Clinical trial NCT02388490
Conditions: Relapsed or Refractory EBV-and CD30-positive Lymphomas
Keywords: Brentuximab vedotin EBV Lymphoma
Sponsor: Seoul National University Hospital
Start date: 2016-03-25; Completion date: 2019-04-02
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, non-randomized, multi-center, phase II trial of brentuximab vedotin to evaluate ORR primarily in patients with EBV- and CD30-positive lymphomas.

Detailed description:
This is an open-label, non-randomized, multi-center, phase II trial of brentuximab vedotin to evaluate ORR primarily in patients with EBV- and CD30-positive lymphomas. The ORR will be evaluated based on the revised Cheson's criteria or modified SWAT criteria in case of cutaneous EBV- and CD30-positive lymphomas.

Arms: arm 1: Brentuximab vedotin is an antibody-drug conjugate (ADC) composed of the anti-CD30 chimeric immunoglobulin G1 (IgG1) monoclonal antibody cAC10 and the potent antimicrotubule drug monomethyl auristatin E connected by a protease-cleavable linker. cAC10 binds to the CD30 antigen, which has a very low expression on normal cells but is found on some tumor cells.
Interventions: intervention 1: brentuximab vedotin
Intervention descriptions: intervention 1: Brentuximab vedotin administered by IV infusion given over approximately 30 minutes on Day 1 of each 21-day cycle. The dose of brentuximab vedotin is 1.8 mg/kg q 3 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
 
A phase II study of brentuximab vedotin in patients with relapsed or 
refractory EBV- and CD30-positive lymphomas 
Indication: 
 
EBV and CD30-positive lymphomas 
Phase:  
 
II 
 
Protocol History 
Original; 15-DEC-2013 (version 1.0) 
Revised; 3-JUN-2014 (version 1.1) 
 
Investigator & Study Center 
Tae Min Kim, MD, PhD, Associate Professor 
Seoul National University Hospital 
101 Daehak-ro, Jongno-gu, Seoul, 110-744, Republic of Korea 
E-mail: gabriel9@snu.ac.kr; Tel: 82-2-2072-3559; Fax: 82-2-742-6689  
 
 
This is an investigator-initiated study.  The principal investigator < (Tae Min Kim)>, (who may 
also be referred to as the sponsor-investigator), is the person conducting the study and acting as 
the sponsor.  Therefore, the legal/ethical obligations of the principal investigator include both 
those of a sponsor and those of an investigator. 


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PROTOCOL SUMMARY 
Study Title: A phase II study of brentuximab vedotin in patients with relapsed or refractory EBV-
and CD30-positive lymphomas 
Phase:  II 
Number of Patients:  25 
Study Objectives   
Primary 
 Objective: To evaluate the overall response rate (ORR) of brentuximab vedotin in EBV- and 
CD30-positive lymphomas 
Secondary 
 Objective 1: To evaluate the safety profile of brentuximab vedotin using CTCAE version 4.03 
 Objective 2: To calculate progression-free survival (PFS) time 
 Objective 3: To calculate the duration of response 
 Objective 4: To calculate overall survival (OS) time 
Exploratory 
 Objective 1: To determine the CD30-positive rate of EBV-positive lymphomas 
 Objective 2: To compare ORR according to the CD30 expression level 
 Objective 3: To compare ORR according to the soluble CD30 level 
 Objective 4: To compare ORR according to the EBV copy number 
Overview of Study Design:   
This is an open-label, non-randomized, multi-center, phase II trial of brentuximab vedotin to 
evaluate ORR primarily in patients with EBV- and CD30-positive lymphomas. The ORR will be 
evaluated based on the revised Cheson’s criteria1 or modified SWAT criteria2 in case of cutaneous 
EBV- and CD30-positive lymphomas. Based on the optimal Simon’s two-stage design, at least 3 
responders among stage 1 patients (N=10) are required to enter into a stage 2. The stage 2 will be 
delayed until the completion of ≥4 cycles of study medication in the last patient in stage 1, so-called 
interim analysis of stage 1. Although an independent data monitoring committee (IDMC) is 
unplanned, central study coordinators will monitor the study and safety. 
Study Population:   
Inclusion criteria 
1. Patients with relapsed or refractory EBV- and CD30-positive lymphomas 
i. 
EBV-positivity determined by EBV in situ hydridization at participating centers 
a. 
Extranodal NK/T-cell lymphoma, nasal type 


