Conditions: Relapsed or Refractory Hodgkin Lymphoma Relapsed or Refractory Anaplastic Large-cell Lymphoma
Keywords: Pediatric Lymphoma Hodgkin Anaplastic Large-cell Relapsed Refractory Drug therapy
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 36
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the safety and pharmacokinetics, and determine the pediatric maximum tolerated dose and/or or recommended phase 2 dose of brentuximab vedotin.

Detailed description:
The drug being tested in this study is called brentuximab vedotin. Brentuximab vedotin is being tested to treat children who have relapsed or refractory (r/r) anaplastic large-cell lymphoma (sALCL) or Hodgkin lymphoma (HL). This study will look at the maximum tolerated dose and/or recommended phase 2 dose, safety and pharmacokinetics of brentuximab vedotin along with overall response of people who took brentuximab vedotin.

The study enrolled 36 patients. In the phase 1 portion of the study, 12 participants were enrolled to receive brentuximab vedotin 1.4-1.8 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle, until there was evidence of disease progression or unacceptable toxicity.

Once the maximum tolerated dose and/or recommended phase 2 dose and pharmacokinetics of brentuximab vedotin was reached, participants were enrolled by diagnosis into two phase 2 study arms: relapsed or refractory sALCL or relapsed or refractory HL and received brentuximab vedotin 1.8 mg/kg as 30-minute IV on Day 1 of every 21-day cycle for up to 16 cycles. One participant received a maximum of 20 cycles at the joint discretion of the sponsor and the investigator for continued clinical benefit.

This multicenter trial is being conducted worldwide. The overall time to participate in this study is approximately 5 years. Participants made multiple visits to the clinic, and were contacted by telephone every 12 weeks for 12 months after the end of treatment (EOT) for progression free survival and then every 6 months until death, study closure, or 2 years after enrollment of the last participant for overall survival.

Arms:
arm 1: Brentuximab vedotin 1.4 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle, until there was evidence of disease progression or unacceptable toxicity. Dose was escalated up to 1.8 mg/kg using a 3 + 3 dose escalation design to determine a maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) depending upon the dose limiting toxicity (DLT). arm 2: Brentuximab vedotin 1.8 mg/kg, 30-minute IV infusion, Day 1 of every 21-day cycle, until there is evidence of disease progression or unacceptable toxicity (Up to 16 cycles). Treatment with brentuximab vedotin beyond 16 cycles was permitted at the joint discretion of the sponsor and the investigator for those participants experiencing continued clinical benefit.

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

Protocol document:
Prot_001.pdf: 
This may include, but is not limited to, redaction of the following: 


•
Title: A Phase 1/2 Study of brentuximab vedotin (SGN-35) in Pediatric Patients With Relapsed or 
Refractory Systemic Anaplastic Large-Cell Lymphoma or Hodgkin Lymphoma
NCT Number: NCT01492088
Protocol Approve Date: 12 June 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 or company confidential information. 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.


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Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
Confidential
2
Rationale for Amendment 4
The length of the follow-up period has been changed to align with the content of the 
pediatric investigation plan (PIP).  The PIP states that patients will be followed for safety 
and survival for 2 years after enrollment. References to follow-up in Amendment 4 have 
been revised to state that patients will be followed for progression-free survival and overall 
survival (OS) every 12 weeks for 12 months after the End of Treatment (EOT) visit.  
Thereafter, assessment for OS will continue every 6 months until the sooner of death or 
study closure or a maximum of 2 years after enrollment of the last patient.
Protocol C25002 Amendment 4 describes the study procedures for patients who continue to 
receive brentuximab vedotin after Cycle 16 and further clarifies several other study 
procedures associated with study conduct.  
The amended protocol clarifies the primary endpoint for the phase 2 portion of the study as 
best overall response rate (ORR) (which was previously written as ORR).  
The following changes have been made to the inclusion/exclusion criteria: The inclusion 
criterion for total bilirubin has been revised to include patients with total serum bilirubin ≤ 3 
times the upper limit of the normal range (ULN) if the abnormal value is due to indirect 
hyperbilirubinemia due to Gilbert’s disease.  Patients with elevated alanine aminotransferase 
(ALT) or aspartate aminotransferase (AST) values 5 times the ULN may be enrolled if the 
elevation can be reasonably ascribed to the presence of metastatic disease in the liver.  The 
exclusions of previous allogeneic stem cell transplant or autologous stem cell infusion have
been changed from within 6 months and 6 weeks before the first dose of study drug, 
respectively, to within 3 months and 4 weeks before the first dose of study drug, 
respectively.  These changes make it possible for patients to receive treatment sooner but 
with a sufficient amount of time for posttransplant recovery. This amendment also includes 
a change to the exclusion criterion for cytochrome P450 (CYP) 3A4 inhibitors to exclude
both strong and listed moderate inhibitors of CYP3A4 within 2 weeks before the first dose 
of study drug, and a change to the timing for the exclusion of corticosteroids.
The following potential risks have been added to the Risks in Children section to align with 
updates to the safety profile of brentuximab vedotin: Stevens-Johnson syndrome (SJS), 
pancreatitis, hepatotoxicity (elevated AST and ALT). 
The amendment also updates the protocol to align with the current Millennium protocol 
standards, and clarifies the collection and reporting requirements for serious adverse events 
(SAEs) that are considered to be drug related to align with the current guidelines of the 
Millennium Department of Pharmacovigilance.  
Purposes for Amendment 4
The purposes of this amendment are to:
Major Content Changes

Revise the length of the follow-up period to align with the PIP

Clarify that the primary endpoint of the phase 2 study is best ORR


Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
Confidential
3

Add safety language regarding the potential risk of SJS 

Add safety language regarding the potential risk of pancreatitis

Add safety language regarding the potential risk of hepatotoxicity

Revise the total bilirubin inclusion criterion to include patients with abnormal values 
due to indirect hyperbilirubinemia due to Gilbert’s disease

Revise study eligibility criterion regarding elevated ALT and AST values due to the 
presence of metastatic disease in the liver

Revise the washout period for systemic corticosteroid treatment in the exclusion 
criteria

Revise the required minimum time between previous allogeneic or autologous stem 
cell transplantation and the first dose of study drug

Add to the exclusion criteria any history of progressive multifocal 
leukoencephalopathy

Revise the CYP3A4 exclusion criterion to exclude listed moderate inhibitors of 
CYP3A4
Minor Content Changes

Modify the contraception language regarding abstinence to align with company 
standards

Revise language regarding dose adjustments for a ≥ 10% weight change; add language 
for patients weighing more than 100 kg

Correct the units of measurement for platelet count, absolute neutrophil count, and 
white blood cell count

Remove the restriction on the use of polyethylene infusion bags for dilution of 
brentuximab vedotin, as previously described in Administrative Letter 2

Update packaging and labeling instructions for brentuximab vedotin

Revise the timing for the development assessment and Tanner Scale

Permit occasional changes in the timing of tests and procedures without permission 
from the project clinician

Revise language regarding premedication for infusion-related reactions to allow the use 
of corticosteroids

Add an assessment for immune reconstitution at the EOT visit, as previously described 
in Administrative Letter 1, and add a window to perform immune reconstitution

Revise the section on Immune Reconstitution; revise the section heading and add 
separate sections for Immunogenicity Assessment and Tumor Specimen Measurements

Add language regarding reporting requirements for SAEs

Delete redundant SAE reporting language, update the period for reporting SAEs to 
Millennium from 1 calendar day to 24 hours, and update SAE reporting contact 
information

Add language regarding the collection of events of peripheral neuropathy


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Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
Confidential
5
Adminstrative and Editorial Changes 

Remove Section 14.4, Strong Cytochrome P450 3A4 (CYP3A4) Inhibitors (the list of 
prohibited CYP3A4 inhibitors is located in the Study Manual)

Replace references to PPDI with Millennium Department of Pharmacovigilance or
designee

Add abbreviations to table footnotes in the Schedule of Events

Add bone marrow (BM) and United States Pharmacopeia (USP) to the List of 
Abbreviations and Glossary of Terms

Update the name of the Group Head on the title page

Replace references to medical monitor or study monitor with project clinician

Correct typographical errors, punctuation, grammar, and formatting
For specific examples of changes in text and where the changes are located, see 
Section 14.7.


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Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
Confidential
7
Overview of Study Design:  This is a phase 1/2, open-label, single-agent, multicenter, 
dose-escalation study of brentuximab vedotin in pediatric patients with relapsed or refractory sALCL 
or HL for which standard, curative, life-prolonging, or palliative treatment does not exist or is no 
longer effective.  Patients with primary mediastinal B cell lymphoma will be eligible during phase 1.  
The primary objectives of the study are to assess the safety and pharmacokinetics, and determine the 
pediatric MTD and/or RP2D of brentuximab vedotin in pediatric patients.  In addition, the 
immunogenicity and antitumor activity of brentuximab vedotin will be evaluated in eligible patients.
Overall response will be evaluated beginning after 2 cycles of therapy.  Objective response over the 
course of the study will be assessed by an independent review facility (IRF) according to the 
International Working Group (IWG) Revised Response Criteria for Malignant Lymphoma.(1)
Patients, including those who achieve a CR, PR, or stable disease may receive brentuximab vedotin
for up to 16 cycles.  Treatment with brentuximab vedotin beyond 16 cycles may be permitted at the 
joint discretion of the sponsor and the investigator for those patients experiencing continued clinical 
benefit.  Following administration of the final dose of brentuximab vedotin, patients will be 
monitored for adverse events for a minimum of 30 days.  Patients will be followed for progression-
free survival (PFS) and overall survival (OS) every 12 weeks for 12 months after the end of 
treatment (EOT) visit.  Thereafter, assessment for OS will continue every 6 months until the sooner 
of death or study closure or a maximum of 2 years after enrollment of the last patient. Patients who
remain on treatment after Cycle 16 will be followed according to the above schedule or until study 
closure.
Sample Size Determination:  Approximately 42 evaluable patients will be enrolled in this study.  In 
the phase 1 portion of the study, at least 12 patients with relapsed or refractory CD30+ malignancies 
will be enrolled in 2 planned dose cohorts (3-6 patients per cohort), according to the standard 3 + 3 
dose escalation scheme.
Once the pediatric MTD and/or RP2D have been reached, patients will be enrolled by diagnosis into 
two phase 2 study arms: relapsed or refractory sALCL or relapsed or refractory HL.  A sufficient 
number of patients will be enrolled in the phase 2 portion of the study to have at least 15 evaluable 
patients with sALCL (including patients treated at the RP2D during phase 1), of whom at least 
10 patients are in first relapse, and at least 15 evaluable patients with HL (including patients treated 
at RP2D during phase 1).
The sample size is not based on statistical consideration.  Based on the exact binomial confidence 
interval (CI) calculation, 10 responses observed from 15 evaluable patients (overall response rate of 
66.7%) will provide 95% CI (38%, 88%).
Study Population:  The study will enroll male or female patients aged 2 to <18 years, with relapsed 
or refractory sALCL or HL (5 to <18 years for HL), and radiographically or clinically evaluable 
tumor per the IWG revised response criteria (patients diagnosed with any relapsed or refractory 
CD30+ hematological malignancy may be included in phase 1 of the study).  Anaplastic lymphoma 
kinase (ALK) status must be documented for patients with sALCL.  Patients with HL must have 
failed systemic chemotherapy, either as induction therapy for advanced-stage disease or salvage 
therapy after initial radiotherapy for early stage disease, and be ineligible for, refused, or previously 
received a stem cell transplant.  Patients with sALCL must be beyond first remission or refractory to 
front-line chemotherapy.
Patients with a current diagnosis of primary cutaneous ALCL, or who received any of the following:
allogeneic stem cell transplant <3 months before the first dose of study medication, systemic therapy 
for chronic graft versus host disease, immunosuppressive therapy, any anti-CD30 antibody, 
therapeutic monoclonal antibodies (mAbs) within the longer of 6 weeks or 5 plasma half-lives, local 
palliative radiation therapy within 14 days, or radiation therapy to more than 25% of bone 


Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
Confidential
8
marrow-containing spaces within 84 days prior to first dose, or prior autologous hematopoietic stem 
cell infusion <4 weeks prior to first study dose will be excluded from the study.  Patients with 
symptomatic cardiac disease, history of another primary malignancy not in remission for at least 
3 years (excluding nonmelanoma skin cancer and cervical carcinoma in situ on biopsy or a squamous 
intraepithelial lesion on Pap smear), or known cerebral/meningeal disease, including signs or 
symptoms or any history of PML, will be excluded.
Duration of Study:  Following a screening period to determine eligibility, patients may receive up 
to 16 cycles (21 days per cycle) of treatment with brentuximab vedotin.  Patients will be followed for 
at least 2 years from enrollment, until the sooner of death or study closure.  Extended brentuximab 
vedotin therapy, beyond 16 cycles, may be permitted at the joint discretion of the sponsor and 
investigator for those patients experiencing continued clinical benefit.  The overall expected study 
duration is approximately 5 years.


Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
Confidential
9
Phase 1 Study Schema – Dose Escalation
Enter 3 additional
patients at
1.4 mg/kg dose
> 1 DLT in
6 patients
1 DLT in
6 patients
Enter 3 patients
SGN-35 1.4 mg/kg
Enter 3 patients
1.8 mg/kg
Reduce dose
to 0.9 mg/kg
0 or 1 DLT
Enter 3 additional
patients at
1.8 mg/kg dose
0 or 1 DLT in 6 patients
MTD/RP2D =
1.8 mg/kg
>1 DLT
MTD/RP2D =
1.4 mg/kg
0 DLT
1 DLT
2-3 DLTs


Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
Confidential
10
Phase 2 Study Overview Diagram
Within 28 
days of 
enrollment
Cycles 1 & 2
21 days each
Infusion of 
brentuximab
vedotin
on Day 1
Subsequent 
courses up to 
16 cycles
Repeat 
disease 
evaluation at 
end of
Cycles 4, 7, 
10, 13, 16, and 
at EOT
CR, PR, or SD
YES
CR, PR, or SD
NO
Disease 
evaluation at 
end of Cycle 2
30 7 days 
from last 
dose of 
brentuximab
vedotin
Disease 
evaluation
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
S
C
R
E
E
N
I
N
G
E
N
R
O
L
L
M
E
N
T


Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
Confidential
11
Schedule of Events
Screening
Enrollment 
(date of 
first dose)
Cycles 1–16
Cycle 17 and 
Beyond (for 
patients who 
continue 
beyond 
16 cycles)
EOTa
PFSFUP/
OSFUPb
Each 21-Day Cycle
Additional 
Assessments 
at Cycles 2, 
4, 7, 10, 13, 
and 16 only
Day (D)
D1c
D2
D3
D5
D14
D15-21 of 
Cycle
D1c
D15-21 
of 
Cycle
30 days 
post last 
dose
q 12 wks for 
12 months/
q 6 months 
thereafter
Visit Window
-28 to D1
7 days
7 days
Screening/ Baseline
Informed consent
X
Enrollment
Inclusion/exclusion
X
Tumor specimen CD30 
expressiond
X
Demographics
X
Medical history
X
Safety 
Assessments
Height 
Xe
Xe
Weight
Xe
Xe
X
Pregnancy testf
X
X
X
Vital signs
X
Xg
Physical examincluding 
focused lymphoma 
assessment
X
Xh
X
Lansky/Karnofsky Scalei
X
X
X
Hematology/serum 
chemistryj
X
Xj
X
12-lead ECGk
X
X
X


Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
Confidential
12
Screening
Enrollment 
(date of 
first dose)
Cycles 1–16
Cycle 17 and 
Beyond (for 
patients who 
continue 
beyond 
16 cycles)
EOTa
PFSFUP/
OSFUPb
Each 21-Day Cycle
Additional 
Assessments 
at Cycles 2, 
4, 7, 10, 13, 
and 16 only
Day (D)
D1c
D2
D3
D5
D14
D15-21 of 
Cycle
D1c
D15-21 
of 
Cycle
30 days 
post last 
dose
q 12 wks for 
12 months/
q 6 months 
thereafter
Visit Window
-28 to D1
7 days
7 days
Disease 
Assessment
Development assessment 
and Tanner Scalel
X
Xl
X
Dedicated CT of chest  
X
X
Xm
Xn
Xo
MRI of  neck, abdomen, 
pelvis
X
X
Xm
Xn
Xo
B symptom assessment
X
X
X
PET
X
Xp
Bone marrow aspirate and 
biopsy
Xq
Xr
Xr
Disease progression status 
and subsequent anticancer 
treatment
X


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CCI


Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
Confidential
14
Screening
Enrollment 
(date of 
first dose)
Cycles 1–16
Cycle 17 and 
Beyond (for 
patients who 
continue 
beyond 
16 cycles)
EOTa
PFSFUP/
OSFUPb
Each 21-Day Cycle
Additional 
Assessments 
at Cycles 2, 
4, 7, 10, 13, 
and 16 only
Day (D)
D1c
D2
D3
D5
D14
D15-21 of 
Cycle
D1c
D15-21 
of 
Cycle
30 days 
post last 
dose
q 12 wks for 
12 months/
q 6 months 
thereafter
Visit Window
-28 to D1
7 days
7 days
according to the above schedule or until study closure.  
c All procedures performed on Day 1 of each cycle should be performed prior to dosing unless otherwise specified.
d Tumor tissue collected at the time of original diagnosis or subsequent procedures (unstained) will be sent to central lab or affiliate for testing.
e Screening assessment must be performed within 14 days prior to the first dose of study drug.  If screening assessment is performed within 4 days of Cycle 1, Day 1 
dosing, it need not be repeated.
f
A serum or urine pregnancy test will be performed for female patients of childbearing potential during screening, prior to dosing on Day 1 during Cycles 1–16, and at 
EOT.  If the screening test was performed within 4 days before the Cycle 1, Day 1 dose, it need not be repeated on Cycle 1, Day 1.  The results must be negative before 
brentuximab vedotin is administered. During Cycle 17 and beyond, a pregnancy test should be performed per institutional guidelines; any samples collected during 
Cycle 17 and beyond should not be sent to the central laboratory and data should not be captured in the eCRF. Additional pregnancy testing may be performed during 
the study at the discretion of the investigator, upon request of the IEC/IRB, or if required by local regulations.
g On Cycle 1, Day 1 only, also perform vital signs measurements at 1 hour (±10 minutes) postdose.
h The Cycle 1, Day 1 physical examination (including height and weight) is not required on Day 1 of Cycle 1 if the screening physical examination was conducted within 
4 days before administration of the first (Cycle 1, Day 1) dose of study drug.
i
The Lansky Scale will be used for patients ≤16 years of age; the Karnofsky Scale will be used for patients >16 years of age.  See Section 14.1 for Lansky Play-
Performance Scale information; see Section 14.2 for Karnofsky Performance Scale information.
j
A blood sample for hematology and serum chemistry will be obtained at screening, prior to dosing on Day 1 during Cycles 1–16, and at EOT.  The hematology and 
chemistry blood samples for Cycle 1, Day 1 must be collected within 4 days prior to dosing to ensure patient eligibility on Cycle 1 Day 1.  If screening clinical 
laboratory testing was performed within 4 days before the Cycle 1, Day 1 dose, it need not be repeated on Cycle 1, Day 1.  See Section 7.4.12 for a listing of the 
required hematology and serum chemistry parameters.  During Cycle 17 and beyond, hematology and serum chemistry tests should be performed per institutional 
guidelines at the local laboratory; samples should not be sent to the central laboratory and data should not be captured in the eCRF, unless the laboratory result is 
assessed to contribute to an AE.
k A 12-lead ECG will be obtained at screening, Cycle 1, Day 1; and end of treatment only, unless clinically indicated.  If the screening ECG is obtained within 4 days of 
study drug administration on Cycle 1, Day 1, the ECG assessment need not be repeated.  ECG assessments are to be performed with the patient supine and rested for 
5 minutes and before any closely timed PK blood collection.


Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
Confidential
15
Screening
Enrollment 
(date of 
first dose)
Cycles 1–16
Cycle 17 and 
Beyond (for 
patients who 
continue 
beyond 
16 cycles)
EOTa
PFSFUP/
OSFUPb
Each 21-Day Cycle
Additional 
Assessments 
at Cycles 2, 
4, 7, 10, 13, 
and 16 only
Day (D)
D1c
D2
D3
D5
D14
D15-21 of 
Cycle
D1c
D15-21 
of 
Cycle
30 days 
post last 
dose
q 12 wks for 
12 months/
q 6 months 
thereafter
Visit Window
-28 to D1
7 days
7 days
l
Development assessment and Tanner Scale to be performed on Day 1 of Cycles 2, 4, 7, 10, 13, and 16 only.  Development assessment to include weight-for-age and 
stature-for-age percentiles; see Section 14.3 for Tanner Scale information.
m Disease assessment, according to IWG Revised Response Criteria for Malignant Lymphoma, should be performed on Day 15-21 of Cycles 20, 24, 28, and every 
4 cycles thereafter.
n Disease assessment should be repeated if not done within the previous 6 weeks.
o Patients who discontinue study treatment with stable disease or better will have CT scans and MRI done every 12 weeks for 12 months.
p PET scans performed at Cycles 2 and 7.  No additional PET scans are required beyond Cycle 7 unless clinically indicated.
q May be obtained within 60 days of first dose of brentuximab vedotin.  If a positive bone marrow aspirate (BMA) and biopsy was taken more than 60 days before the 
first dose and the patient has not received treatment in the interim, these do not need to be repeated.
r
BMA and biopsy required to confirm response if BM positive at baseline.  BMA/biopsy should be obtained within 2 weeks after documentation of response.  Does not 
need to be repeated once bone marrow is found to be negative.
s Patients will be weighed at each dosing visit. The brentuximab vedotin dose must be adjusted if patient weight has increased or decreased by at least 10% from the 
most recent dose calculation; otherwise, institutional practice should be followed.
t
Including serious pretreatment events; see Section 9.3 of the study protocol.
u PK blood samples will be obtained at the following times:  

All Cycles: Day 1: within 4 hours before the start of the brentuximab vedotin infusion and 5 minutes (±1 minute) after the end of the brentuximab vedotin infusion.

Cycles 1 and 8:  
o
Day 2: 24 hours (±4 hours) from the start of the Day 1 brentuximab vedotin infusion.
o
Day 3: 48 hours (±4 hours) from the start of the Day 1 brentuximab vedotin infusion.
o
Day 5: 96 hours (±24 hours) from the start of the Day 1 brentuximab vedotin infusion.
o
Day 14: 312 hours (±48 hours) from the start of the Day 1 brentuximab vedotin infusion.


