete all instructions outlined in the notification, including segregation of 
expired clinical study materials for return to the sponsor or its designee for destruction.  In 
the event of expiry date extension of supplies already at the study site, supplies will be 
relabeled with the new expiry date at the site.  In such cases, the sponsor or its designee will 
prepare additional labels, certificates of analysis, and all necessary documentation for 
completion of the procedure at the sites.
Do not use or destroy the investigational product until you receive documented confirmation 
from Millennium stating the drug may be used or destroyed.
Drug accountability instructions are also provided in the Pharmacy Manual.
7.   
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, good clinical practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines.
7.1   
Study Personnel and Organizations
The contact information for the Millennium project clinician for this study, the central 
laboratory and any additional clinical laboratories, the ICON CRO study team, and IVR 
vendor may be found in the Study Manual.  A full list of investigators is available in the 
sponsor’s investigator database.
7.2   
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians.  If advertisements become 
part of the recruitment strategy, they will be reviewed by the institutional review board 
(IRB)/independent ethics committee (IEC).  It is not envisioned that prisoners (or other 
populations that might be subject to coercion or exploitation) will be enrolled into this study.


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7.3   
Treatment Group Assignments 
Patients are to be stratified by diagnosis: pcALCL or MF.  Patients will be randomized 1:1 
to 1 of 2 treatment arms by interactive voice/web response system (IVRS/IWRS): 

Arm 1: brentuximab vedotin monotherapy:  brentuximab vedotin will be 
administered intravenously over approximately 30 minutes once every 21 days, and 
may continue for up to 16 cycles.

Arm 2: Patients receive either methotrexate PO (5-50 mg PO once weekly dose 
adjustment is guided by patient response and toxicity) or bexarotene (recommended 
total dose of 300 mg/m2 PO once daily with meals) for up to a total of 48 weeks of 
treatment.
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
per local regulations.
7.4.3   
Medical History
During the Screening period, a complete medical history will be compiled for each patient.  
The history will emphasize the background and progress of the patient’s malignancy and 
include a description of prior therapies for it.  In addition, concomitant medications will be 
recorded as specified in Section 7.4.11.
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
Height will be measured only during screening.
7.4.6   
Patient Weight
Weight will be measured as specified in the Schedule of Events.  Dosing with brentuximab 
vedotin 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
(Section 6.1).  
7.4.7   
Vital Signs
Vital sign measurements include blood pressure (determined with the patient in a seated 
position after the patient has been sitting quietly for 5 minutes), heart rate, and body 
temperature.
7.4.8   
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at screening. 
Urine pregnancy tests will be performed prior to dosing on Day 1 of each cycle. Pregnancy 
tests may also be repeated during the study if requested by an IEC/IRB or if required by 
local regulations.  The results of any pregnancy test must be negative before dosing on Day 
1 of all cycles.
7.4.9   
Skin Biopsy
Skin biopsies (at least 2 samples from separate lesions with a minimum of 2 mm diameter 
each for MF, and 1 sample for pcALCL) will be obtained at screening, following the 
mSWAT assessment, to confirm tumor-specific CD30+ expression, and again at the end of 
Cycle 3, and at time of disease progression (EOT or posttreatment follow-up visit).  
7.4.10   
Archived Tissue
If available and consistent with local regulations, tumor tissue collected at the time of 
original diagnosis (unstained slides or a paraffin-embedded block) will be obtained during 
screening after the patient has signed the informed consent form.  The sample may be used 
in the evaluation of a diagnostic test to determine CD30 expression.  


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7.4.11   
Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will 
recorded in the eCRF from screening through 30 days after the last dose of study 
medication.  See Section 6.5 and Section 6.6 for a list of medications and therapies that are 
prohibited and/or allowed during study treatment.
7.4.12   
Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as 
specified in the Schedule of Events.  Refer to Section 10 for details regarding definitions, 
documentation, and reporting of pretreatment events, AEs, and SAEs.  Changes in the 
severity of events relating to peripheral neuropathy will be recorded as described in Section 
10.3. 
7.4.13   
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.
7.4.14   
ECG
A 12-lead electrocardiogram (ECG) will be administered at the time points specified in the 
Schedule of Events.
7.4.15   
Clinical Laboratory Evaluations
Clinical laboratory evaluations must be performed centrally at screening and per the 
Schedule of Events.  For decisions regarding eligibility (values required within 4 days of 
randomization) and treatment, local hematology and chemistry results may be used. Sézary 
cell results must be available from the local lab to determine eligibility and treatment 
decisions.  Handling and shipment of clinical laboratory samples will be outlined in the 
study manual.  
CCI


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Clinical Chemistry, Hematology, and Urinalysis
Blood samples for analysis of the following clinical chemistry and hematological parameters 
and urine samples for urinalysis will be obtained as specified in the Schedule of Events.
Hematology

Hemoglobin

Hematocrit

Platelet count

Leukocytes with differential

Neutrophils (absolute neutrophil count [ANC])
Serum Chemistry

BUN

Creatinine

Bilirubin (total)

Urate

Lactate 
dehydrogenase 
(LDH)

Phosphate

Gamma glutamyl 
transferase (GGT)

Albumin

Alkaline phosphatase
(ALP)

Aspartate 
aminotransferase (AST)

Alanine 
aminotransferase (ALT)

Glucose

Sodium

Potassium

Calcium

Chloride

Carbon dioxide 
(CO2)

Magnesium

Amylase

Lipase
Urinalysis

Turbidity and Color

pH

Specific gravity

Protein

Ketones

Bilirubin

Blood

Nitrite

Urobilinogen

Glucose

Leukocytes
Lipid Panel

Total Cholesterol

HDL

LDL

Triglycerides
Thyroid Panel

TSH

Free T3

Free T4


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Immune Reconstitution Assessments

Lymphocytes counts

Phenotypic T, B, and 
NK cell subsets: 
- CD4+ T cells counts
- CD8+ T cells counts 
- CD8/CD4 ratio
- CD19+ B cells counts

NK cells (CD3−
CD56 CD16+ vs.  
CD3−CD56 CD16-)
Other

Hemoglobin A1C 
7.4.16   
Disease Assessment
A GRS of complete response (CR), partial response (PR), stable disease (SD), progressive 
disease (PD), and relapse will be determined based on sequential tumor burden assessments
of body compartments (skin, lymph nodes, viscera, and blood for MF patients) as further 
described below.  For the purpose of disease assessment in the control arm, a period of 3 
weeks (21 days) is equivalent to 1 cycle.
Response will be determined by a composite assessment of total tumor burden:

Cutaneous disease (mSWAT) (Section 7.4.17.1)

Lymph node involvement (Section 7.4.17.2)

Visceral involvement (Section 7.4.17.2)

Blood (MF patients only) (Section 7.4.17.3)
o
Sézary cells will be enumerated by morphology and immunophenotyping
7.4.17   
Response Assessments
7.4.17.1   Cutaneous Disease Response Assessment
7.4.17.1.1   
mSWAT
The mSWAT assessment tool will be used for MF and pcALCL and will be performed as 
specified in the Schedule of Events.


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The mSWAT score calculation method and skin lesion definitions for MF and pcALCL are 
provided in Table 7-1.  
Table 7-1   
Modified Severity Weighted Assessment Tool
Body Region 
% BSA in 
Body Region
Assessment of Involvement in Patient’s Skin
Patcha
Plaqueb
Tumorc
Head 
7
Neck 
2
Anterior trunk 
13
Arms 
8
Forearms 
6
Hands 
5
Posterior trunk 
13
Buttocks 
5
Thighs 
19
Legs 
14
Feet 
7
Groin 
1
Subtotal of lesion BSA
Weighting factor
x1
x2
x4
Subtotal lesion BSA x
weighting factor
mSWAT score equals summation of each column line.
Abbreviations: BSA = body surface area; mSWAT = modified Severity Weighted Assessment Tool.
a Any size lesion without induration or significant elevation above the surrounding uninvolved skin; 
poikiloderma may be present.  
b Any size lesion that is elevated or indurated; crusting, ulceration, or poikiloderma may be present.
c Any solid or nodular lesion 1 cm in diameter with evidence of deep infiltration in the skin and/or 
vertical growth.
The mSWAT score will be calculated as follows:
   Sum of %TBSA from all body regions affected by patches x severity-weighting factor of 1
+ Sum of %TBSA from all body regions affected by plaques x severity-weighting factor of 2
+ Sum of %TBSA from all body regions affected by tumors x severity-weighting factor of 4
= Total mSWAT (maximum score = 400)


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Figure 7-1 presents the mSWAT % of total body surface area for the 12 main body areas to 
assess disease burden in MF and pcALCL.(60, 61)  The body is divided into 12 regions with 
preassigned % of total body surface area (TBSA) based on methodology used to assess 
burns.(62)  The extent of skin disease is assessed for each region and quantified using the 
patient's palm as a "ruler" to measure the % of TBSA involvement within each region:
Patient's palm with 4 fingers and including the thumb, and measured from wrist to 
fingertips, is approximately 1% of TBSA.
Figure 7-1   
mSWAT % Total Body Surface Area (TBSA) for 12 Main Body Areas


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Table 7-2   
Response in Skin
Response
Definition
Complete response (CR)
100% clearance of skin lesionsa
Partial response (PR)
50%-99% clearance of skin disease from baseline
No new tumors in patients without tumors at baseline (MF)
No new tumors (pcALCL)
Stable disease (SD)
< 25% increase to < 50% clearance in skin disease from baseline
No new tumors in patients without tumors at baseline (MF)
Progressive disease (PD)b
≥25% increase in skin disease from baseline, or
Loss of response: in those with CR or PR, increase of skin score of
greater than the sum of nadir plus 50% baseline score, or
New tumors in patients without tumors at baseline (MF)
Relapse
Any disease recurrence in those with complete response
Response criteria for MF are per Olsen 2011,(41) and for pcALCL per Kempf 2011.(11)
Abbreviations:  CR = complete response; PR = partial response; SD = stable disease; PD = progressive 
disease.
a A biopsy of normal appearing skin is unnecessary to assign a complete response. However, a skin biopsy 
should be performed on a representative area of the skin if there is any question of residual disease 
(persistent erythema or pigmentary change) where otherwise a complete response would exist.  If 
histologic features are suspicious or suggestive of mycosis fungoides/Sézary syndrome, the response 
should be considered a partial response only.
b Whichever criterion occurs first.
7.4.17.1.2   
Photographs 
Each of the designated index lesions (up to a total of 5) and lesions selected for biopsy will 
be serially photographed at screening; before dosing on Day 1 of Cycles 1, 2, and 3; at the 
end of every cycle beginning at Cycle 3 (Days 16 – 21, or prior to dosing on Day 1 of 
subsequent cycles); within 30 days after the last dose of study drug; and at the posttreatment 
follow-up visits. Full body global photographs, including head, trunk, legs, front, back, and 
side, will be taken at the same time points indicated above. Photographs will be uploaded 
for central review, per IRF.
7.4.17.2   Lymph Node and Visceral Evaluation
Lymph nodes and visceral involvement will be assessed by CT scan, and responses are 
defined in Table 7-3 and Table 7-4.


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Table 7-3   
Response in Lymph Nodesa
Response
Definition
CR
All lymph nodes are now ≤1.5 cmb in greatest transverse (long axis) diameter by method 
used to assess lymph nodes at baseline or biopsy negative for lymphoma. In addition, 
lymph nodes that show lymphoma involvement by biopsyc and ≤1.5 cmb in long axis 
diameter and > 1 cm in short axis at baseline, must now be ≤ 1 cm in diameter of the short 
axis or biopsy negative for lymphoma
PR
Cumulative reduction ≥50% of the SPD of each abnormal lymph node at baseline and no 
new lymph node > 1.5 cmb in the diameter of the long axis or > 1.0 cm in the short axis if 
the long axis is 1-1.5 cm diameter
SD
Fails to attain the criteria for CR, PR, and PD
PDd
(1) ≥ 50% increase in SPD from baseline of lymph nodes, or
(2) Any new node > 1.5 cmb in greatest transverse diameter or > 1 cm in the short axis 
diameter if 1-1.5 cm in long axis that is proven to be lymphoma histologicallyc, or
(3) Loss of response: in those with PR (or CR if pcALCL), > 50% increase from nadir in 
SPD of lymph nodes 
Relapse
Any new lymph node > 1.5 cmb in the long axis diameter:
In those with CR (pcALCL)
In those with CR proven to be lymphoma histologicallyc (MF)
Response criteria are per Olsen 2011,(63) Kempf 2011,(11) and Cheson 2007.(64)
Abbreviations: CR = complete response; PR = partial response; SPD = sum of the maximum linear 
dimension (major axis) X longest perpendicular dimension (minor axis); SD = stable disease; PD =
progressive disease.
a Peripheral and central lymph nodes.
b Response criteria are similar for patients with MF and pcALCL. However, per the EORTC, ISCL and 
USCLC consensus recommendations for the treatment of non-MF primary cutaneous CD30-positive 
lymphoproliferative disorders,(11) an abnormal lymph node is considered ≥ 1.5cm and should be 
considered when assessing nodal response in patient with pcALCL. 
c For patients with MF, lymphoma involvement is defined as N3 (ie, partial or complete effacement of 
lymph node architecture by atypical or frankly neoplastic cells)
d Whichever criterion occurs first.
Table 7-4   
Response in Viscera
Response
Definition
CR
Liver or spleen or any organ considered involved at baseline should not be enlarged on 
physical exam and should be considered normal by imaging; no nodules should be present 
on imaging of liver or spleen. Any posttreatment mass must be determined by biopsy to be 
negative for lymphoma
PR
≥ 50% regression in any splenic or liver nodules, or in measureable disease (SPD) in any 
organs abnormal at baseline, No increase in size of liver or spleen and no new sites of 
involvement
SD
Fails to attain the criteria for CR, PR, or PD
PDa
(1) > 50% increase in size (SPD) of any organs involved at baseline, or
(2) New organ involvement, or
(3) Loss of response: in those with PR (or CR if pcALCL), > 50% increase from nadir in 
the size (SPD) of any previous organ involvement 


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Table 7-4   
Response in Viscera
Response
Definition
Relapse
New organ involvement in those with CR
Response criteria are per Olsen 2011(41) and Kempf 2011.(11)
Abbreviations: CR = complete response; PR = partial response; SPD = sum of the maximum linear 
dimension (major axis) X longest perpendicular dimension (minor axis); SD = stable disease; PD = 
progressive disease.
a Whichever criterion occurs first.
Contrast CT scans of the neck, chest, abdomen, and pelvis will be obtained at screening and 
during the study or if clinically indicated as specified in the Schedule of Events and 
Section 4.1.  All CT scans will be taken with IV contrast (unless contraindicated) and they 
will be of diagnostic quality.  Specific disease sites that cannot be adequately imaged by CT 
may be documented by MRI.  FDG-PET scans will be performed at screening only, unless 
clinically indicated.  Anatomical measurements (summed across target lesions) will be 
collected at baseline and each subsequent evaluation using an imaging modality consistent 
with that used at screening.  
Objective assessments will be performed at each time point as described in the Schedule of 
Events.  When possible, the same qualified physician will interpret results to reduce 
variability.  Radiographic images will be maintained at the site, and test results and 
physician’s findings will be filed in patient source documents.  Radiographic studies will be 
reviewed by IRF.
7.4.17.3   Blood Assessment
MF involvement in blood is defined in Section 15.4.  Sézary Syndrome (SS) is defined as 
meeting T4 plus B2 criteria, Section 15.4.(41)