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b. EBV-positive peripheral T-cell lymphoma, not otherwise specified 
c. 
EBV-positive diffuse large B-cell lymphoma of the elderly 
d. Plasmablastic lymphoma 
e. 
Lymphomatoid granulomatosis 
f. 
Hydroa vacciniform-like T-cell lymphoma 
g. Other EBV-positive lymphoproliferative disorders 
ii. 
CD30-positivity determined by a specialized hemato-pathologist 
iii. 
Relapsed or refractory disease that fails to at least one and maximum four regimens 
including anthracycline-based chemotherapy; if anthracycline-based regimen is not 
standard treatment of certain subtypes (e.g. hydroa vacciniforme-like T-cell lymphoma 
or EBV-positive lymphoproliferative disorder, etc), a prior chemotherapy is acceptable. 
2. Age ≥ 18 years 
3. ECOG performance status 0-2 
4. At least one measurable lesion based on revised Cheson’s or modified SWAT criteria 
5. Provision archival tumor tissues (4 μm thickness x 5 unstained slides) and blood samples 
6. Voluntary written informed consent must be given before performance of any study-
related procedure not part of standard medical care, with the understanding that consent may 
be withdrawn by the patient at any time without prejudice to future medical care. 
 
7. Female patient is either post-menopausal for at least 1 year before the screening visit or 
surgically sterile or if 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 agrees to completely abstain from heterosexual 
intercourse. 
 
8. Male patients, even if surgically sterilized, (i.e., status post vasectomy) agree to practice 
effective barrier contraception during the entire study period and through 6 months after the 
last dose of study drug, or agrees to completely abstain from heterosexual intercourse. 
9. Adequate hematologic function: absolute neutrophil count (ANC) ≥1,500/µL, platelet count ≥ 
75,000/µL, and hemoglobin ≥8.0 g/dL  unless there is known hematologic tumor marrow 
involvement (ANC ≥ 1,000/µL and platelet count ≥ 50,000/µL if there is known bone marrow 
involvement) 
10. Adequate liver function: total bilirubin < 1.5 x the upper limit of the normal (ULN) unless the 
elevation is known to be due to Gilbert syndrome and ALT or AST  < 3 x ULN (AST and AST < 5 x 
ULN if their elevation can be reasonably ascribed to the presence of hematologic tumor in liver) 
11. Adequate renal function: serum creatinine < 2.0 mg/dL and/or creatinine clearance or calculated 
creatinine clearance > 40 mL/minute.  
12. Expected survival > 3 months 
 


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Exclusion criteria 
1. Female patient who are both lactating and breast-feeding or have a positive serum pregnancy test 
2. Any serious medical or psychiatric illness 
3. Known cerebral or meningeal involvement (EBV- and CD30-positive lymphoma or any other 
etiology), including signs or symptoms of PML 
4. Symptomatic neurologic disease compromising normal activities or requiring medication 
5. Any sensory or motor peripheral neuropathy greater than or equal to Grade 2  
6. Known history of myocardial infarction within 1 year, NYHA class III/IV heart failure, or 
uncontrolled cardiovascular conditions including cardiac arrhythmias, congestive heart failure 
(CHF), angina, or electrocardiographic evidence of acute ischemia or active conduction system 
abnormalities.  Recent evidence (within 6 months before first dose of study drug) of a left-ventricular 
ejection fraction <50%. 
7. Any active systemic viral, bacterial, or fungal infection within 2 weeks prior to first study drug 
dose 
8. Any prior chemotherapy and/or other investigational agents within at least 5 half-lives of last dose  
9. Prior stem cell transplantation within 100 days or radioimmunotherapy within 8 weeks 
10. Prior exposure to CD30-targeted agents 
11. Known hypersensitivity to recombinant proteins, murine proteins, or to any excipient contained 
in the drug formulation of brentuximab vedotin 
12. Known human immunodeficiency virus (HIV) positive 
13. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection 
14. Another malignancy within 3 years before the first dose or previously diagnosed with another 
malignancy and have evidence of residual disease.  Patients with nonmelanoma skin cancer or 
carcinoma in situ of any type are not excluded if they have undergone complete resection. 
 
Duration of Study:  This study will last approximately 30 months to reach the final analyses of the 
ORR and PFS (24 months of enrollment plus 6 months of additional follow-up after the last patient-
in). 