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Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
Confidential
17
TABLE OF CONTENTS
LIST OF TABLES..................................................................................................................20
LIST OF FIGURES ................................................................................................................20
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ............................................20
1. BACKGROUND AND STUDY RATIONALE ................................................................23
1.1 Scientific Background ..................................................................................................23
1.1.1 Disease Under Treatment.......................................................................................23
1.1.2 Study Drug.............................................................................................................29
1.2 Preclinical Experience ..................................................................................................29
1.2.1 In Vitro Activity of Brentuximab vedotin .............................................................29
1.2.2 Pharmacokinetics and Product Metabolism in Humans ........................................31
1.2.3 Preclinical Toxicology...........................................................................................32
1.2.4 Immune Function...................................................................................................32
1.3 Clinical Experience.......................................................................................................32
1.3.1 Study Rationale......................................................................................................35
1.4 Potential Risks and Benefits.........................................................................................36
1.4.1 Benefit Analysis in Hodgkin Lymphoma..............................................................36
1.4.2 Benefit Analysis in Systemic Anaplastic Large Cell Lymphoma .........................37
1.4.3 Potential Risks in Children ....................................................................................37
2. STUDY OBJECTIVES ......................................................................................................41
2.1 Phase 1 Primary Objectives..........................................................................................41
2.2 Phase 1 Secondary Objectives......................................................................................41
2.3 Phase 1 Exploratory Objectives....................................................................................42
2.4 Phase 2 Primary Objectives..........................................................................................42
2.5 Phase 2 Secondary Objectives......................................................................................42
2.6 Phase 2 Exploratory Objectives....................................................................................42
3. STUDY ENDPOINTS........................................................................................................42
3.1 Phase 1 Primary Endpoints...........................................................................................42
3.2 Phase 1 Secondary Endpoints.......................................................................................43
3.3 Phase 1 Exploratory Endpoints.....................................................................................43
3.4 Phase 2 Primary Endpoints...........................................................................................43
3.5 Phase 2 Secondary Endpoints.......................................................................................44
3.6 Phase 2 Exploratory Endpoints.....................................................................................44
4. STUDY DESIGN ...............................................................................................................44
4.1 Overview of Study Design ...........................................................................................44
4.2 Number of Patients .......................................................................................................46
4.3 Duration of Study .........................................................................................................46
5. STUDY POPULATION.....................................................................................................47
5.1 Inclusion Criteria ..........................................................................................................47
5.2 Exclusion Criteria.........................................................................................................49
6. STUDY DRUG...................................................................................................................51
6.1 Study Drug Administration ..........................................................................................51
6.2 Definitions of Dose-Limiting Toxicity.........................................................................52
6.2.1 Toxicity..................................................................................................................52


Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
Confidential
18
6.2.2 Nonhematologic Toxicity......................................................................................53
6.2.3 Hematologic Toxicity ............................................................................................53
6.2.4 Phase 1:  Dose Modification for an Individual Patient Who Experiences DLT....53
6.2.5 Phase 1:  Dose Elimination/Holding/Reduction for Patients Who Have Not 
Experienced a DLT.........................................................................................54
6.2.6 Maximum Tolerated Dose or Recommended Phase 2 Dose .................................54
6.3 Dose Escalation Rules ..................................................................................................54
6.4 Phase 2 Dose-Modification Guidelines ........................................................................56
6.4.1 Criteria for Dose Modification ..............................................................................56
6.4.2 Criteria for Beginning or Delaying a Subsequent Treatment Cycle......................57
6.4.3 Criteria for Discontinuation of Brentuximab vedotin............................................58
6.5 Excluded Concomitant Medications and Procedures ...................................................59
6.6 Permitted Concomitant Medications and Procedures...................................................59
6.7 Precautions and Restrictions.........................................................................................60
6.8 Management of Clinical Events ...................................................................................61
6.8.1 Management of Peripheral Neuropathy.................................................................61
6.8.2 Management of Progressive Multifocal Leukoencenphalopathy ..........................61
6.8.3 Nausea and/or Vomiting........................................................................................61
6.8.4 Diarrhea .................................................................................................................62
6.9 Blinding and Unblinding ..............................................................................................62
6.10 Description of Investigational Agents ........................................................................62
6.11 Preparation, Reconstitution, and Dispensation...........................................................62
6.12 Packaging and Labeling..............................................................................................63
6.13 Storage, Handling, and Accountability.......................................................................63
7. STUDY CONDUCT...........................................................................................................64
7.1 Study Personnel and Organizations..............................................................................64
7.2 Arrangements for Recruitment of Patients ...................................................................64
7.3 Treatment Group Assignments.....................................................................................64
7.4 Study Procedures ..........................................................................................................64
7.4.1 Informed Consent ..................................................................................................64
7.4.2 Patient Demographics............................................................................................65
7.4.3 Medical History .....................................................................................................65
7.4.4 Physical Examination ............................................................................................65
7.4.5 Patient Height and Weight.....................................................................................65
7.4.6 Vital Signs..............................................................................................................65
7.4.7 Pregnancy Test.......................................................................................................65
7.4.8 Concomitant Medications and Procedures ............................................................66
7.4.9 Adverse Events ......................................................................................................66
7.4.10 Enrollment ...........................................................................................................66
7.4.11 Electrocardiogram................................................................................................66
7.4.12 Clinical Laboratory Evaluations..........................................................................66
7.4.13 Disease Assessment.............................................................................................67
7.4.14 Pharmacokinetic Measurements ..........................................................................68
7.4.15 Pharmacodynamic Measurements .......................................................................69
7.4.16 Immunogenicity...................................................................................................69
7.4.17 Tumor Specimen Measurements .........................................................................70


Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
Confidential
19
7.5 Completion of Treatment..............................................................................................70
7.6 Completion of Study.....................................................................................................70
7.7 Discontinuation of Treatment With Study Drug, and Patient Replacement.................70
7.8 Withdrawal of Patients From Study .............................................................................71
7.9 Study Compliance.........................................................................................................71
7.10 Posttreatment Follow-up Assessments .......................................................................71
8. STATISTICAL AND QUANTITATIVE ANALYSES.....................................................72
8.1 Statistical Methods .......................................................................................................72
8.1.1 Determination of Sample Size...............................................................................72
8.1.2 Randomization and Stratification ..........................................................................73
8.1.3 Populations for Analysis........................................................................................73
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data ............................74
8.1.5 Demographic and Baseline Characteristics ...........................................................74
8.1.6 Efficacy Analysis...................................................................................................74
8.1.7 Pharmacokinetics/Pharmacodynamics...................................................................74
8.1.8 Safety Analysis ......................................................................................................75
8.1.9 Electrocardiogram Analysis...................................................................................76
8.1.10 Interim Analysis...................................................................................................76
8.2 Pharmacokinetic Modeling...........................................................................................76
9. ADVERSE EVENTS..........................................................................................................76
9.1 Definitions ....................................................................................................................76
9.1.1 Pretreatment Event Definition ...............................................................................76
9.1.2 Adverse Event Definition ......................................................................................77
9.1.3 Serious Adverse Event Definition .........................................................................77
9.2 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events .....................................................................................................78
9.3 Monitoring of Adverse Events and Period of Observation ..........................................79
9.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ..........80
10. ADMINISTRATIVE REQUIREMENTS ........................................................................80
10.1 Good Clinical Practice................................................................................................80
10.2 Data Quality Assurance..............................................................................................80
10.3 Electronic Case Report Form Completion..................................................................81
10.4 Study Monitoring........................................................................................................81
10.5 Ethical Considerations................................................................................................82
10.6 Patient Information and Informed Consent ................................................................82
10.7 Patient Confidentiality................................................................................................82
10.8 Investigator Compliance.............................................................................................82
10.9 On-site Audits.............................................................................................................83
10.10 Investigator and Site Responsibility for Drug Accountability .................................83
10.11 Product Complaints and Medication Errors .............................................................83
10.12 Closure of the Study .................................................................................................84
10.13 Record Retention ......................................................................................................85
11. USE OF INFORMATION................................................................................................85
12. INVESTIGATOR AGREEMENT ...................................................................................86
13. REFERENCES .................................................................................................................87
14. APPENDICES ..................................................................................................................93


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14.1 Lansky Play-Performance Scale.................................................................................93
14.2 Karnofsky Performance Scale ....................................................................................94
14.3 Tanner Scale ...............................................................................................................95
14.4 Amendment 1 Rationale and Purposes.......................................................................96
14.5 Amendment 2 Rationale and Purposes (France-Specific Amendment) .....................96
14.6 Amendment 3 Rationale and Purposes.......................................................................97
14.7 Amendment 4 Detailed Summary of Changes .........................................................100
LIST OF TABLES
Table 1-1   
Summary of Results of Chemotherapy Treatment in Pediatric PMBCL 
Studies............................................................................................................ 28
Table 6-1   
Planned Dose Levels...................................................................................... 56
Table 14-1   
Criteria for Distinguishing Tanner Stages 1 to 5 During Pubertal 
Maturation...................................................................................................... 95
Table 14-2   
Pubertal Stages in Boys ................................................................................. 95
LIST OF FIGURES
Figure 1-1   
Schematic Diagram of Brentuximab vedotin ................................................ 30
Figure 6-1   
Dose Escalation Algorithm............................................................................ 55
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
ADC
antibody drug conjugate
AE
adverse event
ALCL
anaplastic large-cell lymphoma
alloSCT
allogeneic stem cell transplant
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCT
autologous stem cell transplant
AST
aspartate aminotransferase
ATA
anti-therapeutic antibody
BFM
Berlin-Frankfurt-Munster
BM
bone marrow
BMA
bone marrow aspirate
BMT
bone marrow transplantation
CBC
complete blood count
CDC
Centers for Disease Control


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Abbreviation
Term
CI
confidence interval
CMV
cytomegalovirus
CR
complete remission
CSF
colony-stimulating factor
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP3A4
cytochrome P450 3A4
DLT
dose-limiting toxicity
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EFS
event-free survival
EOT
end of treatment (visit)
EU
European Union
FAB
French-American-British
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
HL
Hodgkin lymphoma
H/RS
Hodgkin-Reed-Sternberg
HSCT
hematopoietic stem cell transplant
IB
Investigator’s Brochure
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IFRT
involved field radiotherapy
IRB
institutional review board
IRF
independent review facility
IV
intravenous; intravenously
IWG
International Working Group
JCV
John Cunningham virus
KD
dissociation constant
MedDRA
Medical Dictionary for Regulatory Activities
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MMAE
monomethyl auristatin E
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NHL
non-Hodgkin lymphoma
NPM
nucleophosmin
ORR
overall response rate
OS
overall survival


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Abbreviation
Term
PCR
polymerase chain reaction
PD
progressive disease (disease progression)
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic(s)
PMBCL
primary mediastinal B-cell lymphoma
PML
progressive multifocal leukoencephalopathy
PN
peripheral neuropathy
PR
partial remission
RP2D
recommended phase 2 dose
SAE
serious adverse event
sALCL
systemic anaplastic large-cell lymphoma
SCT
stem cell transplant
SD
stable disease
SMQ
standardised MedDRA query
SOE
schedule of events
TNF
tumor necrosis factor
TTP
time to progression
ULN
upper limit of the normal range
USP
United States Pharmacopeia
WBC
white blood cell
WHO
World Health Organization


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1.   
BACKGROUND AND STUDY RATIONALE
1.1   
Scientific Background
1.1.1   
Disease Under Treatment
1.1.1.1   
Hodgkin Lymphoma in Pediatric Population
Classical Hodgkin lymphoma (HL) is defined histopathologically by the presence of 
malignant Hodgkin-Reed-Sternberg (H/RS) cells in a background of inflammatory cells.  
H/RS cells are characterized by the expression of CD30, a surface tumor marker and cell 
membrane protein belonging to the tumor necrosis factor (TNF) receptor superfamily.  HL 
occurs in patients in all age groups and presents a bimodal distribution with peaks at 15 to 
35 years of age and over the age of 60.(2)  The median age at diagnosis is 38 years in adults 
and 13.5 years in the pediatric population.  The disease is very uncommon in children under 
4 years of age and almost nonexistent in those under 2 years of age.(3, 4)
Painless cervical lymphadenopathy is the most common presenting sign (>70%) in children 
with HL, often with a fluctuating course leading to a delay in diagnosis.(5)  Mediastinal 
masses are frequent (about 60% of pediatric patients) and sometimes discovered after 
routine chest X-rays.  Patients with mediastinal adenopathy may present with respiratory 
symptoms such as shortness of breath, chest pain, or cough.  Fewer than 5% present with 
disease limited to the upper cervical lymph nodes, above the level of the hyoid bone.  
Disseminated lymphadenopathy is rare in patients with HL, as is involvement of Waldeyer’s 
ring and occipital, epitrochlear, posterior mediastinal, and mesenteric sites.(5, 6)  
Approximately 25% of patients will have systemic B symptoms at presentation (as defined 
by the Ann Arbor system), typically fatigue, fever, weight loss, and night sweats.  Pruritus 
and intermittent fever usually associated with night sweats are classic symptoms of HL.  The 
frequency of these symptoms increases with advanced stage of the disease.(5, 6)
Accurate disease staging and classification of the histological subtype determine the most 
favorable treatment options and prognosis.(7, 8, 9)  The stage of the disease is assigned 
according to the Ann Arbor staging system with Cotswold modifications for HL.  All cases 
are subclassified to indicate the absence (A) or presence (B) of the systemic symptoms at 
presentation.(8, 10)  Pediatric patients are more likely than adults to present with stage I/II 
disease and less likely to present with stage IV disease.  Adolescents are more likely to have 
B symptoms than pediatric patients younger than 10 years and have a much higher relapse 
rate.(11)


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Standard treatment of pediatric patients with HL requires a risk-based approach.  This 
ensures that those with good prognosis, low-risk disease can be managed with regimens 
associated with minimal toxicity, while those at high risk of treatment failure can be treated 
more aggressively.  Low-risk disease presents favorably and is usually defined as localized 
disease (stage I and II), no bulky disease and absence of B symptoms.  Intermediate-risk 
disease has been defined as all stage I and II patients not classified as early stage and 
stage IIIA.  High-risk disease generally means patients with stage IIIB and IV disease at 
presentation.  Those with favorable risk disease typically receive 2 to 4 cycles of 
combination chemotherapy with low-dose involved field radiotherapy (IFRT), whereas
those with higher-risk disease receive more intensive chemotherapy before IFRT.  In 
contrast to the treatment of adult patients with HL, IFRT remains an important component of 
the treatment of advanced-stage HL in pediatric patients.(12, 13, 14)
HL is the childhood cancer with the highest cure rates with current OS more than 90% in 
low-stage disease and up to 70% for disseminated disease.(13, 15, 16, 17)  Five-year event-free 
survival in pediatric HL is approximately 80 to 85%.(18)  Pediatric patients less than 10 years 
of age had a significantly improved freedom from relapse and survival in comparison with 
adolescents and a highly significant improved outcome compared with adults.  Although 
pediatric patients present high cure rates, multi-agent regimens confer a significant 
morbidity, including secondary malignancies, cardiovascular disease, male infertility, 
pulmonary diseases, and infections.(19, 20, 21, 22)  Some of the serious sequelae of radiation and 
alkylating chemotherapy are most pronounced in younger patients, in whom growth and 
development are particularly active when therapy is administered.  In addition, cardiac 
toxicity appears to be age related, with younger patients at the highest risk.  Secondary 
malignancies represent the leading cause of mortality in survivor patients with HL.(8, 23)
Approximately 10 to 20% of patients presenting with HL will become refractory to initial 
therapy or will relapse.  Given the high rate of success of initial treatment for pediatric HL, 
little has been published on the optimal management for relapsed or refractory patients.  
Historical data reveal that children managed initially with radiation alone and who then 
relapse can achieve cure (as high as 85%), whereas those who were initially treated with 
multi-agent chemotherapy or combined modality therapy have an unfavorable prognosis and 
are much more likely to subsequently experience treatment failure.(14)  For patients with 
favorable disease at diagnosis, eg, with relapse confined to an area of initial involvement 
after chemotherapy and no radiation, salvage therapy consists of further chemotherapy and 
low-dose IFRT.  Patients with an early relapse (between 3-12 months from the end of 
therapy) had a 10-year event-free survival (EFS) of 55% and a 5-year OS of 78%; those with 


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a late relapse (more than 12 months from the end of therapy) had a 10-year EFS and OS of 
86% and 90%, respectively.(24, 25, 26)  For these patients, there is little or no possibility that 
standard-dose chemotherapy will prove to be effective.  High-dose chemotherapy plus 
allogeneic stem cell transplant (alloSCT) is the only curative option in both pediatric and 
adult patients.(27)
Transplantation-related mortality rates of more than 20% and even higher relapse rates in 
pediatric and adult series compromise the survival benefit.  Patients who experience relapse 
or progressive HL post-alloSCT fare dismally and represent a clear unmet need.(28)  A 
pooled analysis from 5 international transplant centers of 756 patients who experienced 
relapsed HL after autologous stem cell transplant (ASCT) revealed a median survival of 
2.4 years, with fewer than 10% of patients alive at 5 years.  When the collected data were 
analyzed by decade in which treatment was received, no difference in treatment outcome 
was apparent, suggesting that introduction of novel treatment approaches and allogeneic 
transplantation has not meaningfully improved OS.
Current therapies for pediatric HL have changed dramatically to reduce these 
toxicitieshigh-dose radiation therapy is no longer utilized, chemotherapy regimens utilize 
lower doses of alkylating agents, hybrid regimens allow for lower doses of anthracycline 
and bleomycinminimizing the current late effects in patients receiving modern therapy.  
However, there is still a need to investigate the efficacy and safety of these regimens versus
chemotherapy alone in children and adolescents.  Because late effects may take 10 to 
30 years or more to become clinically apparent, it is too early to conclude on the long-term 
safety of these treatments.  The proposed pediatric study has been designed to study 
brentuximab vedotin in patients with relapsed or refractory HL, where adult data in this 
disease setting are presently available and where an unmet medical need for new treatments
currently exists.
1.1.1.2   
Anaplastic Large-Cell Lymphoma
Anaplastic large-cell lymphoma (ALCL) accounts for approximately 10% of all childhood 
non-Hodgkin's lymphomas.  ALCL can occur at any age, even in infants, and incidence 
increases steadily with age.  The incidence of non-Hodgkin lymphoma (NHL) in the 
pediatric population is much lower than in adults.  The overall rate in pediatric patients is 
approximately 0.7 per 100,000.(29)  The number of cases with NHL in patients 0 to 4 years of 
age across European regions was very low and cases in pediatric patients less than 2 to 
3 years of age are extremely rare.  Patients may present with isolated lymphadenopathy or 


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varied sites of extranodal disease such as the gastrointestinal tract, soft tissues, lung, liver, 
and/or bone.  Systemic ALCL (sALCL) behaves similarly to other diffuse large-cell 
lymphomas and is aggressive but potentially curable with systemic combination 
chemotherapy.(30, 31)
Approximately 50% to 80% of pediatric ALCL cases are associated with a t(2;5)(p23;q35) 
chromosome translocation prompting the anaplastic lymphoma kinase (ALK) gene on 
chromosome 2 to fuse with the nucleophosmin (NPM) gene on chromosome 5 (ALK 
positivity).  NPM/ALK fusion protein acts as a constitutively activated tyrosine kinase.(32, 33)  
Inappropriate expression and activation of the fusion kinase in the lymphoid compartment 
causes the pathogenesis of some forms of ALCL,(34, 35, 36, 37) however, some lymphomas 
positive for ALK lack this translocation.  In these lymphomas, other chromosomal 
rearrangements, such as inv 2 (p23;q35) and t(1;2)(q25;p23), result in ALK expression.(32, 33)  
In general, ALK-positive sALCL has a superior OS and failure-free survival rate compared 
with ALK-negative sALCL.(38)  ALK positivity is the most important prognostic indicator in 
adult ALCL but is less helpful in childhood sALCL where 80% to 95% of sALCL is ALK 
positive, which precludes comparison of treatment results between pediatric and adult 
studies.
Prognostic factors are crucial for selecting an appropriate treatment strategy.  Prognosis in 
children and adults is determined by staging.  Younger age, absence of B symptoms, 
absence of extranodal disease, and good performance status predict a better prognosis.  
Three main clinical factors are associated with an increased risk of failure in childhood 
sALCL: mediastinal involvement, visceral involvement, and skin lesions.(39, 40, 41, 42, 43)  The 
presence of 1 or more of these has been associated with a poor prognosis: 5-year 
progression-free survival (PFS) ranging from 90 to 61%.  Recent studies have associated 
poor prognosis with the presence of minimal disseminated residual disease and a low titer of 
antibodies to the anaplastic lymphoma kinase (ALK) at diagnosis.  Patients lacking the 
t(2;5) translocation in their tumor cells (ALK-negative ALCL) typically have advanced 
stage disease and a 5-year survival of approximately 40%, whereas ALK-positive disease 
has a more favorable prognosis with 5-year survival as high as 80 to 90%.(39, 40, 41, 42, 43)
In pediatric frontline sALCL, current therapeutic approaches employ combination 
chemotherapy.  Significant hematological toxicity has been observed.  Improvements in 
first-line therapies have increased survival such that today, pediatric patients presenting with 
sALCL have an excellent prognosis.  Event-free-survival (EFS) in pediatric patients 
suffering from sALCL is up to 100% for early stage and 70% in advanced stage.  OS has 


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been reported to be up to 90% for early stage, and 80% for advanced stage.  Recent trials 
from the Pediatric Oncology Group, the Children’s Cancer Group, and European 
cooperative groups have shown disease-free survival for advanced-stage disease in the range 
of 50% to 80% using chemotherapeutic regimens varying in duration and intensity.(39, 41, 44, 
45)
Nonetheless, 25% to 35% of patients develop recurrent disease.(41)  For recurrent or 
refractory sALCL, 40% to 60% of patients can achieve long-term survival.  There is no 
standard treatment approach; chemotherapy, ASCT, and alloSCT have all been employed in 
this setting.  Several studies suggest that alloSCT may result in better outcomes for 
refractory/relapsed sALCL.  The treatment of relapsed sALCL is still a matter of debate.  
Induction therapy followed by high-dose chemotherapy and autologous allogeneic 
hematopoietic stem cell transplant after a second complete remission (CR) is the standard 
treatment for relapsed lymphoma in children and is currently used by most groups as first-
line treatment for relapsed sALCL.  Vinblastine is active as a single agent in 
recurrent/refractory sALCL, in 1 study inducing CR in 25 of 30 evaluable patients (83%) 
with acceptable toxicity.  Nine of the 25 patients experiencing a CR with vinblastine 
monotherapy remained in CR with median follow-up of 7 years since the end of 
treatment.(42)
The choice of salvage therapy for sALCL patients in first relapse is largely driven by 
assessment of prognostic factors at diagnosis and by response to front-line therapy.  
AlloSCT is effective and has acceptable toxicity as rescue therapy for high-risk sALCL
relapse.  It even offers a cure for patients who are refractory to chemotherapy, suggesting a 
graft-versus-ALCL effect.  The Berlin-Frankfurt-Münster group reported outcomes for 
20 children and adolescents with high-risk relapsed or refractory sALCL who underwent 
alloSCT.  Nine patients received alloSCT after their first relapse and 11 patients were 
transplanted after multiple relapses.  Event-free survival at 3 years after allogeneic transplant
was 75% 10%.  There was no influence of donor type or conditioning regimen on outcome.  
Two of 6 patients with progressive disease during frontline therapy survived, compared with 
13 of 14 patients with a first relapse after frontline therapy.(46)  Patients allografted in 
complete remission showed a better PFS and OS.(47)
In our proposed study, patients with very high risk disease, particularly those who progress 
while receiving standard therapy and are eligible for bone marrow transplantation (BMT), 
may use brentuximab vedotin to bridge to alloSCT.  This population constitutes ~50 to 60% 
of the high-risk relapsed patients.  Patients who respond to 2 cycles or more of brentuximab 


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vedotin therapy would be eligible to continue therapy with SCT or BMT.  These patients 
will be transitioned to BMT and may no longer receive brentuximab vedotin.
1.1.1.3   
Primary Mediastinal B-Cell Lymphoma
In addition to sALCL, primary mediastinal B-cell lymphoma (PMBCL) is a CD30-positive 
(CD30+) expressing malignancy.  PMBCL is a pathological and clinical subtype of NHL 
derived from mature thymic B cells.  In children, PBMCL comprises 1.8% and 3.8% of 
patients registered on the Berlin–Frankfurt–Munster (BFM) and the 
French-American-British (FAB) LMB96 B-cell NHL studies, respectively.  PMBCL has the 
poorest survivals in the pediatric age range, but one of the best among adults with large 
B-cell lymphomas.  PMBCL are consistently positive for CD19, CD20, and CD45 and often 
for CD79a, CD11c, and CD23.  CD30 is usually positive while CD10 and CD21 are 
negative.(48, 49, 50, 51, 52)  The BFM group reported 30 PMBCL cases out of 1,650 B-NHL 
pediatric patients, 28 of whom were treated on BFM B-NHL therapy.(53)  From 1984 to 
2003, 116 pediatric patients represented <2% of NHL.  The OS rate was 79% and EFS was 
67%, which were significantly lower than that in other pediatric B-cell lymphomas, such as 
diffuse large B-cell lymphoma or Burkitt’s lymphoma, and inferior to the results obtained in 
adult patients with PMLBL who have up to 100% progression-free survival using 
dose-adjusted EPOCH with rituximab.(54)
Table 1-1   
Summary of Results of Chemotherapy Treatment in Pediatric PMBCL 
Studies
Study
Number of patients
Event-Free Survival
Overall Survival
NHL–BFM 86-90-95(51)
28
5 year 75%
N/A
FAB/LMB 96(52)
43
3 year 66%
3 year 73%
FAB/LMB 96
NHL–BFM 86-90-95
AIEOP LNH 92(53)
116
3 year 67.4%
3 year 78.6%
High-dose therapy followed by ASCT has historically been and remains the standard 
approach for pediatric patients with chemosensitive relapse or primary refractory NHL.  
Won, et al, reported an estimated 2-year OS of 62.8±9.1% and EFS of 59.1±9.3% in 
33 pediatric patients with relapsed (n=16) or refractory (n=17) NHL following high-dose 
therapy and ASCT compared to an EFS of 16.3±4.6% in those who received conventional 
chemotherapy.  The European Group for Blood and Marrow Transplantation reported on one 
of the largest series of 89 pediatric patients with poor risk B-cell lymphoma who underwent 


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high-dose chemotherapy followed by ASCT.  The major factor determining survival in this 
study was the remission status of patients before ASCT.  They report a 5-year EFS of 48.7% 
for patients with chemosensitive relapse but a dismal outcome for patients with primary 
refractory disease, all of whom died within 1 year posttransplant, with a 5-year EFS of only 
8%.(55)
1.1.2   
Study Drug
Brentuximab vedotin is a CD30-directed antibody-drug conjugate (ADC) consisting of 
3 components: 1) the antibody cAC10, specific for human CD30, 2) the highly potent 
antimicrotubule agent monomethyl auristatin E (MMAE), and 3) a protease-cleavable linker 
that covalently attaches MMAE to cAC10.  The biological activity of brentuximab vedotin 
results from a multistep process.  Binding of the ADC to CD30 on the cell surface initiates 
internalization of the ADC-CD30 complex, which then traffics to the lysosomal 
compartment.  Within the cell, a single defined active species, MMAE, is released via 
proteolytic cleavage.  Binding of MMAE to tubulin disrupts the microtubule network within 
the cell, induces M-phase cell cycle arrest, and results in apoptotic death of the 
CD30-expressing tumor cell.
1.2   
Preclinical Experience
1.2.1   
In Vitro Activity of Brentuximab vedotin
The chimeric antibody (cAC10) has a typical structure of the human IgG1 subclass 
(Figure 1-1) and is designed to deliver the cytotoxic agent specifically to tumor cells.  
Brentuximab vedotin binds to the cell surface protein CD30, which is expressed at high 
concentrations on tumor cells in HL and sALCL.  Target antigen specificity allows 
preferential delivery of the drug to tumor cells when drug is conjugated to the antibody as an 
ADC.