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Table 7-5   
Response in Blood
Responsea
Definition
CRb
B0
PRc
> 50% decrease in quantitative measurements of blood tumor burden from baseline in 
those with high tumor burden at baseline (B2)
SD
Fails to attain criteria for CR, PR, or PD
PDd
B0 to B2
or
> 50% increase from baseline and at least 5,000 neoplastic cells/µL
or
Loss of response: in those with PR who were originally B2 at baseline, > 50% increase 
from nadir and at least 5,000 neoplastic cells/µL
Relapse
Increase of neoplastic blood lymphocytes to ≥ B1 in those with CR
Abbreviations: CR = complete response; PR = partial response; SD = stable disease; PD = progressive 
disease.
a As determined by absolute numbers of neoplastic cells/µL.
b If a bone marrow biopsy was performed at baseline and determined to unequivocally be indicative of 
lymphomatous involvement, then to confirm a global CR where blood assessment now meets criteria for 
B0, a repeat bone marrow biopsy must show no residual disease or the response should be considered a 
PR only.
c There is no PR in those with B1 disease at baseline as the difference within the range of neoplastic cells 
that define B1 is not considered significant and should not affect determination of global objective 
response.
d Whichever criterion occurs first.
7.4.17.4   Global Response Score
Global response score (GRS) is an assessment whereby each component of the TNM(B)
staging (skin, nodes, viscera, and blood for MF), has been given its own definition of 
response.  Due to the primacy of the response in the skin in CTCL, no patient with a global 
objective response should have less than a PR in the skin.  The global response score 
definition is provided in Table 7-6.
Response to treatment (CR, PR, SD, PD, relapse) will be monitored on a continual basis.  
For all treated patients, GRS will be assessed at the end of Cycles 3, 6, 9, 12, and 15 (Days 
16-21 or before dosing on Day 1 of the subsequent cycle); at EOT; and then every 12 weeks 
for a minimum of 24 months, and then every 6 months; or until disease progression or study 
closure.  GRS will be determined based upon the most recent disease assessments for each 
component (mSWAT, CT scans, Sezary cell count for MF patients).  For patients without 
baseline nodal/visceral involvement, the schedule for obtaining CT scans will likely not 
correlate with the timing of GRS determinations; thus, the nodal/visceral response 


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component should be based upon the most recent CT scan findings prior to the GRS 
assessment time point.  Additional unscheduled GRS determinations may occur following a 
change in response in skin or at the time of a CT scan.  Relapse will be categorized in the 
study endpoints definition as recurrent disease in patients with complete response.
Table 7-6   
Global Response Score
Global Score
Definition
Skin
Nodes
Blood
Viscera
CR
Complete disappearance of all 
clinical evidence of disease
CR
All categories have CR/NI
PR
Regression of measurable 
disease 
CR
All categories do not have a CR/NI and 
no category has a PD 
PR
No category has a PD and if any other 
category involved at baseline, at least 
one has a CR or PR 
SD
Failure to attain CR, PR or PD 
representative of all disease
PR
No category has a PD and if any other 
category involved at baseline, no CR or 
PR in any
SD
CR/NI,PR,SD in any category and no 
category has a PD 
PD
Progressive disease
PD in any category
Relapse
Recurrence disease in prior CR
Relapse in any category 
Abbreviations:  CR = complete response; NI = noninvolved; PR = partial response; PD = progressive 
disease; SD = stable disease.
For the purpose of this study, patients with B1 involvement at baseline (but no node or viscera), who reach a 
PR in skin and stable B1, will be considered to have reached PR for the GRS.
7.4.17.5   Patient-Reported Outcomes and Health-Related Quality of Life 
Assessments
EQ-5D, FACT-G, and Skindex-29 questionnaires will be employed for health-related 
quality of life (HRQoL) assessment from the patient’s perspective at 3 spectrums:  
comparability across the broadest health-related conditions, cancer-specific, and 
dermatology-specific, respectively.  Patients will be requested to complete each of these 
3 questionnaires at the time of clinical visits according to the Schedule of Events.  If patients 
are not required to return for a visit, questionnaires (except for visual analog scales) will be 
completed over the telephone or by mail.

EQ-5D:  previously known as the EuroQol instrument, EQ-5D is a 5-item generic 
HRQoL measure developed by a group of largely European-based researchers.  It is 
intended to be a simple, self-administered questionnaire that not only contains a 


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descriptive health state classification system but also is capable of generating a 
composite score or index reflecting the preference value associated with a given 
health state.  EQ-5D consists of the EQ-5D descriptive system and the EQ visual 
analogue scale.

FACT-G: the Functional Assessment of Cancer Therapy General Questionnaire is a 
27-item general cancer quality-of-life instrument for evaluating patients receiving 
cancer treatment.  FACT-G (now in version 4) incorporates a 7-day recall period and 
contains 4 primary subscales:  physical well-being, social/family well-being, 
emotional well-being, and functional well-being.  It is considered appropriate for use 
with patients with any form of cancer and demonstrated validity, reliability, and 
sensitivity to change.(65)  The total FACT-G score is obtained by summing individual 
subscale scores.  Higher scores for the total scales and subscales indicate better 
quality of life.  Information on US population norms for the FACT-G is available at 
facit.org.  FACT-G is chosen based on its prior successful use in pivotal and non-
pivotal clinical trials (NCT00050999 and NCT00724061) in support of treatments 
for CTCL.

Skindex-29: Skindex-29 is a 29-item dermatology-specific HRQoL questionnaire.  
Because the skin lesions presented among CTCL patients may impact their quality of 
life widely, there is a need to quantify the quality of life impact of brentuximab 
vedotin along with its effect on the lesions.  Skindex-29 has been extensively studied 
in different populations who have skin diseases.(66, 67, 68, 69, 70)  Skindex-29 has been 
used to assess HRQoL in patients with CTCL.(71)  Good to excellent conceptual 
validity, construct validity, internal consistency, and retest reliability have been 
reported for this instrument.(72)  A total of 29 items are combined to form 3 domains:  
symptoms, emotions, and functioning.  The domain scores and an overall score are 
expressed on a 100-point scale, with higher scores indicating lower levels of 
HRQoL.  Skindex-29 elects a 28-day recall period.  Completion requires 
approximately 5 to 10 minutes.
7.4.18   
Pharmacokinetic Measurements
Pharmacokinetic measurements will be made in all brentuximab vedotin-treated patients.  
Pharmacokinetic parameters to be estimated may include, but are not limited to, the 
maximum concentration for MMAE (Cmax) and concentration at the end of infusion for 
brentuximab vedotin (Ceoi).  Population pharmacokinetics methodologies will be used to 


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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 7.4.19).
Table 7-7 presents the sample collection time points.  Refer to the Research Specimen 
Manual for information on collection, processing, storage, and shipment of samples.
Table 7-7   
Pharmacokinetic Sampling Time Points
Cycle
Study Day
Time
Window
Relative Time
PK
ATA
Arm 1 (All patients randomized to receive brentuximab vedotin)
1, 3, 5, 7, 9,
11, 13, 15
1
Predose
Within prior 4 hrs
Start of SGN-35 infusion
X
X
30 mins 
Postdose
± 25 mins
End of SGN-35 infusion
X
EOT Visit
n/a
n/a
n/a
n/a
X
X
Group Aa (half of patients randomized to receive brentuximab vedotin)
1 and 3
2
24 hr
± 4 hr
Start of SGN-35 infusion
X
4
72 hr
± 4 hr
Start of SGN-35 infusion
X
Group Ba (half of patients randomized to receive brentuximab vedotin)
1 and 3
3
48 hr
± 4 hr
Start of SGN-35 infusion
X
5
96 hr
± 4 hr
Start of SGN-35 infusion
X
Abbreviations:  ATA = antitherapeutic antibodies; EOI = end of infusion; EOT = end of treatment; 
hr = hour; min = minutes; n/a = not applicable; PK = pharmacokinetic.
a Patients randomized to brentuximab vedotin will be assigned to Group A or B at the time of 
randomization for PK sampling.
7.4.19   
Immunogenicity Measurements
Blood (5 mL) for serum samples will be collected as specified in the Schedule of Events to 
evaluate ATA and neutralizing ATA as a safety assessment in all patients receiving 
brentuximab vedotin.  On dosing days, the blood samples for ATA and neutralizing ATA 
assessment must be collected before dosing.  The maximum volume of blood collected for 
immunogenicity will be 5 mL per cycle.  Neutralizing ATA assessment will be performed
only for ATA-positive samples.


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7.4.20   
Pharmacodynamic Measurements
7.4.20.1   Serum Biomarker Measurements
7.4.21   
Tumor Biopsy for Baseline CD30 Expression and Biomarker Measurements
For enrollment, patients will be required to undergo skin biopsies, (a total of at least 
2 samples from separate lesions for MF, and 1 sample for pcALCL) during screening for 
confirmation of CD30 expression. Samples may be obtained up to 28 days prior to the first 
dose of brentuximab vedotin; in the event that a patient rescreens, repeat skin biopsies 
should be discussed with the sponsor, project clinician, or designee.  CD30 positivity is 
defined as ≥10% target lymphoid cells demonstrating membrane, cytoplasmic, and/or Golgi 
staining pattern for CD30 at any intensity above background staining as noted on the 
corresponding negative control.  A minimum of 10% staining in at least 1 sample is 
required.  Percent positivity should be determined using percent neoplastic cells staining 
first. If neoplastic cells cannot be easily distinguished from non-neoplastic, then percent 
positivity should be determined using percent total lymphocytes staining.  In addition, 
biomarkers implicated in sensitivity or resistance to vinca alkyloids and taxanes such as p53, 
beta 3 tubulin, and ABCC transporters may be examined. In order to assess whether 
treatment with brentuximab vedotin affects the overall expression of CD30 leading to a 
decrease in response, patients will have a second biopsy at the Cycle 3 evaluation and again 
at the time of relapse (EOT or during the posttreatment follow-up period) and will be 
assayed for changes from baseline in CD30 expression. If possible, repeat skin biopsies 
should be taken from the same lesions as the samples obtained at screening.
Tissue samples from skin biopsies may be used in the evaluation of the Ventana CD30 (Ber-
H2) assay.  This assay will be used to determine CD30 expression in this study, and is also 
being evaluated as a diagnostic test by Ventana.  Study results may be used to support the 
use of this assay as a diagnostic test for brentuximab vedotin therapy in CTCL.  
Additionally, tissue samples from skin biopsies may be tested for other biomarkers and 
genomic markers of brentuximab vedotin sensitivity and resistance.
CCI


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7.4.22   
Germline DNA Polymorphism Assessment
7.4.23   
Utility Measurement
7.4.24   
Healthcare Utilization Data Collection
7.4.25   
Cost Assessment
The cost of treatment in each arm of the study will be assessed through the collection of HU 
in each arm in terms of healthcare utilization frequency.  Valuation of the costs will be 
undertaken separately.
7.5   
Completion of Treatment
Patients will be considered to have completed study treatment if they meet any of the 
following criteria:
CCI
CCI
CCI


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
Complete up to 16 cycles of treatment with brentuximab vedotin (48 weeks)

Complete up to 48 weeks of treatment with reference therapy
7.6   
Completion of Study
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, or until study closure.  The study is expected to close approximately 
5 years after the first patient starts study treatment.
7.7   
Discontinuation of Treatment With Study Drug, and Patient Replacement
Study drug should be discontinued for patients meeting any of the following criteria:

Completed 16 cycles of brentuximab vedotin therapy or 48 weeks of reference 
therapy

Progressive disease
The reason justifying study treatment withdrawal should be documented in the eCRF.
Patients who discontinue from study treatment will remain on study for follow-up unless 
they withdraw consent for the follow-up phase of the study.  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. Additional patients may be enrolled to ensure an adequate number of 
evaluable patients in the study, ie, approximately 124 patients in the ITT population.
Treatment with study drug may also be discontinued for any of the following reasons: 

Adverse event

Protocol violation

Study terminated by sponsor

Withdrawal by subject

Lost to follow-up


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
Other
Once study drug has been discontinued, all study procedures outlined for the End of 
Treatment visit will be completed as specified in the Schedule of Events.  The primary 
reason for study drug discontinuation will be recorded on the eCRF.
A “real-time” independent review of disease status will be performed at the time of 
treatment discontinuation for all patients.  In the event of suspected progressive disease,
investigators will be encouraged to await the results of the independent review that may 
indicate or confirm progression in GRS before recommending to the patient any treatment or 
management options, such as discontinuation from study drug treatment to pursue 
alternative anticancer therapy.
Note that some patients may discontinue study drug for reasons other than progressive 
disease before completing the full treatment course; these patients will remain in the study 
for posttreatment assessments as outlined in the Schedule of Events.
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 if a patient is withdrawn from study treatment 
or from the study.  The reason(s) for withdrawal should be documented in the patient’s 
medical records and eCRF.  The investigators must make every reasonable effort to keep 
each patient on the study until all planned treatments and assessments have been performed.  
If a patient withdraws from study treatment, every attempt should be made to follow the 


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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.
8.   
STATISTICAL AND QUANTITATIVE ANALYSES
8.1   
Statistical Methods
The statistical methods are outlined below.  Details will be provided in the statistical 
analysis plan (SAP).
8.1.1   
Determination of Sample Size
Approximately 124 patients (approximately 62 patients per treatment arm) will be 
randomized to the study (124 patients are targeted for the ITT population).  The sample size 
was calculated to provide 90% power to detect a 30% improvement in ORR, lasting at least 
4 months, in the brentuximab vedotin treatment group, assuming ORRs lasting at least 4 
months for brentuximab vedotin treatment group and for the MTX or bexarotene alone 
treatment group are 70% and 40%, respectively.  This calculation is based on a two-sided 2 
test with significance level of = 0.05, and a 10% dropout rate using nQuery Advisor 7.0.  
A minimum of 30 patients (15 per treatment arm) with pcALCL will be included in the 
study. This is not based on statistical consideration.
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 Arm 1: brentuximab vedotin or Arm 2:
physician’s choice of methotrexate or bexarotene using an Interactive Voice 


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Response/Interactive Web Response System (IVRS/IWRS), stratified by baseline disease
diagnosis (pcALCL or MF).
8.1.3   
Populations for Analysis
The populations used for analysis will include the following:

The Safety population will include randomized patients who receive at least 1 dose 
of study drug.  All patients in the safety population will be analyzed according to the 
actual treatment received.  Patients receiving any dose of brentuximab vedotin will 
be grouped into the study drug group for the purposes of safety reporting.

The intent-to-treat (ITT) population will include all patients identified as CD30 
positive by the Ventana CD30 (Ber-H2) assay and 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.

The all-enrolled population will include all patients randomized to treatment. All 
patients in the all-enrolled population will be analyzed according to the treatment 
they were randomized to receive and not according to what they actually received, if 
different.

The per-protocol (PP) population will include a subset of ITT patients who do not 
have 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 

The response-evaluable population will include a subset of the ITT patients with 
measurable disease at baseline and with at least 1 post-baseline response assessment.
The response-evaluable population will be used for the supplemental analyses of CR 
rate, objective response rate, time to response, and duration of response, as needed.

The PK population will include 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.

The pharmacodynamics population will include patients with sufficient dosing and 
sufficient pharmacodynamics data to reliably measure pharmacodynamics 
parameters will be used for pharmacodynamics analyses.


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8.1.4   
Procedures for Handling Missing, Unused, and Spurious Data
All available efficacy and safety data will be included in data listings and tabulations.  The 
relevance of missing sample data will be assessed.  Details on any sensitivity analyses and 
data handling details regarding issues such as missing data will be discussed in the SAP.
Data that are potentially spurious or erroneous will be examined according to standard data 
management operating procedures.
8.1.5   
Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized, including gender, age, race, 
weight, height, primary diagnosis, and other parameters as appropriate.  No inferential 
statistics will be carried out.
8.1.6   
Efficacy Analysis
All primary efficacy evaluations for the primary and key secondary efficacy endpoints will 
be conducted using the ITT population.  In addition, sensitivity analysis may be performed 
using the all-enrolled population, per-protocol population, or response-evaluable population.
8.1.6.1   Analysis of Primary Efficacy Endpoints
The primary endpoint, ORR4, proportion of patients achieving an objective response that 
lasts at least 4 months, per IRF, will be analyzed using a Cochran-Mantel-Haenszel test 
stratified by baseline disease diagnosis (pcALCL or MF) based on ITT population.  Details 
are described in the SAP.  The 95% confidence interval of the difference in ORR4 between 
the 2 treatments will be provided.
The primary analysis will be based on the ITT population.  The same analysis for the 
primary endpoint will be performed using the all-enrolled population, and PP population.  
Sensitivity analyses will be performed for ORR per IRF and ORR per investigator’s 
assessment as well as objective response that lasts at least 4 months defined by the response 
criteria used for romidespin approval and published by Whittaker 2010.(21)
8.1.6.2   Analyses of Secondary Efficacy Endpoints
CR rate, progression-free survival, and changes in symptom domain per Skindex-29 
assessment tool are designated as key secondary endpoints.  A fixed sequential testing 
procedure will be used to test between the primary endpoint and the key secondary 


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endpoints; that is, the key secondary endpoints will be tested only if the primary endpoint is 
statistically significant.  To test the key secondary endpoints, a weighted Holm’s procedure 
will be used. Details of the testing procedure will be fully described in the SAP.
Comparison of the CR rates between the 2 treatment groups will be conducted using the 
stratified Cochran-Mantel-Haenszel test.  The 95% confidence interval of the difference of 
the response rates between the 2 treatments will also be provided.  
PFS is defined as the time from randomization until disease progression or death due to any 
cause, whichever occurs first.  Detailed rules of handling missing assessments and censoring 
for the analysis of PFS are described in the SAP.  Stratified log-rank test statistics will be 
used to compare PFS 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 PFS for each treatment.  Median times (if 
estimable), along with the 2-sided 95% CIs will be presented.
Comparison of symptom reductions between the 2 treatment arms will be conducted using 
the ANCOVA model controlling for baseline covariates. Symptom reduction is defined for 
each patient as the maximum reduction from baseline. A longitudinal model will be used for 
the sensitivity analysis. Missing data will be imputed with mean if there is no more than 1 
missing item. Sensitivity analysis will be performed to evaluate impacts of missing data 
imputation.
Other secondary efficacy endpoints include EFS, duration of response, and duration of skin 
response.  EFS is defined as the time from randomization until any cause of treatment 
failure: disease progression, discontinuation of treatment for any reason, or death due to any 
cause, whichever occurs first.  Duration of response in subjects with confirmed response is 
the time between first documentation of response and disease progression.  Duration of skin 
response is the time between the first skin response to progressive disease in skin.  Stratified 
log-rank test statistics will be used to compare EFS 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 EFS for each 
treatment.  Median times (if estimable), along with the 2-sided 95% CIs will be presented.  
Duration of response and duration of skin response will be summarized descriptively using 
the Kaplan-Meier method.  


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8.1.7   
Analyses of Patient-Reported Outcomes and Health Economics 
Analyses of patient reported outcomes and health economics will be performed using the
ITT population.
8.1.7.1   
Patient-Reported Outcomes Analysis
Patient-reported outcome assessments using the FACT-G and Skindex-29 subscale surveys 
will be analyzed to determine if response to therapy and side effects of therapy are 
accompanied by measurable changes in PROs.  The analysis will be performed on summary 
scores as well as on subscales with specific analytical methods outlined in a formal 
statistical analysis plan developed prior to database lock.
The analysis of symptom reduction (Skindex-29) is described in Section 8.1.6.2.
Other subscales of the Skindex-29 questions will be summarized descriptively.
Global score and subscales of FACT-G will be summarized descriptively. Investigation of 
missing data patterns and imputation, if appropriate, will be discussed in statistical analysis 
plan.
8.1.7.2  
Health Economics Analysis Using Healthcare Utilization and Utility
8.1.8   
Pharmacokinetics/Pharmacodynamics/Biomarkers
8.1.8.1   
Pharmacokinetic Analysis
The pharmacokinetics of the antibody drug-conjugate (brentuximab vedotin) and 
unconjugated drug (MMAE) will be derived from serum and plasma concentrations
(respectively) versus time data for all patients who met 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 pharmacokinetic analysis program.  
Exploratory efficacy PK, and if possible, PK-pharmacodynamic relationship, will be 
determined.
8.1.8.2   
Immunogenicity Analysis
All patients who were administered at least 1 dose of brentuximab vedotin will be evaluated 
for antitherapeutic antibody (ATA) development.  A list/table of ATA status will be 
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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.
8.1.8.3   
Pharmacodynamic Analysis
8.1.8.4   
Biomarker Analysis
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, ECOG performance status, and clinical laboratory 
results using the safety population.  Exposure to study drug 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 study drug will be tabulated. Adverse events will be 
tabulated according to the Medical Dictionary for Regulatory Activities (MedDRA) and will 
include the following categories: 
∀
TEAEs
∀
Study drug-related TEAEs
∀
Grade 3 or higher TEAEs
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
Grade 3 or higher study drug-related TEAEs

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 study drug discontinuation will be 
provided.
Descriptive statistics for both the actual values and change from the baseline assessment 
values of the clinical laboratory parameters (hematology and chemistry) will be presented 
for all scheduled measurements over time.  Mean laboratory values over time will be plotted 
for key laboratory parameters.  Shift tables for laboratory parameters will be generated 
based on changes in NCI CTCAE grade from the baseline assessment to the worst 
postbaseline value.
Descriptive statistics for the actual values (and/or the changes from the baseline assessment) 
of vital signs over time will be tabulated by scheduled time point.  
Eastern Cooperative Oncology Group performance status and change from baseline will be 
summarized.  Shifts from baseline to the worst postbaseline score will be tabulated by treatment 
group.  Patients who have ECOG performance scores that worsen postbaseline compared to 
baseline will be listed with other pertinent patient information.
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.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities 
and further define the safety profile of study drug.
9.   
STUDY COMMITTEES
9.1   
Independent Data Monitoring Committee
An Independent Data Monitoring Committee (IDMC) will be established to review safety 
data according to a pre-specified IDMC charter.  The first formal safety review will occur 


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after approximately 30 patients have been randomized in total and received at least 1 cycle 
of study treatment, or 6 months after the first patient is randomized (whichever comes first).  
Thereafter, 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 should 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 
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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, Version 4.03, effective date 14 June 2010.(42) 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 less than 1,000/mm3 to 500/mm3 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 or designee (contact information provided 
below).  This should be done by faxing the SAE Form within 24 hours after becoming aware 
of the event. The SAE Form, created specifically by Millennium, will be provided to each 
clinical study site. A sample of the SAE Form may be found in the Study Manual. Follow-
up information on the SAE or serious pretreatment event may be requested by the 
Millennium Department of Pharmacovigilance or designee. SAE report information must be 
consistent with the data provided on the eCRF.
SAE Reporting Contact Information
Planned hospital admissions or surgical procedures for an illness or disease that existed 
before the patient was enrolled in the trial are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the trial (eg, surgery was performed earlier or 
later than planned).
For both serious and nonserious AEs, the investigator must determine both the intensity of 
the event and the relationship of the event to study drug administration.  For serious 
pretreatment events, the investigator must determine both the intensity of the event and the 
relationship of the event to study procedures.
Intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010.(74)  The criteria are provided in the 
Study Manual and also are available online at http://ctep.cancer.gov/reporting/ctc.html.
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Relationship to study drug administration will be determined by the investigator responding 
yes or no to this question:  Is there a reasonable possibility that the AE is associated with the 
study drug?
10.3   
Monitoring of Adverse Events and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:

AEs will be reported from the first dose of study drug through 30 days after 
administration of the last dose of study drug.  All events relating to peripheral 
neuropathy regardless of seriousness will be followed for all changes in severity until 
resolution to baseline or study closure, whichever occurs first, and recorded in the 
eCRF.

Serious pretreatment events will be reported to the Millennium Department of 
Pharmacovigilance or designee from the time of the signing of the informed consent 
form (ICF) up to first dose of study drug, but will not be recorded in the eCRF.

Related and unrelated SAEs will be reported to the Millennium Department of 
Pharmacovigilance or designee from the first dose of study drug through 30 days 
after administration of the last dose of study drug and recorded in the eCRF.  After 
this period only related SAEs must be reported to the Millennium Department of 
Pharmacovigilance or designee.  SAEs should be monitored until they are resolved 
or are clearly determined to be due to a patient’s stable or chronic condition or 
intercurrent illness(es).  
10.4   
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study, she must inform the investigator immediately and permanently discontinue study 
drug.  The sponsor must also be contacted immediately by faxing a completed Pregnancy 
Form to the Millennium Department of Pharmacovigilance or designee (see Section 10.2).  
The pregnancy must be followed for the final pregnancy outcome.
If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, the sponsor must also be contacted immediately by faxing a 
completed Pregnancy Form to the Millennium Department of Pharmacovigilance or 
designee (see Section 10.2).  Every effort should be made to follow the pregnancy for the 
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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 
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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 the study drug at the trial site is the responsibility of the investigator.  
Drug accountability records indicating the drug’s delivery date to the site, inventory at the 
site, use by each patient, and amount returned to 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 
 
see below) and report the event.  Whenever possible, the associated product 
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should be maintained in accordance with the label instructions pending further guidance 
from a Millennium quality representative.
A medication error is a preventable event that involves an identifiable patient and that leads 
to inappropriate medication use, which may result in patient harm.  While overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not.  
Individuals who identify a potential medication error situation should immediately contact 
 (see below) and report the event.
For Product Complaints or Medication Errors
Product complaints and medication errors in and of themselves are not AEs.  If a product 
complaint or medication error results in an SAE, an SAE form should be completed and sent 
to the Millennium Department of Pharmacovigilance or designee (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
∀
Insufficient, incomplete, and/or unevaluable data
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
Plans to modify, suspend or discontinue the development of the study drug
Should the study be closed prematurely, the site will no longer be able to access the EDC 
application, will not have a right to use the EDC application, and will cease using the 
password or access materials once their participation in the study has concluded.  In the 
event that any access devices for the EDC application have been provided, these will be 
returned to Millennium once the site’s participation in the study has concluded.
Within 15 days of premature closure, Millennium must notify the competent authorities and 
IECs of any member state where the study is being conducted, providing the reasons for 
study closure.  
11.13   Record Retention
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s).  Records will be retained for at least 2 years after the last 
marketing application approval or 2 years after formal discontinuation of the clinical 
development of the investigational product or according to applicable regulatory 
requirement(s).  If the investigator withdraws from the responsibility of keeping the study 
records, custody must be transferred to a person willing to accept the responsibility and 
Millennium notified.  
12.   
USE OF INFORMATION
All information regarding brentuximab vedotin supplied by Millennium to the investigator is 
privileged and confidential information.  The investigator agrees to use this information to 
accomplish the study and will not use it for other purposes without consent from 
Millennium.  It is understood that there is an obligation to provide Millennium with 
complete data obtained during the study.  The information obtained from the clinical study
will be used toward the development of brentuximab vedotin and may be disclosed to 
regulatory authority(ies), other investigators, corporate partners, or consultants as required.
Upon completion of the clinical study and evaluation of results by Millennium, the hospital 
or institution and/or investigator may publish or disclose the clinical trial results pursuant to 
the terms contained in the applicable Clinical Trial Agreement.


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It is anticipated that the results of this study will be presented at scientific meetings and/or 
published in a peer-reviewed scientific or medical journal.  A Publications Group 
comprising Millennium employees and study investigators will be formed to oversee the 
publication of the study results, which will reflect the experience of all participating study 
centers.  Subsequently, individual investigators may publish results from the study in 
compliance with their agreements with Millennium.
A prepublication manuscript or abstract is to be provided to Millennium a minimum of 
30 days before the intended submission date of the manuscript or abstract to a publisher.  
Within 30 days after receipt by Millennium of the notification, Millennium shall inform the
study centers whether it has objections to the publication for reasons including, but not 
limited to, those defined 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 C25001 Amendment 5:  A Randomized, Open-Label, Phase 3 Trial of 
brentuximab vedotin (SGN-35) Versus Physician's Choice (Methotrexate or Bexarotene) in 
Patients With CD30-Positive Cutaneous T-Cell Lymphoma
I agree to conduct the study as detailed herein and in compliance with International 
Conference on Harmonisation Guidelines for Good Clinical Practice and applicable 
regulatory requirements and to inform all who assist me in the conduct of this study of their 
responsibilities and obligations.
Principal investigator printed name
Principal investigator signature
Date
Investigational site or name of institution and 
location (printed)


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Zinzani PL, Baliva G, Magagnoli M, Bendandi M, Modugno G, Gherlinzoni F, et al. 
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25.
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Zackheim HS, Epstein EH, Jr. Low-dose methotrexate for the Sezary syndrome. 
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a review of new discoveries and treatments. Curr Treat Options Oncol 
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28.
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Carretero-Margolis CD, Fivenson DP. A complete and durable response to 
denileukin diftitox in a patient with mycosis fungoides. Journal of the American 
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30.
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Jidar K, Ingen-Housz-Oro S, Beylot-Barry M, Paul C, Chaoui D, Sigal-Grinberg M, 
et al. Gemcitabine treatment in cutaneous T-cell lymphoma: a multicentre study of 
23 cases. British Journal of Dermatology 2009;161(3):660-3.


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Marchi E, Alinari L, Tani M, Stefoni V, Pimpinelli N, Berti E, et al. Gemcitabine as 
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36.
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Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous 
T-cell lymphoma: multinational phase II-III trial results. J Clin Oncol 
2001;19(9):2456-71.
37.
Zackheim HS, Kashani-Sabet M, McMillan A. Low-dose methotrexate to treat 
mycosis fungoides: a retrospective study in 69 patients. Journal of the American 
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38.
Whittaker SJ, Marsden JR, Spittle M, Russell Jones R, British Association of D, 
Group UKCL. Joint British Association of Dermatologists and U.K. Cutaneous 
Lymphoma Group guidelines for the management of primary cutaneous T-cell 
lymphomas. British Journal of Dermatology 2003;149(6):1095-1107.
39.
Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL, et al. 
Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J 
Med 2010;363(19):1812-21.
40.
Brew BJ, Davies NW, Cinque P, Clifford DB, Nath A. Progressive multifocal 
leukoencephalopathy and other forms of JC virus disease. Nature Reviews 
Neuroscience 2010;6(12):667-79.
41.
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End Points and Response Criteria in Mycosis Fungoides and Sezary Syndrome: A 
Consensus Statement of the International Society for Cutaneous Lymphomas, the 
United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma 
Task Force of the European Organisation for Research and Treatment of Cancer. J 
Clin Oncol 2011.
42.
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.
43.
Assaf C, Bagot M, Dummer R, Duvic M, Gniadecki R, Knobler R, et al. Minimizing 
adverse side-effects of oral bexarotene in cutaneous T-cell lymphoma: an expert 
opinion. British Journal of Dermatology 2006;155(2):261-6.
44.
Dummer R. Emerging drugs in cutaneous T-cell lymphomas. Expert Opinion on 
Emerging Drugs 2005;10(2):381-92.
45.
Trautinger F, Knobler R, Willemze R, Peris K, Stadler R, Laroche L, et al. EORTC 
consensus recommendations for the treatment of mycosis fungoides/S&#x00E9;zary 
syndrome. European Journal of Cancer 2006;42(8):1014-30.