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Figure 1-1   
Schematic Diagram of Brentuximab vedotin
Brentuximab vedotin binds to CD30+ cells (ALCL cell line Karpas 299) at a dissociation 
constant (KD) of approximately 2 nM, similar to that of the unconjugated cAC10 anti-CD30 
antibody.  Cell surface and intracellular localization of brentuximab vedotin was 
demonstrated by fluorescence microscopy after binding to CD30+ cells (HL cell line 
L540cy).  Within 16 hours of incubation at 37C, brentuximab vedotin was detected inside 
cells and co-localized with intracellular lysosomes indicating internalization and trafficking 
to lysosomes.  Monomethyl auristatin E (MMAE) was released from brentuximab vedotin
intracellularly by CD30+ human HL (L540cy and L428) and ALCL (Karpas 299) cell lines 
as determined by liquid chromatography with tandem mass spectrometry analysis of cell 
culture medium.  In addition, studies demonstrating release of MMAE from brentuximab 
vedotin by purified cathepsin B and lysosome-enriched tumor cell extracts were performed 
supporting the concept of release of MMAE via the conditionally labile linker (Figure 1-1).  
Free MMAE inhibited microtubule polymerization in vitro and tumor cells (CD30+
embryonal carcinoma Tera-2 cells) treated with MMAE or brentuximab vedotin displayed a 
rounded morphology and disrupted micotubule network.
The primary pharmacodynamic effect of brentuximab vedotin was to induce cell cycle arrest 
in the G2/M phase of the cell cycle.  An increase in the percent of cells in G2/M phase was 
observed over time in cultures of CD30+ cells (HL cell line L540cy and ALCL cell line 
Karpas 299) treated with brentuximab vedotin.  Brentuximab vedotin selectively killed 
CD30+ HL and ALCL cell lines (IC50 of 0.089 and 0.031 nM, respectively), but not 
CD30-negative cells (WSU-NHL) at concentrations of approximately 100-fold higher.  


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1.2.3   
Preclinical Toxicology
Several toxicity studies have been conducted with brentuximab vedotin in vitro and in vivo 
(monkeys and rats).  Overall brentuximab vedotin demonstrated an acceptable safety profile 
in nonclinical studies.  Hypocellularity of the bone marrow and lymphoid depletion of the 
thymus were observed in both rats and monkeys.  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
(10 mg/kg), testicular changes (diffuse seminiferous tubule degeneration) were still evident.  
Further details are provided in the brentuximab vedotin IB.
1.2.4   
Immune Function
Detailed information regarding the nonclinical pharmacology and toxicology of brentuximab 
vedotin may be found in the brentuximab vedotin IB.
1.3   
Clinical Experience
The safety and efficacy of brentuximab vedotin has 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+ 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 (IV) 
every 3 weeks.  The primary objectives of the study were to establish a maximum tolerated 
dose (MTD) of brentuximab vedotin and to assess the associated toxicity profile.  The most 
common adverse events were fatigue (36%), pyrexia (33%), and diarrhea, nausea, peripheral 
neuropathy, and neutropenia (22% each).  Notable serious adverse events considered at least 
possibly related to treatment included anaphylaxis, myocardial infarction, and peripheral 
neuropathy.


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In Study SG035-0002, 44 patients with CD30+ 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 IV weekly for 3 of 4 weeks.  The 
primary objectives explored in this study were to establish the safety profile and MTD of 
weekly brentuximab vedotin monotherapy in patients with relapsed or 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 were observed in 30% of patients.  The most frequent 
AE that led to dose modification or delay was peripheral sensory neuropathy.  Acute 
infusion reaction AEs occurred in a total of 6 patients.  Overall, these acute infusion reaction 
AEs were reported as less than Grade 2 in severity and resolved.  Overall, 2 patients (14%) 
who had an acute infusion reaction also had antitherapeutic antibodies at any postbaseline 
visit.
In SG035-0003, a phase 2, single-arm, open-label study in patients with relapsed or 
refractory HL postASCT, and SG035-0004, a phase 2 study conducted in patients with 
relapsed or refractory sALCL, brentuximab vedotin was administered at a dose of 1.8 mg/kg 
every 3 weeks.  One hundred two patients with relapsed and refractory HL and 58 patients 
with relapsed and refractory sALCL were exposed for a median duration of approximately 
27 weeks (9 cycles) and 20 weeks (6 cycles), respectively.  Most patients (89%) in the two 
phase 2 studies were between the ages of 18 and 65 years.  The primary endpoint of both 
studies was overall response rate (ORR) as assessed by an independent radiographic facility.  
Key secondary endpoints included duration of response, OS, and PFS.  The key efficacy 
results in HL (SG035-0003) include ORR per IRF (75% [95% CI:  64.9-82.6%]), CR rate
(34% [95% CI:  25.2-44.6%]), B symptom resolution rate (77%), and duration of response 
(DOR, 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 


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had treatment-emergent peripheral neuropathy, predominantly sensory neuropathy, with an 
onset and severity pattern consistent with a cumulative effect.  Dose delay and subsequent 
reduction to 1.2 mg/kg was generally effective in managing peripheral neuropathy.  Grade 3 
and Grade 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 occurred in approximately 10% of patients 
and were typically managed by dose delay or reduction.  Infusion-related reaction
prophylaxis in subsequent treatment cycles was instituted at the discretion of the 
investigator.  The clinical laboratory parameters for which the most patients had new or 
worsening shifts to Grade 3 were low neutrophils (11%), lymphocytes (11%), platelets 
(6%), leukocytes (5%), and high glucose (6%).  Only 1 patient in the phase 2 studies had 
Grade 3 increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST).
In the phase 2 studies, 31% of patients had a serious adverse event, 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 SAE preferred terms (2%) 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 patients with HL, likely due to the older age and more 
aggressive nature of the malignancy in this patient population.
A total of 9 deaths were reported within the safety evaluation period (within 30 days of the 
last dose of brentuximab vedotin) in 357 patients across the 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 patients with sALCL.
Four pediatric patients (aged 14-17 years) were included in Study SG035-0004 in sALCL, 
and 1 pediatric patient (aged 15 years) was included in Study SG035-0003 in HL.  All of 
these patients experienced at least 1 adverse event, and the event types observed were
similar to those reported in the adult study population.  Most of the AEs were mild to 
moderate, resolved without action, and were unrelated to brentuximab vedotin.  Three of the 
5 pediatric patients experienced at least 1 event of peripheral neuropathy, ranging from 
Grade 1 to Grade 3, and 2 patients reported events of neutropenia.  One patient experienced 


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treatment-related Grade 3 neutropenia, and 1 patient experienced Grade 3 and Grade 4 
neutropenia and Grade 3 and Grade 4 thrombocytopenia that were assessed as not related to 
brentuximab vedotin.  This same patient experienced an SAE of Grade 2 viral 
gastroenteritis, which was unrelated to study drug.  The patient with HL in Study SG035-
003 achieved a CR and completed treatment.  The patient’s DOR was 50.4 weeks.  Three of 
the 4 pediatric patients with sALCL in Study SG035-004 achieved CR and 1 achieved 
partial remission (PR); 1 patient was transitioned to ASCT.
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 patients with HL and sALCL and B symptoms at 
baseline saw these symptoms resolve during treatment with brentuximab vedotin.  In 
addition, the large majority of patients with sALCL presenting with cutaneous lesions at 
baseline experienced resolution of these symptoms after receiving brentuximab vedotin.
Further details on clinical studies with brentuximab vedotin are provided in the brentuximab 
vedotin IB.
1.3.1   
Study Rationale
Most patients diagnosed with HL or sALCL respond to initial chemotherapy.  However, 
20% to 40% of these patients will eventually relapse, and approximately 10% of patients 
will have refractory disease.  Salvage chemotherapeutic regimens and ASCT are secondary 
options for these patients, but both are associated with a significant morbidity rate.  
Immunotherapy with an ADC represents an additional therapeutic modality with the 
potential to maintain or improve efficacy without concomitant increase in toxicity.
Brentuximab vedotin is a novel ADC directed against the CD30 surface antigen expressed 
on hematologic malignancies including HL and sALCL tumor cells.  Preclinical studies of 
brentuximab vedotin demonstrated antitumor activity in both in vitro and in vivo models.  
This study is the first clinical use of brentuximab vedotin exclusively in pediatric patients 
with relapsed or refractory CD30+ malignancies, the majority of which are expected to be 
HL and sALCL.  The safety, pharmacokinetics (PK), immunogenicity, and antitumor 
activity of brentuximab vedotin will be evaluated in eligible patients.


Brentuximab vedotin (SGN-35)
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As the goal of phase 1 of this study is to establish safety and define the MTD and/or 
recommended phase 2 dose of brentuximab vedotin in pediatric hematological malignancies 
with high expression of CD30, patients with relapsed or refractory CD30+ malignancies 
(including HL and sALCL) are planned for inclusion in the phase 1 study population.
The phase 2 portion of the study will enroll patients into 2 separate arms based on diagnosis 
of relapsed or refractory sALCL, or relapsed or refractory HL; patients will receive 
brentuximab vedotin at the MTD and/or recommended phase 2 dose (RP2D) determined in 
the phase 1 portion of the study.  Best overall response rate (CR+PR) and DOR will be 
evaluated.
Conducting the phase 2 part of the study as a nonrandomized study is consistent with many 
phase 2 pediatric oncology studies.  Based on interactions with various agencies and 
extensive consultation with HL experts, a comparative trial was determined to be not 
feasible because it is anticipated that most patients randomized to the control arm would 
leave the trial to obtain treatment with other investigational products.
1.4   
Potential Risks and Benefits
This trial will be conducted in compliance with the protocol, good clinical practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines.
1.4.1   
Benefit Analysis in Hodgkin Lymphoma
Study SG035-0003, a phase 2 study of brentuximab vedotin evaluated 1.8 mg/kg 
administered IV every 3 weeks in a relatively homogeneous population of 102 adult patients 
with HL 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 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 patients with 
HL treated in the study.


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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.
1.4.2   
Benefit Analysis in Systemic Anaplastic Large Cell Lymphoma
Study SG035-0004, a phase 2 study of brentuximab vedotin 1.8 mg/kg administered IV
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.
As for HL, an intrapatient comparison of PFS per investigator assessment obtained with 
brentuximab vedotin versus the most recent prior therapy was conducted.  In 90% of cases, 
the most recent prior therapy was multiagent chemotherapy, delivered with or without 
ASCT.  The median PFS duration achieved with brentuximab vedotin was approximately 
8 months longer than that achieved with the most recent prior therapy.
1.4.3   
Potential Risks in Children
The recommended dose of brentuximab vedotin in adult patients is 1.8 mg/kg administered 
IV every 3 weeks as long as the patient continues to benefit from and tolerates therapy.  At 
this dose and schedule, the most common adverse events were peripheral sensory 
neuropathy, fatigue, nausea, diarrhea, pyrexia, upper respiratory tract infection, neutropenia, 
and vomiting.  These events have been primarily mild or moderate in severity.
The most notable adverse event associated with brentuximab vedotin is peripheral 
neuropathy that tends to increase in severity with longer duration of therapy, consistent with 
that observed with other antimicrotubule agents such as vinca alkyloids or taxanes.  Sensory 
events were more common than motor events, and the peripheral neuropathy (PN) events 
typically followed a distal to proximal pattern of development, also similar to the PN seen 
with other tubulin disruptors.  Approximately half of patients in the phase 2 studies 
experienced treatment-emergent PN, which was primarily mild to moderate (Grade 1 or 
Grade 2).  The most frequently occurring events were peripheral sensory neuropathy (44%), 
peripheral motor neuropathy (9%), and paresthesia (4%).  Grade 3 peripheral neuropathy 
events occurred in 18 (11%) patients.  No Grade 4 PN events were reported.


Brentuximab vedotin (SGN-35)
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For those patients in the phase 2 study with at least 1 PN Standardised MedDRA Query 
(SMQ) event, the median time to onset of any PN SMQ event was 12.4 weeks.  For
≥Grade 3 events, there was a clear trend toward first onset in later cycles, with the majority 
of events having first onset between Cycles 9 and 16.  Overall, 15% of patients had dose 
modifications for PN SMQ events.  Dose delays for PN SMQ events occurred in 20 patients 
(13%) and dose reductions occurred in 12 patients (8%).  Treatment discontinuations for PN 
SMQ events occurred in 14 patients (9%).  Neuropathy was generally reversible, with a 
median time from onset to resolution or improvement of 6.6 weeks (range, 0.3 to 
54.4 weeks).
The majority of peripheral neuropathy events were Grade 1 or Grade 2 and were 
manageable by dose delay and reduction.  For new or worsening events of Grade 2 or 
Grade 3 neuropathy, dosing should be held until neuropathy improves to ≤Grade 1 and then 
restarted at the 1.2 mg/kg dose level.  For Grade 4 (life-threatening) peripheral neuropathy, 
brentuximab vedotin should be discontinued.
Infusion-related reactions (IRRs) are possible with brentuximab vedotin, especially related 
to the development of clinically significant titers of antitherapeutic antibodies (ATAs).  
Patients must be monitored for the possibility of an acute reaction during brentuximab 
vedotin administration.  If IRR symptoms develop, the infusion should be interrupted and 
appropriate medical management instituted.  Further information on the management of 
IRRs is provided in Section 6.1.
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.(60)  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 6.8.2.


Brentuximab vedotin (SGN-35)
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Stevens-Johnson syndrome (SJS), including toxic epidermal necrolysis, has been reported in 
patients who received brentuximab vedotin.  Patients were concurrently receiving other 
medications (naproxen and tramadol, respectively) that are known to cause SJS and may 
have contributed to the development of SJS. Stevens-Johnson syndrome is considered to be 
an unacceptable study drug-related toxicity.  If SJS occurs, the administration of 
brentuximab vedotin must be discontinued and the appropriate medical therapy 
administered.  
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).
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.
Hepatotoxicity, predominately in the form of asymptomatic mild to moderate transient 
elevations in AST and/or ALT, has been reported in patients treated with brentuximab 
vedotin.  Patients should be monitored for elevated liver enzymes.
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.  Patients of childbearing potential are advised to use adequate and 
effective contraception during brentuximab vedotin treatment and for a 6-month period 
thereafter.


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CCI


Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
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Organization (WHO) international growth charts for children aged 24 months (available at 
cdc.gov/growthcharts) and CDC growth charts in persons aged 2 to 19 years will be used.  
Clinical charts are available for boys and for girls at 
cdc.gov/growthcharts/clinical_charts.htm.  A sexual maturity scale such as the one 
developed by Tanner is used to assess the physical developmental stage of a patient.  This 
scale assigns a Tanner stage of 1 (prepubertal) to 5 (adult) to girls based on breasts and 
pubic hair and to boys based on genitalia and pubic hair.
The multiagent chemotherapy regimens often employed as salvage therapy in patients with 
relapsed or refractory HL or sALCL carry significant toxicities.  Given the benefit observed 
with brentuximab vedotin monotherapy in this population with aggressive disease, the 
manageable adverse event profile is notable.
2.   
STUDY OBJECTIVES
2.1   
Phase 1 Primary Objectives
The primary objectives in phase 1 are:

To assess the safety profile and determine the pediatric maximum tolerated dose 
and/or recommended phase 2 dose of brentuximab vedotin

To assess the pharmacokinetics of brentuximab vedotin
2.2   
Phase 1 Secondary Objectives
The secondary objectives in phase 1 are:

To determine the immunogenicity of brentuximab vedotin

To determine best overall response rate (complete remission, partial remission) with 
brentuximab vedotin

To determine the time to progression, time to response, duration of response, and 
event-free, progression-free, and overall survival with brentuximab vedotin


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Brentuximab vedotin (SGN-35)
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longer effective.  The primary objectives of the study are to assess the safety and 
pharmacokinetics, determine the pediatric MTD and/or RP2D of brentuximab vedotin in 
pediatric patients, and evaluate the antitumor activity of brentuximab vedotin in eligible 
patients.
Approximately 42 evaluable patients will be enrolled in this study.  In the phase 1 portion of 
the study, at least 12 patients with relapsed or refractory CD30+ malignancies (including HL 
and sALCL) will be enrolled in 2 planned dose cohorts (3 to 6 patients per cohort) according 
to the standard 3 + 3 dose escalation scheme.
Once the MTD and/or RP2D have been reached, patients will be enrolled by diagnosis into 
two phase 2 study arms: relapsed or refractory sALCL, or relapsed or refractory HL.  A 
sufficient number of patients will be enrolled in the phase 2 portion of the study to have at 
least 15 evaluable patients with sALCL (including patients treated at the RP2D during 
phase 1), of whom at least 10 patients are in first relapse, and at least 15 evaluable patients 
with HL (including patients treated at RP2D during phase 1).
Brentuximab vedotin will be administered by IV infusion once every 21 days.  Each 21-day 
treatment cycle is composed of 1 day of study drug treatment, followed by a monitoring
period of 20 days.  The starting dose in phase 1 will be 1.4 mg/kg, and escalation will 
proceed using a traditional 3 + 3 design to a maximum dose of 1.8 mg/kg.
Overall response will be evaluated beginning after 2 cycles of therapy.  Objective response 
over the course of the study will be assessed by an IRF according to the IWG Revised 
Response Criteria for Malignant Lymphoma.(1)  Patients, including those who achieve a CR, 
a PR, or stable disease (SD), may receive brentuximab vedotin for up to 16 cycles.  
Treatment with brentuximab vedotin beyond 16 cycles may be permitted at the joint 
discretion of the sponsor and the investigator for those patients experiencing continued 
clinical benefit.  Following administration of the final dose of brentuximab vedotin, patients
will be monitored for adverse events for a minimum of 30 days.  Patients will be followed 
for PFS and OS every 12 weeks for 12 months after the EOT visit.  Thereafter, assessment 
for OS will continue every 6 months until the sooner of death or study closure or a 
maximum of 2 years after enrollment of the last patient.  Patients who remain on treatment 
after Cycle 16 will be followed according to the above schedule or until study closure.
Study drug will be discontinued due to occurrence of unacceptable AE, progressive disease, 
patient withdrawal, or study termination.  Patients may discontinue therapy at any time.  
Additionally, those patients who experience a CR and are candidates for hematopoietic stem 


Brentuximab vedotin (SGN-35)
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cell transplantation must discontinue brentuximab vedotin prior to chemotherapy and 
transplant; these patients will be followed for survival analyses until study closure.
AEs will be assessed, and laboratory values, vital signs, and electrocardiograms (ECGs) will 
be obtained to evaluate the safety and tolerability of brentuximab vedotin.
Serial blood samples for determination of the plasma concentration of brentuximab vedotin, 
total therapeutic antibody, and MMAE will be obtained during Cycle 1 and subsequent 
cycles at prespecified time points as described in the Schedule of Events (SOE) and in 
Section 7.4.14.
Radiological evaluations, (CT scan or magnetic resonance imaging [MRI], and PET as 
clinically indicated), will be employed to assess the status of the patient’s underlying 
disease.  An evaluation of disease response will be assessed by an IRF according to the IWG 
Revised Response Criteria for Malignant Lymphoma(1) evaluated at Cycles 2, 4, 7, 10, 13, 
and 16 and then at the end of treatment.  The scan frequency for patients who receive 
treatment past Cycle 16 is outlined in the Schedule of Events.  Additional evaluations may 
be necessary when clinically indicated.
4.2   
Number of Patients
Approximately 42 evaluable patients will be enrolled in this study from approximately 
25 study centers globally.  At least 12 evaluable patients are planned for the phase 1 portion
of the study, and a sufficient number of patients will be enrolled in phase 2 to have at least 
30 evaluable patients (15 with sALCL and 15 with HL) at RP2D, including the patients from 
the phase 1 portion of the study who receive the RP2D.  A patient is considered enrolled in 
the study at the time of first dose of study drug.
Patients who are withdrawn from treatment during Cycle 1 for reasons other than dose 
limiting toxicities (DLTs) will be replaced; additional patients may be enrolled to ensure up 
to 12 evaluable patients in phase 1.
4.3   
Duration of Study
Patients who achieve a CR, a PR, or SD may receive brentuximab vedotin for up to 
16 cycles, until they experience disease progression.  Extended brentuximab vedotin
therapy, beyond 16 cycles, may be permitted at the joint discretion of the sponsor and 
investigator for those patients experiencing continued clinical benefit.