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46.
Duvic M, Martin AG, Kim Y, Olsen E, Wood GS, Crowley CA, et al. Phase 2 and 3 
clinical trial of oral bexarotene (Targretin capsules) for the treatment of refractory or 
persistent early-stage cutaneous T-cell lymphoma. Archives of Dermatology 
2001;137(5):581-93.
47.
Sherman SI, Gopal J, Haugen BR, Chiu AC, Whaley K, Nowlakha P, et al. Central 
hypothyroidism associated with retinoid X receptor-selective ligands. New England 
Journal of Medicine 1999;340(14):1075-9.
48.
Haugen BR, Brown NS, Wood WM, Gordon DF, Ridgway EC. The thyrotrope-
restricted isoform of the retinoid-X receptor-gamma1 mediates 9-cis-retinoic acid 
suppression of thyrotropin-beta promoter activity. Molecular Endocrinology 
1997;11(4):481-9.
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coronary heart disease in clinical practice: recommendations of the Second Joint 
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1998;140(2):199-270.
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Executive Summary of The Third Report of The National Cholesterol Education 
Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High 
Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285(19):2486-
97.
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National Institutes of Health, National Heart, Lung, and Blood Institute; National 
Cholesterol Education Program. NIH Publication No. 02-5215. Third Report of the 
National Cholesterol Education Program (NCEP) Expert Panel on Detection, 
Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment 
Panel III):  Final Report.  September 2002.
52.
Talpur R, Ward S, Apisarnthanarax N, Breuer-Mcham J, Duvic M. Optimizing 
bexarotene therapy for cutaneous T-cell lymphoma. Journal of the American 
Academy of Dermatology 2002;47(5):672-84.
53.
Hu FB. The Mediterranean diet and mortality--olive oil and beyond. N Engl J Med 
2003;348(26):2595-6.
54.
Jenkins DJ, Kendall CW, Marchie A, Faulkner D, Vidgen E, Lapsley KG, et al. The 
effect of combining plant sterols, soy protein, viscous fibers, and almonds in treating 
hypercholesterolemia. Metabolism: Clinical & Experimental 2003;52(11):1478-83.
55.
Sherman SI. Etiology, diagnosis, and treatment recommendations for central 
hypothyroidism associated with bexarotene therapy for cutaneous T-cell lymphoma. 
Clinical Lymphoma 2003;3(4):249-52.
56.
Knopp RH. Drug treatment of lipid disorders. New England Journal of Medicine 
1999;341(7):498-511.


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combination treatment in the management of hypercholesterolaemia in patients with 
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59.
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the treatment of combined hyperlipidemia. American Journal of Cardiology 
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61.
Mann B, Johnson J, He K, Sridhara R, Farrell A, Dagher R, et al. Utility of 
photography to confirm skin lesion response assessed using a severity weighted 
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62.
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End Points and Response Criteria in Mycosis Fungoides and Sezary Syndrome: A 
Consensus Statement of the International Society for Cutaneous Lymphomas, the 
United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma 
Task Force of the European Organisation for Research and Treatment of Cancer. 
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Revised response criteria for malignant lymphoma. Journal of Clinical Oncology 
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validity and reliability of the Skindex-29: an Italian study on 2,242 dermatological 
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Augustin M, Wenninger K, Amon U, Schroth MJ, x00Fc, ster W, et al. German 
adaptation of the Skindex-29 questionnaire on quality of life in dermatology: 
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Nijsten TE, Sampogna F, Chren MM, Abeni DD. Testing and reducing skindex-29 
using Rasch analysis: Skindex-17. Journal of Investigative Dermatology 
2006;126(6):1244-50.
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Prinsen CA, Lindeboom R, Sprangers MA, Legierse CM, de Korte J. Health-related 
quality of life assessment in dermatology: interpretation of Skindex-29 scores using 
patient-based anchors. Journal of Investigative Dermatology 2010;130(5):1318-22.
71.
Demierre MF, Tien A, Miller D. Health-related quality-of-life assessment in patients 
with cutaneous T-cell lymphoma. Archives of Dermatology 2005;141(3):325-30.
72.
Both H, Essink-Bot ML, Busschbach J, Nijsten T. Critical review of generic and 
dermatology-specific health-related quality of life instruments. Journal of 
Investigative Dermatology 2007;127(12):2726-39.
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molecule: a new cytokine receptor of the tumor necrosis factor receptor superfamily 
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(CTCAE). Version 4.02. 28 May 2009.
75.
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76.
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77.
DuBois D, DuBois E. A formula to estimate the approximate surface area if height 
and weight be known. Arch Int Med 1916;17:863-71.
78.
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for Diagnosis of Diseases of the Heart and Great Vessels. 9 ed. Boston, MA: Little, 
Brown & Co; 1994.


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15.   
APPENDICES
15.1   
Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status
Grade
Description
0
Normal activity.  Fully active, able to carry on all predisease performance without 
restriction.
1
Symptoms but ambulatory.  Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (eg, light 
housework, office work).
2
In bed < 50% of the time.  Ambulatory and capable of all self-care, but unable to 
carry out any work activities.  Up and about more than 50% of waking hours.
3
In bed > 50% of the time.  Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours.
4
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair.
5
Dead.
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al.  Toxicity and 
response criteria of the Eastern Cooperative Oncology Group.  Am J Clin Oncol 1982; 5 (6):649-55.(75)
15.2   
Body Surface Area Nomograms
Body surface area should be calculated using the Mosteller formula or Dubois and Dubois 
formula standard nomogram.  
The Mosteller Formula
BSA (m²) = ( [Height(cm) x Weight(kg) ]/ 3600 )½        
eg, BSA = SQRT( (cm*kg)/3600 )
or in inches and pounds:     BSA (m²) = ( [Height(in) x Weight(lbs) ]/ 3131 )½
Adapted from: Mosteller RD.  Simplified calculation of body-surface area.  N Engl J Med 
1987;317(17):1098.(76)
The Dubois and Dubois Formula
BSA = (W 0.425 x H 0.725) x 0.007184
where the weight is in kilograms and the height is in centimeter
Adapted from: DuBois D, DuBois EF. A formula to estimate the approximate surface area if height and weight 
be known. Arch Intern Medicine. 1916; 17:863-71.(77)


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15.3   
New York Heart Association Classification of Cardiac Disease
The following table presents the NYHA classification of cardiac disease:
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence 
of cardiovascular 
disease.
II
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of 
minimal cardiovascular 
disease.
III
Patients with cardiac disease resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary activity 
causes fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of 
moderately severe 
cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or the 
anginal syndrome may be present even at rest.  If any physical activity 
is undertaken, discomfort is increased.
Objective evidence of 
severe cardiovascular 
disease.
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for Diagnosis 
of Diseases of the Heart and Great Vessels.  9th Ed.  Boston, MA:  Little, Brown & Co; 1994:253-256.(78)
15.4   
Tumor-Node-Metastasis-Blood Classification and Clinical Staging System for 
Mycosis Fungoides
Modified ISCL/EORTC Revisions to the TNMB Classification of MF/SS
TNMB 
Stages
Description of TNMB
Skin*
T1
Limited patches, papules, and/or plaques covering <10% of the skin surface; may further 
stratify into T1a (patch only) v T1b (plaque ± patch)
T2
Patches, papules, or plaques covering ≥ 10% of the skin surface; may further stratify into T2a
(patch only) v T2b (plaque ± patch) 
T3
One or more tumors (≥ 1 cm diameter)
T4
Confluence of erythema covering ≥80% body surface area
Node†
N0
No clinically abnormal lymph nodes; biopsy not required
N1
Clinically abnormal lymph nodes; histopathology Dutch grade 1 or NCI LN0-2
        N1a
Clone negative
        N1b
Clone positive
N2
Clinically abnormal lymph nodes; histopathology Dutch Grade 2 or NCI LN3
        N2a
Clone negative
        N2b
Clone positive
N3
Clinically abnormal lymph nodes; histopathology Dutch grade 3-4 or NCI LN4; clone positive 
or negative
Nx
Clinically abnormal lymph nodes without histologic confirmation or inability to fully 
characterize the histologic subcategories
Visceral
M0
No visceral organ involvement


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Modified ISCL/EORTC Revisions to the TNMB Classification of MF/SS
TNMB 
Stages
Description of TNMB
M1
Visceral involvement (must have pathology confirmation and organ involved should be 
specified)
Blood
B0
Absence of significant blood involvement: ≤5% of peripheral blood lymphocytes are atypical 
(Sézary) cells
        B0a
Clone negative
        B0b
Clone positive
B1
Low blood tumor burden: > 5% of peripheral blood lymphocytes are atypical (Sézary) cells but 
does not meet the criteria of B2
        B1a
Clone negative
        B1b
Clone positive
B2
High blood tumor burden: ≥1,000/µL Sézary cells with positive clone‡; one of the following 
can be substituted for Sézary cells: CD4/CD8 ≥10, CD4+CD7- cells ≥40% or CD4+CD26-
cells ≥30%
Source:  Olsen EA et al. Clinical End Points and Response Criteria in Mycosis Fungoides and Sezary 
Syndrome: A Consensus Statement of the International Society for Cutaneous Lymphomas, the United 
States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European 
Organisation for Research and Treatment of Cancer. J Clin Oncol 2011.(41)
Abbreviations:  ISCL = International Society for Cutaneous Lymphomas; EORTC = European Organisation 
for Research and Treatment of Cancer; MF = mycosis fungoides; SS = Sézary syndrome; NCI = National 
Cancer Institute.  
* Patch = any sized lesion without induration or significant elevation above the surrounding uninvolved skin: 
poikiloderma may be present.  Plaque = any sized lesion that is elevated or indurated: crusting or 
poikiloderma may be present.
Tumor = any solid or nodular lesion ≥1 cm in diameter with evidence of deep infiltration in the skin and/or 
vertical growth.
† Lymph node classification has been modified from 2007 ISCL/EORTC consensus revisions(24) to include 
central nodes.  Lymph nodes are qualified as abnormal if > 1.5 cm in diameter.
‡ The clone in the blood should match that of the skin.  The relevance of an isolated clone in the blood or a 
clone in the blood that does not match the clone in the skin remains to be determined.


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15.5   
Amendment 4 Rationale and Purposes
Rationale for Amendment 4
This amendment incorporates FDA guidance received on Amendment 3, an amendment that 
was not implemented by study sites.  Amendment 4 reverts to text that states that the 
sponsor will be notified in the event that a patient is withdrawn from study treatment or from 
the study, and re-establishes the use of a standard formula to calculate body surface area 
(BSA).  
In order to strengthen safety reporting, this amendment requires all events of peripheral 
neuropathy to be followed for changes in severity until resolution to baseline or study 
closure, whichever occurs first, and removes the requirement to end safety monitoring when 
a patient receives a subsequent anticancer therapy.
Purposes for Amendment 4

The purposes of this amendment are to:

Revert to language that states that the sponsor will be notified of patient withdrawal 
from study treatment or from the study

Specify that BSA is calculated using the Mosteller formula or the Dubois and Dubois 
formula and add a statement to consider the risks of dosing with bexarotene

Remove requirement to end safety monitoring when a patient receives subsequent 
anticancer therapy

Add language regarding the collection of events of peripheral neuropathy 

Correct errors in response tables to align with reference documents

Correct typographical errors, punctuation, grammar, and formatting


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15.6   
Amendment 5 Detailed Summary of Changes
THE PRIMARY SECTION(S) OF THE PROTOCOL AFFECTED BY THE CHANGES 
IN AMENDMENT 5 ARE INDICATED.  THE CORRESPONDING TEXT HAS BEEN 
REVISED THROUGHOUT THE PROTOCOL.
Purpose:  Add safety language regarding the potential risk of pancreatitis
The primary change occurs in Section 1.5, Potential Risks and Benefits:
Added 
text:
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.  Some of the pancreatitis cases were complicated by other 
possible contributory factors, including cholelithiasis and alternate 
etiologies (eg, pancreatic lymphoma progression, displacement of bile 
duct stent, etc).
Purpose:  Add lipase values and amylase levels to pancreatitis exclusion criterion
The primary change occurs in Section 5.2, Exclusion Criteria:
Added 
text:
17. History of pancreatitis or significant risk factors for developing 
pancreatitis (eg, prior pancreatitis, uncontrolled hyperlipidemia, excessive 
alcohol consumption, uncontrolled diabetes mellitus, biliary tract disease, 
and medications known to increase triglyceride levels or to be associated 
with pancreatic toxicity), or elevated lipase value ≥3 ULN with an 
amylase level > ULN at screening.  
Purpose:  Add lipase and amylase to the chemistry lab panel
The primary change occurs in Section 7.4.15, Clinical Laboratory Evaluations:
Added 
text:
Serum Chemistry

BUN

Creatinine

Bilirubin (total)

Urate

Lactate 
dehydrogenase 
(LDH)

Phosphate

Gamma glutamyl 

Albumin

Alkaline 
phosphatase 
(ALP)

Aspartate 
aminotransferase 
(AST)

Alanine 
aminotransferase 
(ALT)

Calcium

Chloride

Carbon dioxide 
(CO2)

Magnesium

Amylase

Lipase


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transferase (GGT)

Glucose 

Sodium

Potassium
Footnote h in the Schedule of Events also contains this change.
Purpose:  Revise text regarding timing of FDG-PET and CT scans
The primary change occurs in Section 4.1, Overview of Study Design:
Formerly 
read:
FDG-PET scans and CT scans of the neck, chest, abdomen, and pelvis will be 
performed at screening.  FDG-PET scans will not be taken after screening 
unless clinically indicated.  For patients without nodal or visceral 
involvement as determined by baseline CT scans, CT scans will be performed 
at the beginning of the cycle following the first skin response, ideally 
corresponding to the confirmation of the skin response, and 6 cycles (a 
minimum of 4 months) after that confirmed skin response.  
Now 
reads:
FDG-PET scans and CT scans of the neck, chest, abdomen, and pelvis will be 
performed at screening.  FDG-PET scans taken within 8 weeks before 
signing the informed consent form (ICF) may be used as the screening 
FDG-PET.  FDG-PET scans will not be taken after screening unless 
clinically indicated.  CT scans taken within 4 weeks before signing the ICF 
may be used as the screening CT scan if all of the following conditions 
are met: 

There is no nodal or visceral disease involvement noted

There is no clinically evident lymphadenopathy or splenomegaly by 
physical exam at the time of screening 

The scan meets all quality criteria as outlined in the Imaging 
Manual
For patients without nodal or visceral involvement as determined by baseline 
CT scans, CT scans will be performed during the cycle following the first 
skin response, ideally corresponding to the confirmation of the skin response, 
and 6 cycles (a minimum of 4 months) after that confirmed skin response.  
Footnotes m and n in the Schedule of Events also contain this change.
Purpose:  Clarify text regarding follow-up for objective response
The primary change occurs in Section 4.1, Overview of Study Design:
Formerly 
read:
Objective response, lasting at least 4 months (ORR4), per independent review 
facility (IRF), will be assessed by global response score (GRS), which 
consists of skin evaluation (mSWAT assessment), nodal and visceral 
radiographic assessment, and detection of circulating Sézary cells (MF only). 
Objective response will be evaluated at the end of Cycles 3, 6, 9, 12, and 15;


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at end of treatment (EOT); then every 12 weeks for a minimum of 24 months;
and then every 6 months, until disease progression or study closure.
Now 
reads:
Objective response, lasting at least 4 months (ORR4), per independent review 
facility (IRF), will be assessed by global response score (GRS), which 
consists of skin evaluation (mSWAT assessment), nodal and visceral 
radiographic assessment, and detection of circulating Sézary cells (MF only).  
Objective response will be evaluated at the end of Cycles 3, 6, 9, 12, and 15, 
and at end of treatment (EOT).  All treated patients without disease 
progression at EOT/ET will then be followed for objective response every 
12 weeks for a minimum of 24 months, and then every 6 months; or until 
disease progression or study closure.  
Sections that also contain this change are:

PROTOCOL SUMMARY

Footnotes b, l, and r in the Schedule of Events

Section 4.3, Duration of Study

Section 7.4.17.4, Global Response Score
Purpose:  Clarify text regarding timing of clinical laboratory assessments
The primary change occurs in Section 5.1, Inclusion Criteria:
Formerly 
read:
8. Clinical laboratory values as specified below within 4 days before the first 
dose of study drug (laboratory values may be performed locally.):
Now 
reads:
8. Clinical laboratory values as specified below within 4 days before 
randomization (laboratory values may be performed locally.):
Purpose:  Revise timing for exclusion of oral retinoid therapy 
The primary change occurs in Section Exclusion Criteria:
Formerly 
read:
15. Oral retinoid therapy for any indication within 3 weeks of study entry.  
Now 
reads:
15. Oral retinoid therapy for any indication within 3 weeks of the first dose 
of study drug.  