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Patients will be followed for safety for a minimum of 30 days after the last dose of 
brentuximab vedotin, to permit the detection of any delayed treatment-related AEs.  Patients
will be followed for PFS and OS every 12 weeks for 12 months after the EOT visit.  
Thereafter, assessment for OS will continue every 6 months until the sooner of death or 
study closure or a maximum of 2 years after enrollment of the last patient.  
The final analyses for the clinical study report will be conducted after all patients enrolled in 
the study have had the opportunity to complete 16 cycles of treatment with brentuximab 
vedotin.
It is anticipated that this study will last for approximately 5 years.
5.   
STUDY POPULATION
5.1   
Inclusion Criteria
Each patient must meet all of the following inclusion criteria for study enrollment:
1. Male or female patients aged 2 to <18 years (5 to <18 years for patients with HL).
2. Have a diagnosis of systemic anaplastic large-cell lymphoma, or Hodgkin lymphoma
for which standard, curative, life-prolonging, or palliative treatment does not exist or 
is no longer effective.  (Patients diagnosed with any relapsed or refractory CD30+ 
hematological malignancy [eg, primary mediastinal B-cell lymphoma] may be 
included in phase 1 of the study.)
3. Patients with sALCL must have documented anaplastic lymphoma kinase (ALK) 
status.
4. Patients with HL must be in their second or later relapse or have failed systemic 
chemotherapy either as induction therapy for advanced stage disease or salvage 
therapy, and be ineligible for, refused, or previously received a stem cell transplant.
5. Patients with relapsed or refractory sALCL must be beyond first remission or 
refractory to front-line chemotherapy.
6. Performance score ≥60 from Lansky Play Performance Scale if ≤16 years


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7. Female patients who:

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed consent 
through 6 months after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods] and withdrawal are not acceptable 
methods of contraception.)
8. Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment  
period and through 6 months after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods for the female partner] and withdrawal 
are not acceptable methods of contraception.)
9. Voluntary written consent (and institution-specific assent as appropriate based upon 
patient comprehension) must be given before performance of any study-related 
procedure not part of standard medical care, with the understanding that 
consent/assent may be withdrawn by the patient or patient guardian at any time 
without prejudice to future medical care.
10. Suitable venous access for the study-required procedures.
11. Clinical laboratory values as specified below within 4 days before the first dose of 
study drug:

Absolute neutrophil count greater than or equal to 1,500/μL.

Platelet count greater than or equal to 75,000/μL.


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
Serum bilirubin level less than or equal to 1.5 upper limits of normal (ULN) or 
less than or equal to 3 ULN for patients with an indirect hyperbilirubinemia 
due to Gilbert’s disease.

Serum creatinine less than or equal to 1.5 ULN.

Alanine aminotransferase (ALT or SGPT) and aspartate aminotransferase (AST 
or SGOT) less than or equal to 2.5 ULN.  AST and ALT levels may be 
elevated up to 5 ULN if their elevation can be reasonably ascribed to the 
presence of metastatic disease in the liver.
12. Patients must have a radiographically or clinically evaluable tumor per the IWG
criteria.(1)
5.2   
Exclusion Criteria
Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, 
immunotherapy, or radiotherapy prior to entering this study.  Patients meeting any of the 
following exclusion criteria are not to be enrolled in the study.  If a patient is positive for 
ANY of the exclusion criteria, the patient will not be eligible for the study.
1. Current diagnosis of primary cutaneous ALCL (those with sALCL are eligible).
2. Received an allogeneic stem cell transplant <3 months prior to first dose of study 
medication, or presence of polymerase chain reaction (PCR)-detectable CMV in any 
post-allogeneic transplant patient. (Prior PCR positivity that was successfully treated 
is acceptable provided the baseline PCR result is negative prior to first dose of study 
drug.)
3. Receiving immunosuppressive therapy.
4. Receiving systemic therapy for chronic graft-versus-host disease (topical therapy is 
allowed).
5. Previous treatment with any anti-CD30 antibody.
6. Therapeutic monoclonal antibody use within the longer of 6 weeks or 5 plasma 
half-lives.


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7. Symptomatic cardiac disease including ventricular dysfunction, coronary artery 
disease, or arrhythmias, if this would, in the opinion of the investigator or project 
clinician, interfere with assessment of efficacy or safety of the drug.
8. History of another primary malignancy not in remission for at least 3 years. (The 
following are exempt from the 3-year limit: nonmelanoma skin cancer and cervical 
carcinoma in situ on biopsy or a squamous intraepithelial lesion on Pap smear.)
9. Known active cerebral/meningeal disease, including signs or symptoms of 
progressive multifocal leukoencephalopathy (PML) or any history of PML.
10. History of cirrhosis.
11. Active systemic viral, bacterial, or fungal infection requiring antimicrobial, antiviral 
therapy or antifungal therapy within 2 weeks prior to first dose of study drug (routine 
antimicrobial prophylaxis is acceptable).
12. Concurrent therapy with other anti-neoplastic or experimental agents.
13. Systemic corticosteroid therapy <7 days prior to first dose of study medication.
14. Any serious underlying medical condition that, in the opinion of the investigator or 
project clinician, would impair the patient’s ability to receive or tolerate the planned 
treatment.
15. Known hypersensitivity to recombinant proteins, murine proteins, or any excipient 
contained in the drug formulation.
16. Received nitrogen mustard agents, melphalan, or BCNU therapy within 6 weeks 
prior to first study dose.
17. Prior autologous hematopoietic stem cell infusion 4 weeks prior to first study dose.
18. Grade 2 or greater unresolved toxicity from prior antineoplastic therapy.
19. Received any strong or listed moderate inhibitor of CYP3A4 2 weeks prior to first 
study dose.  (Please refer to the Study Manual for an example list of prohibited 
CYP3A4 inhibitors.)
20. Grade 2 or greater peripheral neuropathy.


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21. Female patients who are both lactating and breastfeeding, or have a positive serum or 
urine pregnancy test during the screening period or a positive serum or urine 
pregnancy test on Day 1 before the first dose of study drug.
22. Received local palliative radiation therapy 14 days prior to the first dose of study 
medication.
23. Received radiation therapy to more than 25% of the bone marrow-containing spaces 
<84 days prior to first dose of study medication.
6.   
STUDY DRUG
6.1   
Study Drug Administration
Study drug will be administered only to eligible patients under the supervision of the 
investigator or identified subinvestigator(s).
Infusion-related reactions may occur during the infusion of brentuximab vedotin.  The 
infusion should be administered at a site properly equipped and staffed to manage 
anaphylaxis should it occur.  The patient should be observed for 60 minutes after each
infusion of brentuximab vedotin.
During this observation period, the IV line should remain open for at least 1 hour to allow 
administration of IV drugs if necessary.  All supportive measures consistent with optimal 
patient care will be given throughout the study according to institutional standards. 
Medications for infusion-related reactions, such as epinephrine, antihistamines, and 
corticosteroids, should be available for immediate use.
Patients who experience a Grade 1 or Grade 2 infusion-related reaction may receive 
subsequent brentuximab infusions with premedication consisting of acetaminophen (650 mg 
orally) and diphenhydramine (25–50 mg orally or 10–25 mg IV) or according to institutional 
standards, administered 30 to 60 minutes prior to each 30-minute brentuximab vedotin 
infusion. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.
If a Grade 3 or greater infusion-related reaction consistent with anaphylaxis occurs, 
immediately and permanently discontinue administration of brentuximab vedotin and 
administer appropriate medical therapy per institutional guidelines.


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Brentuximab vedotin must not be administered as an IV push or bolus.  Study treatment will 
be administered by outpatient 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 infusion period.  Study treatment will be 
administered through a dedicated IV line and cannot be mixed with other medications.
In the phase 1 portion of the study, the starting dose will be 1.4 mg/kg and escalation will 
proceed using a traditional 3 + 3 design to a maximum dose of 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 the most recent dose 
calculation.  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.
The dose for the phase 2 portion of the study will be the MTD and/or RP2D, as determined 
during phase 1.  Each 21-day treatment cycle is composed of 1 day of study drug treatment, 
followed by a monitoring period of 20 days.
Patients who achieve a CR, a PR, or SD, may receive study drug for up to 16 cycles, until 
they experience disease progression or have unacceptable toxicity.  Additional treatment 
cycles, beyond 16 cycles, may be permitted at the joint discretion of the sponsor and 
investigator for those patients experiencing continued clinical benefit.  Patients eligible for 
alloSCT must discontinue brentuximab vedotin prior to initiating a conditioning regimen; 
these patients will be followed for survival analyses until study closure.  Following 
administration of the final dose of brentuximab vedotin, patients will be followed for safety 
for a minimum of 30 days.
6.2   
Definitions of Dose-Limiting Toxicity
Toxicity will be evaluated according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) version 4.03, effective 14 June 2010.(64)  These 
criteria are provided in the Study Manual.  DLT will be defined as discussed in 
Sections 6.2.2 and 6.2.3.
6.2.1   
Toxicity
The investigators and project clinician will discuss and document the overall toxicity profile 
in detail before deciding whether to initiate cohort expansion, dose escalation, dose 
modification, and/or future prophylaxis with colony-stimulating factors (CSFs).


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6.2.2   
Nonhematologic Toxicity
For nonhematologic toxicities, DLT will be defined as any CTCAE v. 4.03 Grade 3 or 
greater toxicity except for:

Grade 3 fatigue

Grade 3 or 4 nausea and vomiting lasting less than 24 hours

Grade 3 nonhematologic laboratory abnormalities that resolve to Grade 1 or 
baseline (if the patient entered the study with existing toxicity) within 14 days
6.2.3   
Hematologic Toxicity
DLT for hematologic toxicity will be defined as:

Grade 4 neutropenia lasting longer than 7 days

Grade 3 febrile neutropenia requiring antibiotics

Grade 4 febrile neutropenia

Grade 4 platelet count (<25,000/µL) at any time
6.2.4   
Phase 1: Dose Modification for an Individual Patient Who Experiences DLT
Any patient experiencing DLT lasting 14 days or longer will be discontinued from the study.  
Dose modification for further treatments with brentuximab vedotin will only occur for 
individual patients who experience a protocol defined DLT of less than 14 days’ duration, 
yet whom the site investigator and project clinician believe can safely receive additional 
treatment.  Subsequent doses should be decreased to the previous dose level or to 0.9 mg/kg 
for patients in the 1.4-mg/kg cohort.
The DLT experienced by the patient must return to less than or equal to Grade 1 or baseline 
at the time of the next scheduled dose.  If toxicity does not return to less than or equal to 
Grade 1 or baseline within 14 days, the patient should be taken off study; every effort should 
be made to ensure that early termination procedures are followed.


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6.2.5   
Phase 1: Dose Elimination/Holding/Reduction for Patients Who Have Not 
Experienced a DLT
A scheduled dose of brentuximab vedotin may be held up to 14 days in patients who have 
not experienced DLT, but have not yet recovered from an adverse event (AE) before the 
next scheduled dose administration.  For patients with AEs that have returned to baseline or 
Grade 1 values, a held dose may be administered up to 14 days after the scheduled time of 
the dose.  In view of the potential for myelosuppression with brentuximab vedotin, it is 
particularly important that patients are not dosed until any neutrophil toxicity has resolved to 
at least Grade 1.  If the dose is eliminated, and/or the toxicities have not resolved within 
14 days, the patient should be taken off study; every effort should be made to ensure that 
early termination procedures are followed.
6.2.6   
Maximum Tolerated Dose or Recommended Phase 2 Dose
The pediatric MTD and/or RP2D will be the highest dose at which no more than 1 in 6 of 
the patients in the cohort experiences 1 or more DLTs in the first treatment cycle.  The MTD 
and/or RP2D will be established without the use of colony stimulating factors (CSFs) in 
Cycle 1.
6.3   
Dose Escalation Rules
The dose intervals will follow the 3 + 3 traditional escalation rules, starting with the 
treatment of 3 patients at the 1.4-mg/kg dose:

If 0 of 3 patients experiences DLT, dose escalation will proceed to the 1.8-mg/kg 
dose at which 3 patients will be enrolled.

If 1 of 3 patients experiences DLT, 3 additional patients will be enrolled at the 
1.4-mg/kg dose level.

If no more than 1 of 6 patients experiences DLT, escalation will continue to the 
1.8-mg/kg dose level.

If 0 or 1 patient experiences DLT, 3 additional patients will be enrolled at the 
1.8 mg/kg dose level.

If 2 or more patients in either dose level experience DLT, dosing will stop, and the 
previous dose level will be considered the MTD.


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o
If 2 or more DLTs are experienced at the 1.4-mg/kg dose, the dose will be 
reduced to 0.9 mg/kg.
o
If 2 or more DLTs are experienced at the 1.8-mg/kg dose, the previous dose
level (1.4 mg) is considered the MTD and RP2D.
Figure 6-1 is a diagrammatical representation of these rules.
Figure 6-1   
Dose Escalation Algorithm
Enter 3 additional
patients at
1.4 mg/kg dose
> 1 DLT in
6 patients
1 DLT in
6 patients
Enter 3 patients
SGN-35 1.4 mg/kg
Enter 3 patients
1.8 mg/kg
Reduce dose
to 0.9 mg/kg
0 or 1 DLT
Enter 3 additional
patients at
1.8 mg/kg dose
0 or 1 DLT in 6 patients
MTD/RP2D =
1.8 mg/kg
>1 DLT
MTD/RP2D =
1.4 mg/kg
0 DLT
1 DLT
2-3 DLTs


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Table 6-1   
Planned Dose Levels
Dose Level
Dose (mg/kg)
1
1.4
2
1.8
More conservative dose escalation, evaluation of intermediate doses, and expansion of an existing dose level 
are all permissible following discussions between the sponsor and the investigators, if such measures are 
needed for patient safety or for a better understanding of the dose-related toxicity, exposure, or 
pharmacodynamics of brentuximab vedotin.
The starting dose of brentuximab vedotin will be approximately 80% of the adult MTD, 
equal to 1.4 mg/kg, given on Day 1 of a 21-day cycle.  Patients not receiving all doses of
brentuximab vedotin in Cycle 1 for reasons other than DLTs, will be replaced within the 
cohort; additional patients may be enrolled to ensure up to 12 evaluable patients in phase 1.
6.4   
Phase 2 Dose-Modification Guidelines
6.4.1   
Criteria for Dose Modification*
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. The brentuximab vedotin dose should be reduced by at least 1 dose level (or 
to 0.9 mg/kg if the patient is receiving the 1.4-mg/kg dose) if the patient has any of the 
following:

Brentuximab vedotin-related toxicity that results in a delay of more than 14 days in 
the start of a subsequent cycle of treatment because of lack of recovery to the 
specified re-treatment criteria

Grade 4 thrombocytopenia (platelet count 25,000/µL) lasting more than 
7 consecutive days.

Grade 3 or greater nonhematologic toxicity attributed to brentuximab vedotin except 
for the following, which do not require dose reduction:
o
Grade 3 or greater nausea and/or emesis in the absence of optimal anti-emetic 
prophylaxis (Optimal antiemetic prophylaxis is defined as an antiemetic 
regimen that employs both a 5-HT3 antagonist and a corticosteroid given in 
standard doses and according to standard schedules.)


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o
Grade 3 or greater diarrhea that occurs in the absence of optimal supportive 
therapy
o
Grade 3 fatigue
Brentuximab vedotin-related neuropathy should be managed with a combination of dose 
delay and reduction to 1.2 mg/kg (or to 0.9 mg/kg if the patient is receiving the 1.4-mg/kg
dose).  For new or worsening Grade 2 or 3 neuropathy, dosing should be held for up to
21 days until neuropathy improves to ≤Grade 1 and then restarted at 1.2 mg/kg (or to 
0.9 mg/kg if the patient is receiving the 1.4-mg/kg dose).  For Grade 4 peripheral 
neuropathy, brentuximab vedotin should be discontinued.
When a dose reduction of brentuximab vedotin is required, no re-escalation of dose will be 
permitted.*
6.4.2   
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
Treatment with brentuximab vedotin 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/µL

Platelet count must be ≥75,000/µL

For therapy to resume, toxicity considered to be related to treatment with 
brentuximab vedotin must have resolved to Grade 1, to the patient’s baseline 
values, or to a level considered acceptable by the physician (eg, hypophosphatemia 
that can be managed by oral replacement).
For the phase 1 portion of the study, if the patient fails to meet the previously cited criteria 
for retreatment, initiation of the next cycle of treatment may be delayed for 14 days.  At the 
end of that time, the patient should be re-evaluated to determine whether the criteria for 
retreatment have been met.  Should the start of the next cycle during phase 1 need to be 
delayed for more than 14 days because of incomplete recovery from treatment-related 
toxicity, this will be considered a DLT and the patient should be discontinued from study.  If 
a patient recovered from a DLT in less than 14 days, the patient may receive additional 
                                                
*
The phase 2 dose modification guidelines included in Section 6.4 will be applicable to patients who have 
received the RP2D in phase 1 of the study.


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treatment with brentuximab vedotin; the dose will be reduced by at least 1 dose level (or to 
0.9 mg/kg for patients receiving the 1.4-mg/kg dose) when treatment resumes.
6.4.3   
Criteria for Discontinuation of Brentuximab vedotin
Study drug must be discontinued if a patient experiences progressive disease or an 
unacceptable study drug-related toxicity.  Patients may discontinue therapy at any time.  
Additionally, those patients who experience a CR and are candidates for allogeneic stem cell 
transplantation must discontinue brentuximab vedotin prior to chemotherapy and transplant; 
these patients will be followed for overall survival until study closure.
Grade 4 nonhematologic toxicities will in general require that treatment with brentuximab 
vedotin be permanently discontinued.  If, in the opinion of the investigator and the project 
clinician, it is in the patient’s best interest to continue treatment with brentuximab vedotin, 
then the dose of brentuximab vedotin should be reduced by at least 1 dose level (or to 
0.9 mg/kg if the patient is receiving the 1.4-mg/kg dose) after recovery of the toxicity or 
toxicities in question to Grade 1 or to baseline values.
A patient’s treatment with study drug may also be discontinued for any of the following 
reasons:

Patient withdrawal.

Stable disease or better and completed 16 treatment cycles (brentuximab vedotin).

The investigator or patient deems it in the patient’s best interest to discontinue, 
including patients who experience a CR and are candidates for hematopoietic stem 
cell transplantation.  The reason justifying study treatment withdrawal must be 
documented in the CRF.
Patients will attend the end-of treatment-visit 30 days (7 days) after receiving their last 
dose of study drug.
A patient may be discontinued from the study (during treatment cycle or follow-up) for any 
of the following reasons:

Death

Patient withdraws consent for further follow-up


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
Lost to follow-up

Study termination by Millennium (If the sponsor and/or the investigator should 
discover conditions arising during the study that indicate it should be terminated, an 
appropriate schedule for termination will be instituted.)
Patients who discontinue from study treatment will remain on study and followed for a 
minimum of 30 days for safety unless they withdraw consent.  All patients who receive at 
least 1 dose of study drug will be followed PFS and OS every 12 weeks for 12 months after 
the EOT visit. Thereafter, assessment for OS will continue every 6 months until the sooner 
of death or study closure.  Patients who remain on treatment after Cycle 16 will be followed 
according to the above schedule or until study closure.
6.5   
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study:

Radiation therapy for disease under study

Any investigational agent other than brentuximab vedotin, including agents that are 
commercially available for indications other than sALCL or HL that are under 
investigation for the treatment of sALCL or HL

Any anticancer treatment with activity against sALCL and HL other than 
brentuximab vedotin

Myeloid growth factors (eg, G-CSF, GM-CSF) (Cycle 1 only)

Any strong and listed moderate CYP3A4 inhibitors (prohibited CYP3A4 inhibitors 
are listed in the Study Manual).
In addition, the concomitant use of brentuximab vedotin and bleomycin is contraindicated 
due to pulmonary toxicity.
6.6   
Permitted Concomitant Medications and Procedures
The use of intermittent corticosteroid treatment to manage hypersensitivity reactions is 
allowed.  The use of platelets and/or red blood cell supportive growth factors or transfusions 
when applicable is allowed.  Colony-stimulating factors may not be used for any patient in a 
prophylactic setting during the first treatment cycle but can be administered thereafter as per 


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ASCO guidelines or local institutional practice if the patient has experienced complicated 
and/or prolonged neutropenia. However, any patient who experiences a hematological DLT 
may not continue brentuximab vedotin treatment with concomitant CSFs, and CSFs may not 
be used to meet eligibility criteria.
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 and male patients should use effective 
methods of contraception through defined periods during and after study treatment as 
specified.
Female patients of reproductive age must meet 1 of the following:

Surgically sterile, OR

If they are of childbearing potential, agree to practice 2 effective methods of 
contraception from the time of signing of the ICF through 6 months after the last 
dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods] and withdrawal are not acceptable 
methods of contraception.)
Male patients, even if surgically sterile, must agree to 1 of the following:

Practice effective barrier contraception during the entire study treatment period 
and through 6 months after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods for the female partner] and withdrawal 
are not acceptable methods of contraception.).


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6.8   
Management of Clinical Events
6.8.1   
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 delay, reduction, or discontinuation.  Guidelines for brentuximab vedotin dose 
modification in the event of peripheral neuropathy are shown in Section 6.4.
6.8.2   
Management of Progressive Multifocal Leukoencenphalopathy
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 IB 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

Neurology consultation
If PML is confirmed, treatment with brentuximab vedotin should be discontinued 
permanently.
6.8.3   
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.


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6.8.4   
Diarrhea
Prophylactic antidiarrheals (eg, loperamide) will not be used in this protocol; however, 
patients will 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.
6.9   
Blinding and Unblinding
This is an open-label study.
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, United States Pharmacopeia (USP), yields 11 mL 
of brentuximab vedotin solution (5 mg/mL).
6.11   
Preparation, Reconstitution, and Dispensation
Brentuximab vedotin is an anticancer drug, and as with other potentially toxic compounds, 
caution should be exercised when handling brentuximab vedotin.  Recommended safety 
measures for handling and preparation include masks, protective clothing, gloves, and 
vertical laminar airflow safety cabinets.
Study treatment vials are single-use containers.  Any partially used vials or diluted dosing 
solutions are to be discarded using appropriate institutional drug disposal procedures.
Study treatment must be reconstituted with the appropriate amount of Sterile Water for 
Injection, 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.
The appropriate amount of reconstituted study treatment will be withdrawn from the vial(s) 
and diluted in a 50- to 100-mL infusion bag containing 0.9% Sodium Chloride Injection, 
USP.


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There are no known incompatibilities between study treatment and polyvinyl chloride bags.  
The bag should be gently inverted to mix the solution.  The bag must not be shaken; 
excess agitation may cause aggregate formation.  Prior to administration, the reconstituted 
and diluted drug product should be inspected visually for any particulate matter and 
discoloration.
The formulation contains no preservative and is intended for single use only; infusion 
solutions should be prepared and transferred using aseptic technique in a biosafety hood.
Refer to the Directions for Use/ Pharmacy Manual for more specific instructions on 
reconstitution and use.
6.12   
Packaging and Labeling
Brentuximab vedotin vials will be packaged as single-use cartons.  Each carton will contain 
1 vial of the investigational product, and the vial and carton will be labeled to meet
country-specific regulatory requirements.
6.13   
Storage, Handling, and Accountability
Vials of brentuximab vedotin for Injection are to be stored 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 on the same day when stored under refrigeration at 2 oC 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.


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7.   
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and ICH guidelines.
7.1   
Study Personnel and Organizations
The contact information for the project clinician for this study, the central laboratory and 
any additional clinical laboratories, and the ICON contract research organization study team 
may be found in the Study Manual.  A full list of investigators is available in the sponsor’s 
investigator database.
7.2   
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the
investigator’s local practice or referrals from other physicians.  If advertisements become 
part of the recruitment strategy, they will be reviewed by the institutional review board 
(IRB)/independent ethics committee (IEC).  It is not envisioned that prisoners (or other 
populations that might be subject to coercion or exploitation) will be enrolled into this study.
7.3   
Treatment Group Assignments
Patients will be enrolled according to the standard 3 + 3 dose escalation scheme in the 
phase 1 portion of the study.  Two ascending dose cohorts are planned (3 to 6 patients per 
cohort).
Once the MTD and/or RP2D has been reached, patients will be enrolled by diagnosis into 
two phase 2 study arms by diagnosis: relapsed or refractory sALCL or relapsed or 
refractory HL.
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 (or patient’s legal guardian) 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.


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7.4.2   
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening.
7.4.3   
Medical History
During the Screening period, a complete medical history will be compiled for each patient.  
The history will emphasize the background and progress of the patient’s malignancy and 
include a description of prior therapies for it.  In addition, concomitant medications will be 
recorded as specified in Section 7.4.8.
7.4.4   
Physical Examination
A complete physical examination—including assessments of general appearance, skin, head 
(eyes, ears, nose, and throat), neck, lungs, heart, abdomen, back, lymph nodes, extremities, 
and neurological system—will be completed at the times specified in the Schedule of 
Events.
7.4.5   
Patient Height and Weight
Height and weight will be obtained during screening (within 14 days before the first dose of 
brentuximab vedotin) and on Day 1 of each 21-day cycle.
7.4.6   
Vital Signs
Vital signs measurements include supine (after 3-5 minutes in this position) and standing 
(after 3-5 minutes in this position) measurements of diastolic and systolic blood pressure, 
heart rate, and oral temperature.  
7.4.7   
Pregnancy Test
Patients of childbearing potential will complete a serum or urine pregnancy test during 
screening, prior to dosing on Day 1 during Cycles 1 through 16, and at EOT. If the 
screening test was performed within 4 days before the Cycle 1, Day 1 dose, it need not be 
repeated on Cycle 1, Day 1.  A serum or urine pregnancy test will be performed prior to 
dosing on Day 1 of each subsequent cycle.  The results must be negative before brentuximab 
vedotin is administered.  During Cycle 17 and beyond, a pregnancy test should be performed 
per institutional guidelines; any samples collected during Cycle 17 and beyond should not be 
sent to the central laboratory, and data should not be captured in the eCRF. Additional 
pregnancy tests may also be repeated during the study if requested by an IEC/IRB or if 
required by local regulations.  


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7.4.8   
Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will be 
recorded in the electronic case report form (eCRF) from signing of informed consent form
through 30 days after the last dose of brentuximab vedotin.  See Sections 6.5 and 6.6 for a 
list of medications and therapies that are prohibited or allowed during the study.
7.4.9   
Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as 
specified in the Schedule of Events.  Refer to Section 9 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
9.3.
7.4.10   
Enrollment
A patient is considered to be enrolled in the study at the time of first dose of study drug.
Procedures for completion of the enrollment information are described in the Study Manual.
7.4.11   
Electrocardiogram
A 12-lead electrocardiogram (ECG) will be obtained at screening and at Cycle 1, Day 1 
(baseline), and at EOT.  If the screening ECG was obtained within the 4 days prior to the 
Cycle 1, Day 1 dose of study drug, a repeat ECG at Cycle 1, Day 1 is not necessary.  
Additional ECGs may be obtained if clinically indicated.  ECG assessments are to be 
performed with patient supine and rested for 5 minutes and before any closely timed PK 
blood collection.
7.4.12   
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed centrally.  Decisions regarding eligibility 
and study drug dosing may be made by using local laboratory results.  If local clinical 
laboratory values are used for either eligibility or study dosing decisions, the local 
laboratory results do not replace central laboratory testing, and samples for central 
laboratory confirmation must be collected as specified in the Schedule of Events.  
During Cycle 17 and beyond, hematology and serum chemistry tests should be performed 
per institutional guidelines at the local laboratory; samples should not be sent to the central 


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laboratory, and data should not be captured in the eCRF, unless the laboratory result is 
assessed to contribute to an AE.
Handling and shipment of clinical laboratory samples will be outlined in the Study Manual.  
Clinical laboratory evaluations will be performed as outlined:
Clinical Chemistry and Hematology
Blood samples for analysis of the following clinical chemistry and hematological parameters 
will be obtained as specified in the Schedule of Events.
Hematology

Hemoglobin

Hematocrit

Platelet (count)

Total WBC count

Differential WBC count
Machine counts are acceptable.
Serum Chemistry

Blood urea nitrogen

Creatinine

Urate

Bilirubin (total, 
direct, indirect)

Lactate 
dehydrogenase

Gamma glutamyl 
transferase

Phosphorus

Albumin

Alkaline phosphatase

Aspartate 
aminotransferase 
(AST)

Alanine 
aminotransferase 
(ALT)

Fasting glucose

Sodium

Potassium

Calcium

Chloride

Carbon dioxide

Magnesium
7.4.13   
Disease Assessment
7.4.13.1   Development Assessment and Tanner Scale
Development assessment and Tanner Scale are to be performed as specified in the Schedule 
of Events.  The development assessment will include weight-for-age and stature-for-age 
percentiles; see Section 14.3 for Tanner Scale information.


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7.4.13.2   
Imaging
Patients will undergo CT with contrast as appropriate, MRI, and PET to monitor and assess 
disease progression.  CT scans will be used to evaluate the chest only; MRI will be used to 
evaluate the neck, abdomen, and pelvis.  PET, CT, and MRI scans will be performed as 
specified in the Schedule of Events.  Objective response over the course of the study will be 
assessed by an IRF according to the IWG Revised Response Criteria for Malignant 
Lymphoma.(1)  Contrast CT scans of the chest will be obtained at screening.   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.
7.4.13.3   
B Symptom Assessments
B symptom assessments, including fever, night sweats, and weight loss, will be evaluated at 
the time points indicated in the Schedule of Events.
7.4.14   
Pharmacokinetic Measurements
Blood samples for the determination of serum brentuximab vedotin concentrations will be 
collected at the following time points:

All Cycles: Day 1:  within 4 hours before the start of the brentuximab vedotin 
infusion and 5 minutes (±1 minute) after the end of the brentuximab vedotin infusion

Cycles 1 and 8:
o
Day 2: 24 hours (4 hours) from the start of the Day 1 brentuximab vedotin 
infusion
o
Day 3: 48 hours (4 hours) from the start of the Day 1 brentuximab vedotin
infusion
o
Day 5: 96 hours (24 hours) from the start of the Day 1 brentuximab vedotin
infusion
o
Day 14: 312 hours (48 hours) from the start of the Day 1 brentuximab 
vedotin infusion


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dose is administered.  Neutralizing ATA assessment will be performed for ATA-positive 
samples only.  Details regarding the preparation, handling, and shipping of samples are 
provided in the Study Manual.  
7.4.17   
Tumor Specimen Measurements
This sample will be used to confirm CD30 expression by central laboratory review.  Refer to 
the Schedule of Events for details regarding tumor specimen collection.
7.5   
Completion of Treatment
Patients will be considered to have completed study treatment if they complete 16 cycles of 
treatment with brentuximab vedotin.
7.6   
Completion of Study
Patients will be considered to have completed the study if they complete 16 cycles of 
treatment with brentuximab vedotin and complete 30 days of safety follow-up.
7.7   
Discontinuation of Treatment With Study Drug, and Patient Replacement
Study drug must be permanently discontinued for patients meeting any of the following 
criteria:

Completed 16 cycles of brentuximab vedotin therapy (unless extended treatment is 
warranted due to clinical benefit).

The investigator or patient, or patient’s legal guardian deems it is in the patient’s best 
interest to discontinue.  (The reason justifying study treatment withdrawal must be 
documented in the eCRF.)

Progressive disease.
Treatment with study drug may also be discontinued for any of the following reasons:

Adverse event

Protocol violation

Initiation of hematopoietic stem cell or bone marrow transplant

Study terminated by sponsor


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
Withdrawal of consent by patient or patient’s guardian

Lost to follow-up

Other.
Once study drug has been discontinued, all study procedures outlined for the EOT visit will 
be completed as specified in the Schedule of Events.  The primary reason for study drug 
discontinuation will be recorded on the eCRF.
Patients who are withdrawn from treatment during Cycle 1 for reasons other than DLT will 
be replaced; additional patients may be enrolled to ensure at least 12 evaluable patients in
phase 1.
7.8   
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

Lost to follow-up

Study terminated by sponsor

Withdrawal of consent by patient or patient guardian

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.
7.9   
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision 
of the investigator or identified subinvestigator(s).  The appropriate study personnel will 
maintain records of study drug receipt and dispensing.
7.10   
Posttreatment Follow-up Assessments
Patients who stop treatment for any reason other than progressive disease (PD) or the start of 
subsequent anticancer therapy will continue to have follow-up visits to determine time to 


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progression, duration of response, event-free survival, progression-free survival, and overall 
survival.  The follow-up visits for PFS assessment should be conducted at the site every 
12 weeks for 12 months from the EOT visit until the occurrence of PD, the patient 
withdraws consent for further follow-up, or the start of subsequent anticancer therapy.  
After the occurrence of PD or the start of subsequent anticancer therapy, patients will 
continue to have OS follow-up visits every 6 months until the sooner of death or study 
closure or a maximum of 2 years after enrollment of the last patient.  Patients who remain on 
treatment after Cycle 16 will be followed according to the above schedule or until study 
closure.
Survivor information may be collected by methods that include, but are not limited to, 
telephone, e-mail, mail, or retrieved from online or other databases (eg, social security 
indexes).  In addition, information pertaining to the start of another anticancer therapy will 
be collected.
See the Schedule of Events for appropriate assessments during follow-up.
NOTE:  Related SAEs must be reported to the Millennium Department of 
Pharmacovigilance or designee.  This includes deaths that the investigator considers 
related to study drug that occur during the posttreatment follow-up.  Refer to Section 9
for details regarding definitions, documentation, and reporting of SAEs.
8.   
STATISTICAL AND QUANTITATIVE ANALYSES
8.1   
Statistical Methods
Statistical analyses will be primarily descriptive and graphical in nature.  No formal 
statistical hypothesis testing will be performed.  A formal statistical analysis plan will be 
developed and finalized before database lock.
8.1.1   
Determination of Sample Size
Approximately 42 evaluable patients will be enrolled in this study.  In the phase 1 portion of 
the study, at least 12 patients with relapsed or refractory CD30+ malignancies will be 
enrolled in 2 planned dose cohorts (3-6 patients per cohort), according to the standard 3 + 3 
dose escalation scheme.


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Once the MTD and/or RP2D have been reached, patients will be enrolled by diagnosis into 
two phase 2 study arms: relapsed or refractory sALCL or relapsed or refractory HL.  A
sufficient number of patients will be enrolled in the phase 2 portion of the study to have at 
least 15 evaluable patients with sALCL (including patients treated at the RP2D during 
phase 1), of whom at least 10 patients are in first relapse, and at least 15 evaluable patients 
with HL (including patients treated at the RP2D during phase 1).
The sample size is not based on statistical consideration.  Based on the exact binomial 
confidence interval calculation, 10 responses observed out of the 15 evaluable patients
(overall response rate of 66.7%) will provide 95% confidence interval (38%, 88%).
8.1.2   
Randomization and Stratification
In phase 1, patients will be enrolled in successive dose cohorts.  No randomization is 
planned for either phase 1 or phase 2 of this study.
8.1.3   
Populations for Analysis
The populations used for analysis will include the following:

Safety population:  Patients who receive at least 1 dose of study drug will be used for 
all safety analyses, as well as efficacy analyses.

PK population: Patients with sufficient dosing and PK data to reliably estimate PK 
parameters will be used for PK analyses.

Immune reconstitution population: Patients with sufficient dosing and sufficient 
immune reconstitution blood sampling to allow for immune reconstitution evaluation 
will be included in the immune reconstitution population.

Response-evaluable population:  Patients who receive at least 1 dose of study drug, 
have measurable disease at baseline, and 1 postbaseline disease assessment will be 
used for analyses of disease response and duration of response.

The DLT-evaluable population:  Patients who either experience DLT during phase 1 
or receive all scheduled doses and complete all study procedures in phase 1 without 
DLT.


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Shift tables for laboratory parameters will be generated based on changes in NCI CTCAE 
grade from baseline to the worst postbaseline value.  Graphical displays of key safety 
parameters, such as scatter plots of baseline versus worst postbaseline values, may be used 
to understand the brentuximab vedotin safety profile.
All concomitant medications collected from screening through the study period will be 
classified to preferred terms according to the World Health Organization (WHO) drug 
dictionary.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities 
and to further define the safety profile of brentuximab vedotin.
8.1.9   
Electrocardiogram Analysis
ECG intervals (QT and corrected QT intervals [QTcF], PR, QRS, and ventricular rate) will 
be summarized at each scheduled time point, along with mean change from baseline to 
posttreatment time point.
8.1.10   
Interim Analysis
No interim analysis is planned for this study.
8.2   
Pharmacokinetic Modeling
Pharmacokinetic modeling will be performed to obtain pharmacokinetic parameters and 
intrinsic covariates of the pharmacokinetics of brentuximab vedotin and MMAE.
9.   
ADVERSE EVENTS
9.1   
Definitions
9.1.1   
Pretreatment Event Definition
A pretreatment event is any untoward medical occurrence in a patient or subject who has 
signed informed consent to participate in a study but before administration of any study 
medication; it does not necessarily have to have a causal relationship with study 
participation.


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9.1.2   
Adverse Event Definition
Adverse event (AE) means any untoward medical occurrence in a patient or subject 
administered a pharmaceutical product; the untoward medical occurrence does not 
necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product whether 
or not it is related to the medicinal product.  This includes any newly occurring event, or a 
previous condition that has increased in severity or frequency since the administration of 
study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.
9.1.3   
Serious Adverse Event Definition
Serious AE (SAE) means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the 
time of the event.  It does not refer to an event which hypothetically might have 
caused death if it were more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization
(see clarification in the following paragraph on planned hospitalizations).

Results in persistent or significant disability or incapacity.  (Disability is defined 
as a substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event.  This refers to an AE that may not result in death, 
be immediately life threatening, or require hospitalization, but may be considered 
serious when, based on appropriate medical judgment, may jeopardize the patient, 
require medical or surgical intervention to prevent 1 of the outcomes listed above, or 
involves suspected transmission via a medicinal product of an infectious agent.  
Examples of such medical events include allergic bronchospasm requiring intensive 


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treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse; any organism, virus, or infectious particle (eg, prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or nonpathogenic, is 
considered an infectious agent.
In this study, intensity for each AE, including any lab abnormality, will be determined using 
the NCI CTCAE version 4.03, effective 14 June 2010.(64)  Clarification should be made 
between an SAE and an AE that is considered to be severe (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 previously, and is 
usually associated with events that pose a threat to a patient’s life or ability to function.  A 
severe AE (Grade 3 or 4) does not necessarily need to be considered serious.  For example, a 
white blood cell count of 1000/µL to less than 2000/µL is considered Grade 3 (severe) but 
may not be considered to be an SAE.  Seriousness (not intensity) serves as a guide for 
defining regulatory reporting obligations.
9.2   
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events
All AEs spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination, or other diagnostic 
procedures will be recorded on the appropriate page of the eCRF (see Section 9.3 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 9.1) 
must be reported (see Section 9.3 for the period of observation) by the investigator to the 
Millennium Department of Pharmacovigilance or designee (contact information provided 
below).  This should be done by faxing the SAE Form within 24 hours after becoming aware 
of the event.  The SAE Form, created specifically by Millennium, will be provided to each 
clinical study site.  A sample of the SAE Form may be found in the Study Manual.  
Follow-up information on the SAE or serious pretreatment event may be requested by 
Millennium.  SAE report information must be consistent with the data provided on the 
eCRF.


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
Serious pretreatment events will be reported to the Millennium Department of 
Pharmacovigilance or designee from the time of the signing of the ICF up to first 
dose of study drug, but will not be recorded in the eCRF.

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).
9.4   
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a patient becomes pregnant or suspects that she is pregnant while participating in this 
study, the investigator must be informed immediately and the patient must 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 9.2).  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 9.2).  Every effort should be made to follow the pregnancy for the 
final pregnancy outcome.
10.   
ADMINISTRATIVE REQUIREMENTS
10.1   
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 Investigator Brochure.
10.2   
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 


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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.
The study monitor 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.
10.3   
Electronic Case Report Form Completion
Millennium or designee will provide the study sites with secure access to and training on the 
EDC application, sufficient to permit site personnel to enter or correct information in the 
eCRFs for the patients for whom they are responsible.
eCRFs will be completed for each study patient.  It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the 
patient’s eCRF.
The investigator, or designated representative, should complete the eCRF as soon as 
possible after information is collected.
The investigator must provide through the EDC application formal approval of all the 
information in the eCRFs and changes to the eCRFs to endorse the final submitted data for 
the patients for which he or she is responsible.  The audit trail entry will show the user’s 
identification information and the date and time of the correction.
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.
10.4   
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 


Brentuximab vedotin (SGN-35)
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regulatory requirements.  The review of medical records will be performed in a manner that 
ensures that patient confidentiality is maintained.
10.5   
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.
10.6   
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.
10.7   
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.
10.8   
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.


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Brentuximab vedotin (SGN-35)
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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.
10.13   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.
11.   
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.


Brentuximab vedotin (SGN-35)
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12.   
INVESTIGATOR AGREEMENT
I have read Protocol C25002 Amendment 4:  A Phase 1/2 Study of brentuximab vedotin 
(SGN-35) in Pediatric Patients With Relapsed or Refractory Systemic Anaplastic Large-Cell 
Lymphoma or Hodgkin Lymphoma
I agree to conduct the study as detailed herein and in compliance with International 
Conference on Harmonisation Guidelines for Good Clinical Practice and applicable 
regulatory requirements and to inform all who assist me in the conduct of this study of their 
responsibilities and obligations.
Principal investigator printed name
Principal investigator signature
Date
Investigational site or name of institution and 
location (printed)


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48.
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49.
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50.
Boleti E, Johnson PW. Primary mediastinal B-cell lymphoma. Hematological 
Oncology 2007;25(4):157-63.
51.
Seidemann K, Tiemann M, Lauterbach I, Mann G, Simonitsch I, Stankewitz K, et al. 
Primary mediastinal large B-cell lymphoma with sclerosis in pediatric and 
adolescent patients: treatment and results from three therapeutic studies of the 
Berlin-Frankfurt-Munster Group. Journal of Clinical Oncology 2003;21(9):1782-9.
52.
Gerrard M, Cairo M, Weston C, Pinkerton R, Michon J, Auperin A, et al. Primary 
mediastinal large b-cell lymphoma:  Results of the FABLMB 96 study. Pediatric 
Blood & Cancer 2004;43:361; abstr O.134.
53.
Patte C, Auperin A, Sebban C, Bergeron C, Gisselbrecht C, Ribrag V, et al. The 15-
20 Year Old Patients With NHL Treated in France:  Data of Childhood and Adult 
Databases. Pediatric Blood & Cancer 2006;46(Abstract 43):848.
54.
Dunleavy K, Pittaluga S, Tay K, Grant N, Chen C, Shovlin M, et al. Comparative 
Clinical and Biological Features of Primary Mediastinal B-Cell Lymphoma (PMBL) 
and Mediastinal Grey Zone Lymphoma (MGZL). Blood (ASH Annual Meeting 
Abstracts) 2009;114(22):abstr 106.
55.
Ladenstein R, Pearce R, Hartmann O, Patte C, Goldstone T, Philip T. High-dose 
chemotherapy with autologous bone marrow rescue in children with poor-risk 
Burkitt's lymphoma: a report from the European Lymphoma Bone Marrow 
Transplantation Registry. Blood 1997;90(8):2921-30.


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56.
Glade Bender JL, Adamson PC, Reid JM, Xu L, Baruchel S, Shaked Y, et al. Phase I 
trial and pharmacokinetic study of bevacizumab in pediatric patients with refractory 
solid tumors: a Children's Oncology Group Study. Journal of Clinical Oncology 
2008;26(3):399-405.
57.
Trippett TM, Herzog C, Whitlock JA, Wolff J, Kuttesch J, Bagatell R, et al. Phase I 
and pharmacokinetic study of cetuximab and irinotecan in children with refractory 
solid tumors: a study of the pediatric oncology experimental therapeutic 
investigators' consortium. Journal of Clinical Oncology 2009;27(30):5102-8.
58.
Lacroix D, Sonnier M, Moncion A, Cheron G, Cresteil T. Expression of CYP3A in 
the human liver--evidence that the shift between CYP3A7 and CYP3A4 occurs 
immediately after birth. European Journal of Biochemistry 1997;247(2):625-34.
59.
Hines RN, McCarver DG. The ontogeny of human drug-metabolizing enzymes: 
phase I oxidative enzymes. Journal of Pharmacology & Experimental Therapeutics 
2002;300(2):355-60.
60.
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.
61.
Chiarle R, Podda A, Prolla G, Podack ER, Thorbecke GJ, Inghirami G. CD30 
overexpression enhances negative selection in the thymus and mediates programmed 
cell death via a Bcl-2-sensitive pathway. Journal of Immunology 1999;163(1):194-
205.
62.
DeYoung AL, Duramad O, Winoto A. The TNF receptor family member CD30 is 
not essential for negative selection. Journal of Immunology 2000;165(11):6170-3.
63.
Zengin E, Sarper N. Humoral immunity to diphtheria, tetanus, measles, and 
hemophilus influenzae type b in children with acute lymphoblastic leukemia and 
response to re-vaccination. Pediatric Blood & Cancer 2009;53(6):967-72.
64.
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National Cancer Institute. Common Terminology Criteria for Adverse Events 
(CTCAE). Version 4.03. 14 June 2010.


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14.   
APPENDICES
14.1   
Lansky Play-Performance Scale
The Play-Performance Scale for children is designed to provide a standardized measure of 
the performance status of the child with cancer.  Appropriate for use with children aged 1 to 
16.  Have parent select description which best describes child's play during the past week, 
averaging out good days and bad days.
100 - Fully active, normal.
90 - Minor restrictions in physically strenuous activity.
80 - Active, but tires more quickly.
70 - Both greater restriction of and less time spent in play activity.
60 - Up and around, but minimal active play; keeps busy with quieter activities.
50 - Gets dressed but lies around much of the day; no active play; able to participate in all 
quiet play and activities.
40 - Mostly in bed; participates in quiet activities.
30 - In bed; needs assistance even for quiet play.
20 - Often sleeping; play entirely limited to very passive activities.
10 - No play; does not get out of bed.
0 - Unresponsive.


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14.2  
Karnofsky Performance Scale
Karnofsky Performance Scale
100 - Normal; no complaints; no evidence of disease.
90 - Able to carry on normal activity; minor signs or symptoms of disease.
80 - Normal activity with effort; some signs or symptoms of disease.
70 - Cares for self; unable to carry on normal activity or to do active work.
60 - Requires occasional assistance, but is able to care for most of own needs.
50 - Requires considerable assistance and frequent medical care.
40 - Disabled; requires special care and assistance.
30 - Severely disabled; hospitalization is indicated although death is not imminent.
20 - Hospitalization necessary; very sick; active supportive treatment necessary.
10 - Moribund; fatal processes progressing rapidly.
0 - Dead.


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14.3   
Tanner Scale
Table 14-1   Criteria for Distinguishing Tanner Stages 1 to 5 During Pubertal
Maturation
Stage
Breast
Pubic Hair
1 (prepubertal)
No palpable glandular tissue or pigmentation of 
areola; elevation of areola only
No pubic hair; short, fine vellus 
hair only
2
Glandular tissue palpable with elevation of breast 
and areola together as a small mound; areolar 
diameter increased
Sparse, long, pigmented terminal 
hair chiefly along the labia majora
3
Further enlargement without separation of breast 
and areola; although more darkly pigmented, areola 
still pale and immature; nipple generally at or above 
midplane of breast tissue when individual is seated 
upright
Dark, coarse, curly hair, extending 
sparsely over mons
4
Secondary mound of areola and papilla above breast
Adult-type hair, abundant but 
limited to mons and labia
5 (adult)
Recession of areola to contour of breast; 
development of Montgomery's glands and ducts on 
areola; further pigmentation of areola; nipple 
generally below midplane of breast tissue when 
individual is seated upright; maturation independent 
of breast size
Adult-type hair in quantity and 
distribution; spread to inner 
aspects of the thighs in most racial 
groups
Data from Ross GT: Disorders of the ovary and female reproductive tract.  In Wilson JD, Foster DW (eds): 
Textbook of Endocrinology, 7th ed.  Philadelphia, WB Saunders, 1985, p 206.
Table 14-2   Pubertal Stages in Boys
Stage
Pubic Hair
Genital
1
Absence of pubic hair
Childlike penis, testes, and scrotum (testes 2 mL)
2
Sparse, lightly pigmented hair mainly at 
the base of the penis
Scrotum enlarged with early rugation and 
pigmentation; testes begin to enlarge (3–5 mL)
3
Hair becomes coarse, darker, and more 
curled and more extensive
Penis has grown in length and diameter; testes now 8–
10 mL; scrotum more rugated
4
Hair adult in quality, but distribution does 
not include medial aspect of thighs
Penis further enlarged with development of the glans; 
scrotum and testes (10–13 mL) further enlarged
5
Hair is adult and extends to thighs
Penis and scrotum fully adult; testes 15 mL and 
greater
Modified from Marshall WA, Tanner JM: Variation in pattern of pubertal changes in boys.  Arch Dis Child 
1970;45:13–23.