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Purpose:  Add a statement regarding the scheduling of pregnancy tests
The primary change occurs in Section 7.4.8, Pregnancy Test:
Added 
text:
A serum pregnancy test will be performed for women of childbearing 
potential at screening. Urine pregnancy tests will be performed prior to 
dosing on Day 1 of each cycle.  Pregnancy tests may also be repeated 
during the study if requested by an IEC/IRB or if required by local 
regulations.  The results of any pregnancy test must be negative before 
dosing on Day 1 of all cycles. 
Purpose:  Revise the definition of relapse in the text to align with the definition in the 
response tables
The primary change occurs in Section 7.4.17.4, Global Response Score:
Formerly 
read:
For patients without baseline nodal/visceral involvement, the schedule for 
obtaining CT scans will likely not correlate with the timing of GRS 
determinations; thus, the nodal/visceral response component should be based 
upon the most recent CT scan findings prior to the GRS assessment time 
point.  Additional unscheduled GRS determinations may occur following a 
change in response in skin or at the time of a CT scan.  Relapse will be 
categorized as progressive disease in the study endpoints definition.
Now 
reads:
For patients without baseline nodal/visceral involvement, the schedule for 
obtaining CT scans will likely not correlate with the timing of GRS 
determinations; thus, the nodal/visceral response component should be based 
upon the most recent CT scan findings prior to the GRS assessment time 
point.  Additional unscheduled GRS determinations may occur following a 
change in response in skin or at the time of a CT scan.  Relapse will be 
categorized in the study endpoints definition as recurrent disease in patients 
with complete response.
Purpose:  Add relapse to the list of GRS responses
The primary change occurs in Section 7.4.16, Disease Assessment:
Formerly 
read:
A GRS of complete response (CR), partial response (PR), stable disease (SD), 
and progressive disease (PD) will be determined based on sequential tumor 
burden assessments of body compartments (skin, lymph nodes, viscera, and 
blood for MR patients) as further described below.  For the purpose of disease 
assessment in the control arm, a period of 3 weeks (21 days) is equivalent to 1 
cycle.
Now 
reads:
A GRS of complete response (CR), partial response (PR), stable disease (SD), 
progressive disease (PD), and relapse will be determined based on sequential 
tumor burden assessments of body compartments (skin, lymph nodes, viscera, 


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and blood for MF patients) as further described below.  For the purpose of 
disease assessment in the control arm, a period of 3 weeks (21 days) is 
equivalent to 1 cycle.
Section 7.4.17.4, Global Response Score also contains this change.
Purpose:  Clarify text regarding the collection of pharmacokinetic parameters
The primary change occurs in Section 7.4.18, Pharmacokinetic Measurements:
Added 
text:
Pharmacokinetic measurements will be made in all brentuximab vedotin-
treated patients.  Pharmacokinetic parameters to be estimated may include,
but are not limited to, the maximum concentration for MMAE (Cmax) and 
concentration at the end of infusion for brentuximab vedotin (Ceoi).  
Purpose:  Clarify text regarding the amount of blood to be collected for germline DNA 
assessments
The primary change occurs in Section 7.4.22, Germline DNA Polymorphism Assessment:
Added 
text:
Purpose:  Clarify text regarding the discontinuation of study drug
The primary change occurs in Section 7.7, Discontinuation of Treatment With Study
Drug, and Patient Replacement:
Formerly 
read:
At the time of study drug discontinuation, all study procedures outlined for 
the End of Treatment visit will be completed.  The primary reason for study 
drug discontinuation will be recorded on the eCRF.
Now 
reads:
Once study drug has been discontinued, all study procedures outlined for the 
End of Treatment visit will be completed as specified in the Schedule of 
Events.  The primary reason for study drug discontinuation will be recorded 
on the eCRF.
CCI


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Purpose:  Revise text describing safety analysis
The primary change occurs in Section 8.1.9, Safety Analysis:
Formerly 
read:
Safety will be evaluated by the incidence of TEAEs, severity and type of 
AEs, and by changes from baseline in the patient’s vital signs, ECOG 
performance status, and clinical laboratory results using the safety population.  
Exposure to study drug and reasons for discontinuation will be tabulated.
Treatment-emergent AEs will be tabulated by primary system organ class 
(SOC), high-level term (HLT), and preferred term.  A TEAE is defined as any 
AE that occurs after administration of the first dose of study drug and up 
through 30 days after the last dose of study medication.  Adverse events will 
be tabulated according to the Medical Dictionary for Regulatory Activities 
(MedDRA) by system organ class (SOC), high-level terms, and preferred 
terms (PTs) and will include the following categories: 

TEAEs

Study drug-related TEAEs

Grade 3 or higher TEAEs

Grade 3 or higher study drug-related TEAEs

TEAEs resulting in study drug discontinuation

SAEs, including study drug-related SAEs
The most commonly reported TEAEs (ie, those events reported by ≥10% of 
all patients) will be tabulated by high-level term and PT.  
Now 
reads:
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, ECOG performance 
status, and clinical laboratory results using the safety population.  Exposure to 
study drug 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 study drug will be 
tabulated.  Adverse events will be tabulated according to the Medical 
Dictionary for Regulatory Activities (MedDRA) and will include the 
following categories: 

TEAEs

Study drug-related TEAEs

Grade 3 or higher TEAEs

Grade 3 or higher study drug-related TEAEs

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 study drug 


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discontinuation will be provided.
Purpose:  Revise text describing monitoring of adverse events
The primary change occurs in Section 10.3, Monitoring of Adverse Events and Period of 
Observation:
Formerly 
read:
AEs, both nonserious and serious (which include all deaths), will be 
monitored throughout the study as follows:
...

SAEs will be reported to Millennium Pharmacovigilance or designee 
from the first dose of study drug through 30 days after administration of 
the last dose of study drug and recorded in the eCRF.  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 at any time after completion of the study and the 
designated follow-up period that the investigator considers to be related 
to study drug must be reported to PPD.
Now 
reads:
AEs, both nonserious and serious, will be monitored throughout the study as 
follows:
...

Related and unrelated SAEs will be reported to the Millennium 
Department of Pharmacovigilance or designee from the first dose of 
study drug through 30 days after administration of the last dose of study 
drug and recorded in the eCRF.  After this period only related SAEs 
must be reported to the Millennium Department of 
Pharmacovigilance or designee.  SAEs should be monitored until they 
are resolved or are clearly determined to be due to a patient’s stable or 
chronic condition or intercurrent illness(es).  
Purpose:  Revise text regarding the recording and reporting of adverse events and serious 
adverse events (SAEs)
The primary change occurs in Section 10.2, Procedures for Recording and Reporting 
Adverse Events and Serious Adverse Events:
Formerly 
read:
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 Millennium Pharmacovigilence’s Designee 
PPDI Pharmacovigilance (PPD) (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. 


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Now 
reads:
Regardless of causality, SAEs and serious pretreatment events (as defined in 
Section 10.1) must be reported (see Section 10.3 for the period of 
observation) by the investigator to the Millennium Department of
Pharmacovigilance or designee (contact information provided below).  This 
should be done by faxing the SAE Form within 24 hours after becoming 
aware of the event.
Purpose:  Replace references to PPD with Millennium Pharmacovigilance or designee
The primary change occurs in Section 10.2, Procedures for Recording and Reporting 
Adverse Events and Serious Adverse Events:
Formerly 
read:
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 Millennium Pharmacovigilence’s Designee 
PPDI Pharmacovigilance (PPD) (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 PPD or Millennium. SAE 
report information must be consistent with the data provided on the eCRF.
Now 
reads:
Regardless of causality, SAEs and serious pretreatment events (as defined in 
Section 10.1) must be reported (see Section 10.3 for the period of 
observation) by the investigator to the Millennium Department of
Pharmacovigilance or designee (contact information provided below).  This 
should be done by faxing the SAE Form within 24 hours after becoming 
aware of the event.  The SAE Form, created specifically by Millennium, will 
be provided to each clinical study site.  A sample of the SAE Form may be 
found in the Study Manual.  Follow-up information on the SAE or serious 
pretreatment event may be requested by the Millennium Department of 
Pharmacovigilance or designee.  SAE report information must be consistent 
with the data provided on the eCRF.
Sections that also contain this change are:

Section 10.3, Monitoring of Adverse Events and Period of Observation

Section 10.4, Procedures for Reporting Drug Exposure During Pregnancy and Birth 
Events

Section 11.11, Product Complaints and Medication Errors


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Purpose:  Update contact information for reporting SAEs
The primary change occurs in Section 10.2, Procedures for Recording and Reporting 
Adverse Events and Serious Adverse Events:
Formerly 
read:
For SAE and Pregnancy Reporting Contact Information,
please refer to Section 15.5.
Now 
reads:
SAE Reporting Contact Information
Section 15.5, SAE and Pregnancy Reporting Contact Information, has been deleted.
Purpose:  Correct errors in Background and Study Rationale text and in-text references
The primary change occurs in Section 1.4.1, Treatment Options in CTCL, and Section 
1.4.2.1, Bexarotene:
Formerly 
read:
1.4.1   Treatment Options in CTCL
There is no universally accepted single standard of care across first, second,
and advanced lines of treatment of CTCL.  Single-agent therapy has been 
used, including retinoids, interferons, HDAC inhibitors, and chemotherapy; 
these therapies include methotrexate, bexarotene, glucocorticoids, 
cyclophosphamide, cisplatin, etoposide, bleomycin, doxorubicin, vincristine, 
and vinblastine.(27)  Single-agent therapy can yield complete response rates up 
to 30%, but remissions are generally of short duration.  Chemotherapy 
combined with other agents may induce remissions of pcALCL.  More potent 
chemotherapy is complicated by immune deficiency, and infectious 
complications.  Both methotrexate and bexarotene are approved by the FDA 
and remain the most widely used treatments for CTCL across the diagnoses.(5)
…
A second HDACi, romidepsin, is an intravenously administered bicyclic 
peptide that inhibits classes I and II HDACs with activity in not only CTCL, 
but also peripheral T-cell lymphoma (PTCL).  A single-arm, open-label, 
multicenter, pivotal, phase 2 study of romidepsin for the treatment of 
refractory CTCL (stages IB–IVA) was recently completed.  After 6 cycles of 
treatment, a response rate (RR) of 42% was observed in 72 evaluable patients 
CCI


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(including 6 clinical CRs), and pruritus improved in 48%.  Median time to 
response was 1.9 months.(21)  Romidepsin was granted approval by the FDA 
for treatment of patients with CTCL.(21, 35)
Chemotherapy is reserved for relapsed and refractory disease and yields 
moderate to high response rates; however, response durations are short.  
Agents with notable activity include gemcitabine and liposomal doxorubicin.  
In a phase 2 study, gemcitabine showed a response rate of 53% and a CR rate 
of 22%.  In a retrospective analysis of pegylated liposomal doxorubicin, the 
response rate was approximately 85% (30 out of 34 patients) and 
approximately 43% had CR.(22, 23, 24)
1.4.2   Choice of Comparator
1.4.2.1   Bexarotene
Bexarotene (Targretin®) is approved in the United States and European Union 
for the treatment of patients who are refractory to at least 1 prior systemic 
therapy for cutaneous T-cell lymphoma.  In clinical trials, bexarotene was 
administered for up to 97 weeks.  In patients with advanced CTCL, 49% of 
patients achieved an objective response (complete and partial responses) to 
treatment with any dose of bexarotene.  Patient response rates were 45% at a 
dose of 300 mg/m2/day PO and 55% at doses > 300 mg/m2/day PO.  
Responses were seen in patients with erythrodermic CTCL (mycosis 
fungoides) and Sézary syndrome.  Median time to best response was 180 days 
and these responses were durable for a median of 159 days at bexarotene 
doses of 300 mg/m2/day PO.  Median time to response was shorter and the 
duration of response was longer with doses > 300 mg/m2/day PO but the 
incidence of side effects increased substantially at the higher doses.(36)
Now 
reads:
1.4.1   Treatment Option in CTCL
There is no universally accepted single standard of care across first, second,
and advanced lines of treatment of CTCL.  Single-agent therapy has been 
used, including retinoids, interferons, HDAC inhibitors, and chemotherapy; 
these therapies include methotrexate, bexarotene, glucocorticoids, 
cyclophosphamide, cisplatin, etoposide, bleomycin, doxorubicin, vincristine, 
and vinblastine.(26)  Single-agent therapy can yield complete response rates up 
to 30%, but remissions are generally of short duration.  Chemotherapy 
combined with other agents may induce remissions of pcALCL.  More potent 
chemotherapy is complicated by immune deficiency, and infectious 
complications.  Both methotrexate and bexarotene are approved by the FDA 
and are widely used treatments for CTCL across the diagnoses.(27)
…
A second HDACi, romidepsin, is an intravenously administered bicyclic 
peptide that inhibits classes I and II HDACs with activity in not only CTCL, 
but also peripheral T-cell lymphoma (PTCL).  A single-arm, open-label, 
multicenter, pivotal, phase 2 study of romidepsin for the treatment of 
refractory CTCL (stages IB–IVA) was recently completed.  After 6 cycles of 


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treatment, a response rate (RR) of 34% was observed in 96 evaluable patients 
(including 6 clinical CRs), and pruritus improved in 43%.  Median time to 
response was 2 months.   Romidepsin was granted approval by the FDA for 
treatment of patients with CTCL.(21)
Chemotherapy is reserved for relapsed and refractory disease and yields 
moderate to high response rates; however, response durations are short.  
Agents with notable activity include gemcitabine and liposomal doxorubicin.  
In a phase 2 study, gemcitabine showed a response rate of 53% and a CR rate 
of 22%.  In a retrospective analysis of pegylated liposomal doxorubicin, the 
response rate was 88% (30 out of 34 patients) and approximately 43% had 
CR.(22, 34, 35)
1.4.2   Choice of Comparator
1.4.2.1   Bexarotene
Bexarotene (Targretin®) is approved in the United States and European Union 
for the treatment of patients who are refractory to at least 1 prior systemic 
therapy for cutaneous T-cell lymphoma.  In clinical trials, bexarotene was 
administered for up to 97 weeks.  In patients with advanced CTCL, 49% of 
patients achieved an objective response (complete and partial responses) to 
treatment with any dose of bexarotene.  Patient response rates were 45% at a 
dose of 300 mg/m2/day PO and 55% at doses > 300 mg/m2/day PO.  
Responses were seen in patients with erythrodermic CTCL (mycosis 
fungoides) and Sézary syndrome.  Median time to best response was 180 days 
and these responses were durable for a median of 299 days at bexarotene 
doses of 300 mg/m2/day PO.  Median time to response was shorter and the 
duration of response was longer with doses > 300 mg/m2/day PO but the 
incidence of side effects increased substantially at the higher doses.(36)
Section 1.1.2.1, Mycosis Fungoides Treatment and Staging, also contains this change.
Purpose:  Correct typographical errors, punctuation, grammar, and formatting
These changes are not listed individually.


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PPD

SAP_000.pdf: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Randomized, Open-Label, Phase 3 Trial of brentuximab vedotin (SGN-35) Versus 
Physician's Choice (Methotrexate or Bexarotene) in Patients With CD30-Positive Cutaneous 
TCell Lymphoma
NCT Number: NCT01578499
SAP Approve Date: May 25, 2016
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


PPD


Brentuximab vedotin (SGN-35) 
Statistical Analysis Plan, Study C25001 
Confidential 
2
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...........................................4 
1. INTRODUCTION ................................................................................................................6 
1.1 Study Design ...................................................................................................................6 
1.2 Study Objectives .............................................................................................................7 
1.2.1 Primary Objectives ..................................................................................................7 
1.2.2 Secondary Objectives ..............................................................................................7 
1.2.3 Exploratory Objectives ............................................................................................8 
2. POPULATIONS FOR ANALYSIS .....................................................................................8 
2.1 Intent-to-Treat Population ..............................................................................................8 
2.2 All-Enrolled Population ..................................................................................................8 
2.3 Per-Protocol Population ..................................................................................................9 
2.4 Response-Evaluable Population .....................................................................................9 
2.5 Safety Population ............................................................................................................9 
2.6 Pharmacokinetics Population .........................................................................................9 
2.7 Pharmacodynamics Population .......................................................................................9 
3. HYPOTHESES AND DECISION RULES ........................................................................10 
3.1 Statistical Hypotheses ...................................................................................................10 
3.2 Statistical Decision Rules .............................................................................................10 
4. INTERIM ANALYSIS .......................................................................................................12 
4.1 Interim Analysis ...........................................................................................................12 
4.2 Independent Data Monitoring Committee ....................................................................12 
5. STATISTICAL METHODOLOGY ...................................................................................12 
5.1 Sample Size Justification ..............................................................................................12 
5.2 Randomization and Stratification .................................................................................12 
5.3 Unblinding ....................................................................................................................13 
5.4 Data Handling ...............................................................................................................13 
5.4.1 Methods for Handling Missing Data .....................................................................13 
5.4.2 Definition of Baseline Values ................................................................................13 
5.4.3 Windowing of Visits ..............................................................................................13 
5.4.4 Justification of Pooling ..........................................................................................13 
5.4.5 Withdrawals, Dropouts, Loss to Follow-up ...........................................................13 
5.5 Patient Disposition ........................................................................................................14 
5.6 Demographics and Baseline Disease Characteristics ...................................................14 
5.6.1 Demographics ........................................................................................................14 
5.6.2 Medical History .....................................................................................................14 
5.7 Treatments and Medications .........................................................................................14 
5.7.1 Concomitant Medications ......................................................................................14 
5.7.2 Study Treatments ...................................................................................................15 
5.8 Efficacy Analyses .........................................................................................................16 
5.8.1 Primary Efficacy Endpoint ....................................................................................16 
5.8.2 Key Secondary Efficacy Endpoints .......................................................................19 
5.8.3 Other Secondary Efficacy Endpoints .....................................................................22 
5.9 Pharmacokinetic, Pharmacodynamic, and Biomarker Analysis ...................................23 


Brentuximab vedotin (SGN-35) 
Statistical Analysis Plan, Study C25001 
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5.9.1 Pharmacokinetic Analyses .....................................................................................23 
5.9.2 Pharmacodynamic Analyses ..................................................................................24 
5.9.3 Immunogenicity Analysis ......................................................................................24 
5.9.4 Biomarker Analysis ...............................................................................................24 
5.10 Analyses of Patient-Reported Outcomes and Health Economics ...............................24 
5.10.1 Patient-Reported Outcomes Analysis ..................................................................25 
5.10.2 Health Economics Analysis Using Medical Resource Utilization ......................25 
5.11 Safety Analyses ..........................................................................................................25 
5.11.1 Adverse Events ....................................................................................................25 
5.11.2 Laboratory Data ...................................................................................................26 
5.11.3 Electrocardiograms ..............................................................................................28 
5.11.4 Vital Signs ...........................................................................................................28 
5.11.5 Eastern Cooperative Oncology Group Performance Status .................................28 
5.11.6 Other Safety Assessments ....................................................................................28 
6. CHANGES TO PLANNED ANALYSES FROM PROTOCOL .......................................28 
7. PROGRAMMING CONSIDERATIONS ..........................................................................29 
7.1 Statistical Software .......................................................................................................29 
7.2 Rules and Definitions ...................................................................................................29 
8. REFERENCES ...................................................................................................................29 
 


Brentuximab vedotin (SGN-35) 
Statistical Analysis Plan, Study C25001 
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List of Abbreviations and Definitions of Terms 
Abbreviation 
Term 
ADC 
antibody-drug conjugate 
AE 
adverse event 
AIC 
Akaike information criterion 
ALCL 
anaplastic large cell lymphoma 
ALK 
anaplastic lymphoma kinase 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
ATA 
antitherapeutic antibodies 
ATC 
anatomical therapeutic chemical  
BIC 
Bayesian information criterion 
BSA  
body surface area 
BUN 
blood urea nitrogen 
BV 
brentuximab vedotin  
CD30+ 
CD30-positive 
CDF 
cumulative distribution function 
CI 
confidence interval  
Cmax 
maximum plasma concentration 
Cmin 
minimum plasma concentration 
CO2 
carbon dioxide 
CR 
complete response 
CT 
computed tomography 
CTCL 
cutaneous T-cell lymphoma 
Ctrough 
trough concentration 
CV 
coefficient of variation 
DOR 
duration of response  
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EFS 
event-free survival 
EOT 
end of treatment 
GGT 
gamma-glutamyl transpeptidase 
GRS 
global response score 
HDL 
high-density lipoprotein 
HLT 
High Level Term 
IDMC 
independent data monitoring committee 
IRF 
independent review facility 


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Abbreviation 
Term 
ITT 
intent-to-treat 
IV 
intravenous; intravenously 
IVRS 
interactive voice response system 
LDH 
lactic dehydrogenase 
LDL 
low density lipoprotein 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
mycosis fungoides 
MID 
minimum important difference 
MMAE 
monomethylauristatin E  
MRU 
medical resource utilization 
mSWAT 
modified severity weighted assessment tool 
MTX 
methotrexate 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
ORR 
objective response rate 
ORR4 
objective response lasting at least 4 months 
pcALCL 
primary cutaneous anaplastic large cell lymphoma 
PD 
progressive disease (disease progression) 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PP 
per protocol 
PR 
partial response 
PRO 
patient-reported outcome 
PT 
Preferred Term 
SAE 
serious adverse event 
SAP 
statistical analysis plan  
sCD30 
soluble CD30 
SOC 
System Organ Class 
SOE 
Schedule of Events 
T3 
triiodothyronine 
T4 
thyroxine 
TEAE 
treatment-emergent adverse event 
TSH 
thyroid-stimulating hormone 
WHO 
World Health Organization 
 


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1.    INTRODUCTION 
In general, the purpose of the Statistical Analysis Plan (SAP) is to provide a framework that 
addresses the protocol objectives in a statistically rigorous fashion, with minimized bias or 
analytical deficiencies.  Specifically, this plan has the following purpose: 
To prospectively (a priori) outline the types of analyses and data presentations that addresses 
the study objectives outlined in the protocol, and to explain in detail how the data will be 
handled and analyzed, adhering to commonly accepted standards and practices of 
biostatistical analysis in the pharmaceutical industry. 
1.1    Study Design 
This is an open-label, randomized, multicenter study.  All patients must have histologically-
confirmed CD30-positive (CD30+) cutaneous T-cell lymphoma (CTCL) by central 
laboratory assessment and pathology review.  Patients are to be stratified by diagnosis:  
primary cutaneous anaplastic large cell lymphoma (pcALCL) or mycosis fungoides (MF), 
and randomized to treatment with brentuximab vedotin monotherapy (Arm 1) up to 16 
cycles total (48 weeks), or methotrexate (MTX) or bexarotene per physician’s choice (Arm 
2) up to a total of 48 weeks.  
Objective response, lasting at least 4 months (ORR4), per independent review facility (IRF) 
will be assessed by global response score (GRS), which consists of skin evaluation 
(mSWAT assessment), nodal and visceral radiographic assessment, and detection of 
circulating Sézary cells (MF only).  Complete response (CR) or partial response (PR) per 
GRS will be confirmed by sustained response in skin per mSWAT assessment at the 
subsequent cycle.  All randomized patients will be followed for survival every 12 weeks for 
a minimum of 24 months after the EOT visit, and then every 6 months until patient 
withdrawal, death, or study closure.   
Patients with a documented PR or CR at the end of Cycle 3 and at any disease assessment 
thereafter may continue treatment with study drug for up to 16 cycles with brentuximab 
vedotin or 48 weeks with bexarotene or methotrexate; patients with stable disease may 
continue therapy at the discretion of the investigator.  Patients with progressive disease (PD) 
at any time during the study will be discontinued from study treatment.  Patients with 
increasing mSWAT before assessment at the end of Cycle 3 will be allowed to continue 
therapy until the Cycle 3 assessment if, in the investigator’s opinion, the findings are due to 
tumor flare rather than disease progression.    


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1.2    Study Objectives 
1.2.1    Primary Objectives 
The primary objective is: 
 To determine ORR, lasting at least 4 months, with brentuximab vedotin in patients 
with CD30+ MF or pcALCL compared to that achieved with therapy in the control 
arm 
1.2.2    Secondary Objectives 
The key secondary objectives are: 
 To determine complete response (CR) rate with brentuximab vedotin compared to 
that achieved with therapy in the control arm 
 To determine progression-free survival (PFS) with brentuximab vedotin compared to 
that achieved with therapy in the control arm 
 To determine burden of symptoms during treatment with brentuximab vedotin 
compared to that achieved with therapy in the control arm 
Other secondary objectives include: 
 To assess duration of response (DOR) with brentuximab vedotin 
 To assess duration of skin response with brentuximab vedotin 
 To determine event-free survival (EFS) with brentuximab vedotin compared to that 
achieved with therapy in the control arm 
 To describe the pharmacokinetics (PK) of brentuximab vedotin and 
monomethylauristatin E (MMAE) in blood 
 To determine the immunogenicity of brentuximab vedotin 
 To assess patient-reported quality of life outcomes 
 To assess the safety of brentuximab vedotin 


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1.2.3    Exploratory Objectives 
The exploratory objectives include: 
2.    POPULATIONS FOR ANALYSIS 
2.1    Intent-to-Treat Population 
The Intent-to-Treat (ITT) population will include all patients identified as CD30+ by the 
Ventana CD30 (Ber-H2) assay and 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. 
The ITT population will be used for the primary efficacy analysis and analyses on all 
efficacy endpoints unless specified otherwise. 
2.2    All-Enrolled Population 
The All-Enrolled population will include all patients randomized to treatment.  All patients 
in the All-Enrolled population will be analyzed according to the treatment they were 
randomized to receive and not according to what they actually received, if different. 
The all-enrolled population will be used as a supplement to the analysis of the ITT 
population for the primary efficacy endpoint.   
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2.3    Per-Protocol Population 
The Per-Protocol (PP) population will include a subset of ITT patients who do not have 
major protocol violations as determined by the medical monitor.  All decisions to exclude 
patients from the PP population will be made before the study database lock. 
The PP population will be used as a supplement to the analysis of the ITT population for the 
primary efficacy endpoint.   
All patients in the PP population will be analyzed according to the actual treatment received. 
2.4    Response-Evaluable Population 
The Response-Evaluable population is defined as a subset of the ITT population with 
measurable disease at baseline and with at least 1 post baseline response assessment.  The 
Response-Evaluable population will be used for the sensitivity analyses of ORR4, CR rate, 
ORR, time to response, and duration of response, as needed. 
2.5    Safety Population 
The Safety population will include patients who receive at least 1 dose of study drug.  All 
patients in the Safety population will be analyzed according to the actual treatment received.  
Patients receiving any dose of brentuximab vedotin will be grouped into the study drug 
group for the purposes of safety reporting. 
All safety analyses will be performed using the Safety population. 
2.6    Pharmacokinetics Population 
The PK population will include patients with sufficient dosing and PK data to reliably 
estimate PK parameters as determined by a clinical pharmacologist.   
PK analyses will be performed using the PK population. 
2.7    Pharmacodynamics Population 
The Pharmacodynamics population will include patients with sufficient dosing and 
sufficient pharmacodynamics data to reliably measure pharmacodynamics parameters. 
Pharmacodynamic analyses will be performed using the Pharmacodynamics population. 
 


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3.    HYPOTHESES AND DECISION RULES 
3.1    Statistical Hypotheses 
The primary null hypothesis to be tested is that the proportion of patients achieving ORR4 
per IRF is not different between the brentuximab vedotin (BV) treatment group and the 
physician’s choice treatment group (MTX or bexarotene); i.e., 
H0:  ORR4BV = ORR4Control 
The alternative hypothesis is that ORR4 per IRF in the brentuximab vedotin treatment group 
is higher than that of the physician’s choice group, i.e., 
HA:  ORR4BV > ORR4Control 
The key secondary hypotheses to be tested include: 
 CR rate per IRF is not different between the brentuximab vedotin treatment group 
and the physician’s choice treatment group. 
 PFS is not different between the brentuximab vedotin treatment group and the 
physician’s choice treatment group. 
 Changes in symptom domain per the Skindex-29 assessment tool are not different 
between the brentuximab vedotin treatment group and the physician’s choice 
treatment group. 
3.2    Statistical Decision Rules 
The primary null hypothesis will be tested at a type I error rate of 0.05 (2 sided).  We will 
conclude that brentuximab vedotin treatment can significantly improve the ORR4 compared 
to the physician’s choice (MTX or bexarotene) in patients with CD30+ CTCL if the ORR4 
for the brentuximab vedotin treatment group is statistically significantly higher than that of 
the physician’s choice treatment group in the primary efficacy analysis (refer to Section 
5.8.1.1). 
A fixed sequential testing procedure will be used to test between the primary endpoint and 
the key secondary endpoints; that is, the key secondary endpoints will be tested only if the 
primary endpoint is statistically significant.  


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To test the key secondary endpoints, a weighted Holm procedure(1) will be used.  The 
weighted Holm testing procedure is applied at the final analysis at the 0.05 level (2-sided) 
with weights:  0.7, 0.2, and 0.1 for CR, PFS, and the symptom domain of the Skindex-29, 
respectively.  Once the unadjusted 2-sided p-values 
3,2,1
 , 
i
pi
 are obtained for each 
endpoint, q-values 
3,2,1
 , 
i
qi
 are calculated by dividing the p-values with their respective 
weights 
i
i
i
c
p
q 
, where ci is the weight for endpoint i, i = 1,2,3.  Then the ordered q-values, 
]
3
[
]
2
[
]
1
[
q
q
q


, are compared with 0.05 divided by the sum of weights corresponding to 
that q-value and any larger q-values in a step-down fashion starting with the smallest q-
value.  Specifically, we identify the smallest i such that 



3
]
[
]
[
05
.0
i
j
j
i
c
q
, and claim significance 
for endpoints corresponding to 
]
1
[
]
1
[ ,...,

i
q
q
.  If i = 1, then no endpoint is significant, and if i 
does not exist, then all endpoints are significant. 
Assuming that the probabilities of success for the endpoints are 0.85, 0.55, and 0.50 with a 
0.05 (2-sided) individual alpha level and a multivariate normal distribution with an equal 
correlation of 0.5 among all endpoints, the power to detect at least 1 significant endpoint is 
84%, and the powers to show significance for CR, PFS, and the symptom domain of the 
Skindex-29 using the weighted Holm method are 82%, 48%, and 40%, respectively. 
The weighted Holm testing procedure controls the type I error unconditionally.  The impact 
on power has been evaluated through simulation for a range of correlation and/or success 
probability assumptions.  Holding the success probabilities as assumed, the power to detect 
at least 1 significant endpoint decreases from 89% to 81% when correlation between 
endpoints increases from 0.1 to 0.9.  Holding the correlation as assumed, the power to detect 
at least 1 significant endpoint increases from 79% to 88% when probabilities of success for 
all 3 endpoints increases from 0.8, 0.5, and 0.45 to 0.9, 0.6, and 0.55, respectively. 
Primary and key secondary endpoints are tested at the 0.05 level, and the key secondary 
endpoints are gated by the primary endpoint.  Due to the sequential procedure property, the 
overall type I error rate for testing the primary and key secondary endpoints is strongly 
controlled at the 0.05 level. 
 