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14.4   
Amendment 1 Rationale and Purposes
Rationale for Amendment 1
This amendment seeks to promote patient safety by reducing the opportunity for potential 
drug-drug interactions, using an objective definition of dose-limiting toxicity (DLT), and 
specifying administration equipment that ensures drug compatibility.
Purposes for Amendment 1

Exclude those patients receiving strong inhibitors of CYP3A4 and institute a 2-week 
washout period prior to first brentuximab vedotin dose for those patients who have 
received strong inhibitors of CYP3A4

Prohibit concomitant administration of strong inhibitors of CYP3A4 during the 
brentuximab vedotin treatment period

Remove investigator attributions from the definitions of dose-limiting toxicities 
(DLTs)

Prohibit the use of polyethylene IV bags for the administration of brentuximab vedotin 
in this trial

Correct typographical errors, punctuation, grammar, and formatting
14.5   
Amendment 2 Rationale and Purposes (France-Specific Amendment)
Rationale for Amendment 2
One case of progressive multifocal leukoencephalopathy (PML) was reported in a 
48-year-old male patient with Hodgkin lymphoma (HL) who developed progressive disease 
after undergoing an autologous bone marrow transplant.  He subsequently received both 
local radiation therapy and 2 cycles of combination chemotherapy before receiving the first 
of 3 doses of brentuximab vedotin.  Two months after his initial dose, he presented with 
focal neurologic symptoms and was later diagnosed with PML.  As HL and
immunosuppressive therapies are known risk factors for PML, it is unclear what role 
brentuximab vedotin played in the development of PML, although a contributory role cannot 
be excluded. Therefore, the protocol now excludes patients with signs or symptoms of PML 
and contains instructions for the suggested management of suspected PML that include 
immediate brentuximab vedotin discontinuation.
Purposes for Amendment 2

Revise exclusion criteria to exclude patients with signs or symptoms of PML

Add instructions for the management of suspected PML

Add PML and John Cunningham virus (JCV) to the List of Abbreviations


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14.6   
Amendment 3 Rationale and Purposes
Rationale for Amendment 3
Events of progressive multifocal leukoencephalopathy (PML) have been reported in patients 
who received brentuximab vedotin.  The protocol now excludes patients with signs or 
symptoms of PML and contains instructions for the suggested management of suspected 
PML that include brentuximab vedotin discontinuation.
Infusion-related reactions (IRRs) have been reported in previous studies with brentuximab 
vedotin.  Information has been added on the management of infusion-related reactions, 
including instructions to immediately and permanently discontinue administration of 
brentuximab vedotin for Grade 3 or higher infusion-related reactions consistent with 
anaphylaxis.
Events of pulmonary toxicity were reported in a study with brentuximab vedotin given with 
bleomycin as part of a combination regimen.  The protocol now includes information on the 
occurrence of pulmonary toxicity and specifies that the concomitant use of bleomycin with 
brentuximab vedotin is contraindicated.
Peripheral neuropathy has been a frequently reported adverse event in previous studies with 
brentuximab vedotin.  Cumulative dosing with brentuximab vedotin has been associated 
with an increased incidence of peripheral neuropathy.  The original protocol states that the 
brentuximab vedotin dose should be held in the case of new or worsening events of Grade 2 
or 3 neuropathy.  To ensure patient safety and conform to dosing guidelines, an exclusion 
criterion has been added for patients with Grade 2 or higher peripheral neuropathy at the 
time of screening.
Patients who are pregnant or both lactating and breastfeeding are not eligible for the study.  
This exclusion criterion was inadvertently omitted from the original protocol and has been 
added to this amendment.
A washout period of at least 14 days is required for patients who received local palliative 
radiation therapy; a washout period of at least 84 days is required for patients who receive 
radiation therapy to more than 25% of bone marrow-containing spaces.  Exclusion criteria 
have been added to specify these restrictions on receiving radiation therapy prior to the first 
dose of study drug.
Planned imaging assessments have been revised in order to minimize radiation exposure in 
this pediatric population.  Magnetic resonance imaging (MRI) will be performed for neck, 
abdomen, and pelvis evaluations; computed tomography (CT) scans will be used for chest 
evaluations only.
Patient enrollment was defined as at the time of informed consent in the original version of 
the protocol.  To conform to Millennium protocol standards, the definition of enrollment has 
been changed to at the time of first dose of study drug.
The contact information for serious adverse events (SAEs) and events of pregnancy has been 
revised.  Section 14.5 has been added and contains phone, fax, and e-mail contact 
information by country for reporting SAEs and events of pregnancy.


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Purposes for Amendment 3
The purposes of this amendment are to:

Add information on the occurrence and management of progressive multifocal 
leukoencephalopathy (PML).

Add information on the occurrence and management of infusion-related reactions.

Add information on the risk of pulmonary toxicity with brentuximab vedotin when given 
in combination with bleomycin.

Add exclusion criterion for patients with signs or symptoms of PML.

Add exclusion criterion for patients with Grade 2 or higher peripheral neuropathy.

Add exclusion criterion for patients who are pregnant or both lactating and 
breastfeeding.

Add exclusion criterion for patients who received local palliative radiation therapy 
within 14 days prior to first dose of study drug.

Add exclusion criterion for patients who received radiation therapy to more than 25% of 
bone marrow-containing spaces within 84 days prior to first dose of study drug.

Revise planned imaging assessments to include MRI.

Change the definition of enrollment to at the time of first dose of study drug.

Add section in the appendix containing updated SAE and pregnancy reporting contact 
information.

Add development assessment and Tanner Scale and B symptom assessments to study 
procedures section.

Revise inclusion criterion for pregnancy.

Revise dose modification section for clarity.

Revise time frame for reporting SAEs to the sponsor.

Revise time frames for prior alloSCT and autologous hematopoietic stem cell 
transplantation for study eligibility.

Revise exclusion criteria for corticosteroid therapy.

Revise assessment times for pregnancy tests.

Specify that patients must have recovered from any toxic effects of prior radiotherapy, 
chemotherapy, or immunotherapy prior to enrollment.

Specify that direct and indirect bilirubin assessments will be performed.

Specify that weight and height screening assessments must be performed within 14 days 
prior to the first dose of study drug.

Clarify that an independent review facility (IRF) will assess objective response over the 
course of the study, per International Working Group (IWG) criteria.

Clarify that concomitant medications will be monitored starting at the time of signed 
informed consent form.

Clarify that a 10% or greater change in patient weight (increase or decrease) will require 
brentuximab vedotin dose adjustment.


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
Clarify that patients who are withdrawn from treatment during Cycle 1 for reasons other 
than dose-limiting toxicities (DLTs) will be replaced.

Clarify the use of concomitant colony-stimulating factors (CSFs).

Clarify that the central laboratory will be used for clinical chemistry, hematology, and 
immune reconstitution evaluations, and that local labs may be used for dosing decisions 
only.

Clarify that medical history is not obtained on Day 1, Cycle 1.

Clarify timing of hematology and serum chemistry samples.

Clarify that patients who respond may receive up to 16 cycles of brentuximab until 
disease progression.

Remove Eastern Cooperative Oncology Group (ECOG) Performance Status from 
appendices.

Rename the Pharmacodynamics/Biomarkers Analysis section to Immune Reconstitution 
Analysis.

Correct typographical errors, punctuation, grammar, and formatting.
For specific examples of changes in text and where the changes are located, see 
Section 14.7.


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14.7   Amendment 4 Detailed Summary of Changes
THE PRIMARY SECTIONS OF THE PROTOCOL AFFECTED BY THE CHANGES 
IN AMENDMENT 4 ARE INDICATED.  THE CORRESPONDING TEXT HAS BEEN 
REVISED THROUGHOUT THE PROTOCOL.
Purpose:  Revise the length of the follow-up period to align with the PIP
The primary change occurs in Section 4.1, Overview of Study Design:
Formerly 
read:
Patients will be followed for 12 months following the last dose of 
brentuximab vedotin to assess overall survival.
Now 
reads:
Patients will be followed for PFS and OS every 12 weeks for 12 months 
after the EOT visit.  Thereafter, assessment for OS will continue every 6 
months until the sooner of death or study closure or a maximum of 2 
years after enrollment of the last patient.  Patients who remain on 
treatment after Cycle 16 will be followed according to the above schedule 
or until study closure.
Sections that also contain this change are:

PROTOCOL SUMMARY

Schedule of Events

Section 4.3, Duration of Study

Section 6.4.3, Criteria for Discontinuation of Brentuximab vedotin

Section 7.10, Posttreatment Follow-up Assessments
Purpose:  Clarify that the primary endpoint of the phase 2 study is best ORR
The primary change occurs in Section 2.4, Phase 2 Primary Objectives:
Formerly 
read:
The primary objectives in phase 2 include:

To determine the overall response rate (complete remission, partial 
remission) with brentuximab vedotin at the recommended phase 2 dose
Now 
reads:
The primary objective in phase 2 is:

To determine the best overall response rate (complete remission, partial 
remission) with brentuximab vedotin at the recommended phase 2 dose
Sections that also contain this change are:

PROTOCOL SUMMARY

Section 1.3.1, Study Rationale

Section 2.2, Phase 1 Secondary Objectives


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
Section 3.2, Phase 1 Secondary Endpoints

Section 3.4, Phase 2 Primary Endpoints

Section 8.1.6, Efficacy Analysis  
Purpose:  Add safety language regarding the potential risk of SJS
The primary change occurs in Section 1.4.3, Potential Risks in Children:
Added 
text:
Stevens-Johnson syndrome (SJS), including toxic epidermal necrolysis,
has been reported in patients who received brentuximab vedotin.  
Patients were concurrently receiving other medications (naproxen and 
tramadol, respectively) that are known to cause SJS and may have 
contributed to the development of SJS.  Stevens-Johnson syndrome is 
considered to be an unacceptable study drug-related toxicity.  If SJS 
occurs, the administration of brentuximab vedotin must be discontinued 
and the appropriate medical therapy administered.
Purpose:  Add safety language regarding the potential risk of pancreatitis
The primary change occurs in Section 1.4.3, Potential Risks in Children:
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).
Purpose:  Add safety language regarding the potential risk of hepatotoxicity
The primary change occurs in Section 1.4.3, Potential Risks in Children:
Added 
text:
Hepatotoxicity, predominately in the form of asymptomatic mild to 
moderate transient elevations in AST and/or ALT, has been reported in
patients treated with brentuximab vedotin.  Patients should be monitored 
for elevated liver enzymes.
Purpose:  Revise the total bilirubin inclusion criterion to include patients with abnormal 
values due to indirect hyperbilirubinemia due to Gilbert’s disease
The primary change occurs in Section 5.1, Inclusion Criteria, criterion 11:  
Formerly 
read:

Serum bilirubin level less than or equal to 1.5 × upper limits of normal 
(ULN).


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Now 
reads:

Serum bilirubin level less than or equal to 1.5 × upper limits of normal 
(ULN) or less than or equal to 3 × ULN for patients with an indirect 
hyperbilirubinemia due to Gilbert’s disease.
Purpose:  Revise study eligibility criterion regarding elevated ALT and AST values due 
to the presence of metastatic disease in the liver
The primary change occurs in Section 5.1, Inclusion Criteria, criterion 11:  
Formerly 
read:

Alanine aminotransferase (ALT or SGPT) and aspartate 
aminotransferase (AST or SGOT) less than or equal to 2.5 × ULN.  
Now 
reads:

Alanine aminotransferase (ALT or SGPT) and aspartate 
aminotransferase (AST or SGOT) less than or equal to 2.5 × ULN.  AST 
and ALT levels may be elevated up to 5 × ULN if their elevation can 
be reasonably ascribed to the presence of metastatic disease in the 
liver.
Purpose:  Revise the washout period for systemic corticosteroid treatment in the 
exclusion criteria
The primary change occurs in Section 5.2, Exclusion Criteria, criterion 13:  
Formerly 
read:
13. Systemic corticosteroid therapy <14 days prior to first dose of study 
medication.
Now 
reads:
13. Systemic corticosteroid therapy <7 days prior to first dose of study 
medication.
Purpose:  Revise the required minimum time between previous allogeneic or autologous 
stem cell transplantation and the first dose of study drug
The primary changes occur in Section 5.2, Exclusion Criteria, criteria 2 and 17:
Formerly
read:
2. Received allogeneic stem cell transplant <6 months prior to first dose of 
study medication, or presence of polymerase chain reaction (PCR)-
detectable CMV in any post-allogeneic transplantation patient. (Prior 
PCR positivity that was successfully treated is acceptable provided the 
baseline PCR result is negative prior to first dose of study drug.)
…
17. Prior autologous hematopoietic stem cell infusion <6 weeks before first 
study dose.  


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Now 
reads:
2. Received allogeneic stem cell transplant <3 months prior to first dose of 
study medication, or presence of polymerase chain reaction (PCR)-
detectable CMV in any post-allogeneic transplantation patient. (Prior 
PCR positivity that was successfully treated is acceptable provided the 
baseline PCR result is negative prior to first dose of study drug.)
…
17. Prior autologous hematopoietic stem cell infusion <4 weeks before first 
dose of the study drug.
The PROTOCOL SUMMARY also contains this change.
Purpose:  Add to the exclusion criteria any history of PML
The primary change in Section 5.2, Exclusion Criteria, criterion 9:  
Formerly 
read:
9. Known active cerebral/meningeal disease, including signs or symptoms of 
progressive multifocal leukoencephalopathy (PML).
Now 
reads:
9. Known active cerebral/meningeal disease, including signs or symptoms of 
progressive multifocal leukoencephalopathy (PML) or any history of 
PML.
The PROTOCOL SUMMARY also contains this change.
Purpose:  Revise the CYP3A4 exclusion criterion to exclude listed moderate inhibitors of 
CYP3A4
The primary change occurs in Section 5.2, Exclusion Criteria, criterion 19:  
Formerly 
read:
19. Received a strong inhibitor of CYP3A4 2 weeks prior to first study 
dose.  (Strong inhibitors of CYP3A4 are listed in Appendix.)
Now 
reads:
19. Received any strong or listed moderate inhibitor of CYP3A4 2 weeks 
prior to first study dose.  (Please refer to the Study Manual for an 
example list of prohibited CYP3A4 inhibitors.)
Section 6.5, Excluded Concomitant Medications and Procedures, also contains this 
change.


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Purpose:  Modify the contraception language regarding abstinence to align with company 
standards
The primary change occurs in Section 5.1, Inclusion Criteria, criterion 7:
Formerly 
read:
7. Female patients who are of childbearing potential, agree to practice 
2 effective methods of contraception, at the same time, from the time of 
signing the informed consent form (ICF) through 6 months after the last 
dose of study drug, or agree to completely abstain from heterosexual 
intercourse.
8. Male patients, even if surgically sterile, 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 completely abstain 
from heterosexual intercourse.
Now 
reads:
7. Female patients who:

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 2 effective 
methods of contraception, at the same time, from the time of signing the 
informed consent through 6 months after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the 
preferred and usual lifestyle of the subject.  (Periodic abstinence (eg, 
calendar, ovulation, symptothermal, postovulation methods] and 
withdrawal are not acceptable methods of contraception.)
8. Male patients, even if surgically sterilized (ie, status postvasectomy), 
who:

Agree to practice effective barrier contraception during the entire study 
treatment  period and through 6 months after the last dose of study drug, 
or

Agree to practice true abstinence, when this is in line with the 
preferred and usual lifestyle of the subject.  (Periodic abstinence [eg, 
calendar, ovulation, symptothermal, postovulation methods for the 
female partner] and withdrawal are not acceptable methods of 
contraception.)
Section 6.7, Precautions and Restrictions, also contains this change.  


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Purpose:  Revise language regarding dose adjustments for a ≥ 10% weight change; add 
language for patients weighing more than 100 kg
The primary change occurs in Section 6.1, Study Drug Administration:
Added 
text:
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 the most recent dose calculation.  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.
The Schedule of Events, footnote s, also contains this change.
Purpose:  Correct the units of measurement for platelet count, absolute neutrophil count, 
and white blood cell count
The primary change occurs in Section 6.4.2, Criteria for Beginning or Delaying a 
Subsequent Treatment Cycle:
Formerly 
read:

ANC must be ≥1,000/mm3

Platelet count must be ≥75,000/mm3
Now 
reads:

ANC must be ≥1,000/µL

Platelet count must be ≥75,000/µL
The sections that also contain this change are:

Section 6.2.3, Hematologic Toxicity

Section 6.4.1, Criteria for Dose Modification*

Section 9.1.3, Serious Adverse Event Definition
Purpose:  Remove the restriction on the use of polyethylene infusion bags for dilution of 
brentuximab vedotin, as previously described in Administrative Letter 2
The primary change occurs in Section 6.11, Preparation, Reconstitution, and 
Dispensation:
Deleted 
text:
The appropriate amount of reconstituted study treatment will be withdrawn 
from the vial(s) and diluted in a 50- to 100-mL infusion bag containing 0.9% 
Sodium Chloride Injection, USP.  Do not use polyethylene infusion bags.


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Purpose:  Update packaging and labeling instructions for brentuximab vedotin
The primary change occurs in Section 6.12, Packaging and Labeling:
Formerly 
read:
Brentuximab vedotin for Injection is supplied in 5 mL (10 mg) single use, 
Type 1 borosilicate glass vials.
Now 
reads:
Brentuximab vedotin vials will be packaged as single-use cartons.  Each 
carton will contain 1 vial of the investigational product, and the vial and 
carton will be labeled to meet country-specific regulatory requirements.
Purpose:  Revise the timing for the development assessment and Tanner Scale
The primary change occurs in the Schedule of Events:  
Removed the X in the Development assessment and Tanner Scale row under the D15-21 
of Cycle column. 
Added an X in the Development assessment and Tanner Scale row in the Each 21-Day 
Cycle:  D1 column.
Purpose:  Permit occasional changes in the timing of tests and procedures without 
permission from the project clinician
The primary change occurs in the Schedule of Events footnotes:  
Formerly 
read:  
Tests and procedures should be performed on schedule, but occasional 
changes are allowable (±2 days) with permission of the medical monitor for 
holidays, vacations, and other administrative reasons.
Now 
reads:  
Tests and procedures should be performed on schedule, but occasional 
changes are allowable (±2 days) for holidays, vacations, and other 
administrative reasons, unless otherwise indicated.
Purpose: Revise language regarding premedication for infusion-related reactions to 
allow the use of corticosteroids
The primary change occurs in Section 6.1, Study Drug Administration:  
Formerly 
read:  
Patients who experience a Grade 1 or Grade 2 infusion-related reaction may 
receive subsequent brentuximab infusions with premedication consisting of 
acetaminophen (650 mg orally) and diphenhydramine (25–50 mg orally or 
10–25 mg IV) or according to institutional standards, administered 30 to 60 
minutes prior to each 30-minute brentuximab vedotin infusion.  The routine 
use of steroids as premedication is discouraged.
Now 
reads:  
Patients who experience a Grade 1 or Grade 2 infusion-related reaction may 
receive subsequent brentuximab infusions with premedication consisting of 


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CCI


Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
Confidential
108
Now 
reads:
7.4.15.1  Immune Reconstitution
The effects of brentuximab vedotin on the pediatric peripheral immune system 
will be examined by measuring peripheral blood cell populations and the
circulating Ig subclasses as outlined:
Immune Reconstitution

IgG

IgM

IgA

Tetanus antibodies

HiB

Polioserotypes

Total immunoglobulin

Lymphocyte count

Lymphocyte subsets
Peripheral cell populations will be examined using serum from the
heparinized blood specimens obtained at the designated time points, as 
specified in the Schedule of Events.  Cellular populations including T cell
subsets (T helper, cytotoxic, and memory cells), B cells, NK cells, and 
granulocytes will be measured by using flow cytometry.  Immunoglobulin
subclasses will be examined using standard clinical laboratory procedures.  
Added 
text:
7.4.16  Immunogenicity
Blood samples will be collected as specified in the Schedule of Events to 
evaluate ATAs and neutralizing ATAs.  On the days of dose 
administration, the blood samples for ATA and neutralizing ATA 
assessment must be collected before the brentuximab vedotin dose is 
administered.  Neutralizing ATA assessment will be performed for 
ATA-positive samples only.  Details regarding the preparation, handling, 
and shipping of samples are provided in the Study Manual.
Added 
text:
7.4.17  Tumor Specimen Measurements
This sample will be used to confirm CD30 expression by central 
laboratory review.  Refer to the Schedule of Events for details regarding 
tumor specimen collection.
Purpose:  Add language regarding reporting requirements for SAEs
The primary change occurs in Section 7.10, Posttreatment Follow-up Assessments:
Added 
text:
NOTE:  Related SAEs must be reported to the Millennium Department 
of Pharmacovigilance or designee.  This includes deaths that the 
investigator considers related to study drug that occur during the 
posttreatment follow-up.  Refer to Section 9 for details regarding 
definitions, documentation, and reporting of SAEs.


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CCI


Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
Confidential
111
The most commonly reported treatment-emergent AEs (ie, those events 
reported by 10% of all patients) will be tabulated by high level term and 
preferred term.
Now 
reads:
A listing of DLTs for each dose level will be provided.  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, neurotoxicity assessment, ECGs, 
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.  AEs will be tabulated according to the Medical Dictionary for 
Regulatory Activities (MedDRA) and will include the following categories:

Treatment-emergent AEs

Study drug-related treatment-emergent AEs

Grade 3 or higher treatment-emergent AEs

Grade 3 or higher study drug-related treatment-emergent AEs

The most commonly reported treatment-emergent AEs (ie, those 
events reported for 10% of all patients)

SAEs
A listing of treatment-emergent AEs resulting in study drug 
discontinuation will be provided.
Purpose:  Remove text regarding the start of antineoplastic or anticancer therapy as it 
relates to follow-up of AEs
The primary change occurs in Section 9.3, 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:

AEs will be reported from the first dose of study drug through 30 days 
after administration of the last dose of study drug or the start of 
subsequent anticancer therapy, whichever occurs first, and recorded in 
the eCRFs.  That is, if a patient begins a new anticancer therapy, the AE 
reporting period for nonserious AEs ends at the time the new treatment 
is started.
…

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 


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Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
Confidential
113
Purpose:  Clarify the sample size for the phase 1 and phase 2 portions of the study
The primary change occurs in Section 4.1, Overview of Study Design:  
Formerly 
read:
Approximately 42 evaluable patients will be enrolled in this study.  In the 
phase 1 portion of the study, up to 12 patients with relapsed or refractory 
CD30+ malignancies (including HL and sALCL) will be enrolled in 
2 planned dose cohorts (3 to 6 patients per cohort) according to the standard 
3 + 3 dose escalation scheme.
Once the MTD and/or RP2D have been reached, patients will be enrolled by 
diagnosis into two phase 2 study arms: relapsed or refractory sALCL, or 
relapsed or refractory HL.  The phase 2 portion of the study study plans to 
enroll 15 evaluable patients with sALCL (including patients treated at the 
RP2D during phase 1), of whom at least 10 patients are in first relapse, and 
15 evaluable HL patients (including patients treated at RP2D during phase 1).
Now 
reads:
Approximately 42 evaluable patients will be enrolled in this study.  In the 
phase 1 portion of the study, at least 12 patients with relapsed or refractory 
CD30+ malignancies (including HL and sALCL) will be enrolled in 
2 planned dose cohorts (3 to 6 patients per cohort) according to the standard 
3 + 3 dose escalation scheme.
Once the MTD and/or RP2D have been reached, patients will be enrolled by 
diagnosis into two phase 2 study arms: relapsed or refractory sALCL, or 
relapsed or refractory HL.  A sufficient number of patients will be enrolled 
in the phase 2 portion of the study to have at least 15 evaluable patients with
sALCL (including patients treated at the RP2D during phase 1), of whom at 
least 10 patients are in first relapse, and at least 15 evaluable patients with
HL (including patients treated at RP2D during phase 1).
Sections that also contain this change are:

PROTOCOL SUMMARY

Section 4.2, Number of Patients

Section 6.3 Dose Escalation Rules

Section 7.7, Discontinuation of Treatment With Study Drug, and Patient 
Replacement

Section 8.1.1, Determination of Sample Size.


Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
Confidential
114
Purpose:  Revise language in the Study Design section of the Protocol Summary to align 
with previous updates made in the protocol body text
The primary change occurs in the PROTOCOL SUMMARY:
Formerly 
read
This is a phase 1/2, open-label, single-agent, multicenter, dose-escalation 
study of brentuximab vedotin in pediatric patients with relapsed or refractory 
sALCL or HL.  Patients with primary mediastinal B cell lymphoma will be 
eligible during phase 1.  The primary objectives of the study are to assess the 
safety and pharmacokinetics, and determine the pediatric maximum tolerated 
dose (MTD) and/or RP2D of brentuximab vedotin in pediatric patients.  In 
addition, the immunogenicity and antitumor activity of brentuximab vedotin 
will be evaluated in eligible patients.
Overall response will be evaluated beginning after 2 cycles of therapy.  
Objective response over the course of the study will be assessed by an 
independent review facility (IRF) according to the International Working 
Group (IWG) Revised Response Criteria for Malignant Lymphoma.(1)  
Patients who respond or experience stable disease may receive up to 16 cycles 
of brentuximab vedotin.  
Now 
reads:
Overview of Study Design:  This is a phase 1/2, open-label, single-agent, 
multicenter, dose escalation study of brentuximab vedotin in pediatric patients 
with relapsed or refractory sALCL or HL for which standard, curative, life-
prolonging, or palliative treatment does not exist or is no longer effective.  
Patients with primary mediastinal B cell lymphoma will be eligible during 
phase 1.  The primary objectives of the study are to assess the safety and 
pharmacokinetics, and determine the pediatric MTD and/or RP2D of 
brentuximab vedotin in pediatric patients.  In addition, the immunogenicity 
and antitumor activity of brentuximab vedotin will be evaluated in eligible 
patients.
Overall response will be evaluated beginning after 2 cycles of therapy.  
Objective response over the course of the study will be assessed by an 
independent review facility (IRF) according to the International Working 
Group (IWG) Revised Response Criteria for Malignant Lymphoma.(1)  
Patients, including those who achieve a CR, PR, or stable disease may 
receive brentuximab vedotin for up to 16 cycles.  Treatment with 
brentuximab vedotin beyond 16 cycles may be permitted at the joint 
discretion of the sponsor and the investigator for those patients 
experiencing continued clinical benefit.  


Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
Confidential
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Purpose:  Clarify the planned study procedures for patients who remain on treatment after 
Cycle 16, as previously outlined in Administrative Letter #3
The primary change occurs in the Schedule of Events:
A column has been added in the Schedule of Events under the column header Cycle 17 
and Beyond (for patients who continue beyond 16 cycles) that indicates which procedures 
are to be performed after Cycle 16.  Footnote m has also been added to the Schedule of 
Events.
Purpose:  Specify that serum or urine pregnancy tests are acceptable at screening and 
before dosing on Day 1, and add a statement regarding the scheduling of pregnancy tests
The primary change occurs in Section 7.4.7, Pregnancy Test:
Formerly 
read:
Patients of childbearing potential will complete a serum pregnancy test during 
screening and at Cycle 1 Day 1; this test must be confirmed negative prior to 
receipt of the first dose of brentuximab vedotin.  A urine pregnancy test will 
be performed prior to dosing on Day 1 of each subsequent cycle.
Now 
reads:
Patients of childbearing potential will complete a serum or urine pregnancy 
test during screening, prior to dosing on Day 1 during Cycles 1 through 16,
and at EOT.  If the screening test was performed within 4 days before the 
Cycle 1, Day 1 dose, it need not be repeated on Cycle 1, Day 1.  A serum 
or urine pregnancy test will be performed prior to dosing on Day 1 of each 
subsequent cycle.  The results must be negative before brentuximab 
vedotin is administered.  During Cycle 17 and beyond, a pregnancy test 
should be performed per institutional guidelines; any samples collected 
during Cycle 17 and beyond should not be sent to the central laboratory,
and data should not be captured in the eCRF. Additional pregnancy 
tests may also be repeated during the study if requested by an IEC/IRB 
or if required by local regulations.  
The sections that also contain this change are:

Schedule of Events, footnote f

Section 5.2, Exclusion Criteria, criterion 21
Purpose:  Clarify that the timeframe for collecting clinical laboratory values at screening 
is within 4 days before the first dose of the study drug
The primary change occurs in Section 5.1, Inclusion Criteria, criterion 11:
Formerly 
read:
11. Clinical laboratory values as specified within 14 days before the first 
dose of study drug:
Now 
reads:
11. Clinical laboratory values as specified within 4 days before the first dose 
of study drug:


Brentuximab vedotin (SGN-35)
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Purpose:  Clarify that patients should be observed for anaphylaxis after each infusion of 
brentuximab vedotin
The primary change occurs in Section 6.1, Study Drug Administration:
Formerly 
read:
The patient should be observed for 60 minutes following the first infusion of 
brentuximab vedotin.
Now 
reads:
The patient should be observed for 60 minutes after each infusion of 
brentuximab vedotin.
Purpose:  Clarify that Grade 4 neutropenia lasting more than 7 days is considered a DLT
The primary change occurs in Section 6.2.3, Hematologic Toxicity:
Formerly 
read:
DLT for hematologic toxicity will be defined as:

Grade 4 neutropenia lasting greater than 7 days
Now 
reads:
DLT for hematologic toxicity will be defined as:

Grade 4 neutropenia lasting longer than 7 days
Purpose:  Clarify that unacceptable study drug-related toxicity or disease progression will 
result in mandatory, permanent discontinuation of the study drug
The primary change occurs in Section 6.4.3, Criteria for Discontinuation of Brentuximab 
vedotin:
Formerly 
read:
Study drug will be discontinued early if a patient experiences unacceptable 
study drug-related toxicities.  
…
A patient’s treatment with study drug may also be discontinued for any of the 
following reasons:

Unacceptable AE.

Disease progression.

Patient withdrawal.

Stable disease or better and completed 16 treatment cycles (brentuximab 
vedotin).

The investigator or patient deems it in the patient’s best interest to 
discontinue, including patients who experience a CR and are candidates 
for hematopoetic stem cell transplantation.  The reason justifying study 
treatment withdrawal must be documented in the CRF.


Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
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117
Now 
reads:
Study drug must be discontinued if a patient experiences progressive disease
or an unacceptable study drug-related toxicity.  
…
A patient’s treatment with study drug may also be discontinued for any of the 
following reasons:

Patient withdrawal.

Stable disease or better and completed 16 treatment cycles (brentuximab 
vedotin).

The investigator or patient deems it in the patient’s best interest to 
discontinue, including patients who experience a CR and are candidates 
for hematopoetic stem cell transplantation.  The reason justifying study 
treatment withdrawal must be documented in the CRF.
Sections that also contain this change are:

Section 4.3, Duration of Study

Section 7.7, Discontinuation of Treatment With Study Drug, and Patient 
Replacement.
Purpose:  Clarify that initiation of hematopoietic stem cell transplantation is a reason for 
study drug discontinuation
The primary change occurs in Section 7.7, Discontinuation of Treatment With Study 
Drug, and Patient Replacement:
Added 
text:
Treatment with study drug may also be discontinued for any of the following 
reasons:
…

Initiation of hematopoietic stem cell or bone marrow transplant
Section 6.4.3, Criteria for Discontinuation of Brentuximab vedotin, also contains this 
change.  
Purpose:  Clarify that development assessments include weight-for-age and 
stature-for-age percentiles
The primary change occurs in Section7.4.13.1, Development Assessment and Tanner 
Scale:  
Formerly 
read:
Development assessment and Tanner Scale to be performed according to the 
timelines in the Schedule of Events.  The development assessment will 
include height and weight; see Section 14.3 for Tanner Scale information.


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Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
Confidential
120

Creatinine

Urate

Bilirubin (total, 
direct, indirect)

Lactate 
dehydrogenase

Gamma glutamyl 
transferase

Phosphorus

Aspartate 
aminotransferase 
(AST)

Alanine 
aminotransferase 
(ALT)

Fasting glucose

Sodium

Potassium

Carbon 
dioxide

Magnesium
The Schedule of Events, footnote j, also contains this change.
Purpose:  Clarify the timing for collection of blood samples for PK assessments and 
remove reference to total blood volumes to be collected for these assessments
The primary change occurs in Section 7.4.14, Pharmacokinetic Measurements:
Formerly 
read:
Blood samples for the determination of serum brentuximab vedotin
concentrations will be collected at the following time points:

All Cycles: Day 1 immediately before and 5 minutes after the 
brentuximab vedotin infusion

Cycle 1: Days 2, 3, 5, 14

Cycle 2:  Days 2 (phase 1 only), 3, 5

Cycle 8: Days 2, 3, 5, 14
Postdose PK samples on Day 1 should be obtained at 5 (±1) minutes after the 
end of the brentuximab vedotin infusion.  The total amount of blood drawn 
for obtaining serum or plasma from each patient for PK measurements will be 
approximately 172 mL (43 specimens × 4 mL blood per specimen) over 
16 cycles of treatment.
Now 
reads:
Blood samples for the determination of serum brentuximab vedotin 
concentrations will be collected at the following time points:

All Cycles:  Day 1: within 4 hours before the start of the 
brentuximab vedotin infusion and 5 minutes (±1 minute) after the 
end of the brentuximab vedotin infusion

Cycles 1 and 8:  
o
Day 2: 24 hours (4 hours) from the start of the Day 1 
brentuximab vedotin infusion
o
Day 3: 48 hours (4 hours) from the start of the Day 1 
brentuximab vedotin infusion
o
Day 5: 96 hours (24 hours) from the start of the Day 1 
brentuximab vedotin infusion


Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
Confidential
121
o
Day 14: 312 hours (48 hours) from the start of the Day 1 
brentuximab vedotin infusion

Cycle 2:  
o
Day 2 (phase 1 only): 24 hours (4 hours) from the start of 
the Day 1 brentuximab vedotin infusion 
o
Day 3: 48 hours (4 hours) from the start of the Day 1 
brentuximab vedotin infusion 
o
Day 5: 96 hours (24 hours) from the start of the Day 1 
brentuximab vedotin infusion.
The Schedule of Events, footnote u, also contains this change.
Purpose:  Clarify the descriptions of Completion of Treatment and Completion of Study,
and clarify language for posttreatment assessments
The primary changes occur in Section 7.5, Completion of Treatment and Section 7.6, 
Completion of Study:
Deleted 
text:
Section 7.5   Completion of Treatment
Patients will be considered to have completed study treatment if they 
complete up to 16 cycles of treatment with brentuximab vedotin or experience 
progressive disease or unacceptable toxicity, and have 30 days of safety 
follow-up.
Regardless of the duration of treatment, all patients will remain on study for 
up to 12 months following the last dose of study treatment for posttreatment 
follow-up assessments, or until they withdraw consent for further follow-up, 
or are lost to follow-up.  The study is expected to close approximately 5 years 
after the first patient starts study treatment.
Patients will be followed for overall survival and disease status every 12 
weeks until 12 months after the end of treatment (EOT) visit.  Information 
regarding the initiation of an alternative form of treatment for lymphoma will 
also be collected.  For patients who have progressive disease, survival/disease 
status and information regarding the initiation of an alternative lymphoma 
treatment may be obtained by phone call.
Section 7.6   Completion of Study
Patients will be considered to have completed the study if they complete up to
16 cycles of treatment with brentuximab vedotin or experience progressive 
disease or unacceptable toxicity, and complete 30 days of safety follow-up.


Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
Confidential
122
Purpose:  Clarify efficacy analysis language to specify that the Kaplan-Meier method will 
be used to analyze efficacy parameters and specify the percentiles to be provided
The primary change occurs in Section 8.1.6, Efficacy Analysis:  
Formerly 
read:  
Duration of response (DOR), time to response, time to progression (TTP), 
EFS, PFS, and OS will be analyzed using standard survival analysis 
techniques based on Kaplan-Meier life test method.  Time to event data will 
be summarized by 25th, 50th (median), and 75th percentiles with associated 
2-sided 95% confidence interval, as well as the percentage of censored 
observations.
Now 
reads:  
Duration of response (DOR), time to response, time to progression (TTP), 
EFS, PFS, and OS will be analyzed using the Kaplan-Meier method.  The
25th, 50th (median), and 75th percentiles (if estimable) with associated 2-
sided 95% confidence interval will be provided.
Purpose:  Clarify that assessments to be performed for the EOT visit are listed in the 
Schedule of Events
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.
Now 
reads:
Once study drug has been discontinued, all study procedures outlined for the 
EOT visit will be completed as specified in the Schedule of Events.
Purpose:  Clarify that the frequency of radiological evaluations for patients who receive 
treatment past Cycle 16 is outlined in the Schedule of Events
The primary change occurs in Section 4.1, Overview of Study Design:
Added 
text:
An evaluation of disease response will be assessed by an IRF according to the 
IWG Revised Response Criteria for Malignant Lymphoma(1) evaluated at 
Cycles 2, 4, 7, 10, 13, and 16 and then at the end of treatment.  The scan 
frequency for patients who receive treatment past Cycle 16 is outlined in 
the Schedule of Events.  Additional evaluations may be necessary when 
clinically indicated..


Brentuximab vedotin (SGN-35)
Clinical Study Protocol C25002 Amendment 4, EudraCT:  2011-001240-29
Confidential
123
Purpose:  Clarify reasons for study withdrawal.
The primary change occurs in Section 7.8, Withdrawal of Patients From Study:
Formerly 
read:
A patient may be withdrawn from the study for any of the following reasons:

Completed study 

Lost to follow-up 

Study terminated by sponsor

Withdrawal of consent by patient or patient guardian

Death

Other
Now 
reads:
A patient may be withdrawn from the study for any of the following reasons:

Lost to follow-up 

Study terminated by sponsor

Withdrawal of consent by patient or patient guardian

Death

Other
Purpose:  Remove Section 14.4, Strong Cytochrome P450 3A4 (CYP3A4) Inhibitors (the 
list of prohibited CYP3A4 inhibitors is located in the Study Manual)
The primary change occurs in deleted Section 14.4, Strong Cytochrome P450 3A4 
(CYP3A4) Inhibitors:
Deleted 
text:
Section 14.4, Strong Cytochrome P450 3A (CYP3A) Inhibitors
The following are considered to be strong inhibitors of CYP3A:

atazanavir

clarithromycin

indinavir

itraconazole

ketoconazole

nefazodone

nelfinavir

posaconazole

ritonavir

saquinavir

telithromycin

voriconazole.


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SAP_000.pdf: 
This may include, but is not limited to, redaction of the following: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1/2 Study of brentuximab vedotin (SGN-35) in Pediatric Patients with Relapsed or
Refractory Systemic Anaplastic Large-Cell Lymphoma or Hodgkin Lymphoma
NCT Number: NCT01492088
SAP Approve Date: 01 December 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 information or company confidential information. 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: C25002
A Phase 1/2 Study of brentuximab vedotin (SGN-35) in Pediatric Patients with Relapsed or 
Refractory Systemic Anaplastic Large-Cell Lymphoma or Hodgkin Lymphoma
PHASE 1/2
Version: Final
Date:'HFHPEHU
Prepared by:
Based on:
Protocol Version: Amendment 4
Protocol Date: 12 June 2014
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda.
PPD


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Statistical Analysis Plan Final
01 December 2016
CONFIDENTIAL
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.


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CONFIDENTIAL
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
List of In-Text Tables............................................................................................................4
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................6
4.1
Primary Objectives ....................................................................................................6
4.2
Secondary Objectives.................................................................................................6
4.3
Exploratory Objectives ..............................................................................................6
4.4
Study Design .............................................................................................................6
5.0
ANALYSIS ENDPOINTS...............................................................................................9
5.1
Phase 1 Primary Endpoints ........................................................................................9
5.2
Phase 1 Secondary Endpoints.....................................................................................9
5.3
Phase 1 Exploratory Endpoints ..................................................................................9
5.4
Phase 2 Primary Endpoints ........................................................................................9
5.5
Phase 2 Secondary Endpoints.....................................................................................9
5.6
Phase 2 Exploratory Endpoints ................................................................................10
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................11
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................12
7.1
General Principles....................................................................................................12
7.1.1
Definition of Study Days....................................................................................12
7.1.2
Definition of Study Visit Windows ....................................................................12
7.1.3
Conventions for Missing Adverse Event Dates...................................................12
7.1.4
Conventions for Missing Concomitant Medication Dates...................................13
7.2
Analysis Sets ...........................................................................................................13
7.2.1
Safety Population...............................................................................................13
7.2.2
PK Population....................................................................................................14
7.2.3
Immune Reconstitution Population.....................................................................14
7.2.4
Response-Evaluable Population .........................................................................14
7.2.5
Dose-Limiting Toxicity (DLT)-Evaluable Population ........................................14
7.3
Disposition of Subjects ............................................................................................14
7.4
Demographic and Other Baseline Characteristics.....................................................14
7.4.1
Demographics....................................................................................................14
7.4.2
Other Baseline Characteristics............................................................................15


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Statistical Analysis Plan Final
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CONFIDENTIAL
7.5
Medical History and Concurrent Medical Conditions...............................................15
7.6
Medication History and Concomitant Medications...................................................15
7.7
Study Drug Exposure and Compliance.....................................................................16
7.8
Efficacy Analysis.....................................................................................................16
7.8.1
Primary Efficacy Endpoints ...............................................................................16
7.8.2
Secondary Efficacy Endpoints............................................................................16
7.8.3
Additional Efficacy Endpoint(s).........................................................................18
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................18
7.9.1
Pharmacokinetic Analysis ..................................................................................18
7.9.2
Pharmacodynamic Analysis ...............................................................................18
7.10
Other Outcomes.......................................................................................................19
7.10.1 Immune Reconstitution Analysis........................................................................19
7.10.2 Immunogenicity Analysis...................................................................................19
7.11
Safety Analysis........................................................................................................20
7.11.1 Adverse Events ..................................................................................................20
7.11.2 Clinical Laboratory Evaluations .........................................................................21
7.11.3 Vital Signs and Development Assessment..........................................................21
7.11.4 12-Lead ECGs ...................................................................................................22
7.11.5 Other Observations Related to Safety.................................................................22
7.12
Interim Analysis ......................................................................................................22
7.13
Changes in the Statistical Analysis Plan...................................................................22
8.0
REFERENCES..............................................................................................................23
LIST OF IN-TEXT TABLES
Table 7.1
Imputation Rules for Missing AE Start Dates


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3.0
LIST OF ABBREVIATIONS
AE
adverse event
ALCL
anaplastic large cell lymphoma
alloSCT
allogeneic stem cell transplant
ATA
antitherapeutic antibodies
CI
confidence interval 
CR
complete remission
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLT
dose-limiting toxicity
DOR
duration of response 
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EFS
event-free survival
HL
Hodgkin lymphoma
IRF
independent review facility
IV
intravenous; intravenously
IWG
International Working Group
MedDRA
medical dictionary for regulatory activities
MMAE
monomethyl auristatin E
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
ORR
overall response rate
OS
overall survival
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial remission
RDI
relative dose intensity
RP2D
recommended phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan 
sALCL
systemic anaplastic large-cell lymphoma
SCT
stem cell transplant
SD
stable disease
StdDev
standard deviation 
TTP
time to progression
WHO
World Health Organization


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4.0
OBJECTIVES
4.1
Primary Objectives
Phase 1 primary objectives are:
!
To assess the safety profile and determine the pediatric maximum tolerated dose (MTD) 
and/or RP2D of brentuximab vedotin
!
To assess the pharmacokinetics (PK) of brentuximab vedotin
Phase 2 primary objective is:
!
To determine the best overall response rate (CR, PR) with brentuximab vedotin at RP2D
4.2
Secondary Objectives
Phase 1 secondary objectives are:
!
To determine the immunogenicity of brentuximab vedotin
!
To determine the best overall response rate (CR, PR) with brentuximab vedotin
!
To determine the time to progression, time to response, duration of response, and event-free, 
progression-free, and overall survival with brentuximab vedotin
Phase 2 secondary objectives are:
!
To determine the time to progression, time to response, duration of response, and event-free, 
progression-free, and overall survival with brentuximab vedotin
!
To assess the PK and safety profile of brentuximab vedotin
!
To determine the immunogenicity of brentuximab vedotin
4.3
Exploratory Objectives
Phase 1 exploratory objective is:
Phase 2 exploratory objective is:
4.4
Study Design
This is a phase 1/2, open-label, single-agent, multicenter, dose-escalation study of brentuximab 
vedotin in pediatric patients with relapsed or refractory sALCL or HL for which standard, 
curative, life-prolonging or palliative treatment does not exist or is no longer effective. The 
primary objectives of the study are to assess the safety and pharmacokinetics, determine the 
pediatric MTD and/or RP2D of brentuximab vedotin in pediatric patients, and evaluate the 
antitumor activity of brentuximab vedotin in eligible patients. 
CCI
CCI


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Approximately 42 evaluable patients will be enrolled in this study. In the phase 1 portion of the 
study, up to 12 patients with relapsed or refractory CD30+ malignancies (including HL and 
sALCL) will be enrolled in 2 planned dose cohorts (3 to 6 patients per cohort) according to the 
standard 3 + 3 dose escalation scheme.
Once the MTD and/or RP2D have been reached, patients will be enrolled by diagnosis into two 
phase 2 study arms: relapsed or refractory sALCL, or relapsed or refractory HL. A sufficient 
number of patients will be enrolled in the phase 2 portion of the study to have at least 15 
evaluable patients with sALCL (including patients treated at the RP2D during phase 1), of whom 
at least 10 patients are in first relapse, and at least 15 evaluable patients with HL (including 
patients treated at RP2D during phase 1).
Brentuximab vedotin will be administered by IV infusion once every 21 days. Each 21-day 
treatment cycle is composed of 1 day of study drug treatment, followed by a monitoring period 
of 20 days. The starting dose in phase 1 will be 1.4 mg/kg, and escalation will proceed using a 
traditional 3 + 3 design to a maximum dose of 1.8 mg/kg.
Overall response will be evaluated beginning after 2 cycles of therapy. Objective response over 
the course of the study will be assessed by an IRF according to the IWG Revised Response 
Criteria for Malignant Lymphoma [1]. Patients, including those who achieve a CR, a PR, or 
stable disease (SD), may receive brentuximab vedotin for up to 16 cycles. Treatment with 
brentuximab vedotin beyond 16 cycles may be permitted at the joint discretion of the sponsor 
and the investigator for those patients experiencing continued clinical benefit. Following 
administration of the final dose of brentuximab vedotin, patients will be monitored for adverse 
events for a minimum of 30 days. Patients will be followed for PFS and OS every 12 weeks for 
12 months after the EOT visit. Thereafter, assessment for OS will continue every 6 months until 
the sooner of death or study closure or a maximum of 2 years after enrollment of the last patient. 
Patients who remain on treatment after Cycle 16 will be followed according to the above 
schedule or until study closure. 
Study drug will be discontinued due to occurrence of unacceptable AE, progressive disease, 
patient withdrawal, or study termination. Patients may discontinue therapy at any time. 
Additionally, those patients who experience a CR and are candidates for hematopoietic stem cell 
transplantation must discontinue brentuximab vedotin prior to chemotherapy and transplant; 
these patients will be followed for survival analyses until study closure.
AEs will be assessed, and laboratory values, vital signs, and electrocardiograms (ECGs) will be 
obtained to evaluate the safety and tolerability of brentuximab vedotin.
Serial blood samples for determination of the concentration of brentuximab vedotin, total 
therapeutic antibody, and MMAE will be obtained during Cycle 1 and subsequent cycles at 
prespecified time points as described in the Schedule of Events (SOE) in the protocol.
Radiological evaluations, (CT scan or magnetic resonance imaging [MRI], and PET as clinically 
indicated), will be employed to assess the status of the patient’s underlying disease. An 
evaluation of disease response will be assessed by an IRF according to the IWG Revised 
Response Criteria for Malignant Lymphoma [1] evaluated at Cycles 2, 4, 7, 10, 13, and 16 and 


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Statistical Analysis Plan Final
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CONFIDENTIAL
then at the end of treatment. The scan frequency for patients who receive treatment past Cycle 16 
is outlined in the Schedule of Events. Additional evaluations may be necessary when clinically 
indicated.