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4.    INTERIM ANALYSIS 
4.1    Interim Analysis 
There will be no interim efficacy analysis.   
4.2    Independent Data Monitoring Committee  
An independent data monitoring committee (IDMC) will be established to review safety 
data periodically per the IDMC charter.  The first formal safety review will occur after 
approximately 30 patients have been randomized in total and received at least 1 cycle of 
study treatment, or 6 months after the first patient is randomized (whichever comes first).   
Detailed information regarding the composition of the IDMC and IDMC procedures will be 
provided in the IDMC charter. 
 
5.    STATISTICAL METHODOLOGY 
In general, summary tabulations will be presented that display the number of observations, 
mean, standard deviation, median, minimum, and maximum for continuous variables, and 
the number and percentage (of nonmissing) per category for categorical data, unless 
specified otherwise.   
5.1    Sample Size Justification 
Approximately 124 patients (approximately 62 patients per treatment arm) will be 
randomized to the study (124 patients are targeted for the ITT population).  The sample size 
was calculated to provide 90% power to detect a 30% improvement in ORR4 in the 
brentuximab vedotin treatment group, assuming ORR4 for the MTX or bexarotene alone 
treatment group is 40%.  This calculation is based on a 2-sided 2 test with a significance 
level of  = 0.05, and a 10% dropout rate using nQuery Advisor 7.0.  A minimum of 30 
patients (15 per treatment arm) with pcALCL will be included in the study.   
5.2    Randomization and Stratification  
The randomization scheme will be generated by Millennium.  Before dosing, a 
randomization number will be assigned to each patient.  The randomization schedule will 
also include the study-specific identifiers (company name, protocol name, and protocol 
number) and the date and time the schedule was generated. 


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Patients will be randomized in an overall ratio of 1:1 to Arm 1 (brentuximab vedotin) or 
Arm 2 (physician’s choice of MTX or bexarotene) using an interactive voice response 
system (IVRS), stratified by baseline disease diagnosis (MF or pcALCL).  
5.3    Unblinding 
This is an open-label study; investigators and patients will know their individual treatment 
assignment.  However, aggregate efficacy results by treatment group will be blinded to the 
study team, investigators, patients, and IRF throughout the study conduct.  
5.4    Data Handling 
5.4.1    Methods for Handling Missing Data 
All available efficacy and safety data will be included in data listings and tabulations.  The 
relevance of missing sample data will be assessed.  Data that are potentially spurious or 
erroneous will be examined according to standard data management operating procedures. 
In general, missing data will be treated as missing, and no data imputation will be applied 
unless otherwise specified. 
5.4.2    Definition of Baseline Values 
Unless otherwise specified, the baseline value is defined as the value collected at the time 
closest to, but before, the start of study drug administration.   
5.4.3    Windowing of Visits 
All data will be categorized based on the scheduled visit at which they were collected.  
These visit designators are predefined values that appear as part of the visit tab in the 
electronic case report form (eCRF).   
5.4.4    Justification of Pooling 
All data from all sites will be pooled.  Study center or treatment-by-center interaction will 
not be included in any statistical analysis due to the rarity of the disease and potentially 
limited number of patients at each center. 
5.4.5    Withdrawals, Dropouts, Loss to Follow-up 
No dropouts will be replaced in this study.   


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5.5    Patient Disposition 
The disposition of patients includes the number and percentage of patients for the following 
categories:  patients treated (safety population), patients in the ITT population, patients in 
the All-Enrolled population, patients in the PP population, patients in the Response-
Evaluable population, patients in the PK and Pharmacodynamics populations, patients 
completed, and patients discontinued from the study.  All percentages will be based on the 
number of patients randomized.   
The primary reason for study and treatment discontinuation will also be summarized in this 
table.   
A listing will present data concerning patient disposition. 
5.6    Demographics and Baseline Disease Characteristics 
5.6.1    Demographics 
Demographic and baseline characteristics will be summarized by treatment groups.  
Baseline demographics and baseline characteristics to be evaluated will include age, gender, 
race, height, weight, body surface area (BSA), primary diagnosis (stratification factor), 
Eastern Cooperative Oncology Group (ECOG) performance status (0, 1, 2), and other 
parameters as appropriate. 
No inferential statistics will be generated. 
5.6.2    Medical History 
General medical history and prior medications will be listed for all patients. 
5.7    Treatments and Medications 
5.7.1    Concomitant Medications 
Concomitant medications will be coded by generic term using the 2002 version of the World 
Health Organization (WHO) Drug Dictionary.  The number and percentage of normal 
subjects taking concomitant medications from screening through the end of the on-study 
period will be tabulated by Anatomical Therapeutic Chemical (ATC) classification 
pharmacological subgroup and WHO drug generic term.   
Concomitant procedures will not be coded but will be presented in a data listing. 


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5.7.2    Study Treatments 
Patients will be randomized to receive study treatment, either brentuximab vedotin or 
bexarotene or MTX.  
Brentuximab vedotin will be administered by outpatient intravenous (IV) infusion given 
over approximately 30 minutes on Day 1 of each 21-day cycle.  The dose of brentuximab 
vedotin is 1.8 mg/kg.  Study treatment will be administered through a dedicated IV line and 
cannot be mixed with other medications.  Details on the dosing of study drug can be found 
in the protocol. 
MTX will be given once weekly as a single dose of 5 to 50 mg orally.  Dosages may be 
gradually adjusted to achieve optimal clinical response but must not exceed 50 mg/week.  
Once optimal clinical response is achieved, the MTX dosage should be decreased to the 
lowest effective dose.  For patients deriving benefit, MTX dosing should be continued up to 
48 weeks.   
The recommended initial dose of bexarotene capsules is 300 mg/m2/day.  Bexarotene 
capsules should be taken as a single oral daily dose with a meal.  Bexarotene capsules 
should be continued as long as the patient is deriving benefit, up to 48 weeks.  All patients 
(with normal or normalized triglyceride levels) who are to be given bexarotene should 
receive 7 days of pretherapy with fenofibrate 145 to 200 mg daily starting from Cycle 1 Day 
1 (i.e., the initial dose of bexarotene starts on Day 8 of Cycle 1). 
5.7.2.1    Extent of Exposure  
The exposure to study drug will be characterized by total amount of dose taken in mg, total 
number of dose taken, number of treated cycles, duration of treatment, numbers and 
percentages of patients in treated cycle categories (1, 2…,16), and dose intensity (mg/week).  
Dose intensity (mg/week) will be calculated as total dose administered (mg)/(3 * number of 
treated cycles) where a treated cycle is defined as a 21-day period during which the patient 
received any amount of brentuximab vedotin (scheduled for a single dose in a 21-day cycle), 
MTX (single weekly dose), or bexarotene (single oral daily dose).  The duration of treatment 
is defined as time from the first study dose to 21 days after the last study dose ([last dose date + 
21] – first dose date) of brentuximab vedotin, or time from the first study dose to 7 days after 
the last study dose ([last dose date + 7] – first dose date) of MTX, or time from the first study 
dose to 1 days after the last study dose ([last dose date + 1] – first dose date) of bexarotene.  


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Relative dose intensity (%) will be calculated as (Total Dose Administered/Total Dose 
Expected) * 100 and summarized by treatment group.   
All extent-of-exposure data will be summarized as continuous variables for brentuximab 
vedotin, methotrexate, and bexarotene in the safety population.  Study drug administration 
and exposure information will also be presented in a by-patient data listing. 
5.7.2.2    Treatment Modifications 
Action on study drug (including dose reduction) will be summarized by treatment group, by 
cycle, and overall. 
5.8    Efficacy Analyses 
All efficacy evaluations will be conducted using the ITT population unless specified 
otherwise. 
5.8.1    Primary Efficacy Endpoint 
The primary endpoint of this study is ORR4 per IRF.  ORR4 per IRF is defined as the 
proportion of patients achieving an objective response that lasts at least 4 months (i.e., 
duration from first response to last response is  4 months) on study as determined by an 
IRF.  Patients whose first response occurs after the start of subsequent anti-cancer therapy 
but otherwise meet the primary endpoint criteria will be excluded.  For objective response, a 
patient must achieve a CR or PR. The objective response will be considered maintained for 
patients with a previous CR who experience recurrent disease (i.e. Relapse) unless the 
criteria for progressive disease are met. Determination of objective response will be based 
on a GRS, which consists of skin evaluation (mSWAT assessment) by investigator, nodal 
and visceral radiographic assessment by IRF, and detection of circulating Sézary cells (MF 
only) by IRF.  Skin evaluation is done at screening, before dosing on Day 1 of Cycles 1, 2, 
and 3, at the end of every cycle beginning at Cycle 3, EOT, and at post treatment follow-up 
visits.  Radiographic and blood assessments are less frequent due to ethical and logistical 
considerations.   
For patients without nodal or visceral involvement (as determined by baseline CT scans), 
CT scans will be performed at screening and: 


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 During the cycle following the first skin response, ideally corresponding to the 
confirmation of the skin response, and 6 cycles (a minimum or 4 months) after that 
confirmed skin response. 
 If there is a question of new or progressive disease in the LN/viscera  
For patients with baseline nodal/visceral disease, CT scans will be performed at screening 
and: 
 At the end of Cycles 3, 6, 9, 12, and 15, and per the follow-up schedule until disease 
progression 
 If there is a question of new or progressive disease in the LN/viscera 
 At EOT if the previous CT scan was performed more than 8 weeks before EOT 
A blood sample for Sézary cell enumeration in patients with MF will be collected at 
screening; at the end of Cycles 3, 6, 9, 12, and 15, at EOT, and per the follow-up schedule 
until progressive disease or study closure.   
GRS will be determined by IRF at the end of each cycle beginning at Cycle 3, EOT, and at 
post treatment follow-up visits until disease progression, death or study closure.  The GRS 
assessment at each cycle will incorporate the skin response at that cycle as well as the most 
recent nodal, visceral, and blood responses prior to or at the time of the GRS assessment 
time point. CR or PR per GRS will be confirmed by sustained response in skin per mSWAT 
assessment at the subsequent cycle.   
For patients with skin only disease at baseline, GRS is essentially determined by skin 
response because disease progression in node/viscera/blood is atypical in the presence of a 
continuing skin response. In addition, the primary endpoint is further supported by CT 
confirmation of continued nodal/visceral noninvolvement at the cycle after the first skin 
response and 6 cycles after the first confirmed skin response.  For patients with baseline 
nodal/viscera/blood involvement, GRS assessment at each cycle will incorporate the skin 
response at that cycle as well as nodal, visceral, and blood responses based upon the most 
recent respective compartment assessments prior to the GRS assessment time point. Blood 
results should be within 3 cycles. The CT scans should also be within 3 cycles for patients 
with nodal/viscera involvement. 


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5.8.1.1    Primary Efficacy Analysis 
The primary endpoint, ORR4 per IRF, will be analyzed using a Cochran-Mantel-Haenszel 
test stratified by baseline disease diagnosis (pcALCL or MF) based on the ITT population.  
The 95% confidence interval (CI) of the difference in ORR4 between the 2 treatments will 
be provided.  No imputation will be conducted for missing data.  Patients who do not have 
any post baseline response assessment as specified in the protocol, or patients who have no 
response before dropout, will be counted as nonresponders. 
Sensitivity analyses will be performed for ORR per IRF in the study as well as ORR4 per 
IRF defined by the response criteria used for Romidepsin approval and published by 
Whittaker 2010.(2)  Analysis for ORR4 per IRF defined by the response criteria used for 
Romidepsin approval will also be performed for MF patients only.  Sensitivity analyses will 
be performed for ORR and ORR4 based on investigator’s GRS assessment as well. 
Another sensitivity analysis will be conducted for ORR4 per IRF in the ITT population to 
assess the robustness of the primary analysis’s use of most recently available CT scans and 
blood assessments for GRS.  For patients with baseline nodal/visceral/blood disease, the 
sensitivity analysis will only use GRS assessed at time points with concurrent 
nodal/viscera/blood component assessments as specified in the protocol SOE while for 
patients with skin-only disease, the analysis will use the same GRS assessment frequency as 
the primary analysis.    
5.8.1.2    Other Analysis 
The same analysis on ORR4 per IRF using a Cochran-Mantel-Haenszel test stratified by 
baseline disease diagnosis (pcALCL and MF) will be performed for the All-Enrolled 
population, Response-Evaluable population, as well as the PP population.  The 95% CI of 
the difference in ORR4 between the 2 treatments will be provided.  No imputation will be 
conducted for missing data.  Patients who do not have any post baseline response assessment 
as specified in the protocol, or patients who have no response before dropout, will be 
counted as nonresponders. 
Similarly, analyses will also be performed for the primary endpoint on, but not limited to, 
the following subgroups (with at least 10 patients in each subgroup per treatment arm), as 
applicable: 


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Subgroup  
Group Definition 
Baseline disease diagnosis  
MF, pcALCL 
ECOG performance status  
0, 1, 2  
Gender  
Female, male  
Age  
< 65 years, ≥ 65 years  
Region  
North America, Europe, Asia, and rest of world  
Race  
White, nonwhite  
Physician’s choice (bexarotene) 
Brentuximab vedotin vs bexarotene  
Physician’s choice (MTX) 
Brentuximab vedotin vs MTX 
 
Concordance between the IRF and investigator’s GRS assessment for ORR4 will be 
assessed by percent positive, negative, and overall agreement. 
5.8.2    Key Secondary Efficacy Endpoints 
CR rate, PFS, and changes in symptom domain per Skindex-29 assessment tool are 
designated as key secondary endpoints. 
CR rate is defined as the proportion of patients who achieved a CR as their best response on 
study as determined by an IRF.  A sensitivity analysis will be performed for CR per the 
investigator’s GRS assessment.  PFS is defined as the time from randomization until PD per 
IRF or death due to any cause, whichever occurs first.  The symptom domain of Skindex-29 
includes 7 items:  1) My skin hurts; 2) My skin condition burns or stings; 3) My skin itches; 
4) Water bothers my skin conditions (bathing, washing hands); 5) My skin is irritated; 6) My 
skin is sensitive; and 7) My skin condition bleeds.  The following scoring system is used for 
all items:  never (0), rarely (1), sometimes (2), often (3), and always (4).  The total score for 
all 7 items will be converted to a scale of 0 (no impact on quality of life) to 100 (maximum 
impact on quality of life) by linear transformation.  The questionnaire is administered on 
Day 1 of Cycles 1, 2, 4, 6, 8, 10, 12, 14, and 16. 
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5.8.2.1    Analysis on Key Secondary Efficacy Endpoint  
5.8.2.1.1    Handling of Missing Assessment and Censoring for Analysis of 
Progression-free Survival 
Disease assessment data should be collected according to the intended schedule of 
assessment, and the date of PD/response should be assigned based on the time of the first 
documentation of PD/response regardless of violations or discontinuation of study drug.  
For the PFS endpoint, patients who are lost to follow-up, withdraw consent, or those who 
discontinue treatment due to undocumented PD after the last adequate disease assessment 
will be censored at the last disease assessment.  If death or PD occurs after a missed visit, 
then the patient is treated as progressed at the date of death or PD.  Patients without baseline 
and/or no sufficient post baseline data for disease assessment and with no death recorded 
will be censored at the date of randomization.  If PD is documented between scheduled 
visits, then the date of the documented PD is the date of progression.  If the patient starts 
new antineoplastic therapy before PD, then the patient is treated as progressed at the date of 
assessment at which PD was documented. 
The following sensitivity analyses will be performed for PFS to evaluate the robustness of 
treatment effects.  They will be performed on the basis of 1 alteration at a time, not on 
combined alterations, unless specified otherwise.  
 If the PD is documented between scheduled visits, then the date of the next 
scheduled visit is the date of progression.   
 If treatment is discontinued for undocumented PD, then the patient is treated as 
progressed at the date of last disease assessment. 
 Patients who start new antineoplastic therapy before PD will be censored at the date 
of the last disease assessment. 
 Patients who start new antineoplastic therapy before PD will be treated as progressed 
at the date of the last disease assessment.  
 If death or PD occurs after more than 1 missed visit, then the patient will also be 
censored at the last disease assessment before the missed visits.  
Another sensitivity analysis will be conducted for PFS per IRF in the ITT population to 
assess the robustness of the primary analysis’s use of most recently available CT scans and 


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blood assessments for GRS.  For patients with baseline nodal/visceral/blood disease, the 
sensitivity analysis will only use GRS assessed at time points with concurrent 
nodal/viscera/blood component assessments as specified in the protocol SOE while for 
patients with skin-only disease, the analysis will use the same GRS assessment frequency as 
the primary analysis.     
5.8.2.1.2    Key Secondary Efficacy Analysis 
Because a fixed sequential testing procedure is used between the primary endpoint and the 
key secondary endpoints, the key secondary endpoints will be tested only if the primary 
endpoint is statistically significant.  The weighted Holm procedure(1) will be used for testing 
the key secondary endpoints.  See Section 3.2 for details of the statistical decision rules. 
Stratified log-rank test statistics will be used to compare PFS 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 time-to-
event endpoints for each treatment.  Median times (if estimable), along with the 2-sided 
95% CIs, will be presented.  
Assuming the median PFS for the brentuximab vedotin treatment group and the physician’s 
choice treatment group (MTX or bexarotene) are 9 and 6 months, respectively, the number 
of PFS events is projected to be approximately 101 at the time of the planned final analysis.  
This is based on an approximately 2-year enrollment period, a dropout rate of 10%, and an α 
level of 0.01 (2-sided), as specified in Section 3.2 per the weighted Holm procedure. 
Comparison of the CR rates between the 2 treatment groups will be conducted using the 
stratified Cochran-Mantel-Haenszel test.  The 95% CI of the difference in the response rates 
between the 2 treatments will also be provided.  No imputation will be conducted for 
missing data.  Patients who do not have any post baseline response assessment as specified 
in the protocol will be counted as nonresponders. 
For skin symptoms (Skindex-29), the primary analysis will be comparing the mean symptom 
reduction between brentuximab vedotin and the control arms.  ‘Symptom reduction’ is 
defined for each patient as the maximum reduction from baseline (sum of the 7 items related 
to skin symptoms normalized to a 1-100 scale).  The analysis of covariance (ANCOVA) 
model controlling for baseline covariates (treatment group, baseline score, disease diagnosis, 
ECOG) will be employed for the analysis.  As a sensitivity analysis, comparison of the 2 
treatment groups will be conducted using the linear mixed model with repeated measures at 


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each time point specified in the protocol SOE.  The estimation of variancecovariance 
matrix and statistics such as Akaike information criterion (AIC) and Bayesian information 
criterion (BIC) will be included in evaluating the linear mixed model.  The 95% CIs of the 
difference of the changes from baseline between the 2 treatments will also be provided.   
The total score for skin symptoms (Skindex-29) will be imputed with the mean of the other 
items if there is no more than 1 missing item; otherwise, it will be considered invalid and 
excluded from the analysis.   
In addition, the entire distribution of change in Skindex-29 symptom scores at the individual 
patient level will be presented for each arm, respectively.  The patient’s largest score of 
change from baseline will be determined first, and then a cumulative distribution function 
(CDF) curve will be used to display the cumulative percentage of patients experiencing that 
change.  It is noteworthy that the higher scores in Skindex-29 indicate worse levels of 
symptoms; therefore, the patient’s largest score of change from baseline needs to be 
presented in the format of “reduction in scores” (e.g., a -10 of change needs to be presented 
as +10 in reduction) on the X-axis.  Categorical definitions of responders or minimum 
important difference (MID) will be determined by scrutinizing these CDF curves. 
Primary analyses of key secondary endpoints will be performed based on the ITT 
population.  Sensitivity analyses will be performed for CR using similar statistical analyses 
based on the Response-Evaluable population. 
5.8.3    Other Secondary Efficacy Endpoints  
Other secondary endpoints include EFS, DOR, and duration of skin response.  EFS is 
defined as the time from randomization until any cause of treatment failure:  PD, 
discontinuation of treatment for any reason, or death due to any cause, whichever occurs 
first.  DOR in subjects with a confirmed response is the time between first documentation of 
response and PD.  Duration of skin response is the time between the first skin response and 
PD in skin.    
5.8.3.1    Other Secondary Efficacy Analysis 
The ITT principle will be used to determine the event time or censoring time for the EFS 
analysis.  Disease assessment data should be collected according to the intended schedule of 
assessment, and the date of progression should be assigned based on the time of the first 
documentation of PD regardless of violations or discontinuation of study drug.  


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For EFS, patients who are lost to follow-up will be censored at last disease assessment.  
Patients who withdraw consent or start new antineoplastic therapy will be treated as if 
experiencing an EFS event.  Patients without baseline and/or sufficient post baseline data for 
disease assessment and no treatment discontinuation or death recorded will be censored at 
the date of randomization.  Analyses of EFS will be performed based on the ITT population. 
DOR will be analyzed for the subgroup of patients with confirmed response (CR or PR) in the 
ITT population.  Patients who are lost to follow-up, withdraw consent, or discontinue 
treatment due to undocumented PD after the last adequate disease assessment will be 
censored at the last disease assessment.  If the patient starts new antineoplastic therapy 
before PD, the patient is treated as progressed at the date of assessment at which PD was 
documented. 
Duration of skin response will be analyzed for the subgroup of patients with skin response (CR 
or PR in skin) in the ITT population.  Patients who are lost to follow-up, withdraw consent, or 
discontinue treatment due to undocumented PD in skin after the last adequate skin 
assessment will be censored at the last skin assessment.  Patients without sufficient skin 
assessment data after the initial skin response and with no death recorded will be censored at 
the date of the initial skin response.  If the patient starts new antineoplastic therapy before 
skin PD, then the patient is treated as progressed at the date of the skin assessment at which 
PD in skin was documented. 
EFS will be analyzed similarly as the key secondary efficacy endpoint PFS as described in 
Section 5.8.1.  DOR and duration of skin response will be summarized descriptively using 
the Kaplan-Meier method. 
5.9    Pharmacokinetic, Pharmacodynamic, and Biomarker Analysis 
5.9.1    Pharmacokinetic Analyses 
The PK of the antibody drug-conjugate (brentuximab vedotin), total antibody, and 
unconjugated drug (MMAE) will be derived from serum concentration versus time data for 
all patients who met 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.   
.  
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5.9.2    Pharmacodynamic Analyses  
Absolute and change from baseline values of circulating pharmacodynamic biomarkers such 
as soluble CD30 (sCD30), thymus and activation regulated chemokine (TARC or CCL17), 
and CTACK (CCL27) will be summarized by time point using descriptive statistics (e.g., 
number of patients, mean, standard deviation, median, minimum, maximum), as applicable.  
Descriptive statistics will also be provided to summarize biopsy pharmacodynamic 
parameters, such as pHisH3, and change from baseline values, as applicable. 
5.9.3    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. 
The relationship between antibody status and efficacy and/or safety will be explored. 
5.9.4    Biomarker Analysis 
5.10    Analyses of Patient-Reported Outcomes and Health Economics  
PRO endpoints include subscales of Skindex-29 and global and subscale scores of the EQ-
5D and FACT-G questionnaires.  The health economic endpoint includes medical resource 
utilization (MRU) enumerations.  Furthermore, the symptom domain of Skindex-29 is one 
of the key secondary endpoints.  Its analysis is described separately in Section 5.8.2.1.2.  
The analyses of the remaining PRO and MRU endpoints and the additional analysis of 
Skindex-29 symptom scores are described below. 
Analyses of PROs and health economics will be performed using the ITT population. 
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5.10.1    Patient-Reported Outcomes Analysis 
All PRO scores will first be scaled into numeric scores following published or prespecified 
scoring guidelines for each PRO instrument employed in this trial.  The maximum allowed 
number of missing items to adequately measure a domain is instrument specific and found in 
the relevant guidelines.  Missing pattern of PRO data (noncompliance, missing, dropout) 
will be examined and summarized.  Additional imputation methods, such as last observation 
carried forward, or multiple imputation may be considered if appropriate. 
For Skindex-29 (global, symptoms, emotions, and functioning), EQ-5D (global, EQ-5D 
descriptive system and the EQ visual analogue scale), and FACT-G (global, physical well-
being, social/family well-being, emotional well-being, and functional well-being), scores 
will be summarized in descriptive statistics for the 2 treatment groups over time. 
5.10.2    Health Economics Analysis Using Medical Resource Utilization 
MRU data are collected through the medical encounter page of the eCRF.   
MRU data will be summarized in descriptive statistics of hospitalization (length of stay, 
inpatient, outpatient, and reason), number of missing days from work or other activities by 
subject, and care-giver for the 2 treatment groups. 
5.11    Safety Analyses 
Safety evaluations will be based on the incidence, severity, type of adverse events (AEs), 
clinically significant changes, or abnormalities in the subject’s physical examination, vital 
signs, ECOG performance status, and clinical laboratory results.   
These analyses will be performed using the safety population. 
5.11.1    Adverse Events 
5.11.1.1    Adverse Events 
Treatment-emergent AEs (TEAEs) will be tabulated by primary System Organ Class (SOC), 
High Level Term (HLT), and Preferred Term (PT).  A TEAE is defined as any AE that 
occurs after administration of the first dose of study drug and up through 30 days after the 
last dose of study medication.  AEs will be tabulated according to the most recent version 
(Version 8.1 or higher) of the Medical Dictionary for Regulatory Activities (MedDRA) by 
SOC, HLT, and PT and will include the following categories:  


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 TEAEs 
 Study drug-related TEAEs 
 Grade 3 or higher TEAEs 
 Grade 3 or higher drug-related TEAEs 
 TEAEs resulting in study drug discontinuation 
 Serious AEs (SAEs), including study drug-related SAEs 
 AEs of peripheral neuropathy identified by the broad search MedDRA SMQ 
“Peripheral neuropathy” 
 
Additional analyses of peripheral neuropathy may also be presented.  
The most commonly reported TEAEs (i.e., those events reported by  10% of all patients) 
will be tabulated by HLT and PT.   
5.11.1.2    Serious Adverse Events 
The number and percentage of subjects experiencing at least 1 treatment-emergent SAE will 
be summarized by MedDRA primary SOC, HLT, and PT. 
In addition, a by-subject listing of the SAEs will be presented (the subject listing will 
contain all SAEs regardless of treatment-emergent status). 
5.11.1.3    Deaths 
A by-subject listing of the deaths will be presented.  All deaths occurring on-study and 
during follow-up will be displayed (regardless of treatment-emergent status). 
5.11.1.4    Adverse Events Resulting in Discontinuation of Study Drug 
A by-subject listing of AEs resulting in discontinuation of study drug will be presented.   
5.11.2    Laboratory Data 
For the purposes of summarization in both the tables and listings, all laboratory values will 
be converted to standardized units.  If a lab value is reported using a nonnumeric qualifier 


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(e.g., less than (<) a certain value, or greater than (>) a certain value), the given numeric 
value will be used in the summary statistics, ignoring the nonnumeric qualifier.   
If a subject has repeated laboratory values for a given time point, the value from the last 
evaluation will be used. 
The parameters to be analyzed are as follows: 
 Hematology:  hemoglobin, hematocrit, platelet count, neutrophils (absolute 
neutrophil count [ANC]), lymphocytes, monocytes, eosinophils, basophils, and 
leukocyte counts 
 Clinical chemistries:  blood urea nitrogen (BUN), creatinine, bilirubin (total), urate, 
lactate dehydrogenase (LDH), phosphate, gamma-glutamyl-transferase (GGT), 
albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), glucose, sodium, potassium, calcium, chloride, CO2,  
magnesium, amylase, and lipase  
 Urinalysis:  turbidity and color, pH, specific gravity, protein, ketones, bilirubin, 
blood, nitrite, urobilinogen, glucose, leukocytes 
 Lipid panel:  total cholesterol, high-density lipoprotein (HDL), low-density 
lipoprotein (LDL), triglycerides 
 Thyroid panel:  thyroid-stimulating hormone (TSH), triiodothyronine (T3), and 
thyroxine (T4) 
 Immune reconstitution assessments:  lymphocyte counts, phenotypic T, B, and 
natural killer (NK) cell subsets (CD4+ T cell counts, CD8+ T cell counts, CD8/CD4 
ratio, CD19+ B cell counts), and NK cells (CD3− CD56 CD16+ vsCD3− CD56 CD16-) 
 Other:  hemoglobin A1C 
The actual values in clinical laboratory parameters (hematology and serum chemistry, 
including lipid panel and thyroid panel) will be summarized at baseline and over time by 
treatment group; summary statistics for change from baseline in laboratory parameters will 
also be presented.   


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In addition, hematology and serum chemistry parameters will be summarized in shift tables 
comparing the baseline visit to the worst post baseline value (National Cancer Institute 
[NCI] Common Terminology Criteria for Adverse Events [CTCAE] grade, version 4.03, 
effective 14 June 2010(3)) for the following parameters. 
 Hematology:  hemoglobin, , platelet count, neutrophils (absolute neutrophil count 
[ANC]), lymphocyte counts, and leukocyte counts 
 Clinical chemistries:  bilirubin (total), alkaline phosphatase (ALP), aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), amylase, and lipase 
Urinalysis results will be presented in a listing. 
5.11.3    Electrocardiograms 
Electrocardiogram results will be presented in a listing. 
5.11.4    Vital Signs 
The actual values of vital sign parameters, including blood pressure (determined with the 
patient in a seated position after the patient has been sitting quietly for 5 minutes), heart rate, 
and oral temperature, when available, will be summarized over time.   
5.11.5    Eastern Cooperative Oncology Group Performance Status 
Eastern Cooperative Oncology Group performance status and change from baseline will be 
summarized.  Shifts from baseline to the worst postbaseline score will be tabulated by treatment 
group.  Patients who have ECOG performance scores that worsen postbaseline compared to 
baseline will be listed with other pertinent patient information. 
5.11.6    Other Safety Assessments 
Pregnancy testing results will be presented in a by-patient listing. 
Additional safety analyses may be performed to most clearly enumerate rates of toxicities 
and to further define the safety profile of study drugs. 
 
6.    CHANGES TO PLANNED ANALYSES FROM PROTOCOL 
Not applicable 


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7.    PROGRAMMING CONSIDERATIONS 
7.1    Statistical Software  
SAS version 9.1 (or higher) will be used for all analyses.   
7.2    Rules and Definitions 
Subject populations are defined in Section 2. 
Baseline values are defined in Section 5.4.2. 
Treatment-emergent AEs are defined in Section 5.11.1.1. 
 
8.    REFERENCES 
1. 
Holm S. A simple sequentially rejective multiple test procedure. Scandinavian 
Journal of Statistics 1979;6:65-70. 
2. 
Whittaker SJ, Demierre MF, Kim EJ, Rook AH, Lerner A, Duvic M, et al. Final 
results from a multicenter, international, pivotal study of romidepsin in refractory 
cutaneous T-cell lymphoma. Journal of Clinical Oncology 2010;28(29):4485-91. 
3. 
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.