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Statistical Analysis Plan Final
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5.0
ANALYSIS ENDPOINTS
5.1
Phase 1 Primary Endpoints
!
Adverse events (AEs), serious adverse events (SAEs), assessments of clinical laboratory 
values, and vital signs measurements
!
Serum concentrations of brentuximab vedotin, total therapeutic antibody, and plasma 
concentrations of MMAE
5.2
Phase 1 Secondary Endpoints
!
Antitherapeutic antibody (ATA), ATA titer, and neutralizing ATA
!
Best overall response rate (CR, PR) as determined by an independent review facility (IRF) 
using positron emission tomography (PET), computed tomography (CT), magnetic resonance 
imaging (MRI), and clinical assessment, according to International Working Group (IWG) 
revised response criteria
!
Time to progression
!
Time to response
!
Duration of response
!
Event-free survival
!
Progression-free survival
!
Overall survival
5.3
Phase 1 Exploratory Endpoints
!
5.4
Phase 2 Primary Endpoints
!
Best overall response rate (CR, PR) as determined by an IRF using PET, CT, MRI, and 
clinical assessment according to IWG revised response criteria
5.5
Phase 2 Secondary Endpoints
!
Time to progression
!
Time to response
!
Duration of response
!
Event-free survival
CCI


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Statistical Analysis Plan Final
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CONFIDENTIAL
!
Progression-free survival
!
Overall survival
!
Adverse events, serious adverse events, assessments of clinical laboratory values, and vital 
signs measurements
!
Serum concentrations of brentuximab vedotin, total therapeutic antibody, and plasma 
concentrations of MMAE
!
Antitherapeutic antibody (ATA), ATA titer, and neutralizing ATA
5.6
Phase 2 Exploratory Endpoints
!
CCI


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6.0
DETERMINATION OF SAMPLE SIZE
Approximately 42 evaluable patients will be enrolled in this study. In the phase 1 portion of the 
study, up to 12 patients with relapsed or refractory CD30+ malignancies will be enrolled in 2 
planned dose cohorts (3-6 patients per cohort), according to the standard 3 + 3 dose escalation 
scheme. 
Once the MTD and/or RP2D have been reached, patients will be enrolled by diagnosis into two 
phase 2 study arms: relapsed or refractory sALCL or relapsed or refractory HL. A sufficient 
number of patients will be enrolled in the phase 2 portion of the study to have at least 15 
evaluable patients with sALCL (including patients treated at the RP2D during phase 1), of whom 
at least 10 patients are in first relapse, and at least 15 evaluable patients with HL (including 
patients treated at the RP2D during phase 1).
The sample size is not based on statistical consideration. Based on the exact binomial confidence 
interval calculation, 10 responses observed out of the 15 evaluable patients (overall response rate 
of 66.7%) will provide a 95% confidence interval of (38%, 88%).


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Statistical Analysis Plan Final
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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
In general, descriptive statistics (number of observations, mean, standard deviation (StdDev), 
median, minimum, and maximum) will be used to summarize continuous variables. Frequencies 
and percentages will be used to summarize categorical variables. Time-to-event data will be 
analyzed using the Kaplan-Meier method and results will be summarized by the 25th, 50th 
(median), and 75th percentiles, if estimable, with associated 2-sided 95% confidence intervals, as 
well as the percentage of censored observations.
Unless otherwise specified, safety and efficacy data will be summarized in the following 7 
groups: 1.4 mg/kg phase 1 only; 1.8 mg/kg phase 1 only; 1.8 mg/kg phase 1&2 HL only; 
1.8 mg/kg phase 1&2 sALCL only; 1.8 mg/kg phase 1&2 sALCL in first relapse only; 1.8 mg/kg 
all patients; all patients. Pharmacokinetic analyses will be summarized by dose and treatment 
cycle.
The baseline value is defined as the value collected at the time closest to, but prior to, the start of 
study drug administration, unless otherwise specified. A windowing convention will be used to 
determine the analysis value for a given study visit for observed data analyses.
All available efficacy and safety data will be included in data listings and tabulations. Data that 
are potentially spurious or erroneous will be examined under the auspices of standard data 
management operating procedures. In general, there will be no imputation of missing data. For 
time-related endpoints, subjects who have no specified events will be censored as specified for 
each respective endpoint in Section 7.8. Imputation rules for missing dates of AEs and 
concomitant medications are detailed in Sections 7.1.3 and 7.1.4.
SAS Version 9.2 (or higher) will be used for all analyses.
7.1.1
Definition of Study Days
Study Day 1 is defined as the date on which a subject is administered their first dose of the 
medication. Other study days are defined relative to the Study Day 1 with Day 1 being Study 
Day 1 and Day -1 being the day prior to Study Day 1.
7.1.2
Definition of Study Visit Windows
All data will be categorized based on the scheduled visit at which it was collected. These visit 
designators are predefined values that appear as part of the visit tab in the eCRF.
7.1.3
Conventions for Missing Adverse Event Dates
Missing or partial AE start dates will be imputed according to the following rules.


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Statistical Analysis Plan Final
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Table 7.1
Imputation Rules for Missing AE Start Dates
Non-
missing
Missing
Estimated
Month and
Year
Day
Day of first dose date of STUDY DRUG, if month and year of onset date are the
same as month and year of date of first dose.
The last day of the month, if the month and year of onset date are before the
month and year of date of first dose of STUDY DRUG.
The first day of the month, if the month and year of onset date are after the
month and year of date of first dose of STUDY DRUG.
Year
Day and Month
Day and month of first dose date of STUDY DRUG, if the year of onset date is 
the same as the year of date of first dose of STUDY DRUG.
December 31st, if the year of onset date is prior to the year of date of first dose of
STUDY DRUG.
January 1st, if the year of onset date is after the year of date of first dose of
STUDY DRUG.
Day, Month
and Year
Date of first dose of STUDY DRUG
Missing or partial AE stop dates will be imputed according to the following rules. If only the day 
is missing, use 15th of the month; if both month and day are missing, use June 30th. For a record 
with a start date and a partial stop date, if the estimated stop date is before the start date, the stop 
date will not be estimated.
If AE stop date is not missing and AE stop date < estimated start date, let estimated onset date = 
AE stop date.
All dates presented in listings are recorded dates without imputation.
7.1.4
Conventions for Missing Concomitant Medication Dates
If only the day is missing, use 15th of the month; if both month and day are missing, use June 
30th. For a record with a start date and a partial stop date, if the imputed stop date is before the 
start date, the stop date will not be estimated.
All dates presented in listings are recorded dates without imputation.
7.2
Analysis Sets
7.2.1
Safety Population
The safety population will include patients who have received at least 1 dose of study drug. 
Safety population will be used for all safety, efficacy, and immunogenicity analyses, unless 
otherwise specified.


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Statistical Analysis Plan Final
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7.2.2
PK Population
The PK population will include patients with sufficient dosing and PK data to reliably estimate 
PK parameters. 
The PK population will be used for PK analyses.
7.2.3
7.2.4
Response-Evaluable Population
The response-evaluable population will include patients who receive at least 1 dose of study 
drug, have measurable disease at baseline, and have 1 postbaseline disease assessment.
The response-evaluable population will be used for analyses of disease response, time to 
response and duration of response.
7.2.5
Dose-Limiting Toxicity (DLT)-Evaluable Population
The DLT-evaluable population will include patients who either experience a DLT during phase 1 
or receive all scheduled doses and complete all study procedures in phase 1 without a DLT. 
The DLT-evaluable population will be used for the analysis of DLTs.
7.3
Disposition of Subjects
Disposition of patients includes the number and percentage of patients for the following 
categories: patients in each of the study populations in Section 7.2, primary reason to discontinue 
from the treatment, patients discontinued from the study, and primary reason to discontinue from 
the study. All percentages will be based on the number of patients in the safety population.
A listing will be used to present data concerning the patient disposition.
7.4
Demographic and Other Baseline Characteristics
7.4.1
Demographics
Demographic and baseline characteristics will be summarized for patients in the safety 
population by dose level and disease type. Baseline demographic data to be evaluated will 
include sex, age, ethnicity, race, body weight, height, body surface area (BSA). The formulation 
for BSA is:
BSA (m2) =
3600
)
(
)
(
kg
Wt
cm
Ht
∀
CCI
CCI


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Statistical Analysis Plan Final
01 December 2016
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7.4.2
Other Baseline Characteristics
The following baseline characteristics will be summarized for patients in the safety population 
by dose level and disease type.
At initial diagnosis

Months since initial diagnosis

Disease Type

Ann Arbor Stage

Evidence of Bone Marrow Involvement 

Evidence of Extranodal Involvement 
At Study Entry

Evidence of Bone Marrow Involvement

B Symptoms
7.5
Medical History and Concurrent Medical Conditions
General medical history of all patients will be presented in a by-patient listing in reported terms, 
ie, not coded.
B symptom assessments (fever, night sweats, and weight loss) and clinical evaluation of palpable 
liver and spleen will be presented over time in by-patient listings. 
7.6
Medication History and Concomitant Medications
Medication history including prior antineoplastic therapy, prior surgery, prior radiation, and prior 
transplant procedure information will be presented in by-patient listings. The number and 
percentage of patients with any prior event will be tabulated by dose and by disease type. 
Concomitant medications will be coded by preferred term using the World Health Organization 
(WHO) Drug Dictionary (March 2012 Version). Concomitant medication is defined as any 
medication administered between the first and the last days (inclusive) of the study. The number 
and percentage of patients taking concomitant medications from signing of informed consent 
form through 30 days after the last dose of brentuximab vedotin will be tabulated by Anatomical 
Therapeutic Chemical (ATC) classification pharmacological subgroup and WHO drug generic 
term.
Patients are counted once for each ATC pharmacological subgroup and once for each WHO 
preferred term.
Concomitant procedures will not be coded, but will be presented in a by-patient listing.


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7.7
Study Drug Exposure and Compliance
The exposure to brentuximab vedotin will be characterized by total dose of drug received in mg, 
number of treated cycles, duration of treatment, and relative dose intensity (RDI, %). 
RDI (%) =100% * (total dose administered (mg) / total dose expected (mg))  
Total dose expected is the summation of expected dose (dose level initially assigned multiply by 
weight) in each cycle during treatment.
A treated cycle is defined as a 21-day period, during which the patient receive any amount of 
brentuximab vedotin (scheduled for single dose in 21-day period). The duration of treatment is 
defined as time from the first study dose to 21 days after the last study dose:
Duration of treatment = Last dose date + 21 - First dose date
Action on study drug (including dose reduction) will be summarized by Cycle 1 through 16.
Dosing data including dose modification and action on drug will also be presented in a by-
patient, by-cycle listing.
7.8
Efficacy Analysis
Response rates (OR, CR, PR), time to response, and duration of response will be conducted 
using the response-evaluable population. The other efficacy evaluations will be conducted using 
the safety population unless otherwise specified. All efficacy data will be summarized for the 7 
groups listed in Section 7.1. If the sample size is too small to do a certain analysis in a group, no 
results will be presented for that group.
7.8.1
Primary Efficacy Endpoints
There is no primary efficacy endpoint in phase 1. The primary endpoint in phase 2 is overall 
response rate (ORR) of patients who achieve CR or PR as determined by an independent review 
facility (IRF) using PET, CT, MRI, and clinical assessment according to IWG revised response 
criteria. 
The primary efficacy endpoint of ORR per IRF, along with CR rate, and PR rate will be 
summarized with 2-sided 95% exact confidence intervals. Response rates (OR, CR, and PR) will 
be summarized using the response-evaluable population.
7.8.2
Secondary Efficacy Endpoints
Besides response rates per IRF, response rates (ORR, CR, PR) per investigator assessments will 
also be summarized for all 7 groups listed in Section 7.1. Response rates will be summarized 
with 2-sided 95% exact confidence intervals.
The other secondary efficacy endpoints include time to progression (TTP), time to response, 
duration of response (DOR), event-free survival (EFS), progression-free survival (PFS), and 
overall survival (OS). TTP, DOR, EFS, and PFS will be estimated using independent review 
facility (IRF) assessment unless otherwise specified. Time to response and DOR will be 


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summarized using the response-evaluable population; TTP, EFS, PFS, and OS will be 
summarized using the safety population.
TTP is defined as the time from the first dose until the first subsequent documentation of 
objective tumor progression. TTP will be censored on the last radiological assessment of 
measured lesions documenting absence of PD for patients who do not have objective tumor 
progression.
Time to response is defined as the time from the first dose until the first documentation of 
objective tumor response (CR or PR). Time to response will be censored on the last radiological 
assessment of measured lesions documenting absence of CR or PR for patients who do not have 
a CR or PR.
Duration of response in subjects with response (CR or PR) is defined as the time from start of the 
first documentation of objective tumor response (CR or PR) to the first subsequent 
documentation of objective tumor progression or to death due to any cause, whichever comes 
first. Duration of response will be censored on the day following the date of the last radiological 
assessment of measured lesions documenting absence of PD for patients who do not have 
objective tumor progression and are still on study at the time of analysis, are given antitumor 
treatment other than the study treatment or stem cell transplant (SCT), or are removed from study 
prior to documentation of objective tumor progression.
EFS is defined as the time from the first dose until any cause of treatment failure: disease 
progression per IRF (including progression events during follow-up period), premature 
discontinuation of treatment for any reason (ie, not completing 16 cycles of treatment due to any 
reason), or death due to any cause, whichever occurs first. EFS will be censored on the last PFS 
assessment date if none of the above events occur during the study.
PFS is defined as the time from the first dose until disease progression or death due to any cause, 
whichever occurs first. PFS will be censored on the day following the date of the last 
radiological assessment of measured lesions documenting absence of PD for patients who do not 
have objective tumor progression and are still on study at the time of analysis, are given 
antitumor treatment other than the study treatment or SCT, or are removed from study prior to 
documentation of objective tumor progression. Patients lacking an evaluation of tumor response 
after their first dose will have their event time censored at the day of first dose.
OS is defined as the time from the first dose until death due to any cause. In the absence of 
confirmation of death, survival time will be censored at the last date the patient is known to be 
alive. Patients lacking data beyond the day of first dose will have their survival time censored at 
the day of first dose.
TTP, time to response, DOR, EFS, PFS, and OS will be analyzed using the Kaplan-Meier 
method,  the 25th, 50th (median), and 75th percentiles, if estimable, will be presented along with 
the associated 2-sided 95% confidence intervals. The results will also be presented in figures 
(Kaplan-Meier plots). 
A waterfall plot may be used to compare PFS per investigator from the current study versus PFS 
achieved with the last therapy received prior to study entry.


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A waterfall plot will be used to summarize the greatest percent reduction in target lesions for 
individual patients.
Efficacy data will also be listed by patient.
7.8.3
Additional Efficacy Endpoint(s)
Not applicable 
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
Serum concentrations of brentuximab vedotin (ADC) and total therapeutic antibody (TAb), and 
plasma concentrations of monomethyl auristatin E (MMAE) will be determined using validated 
assays.
Descriptive statistics (eg, number of patients, arithmetic mean, geometric mean, StdDev, median, 
percentage of coefficient of variation (%CV), minimum, and maximum) will be used to 
summarize serum ADC, serum TAb, and plasma MMAE concentrations at each time point in 
Cycles 1 and 8 at each dose level. The mean concentrations-time profiles of ADC, TAb, and 
MMAE will be plotted for cycles 1 and 8. The complete set of the same data (Cycles 1-16 or up 
to the cycle where N ≥3) will also be plotted for each dose level for ADC on a single plot. 
Similar plots will be provided for the TAb and the MMAE. Individual patient concentration data 
will be listed and plotted over time by cycle and by dose level.
Noncompartmental analysis for the determination of PK parameters such as tmax, Cmax, AUC0-21 
day, AUC0-∞, t1/2, CL, and Vss will be performed as data permits for ADC and TAb. The PK 
parameters of tmax, Cmax, AUC0-21 day, AUC0-∞, and t1/2 will be estimated for MMAE. These 
parameters will be summarized by dose level and cycle. The summary statistics will consist of N, 
mean, StdDev, %CV, median, min, max, and geometric mean. AUC0-21 day or AUC0-∞of ADC at 
1.4 mg/kg will be scaled to 1.8 mg/kg (parameter to be scaled with multiplication of 1.29) for 
purposes of evaluating estimated exposures at the 1.8 mg/kg dose across the PK population. The 
individual CL of ADC and TAb will also be computed by normalizing for the baseline body 
weight and body surface area. Individual patient values of the parameters will be listed by cycle.
The 1.8 mg/kg and scaled 1.8 mg/kg AUC0-21 day or AUC0-∞of ADC will be plotted against age 
and/or body weight. More exploratory plots may be presented in the CSR as needed.
7.9.2
Pharmacodynamic Analysis
Not applicable


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7.10
Other Outcomes
7.10.1
7.10.2 Immunogenicity Analysis
Immunogenicity will be summarized using descriptive statistics into the following categories: 
ATA negative, transiently ATA positive, persistently ATA positive, low and high ATA titer, and 
neutralizing ATA (nATA).
!
ATA Negative - defined as patients who do not have positive ATA in any postbaseline 
sample 
!
Transiently ATA positive - defined as patients who have positive ATA in 1 or 2 postbaseline 
samples 
!
Persistently ATA positive - defined as patients who have positive ATA in more than 2 
postbaseline samples
!
High ATA Titer: >25
!
Low ATA titer: ≤25
!
nATA negative: defined as patients who do not have positive nATA in any postbaseline ATA 
positive sample 
!
nATA positive: defined as patients who have positive nATA in any postbaseline ATA 
positive sample.
ATA status, ATA titer and neutralizing ATA will be listed by patient. Neutralizing ATA status 
(nATA negative and positive) will also be listed for patients who have positive antibody status.
For effect of ATA on efficacy, the proportion of patients in CR and PR will be summarized 
within each ATA response status (negative, transiently positive, persistently positive) by disease 
type. The same analysis may be repeated based on ATA titer (high, >25; low, ≤25). In addition, 
patient level ATA and efficacy (overall response) data will be listed together by time.
For effect of ATA on safety, patient incidence of AEs (preferred term) by ATA response status 
(negative, transiently positive, persistently positive, high and low titer) will be provided for both 
HL and sALCL. Infusion-related reactions (preferred term) will also be summarized by ATA 
status, ATA titer and nATA status.
The relationship between immunogenicity status (ATA, ATA titer, nATA) and PK may be 
explored. 
CCI
CCI


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7.11
Safety Analysis
Safety will be evaluated by the incidence of treatment-emergent AEs, severity and type of AEs, 
and by changes from baseline in the patient’s vital signs, neurotoxicity assessment, ECGs, and 
clinical laboratory results. Exposure to study drug and reasons for discontinuation will be 
tabulated.
These analyses will be performed using the safety population.
7.11.1 Adverse Events
AEs will be tabulated according to the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 19.0 by system organ class, high-level terms, preferred terms and intensity. AEs with 
missing start and/or end dates will be imputed according rules specified in Section 7.1.3. 
Treatment emergent AE is defined as any AE that occurs after administration of the first dose of 
study treatment and up through 30 days after the last dose of study drug. Patients with the same 
AE more than once will have that event counted only once within each body system, once within 
each high-level term, and once within each preferred term. AEs will be summarized and will 
include the following categories: 

Treatment-emergent AEs

Drug-related treatment-emergent AEs

Grade 3 or higher treatment-emergent AEs

Grade 3 or higher drug-related treatment-emergent AEs

Treatment-emergent AEs resulting in study drug discontinuation

SAEs

AEs of peripheral neuropathy identified by the broad search MedDRA SMQ “Peripheral 
neuropathy”
Treatment-emergent AEs will be tabulated by system organ class, high-level term and preferred 
term. The most commonly reported treatment-emergent AEs (i.e., those events reported by ≥ 
10% of all patients) will be tabulated by preferred term. The individual patient’s information on 
the DLTs will be presented in a listing. Additional analyses of peripheral neuropathy may also be 
presented.
7.11.1.1 Serious Adverse Events
The number and percentage of patients experiencing at least 1 treatment emergent serious AE 
(SAE) will be summarized by MedDRA (Version 19.0) primary system organ class, high-level 
term, and preferred term. Drug-related SAE will be summarized similarly.
In addition, a by-subject listing of the SAEs will be presented (the subject listing will contain all 
SAEs regardless of treatment-emergent AE status).


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7.11.1.2 Peripheral Neuropathies
Peripheral Neuropathy (PN) is defined by the peripheral neuropathy SMQ broad search. The 
incidence of treatment-emergent PN and treatment-emergent treatment-related PN will each be 
summarized by preferred term and severity. Time to onset, resolution and improvement of PN 
events will be summarized. Individual plot by preferred term for treatment-emergent peripheral 
neuropathy (SMQ) will also be presented.
7.11.1.3 Deaths
A by-subject listing of the deaths will be presented. All deaths occurring on-study and during 
follow-up will be displayed (regardless of treatment-emergent AE status). On-study death is 
defined as a death that occurs between the first dose of study drug and 30 days after the last dose 
of study drug.
7.11.1.4 Adverse Events Resulting in Discontinuation of Study Drug
AEs resulting in discontinuation of study drug will be presented in a by-patient listing and also in 
a summary table by system organ class, high-level term and preferred term.
7.11.2 Clinical Laboratory Evaluations
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change from 
baseline in clinical laboratory parameters) will be presented for all scheduled measurements over 
time. Mean laboratory values over time will be plotted for key laboratory parameters.
If a patient has repeated laboratory values for a given time point, the value from the last 
evaluation will be used.
The parameters to be analyzed are as follows:
!
Hematology:  hemoglobin, hematocrit, platelet count, total white blood cell (WBC) count, 
and differential WBC count
!
Serum chemistry: blood urea nitrogen, creatinine, total bilirubin, urate, lactate 
dehydrogenase, gamma-glutamyl-transpeptidase (GGT), phosphate, albumin, alkaline 
phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), glucose, 
sodium, potassium, calcium, chloride, carbon dioxide, magnesium and uric acid
!
Shift tables for laboratory parameters will be generated based on changes in National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grades from baseline 
to the worst postbaseline value.
7.11.3 Vital Signs and Development Assessment
Descriptive statistics for the actual values (and/or the changes from baseline) of vital signs and 
weight will be tabulated over time. A by-patient listing will also be presented.
CCI


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Development assessment and Tanner Scale data will be listed by patient.
7.11.4 12-Lead ECGs
ECG (QT, corrected QT [QTcF], PR, and QRS intervals, ventricular rate) will be summarized at 
each scheduled time point, along with mean change from baseline to posttreatment time point.
7.11.5 Other Observations Related to Safety
Performance Status, as measured by Lansky or Karnofsky Scale status over time will be listed by 
patient.
7.12
Interim Analysis
Not applicable
7.13
Changes in the Statistical Analysis Plan 
None


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8.0
REFERENCES
1. 
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant 
lymphoma. J Clin Oncol. 2007;25(5):579-586.


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