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STUDY OVERVIEW DIAGRAM 
 
 


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SCHEDULE OF EVENTS 
Timetables: screening ~ end of treatment 
 
 
Screening 
Cycle 1 Cycle 2 
Cycles 
3~15 
Cycle 
16 
EOT/EOS 
FUa 
-28 to D1 
D1 
D1 
D1 
D1 
30 ± 7 
after last 
IP dose 
q 3 mo till 
study 
closure 
Visit window, days 
 
± 3 
± 3 
± 3 
± 3 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Tumor specimen and 
biomarker sample 
Xb 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
 
 
Physical exam 
X 
Xc 
X 
X 
X 
X 
X 
Serum -hCG 
 Xd 
 
 
 
 
 
 
Urine pregnancy test 
 
X 
 
 
 
 
 
Vital signs 
X 
Xe 
X 
X 
X 
X 
X 
ECOG performance status 
X 
 
X 
X 
X 
X 
 
B symptoms 
X 
X 
X 
X 
X 
X 
X 
Hematology and chemistryf 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
Concomitant medication 
Concomitant medications and procedures will be recorded from signing the main ICF through 
30 days after the last dose of brentuximab vedotin. 
AE reporting 
 
Recorded from first dose of study drugs through 30 days 
after the last dose of brentuximab vedotin. 
 
SAEs 
SAEs will be collected from signing of the main ICF through 30 days after the 
last dose of brentuximab vedotin. 
 
CTs of the neck, abdomen, 
and pelvisg 
X 
 
X 
X 
 
X 
 
Skin evaluationh 
X 
 
X 
X 
 
X 
 
PET/CTi 
X 
 
X 
 
 
 
 
Survival and disease status 
 
 
 
 
 
 
Xj 


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a. All treated patients will be followed for PFS and OS status every 12 weeks (± 1 week) until the study 
closure. For patients who have progressive disease, survival/disease status and information regarding 
the initiation of an alternative lymphoma treatment may be obtained by phone call.  
b. Tumor tissue at any time will be collected (five unstained slides at 4μm thickness or a paraffin-
embedded block) after the patient has signed the screening ICF. This will be used to assess CD30 
status using Ber-H2 antibody (DAKO, Glostrup, Denmark) and biomarkers associated with sensitivity or 
resistance to brentuximab vedotin (eg, beta3- tubulin etc). Biomarker samples will be collected (EDTA 
5mL x1 plus SST 3mL x1) to assess lymphocyte subsets and soluble CD30 quantification. 
c. The Cycle 1 Day 1 physical exam is not required if the screening physical examination was 
conducted within 7 days before administration of the first dose of brentuximab vedotin. A limited 
physical exam may be administered at the treating physician’s discretion. 
d. A serum β-hCG pregnancy test will be performed for women of childbearing potential during 
screening. A negative urine pregnancy test is required if the serum pregnancy test was not done within 
7 days of the first dose of study drug.  
e. Vital signs should be measured at screening and within 1 hour prior to infusion of brentuximab at day 
1 of each cycle and EOT. 
f. A blood sample for hematology and serum chemistry including LDH will be obtained at screening and 
pre-dose at day 1 of each cycle and EOT. Hematology and chemistry blood samples for cycle 1, day 1 
may be collected within 7 days prior to dosing to ensure patient eligibility on study day 1. 
g. Response to treatment and disease status assessments will be evaluated according to the Revised 
Response Criteria for Malignant Lymphomas1 and the modified SWAT criteria.2 MRI scans may be 
substituted for CT scans only if a patient 1) has a glomerular filtration rate of less than 60 mL/min such 
that IV contrast presents a risk of renal failure, 2) develops anaphylaxis to IV contrast, or 3) becomes 
pregnant during long-term follow-up. If use of MRI is required, a consistent scanning modality must be 
maintained. 
 
During the treatment phase CT scans will be performed at: 
 1) Screening 
 2) CT scans of involved sites after cycle 2 of brentuximab every 6 weeks (window, ± 7 days) until 
progressive disease or 16th cycle of brentuximab vedotin. After last dose of cycle 16: between 4 
and 8 weeks following last dose of brentuximab. During the follow-up period: every 3 months until 
the study closure. 
 
h. In case of cutaneous lymphomas, total body skin scoring is calculated based on modified Severity 
Weighted Assessment Tool (mSWAT). This involves the direct assessment of the BSA of each type of 
skin lesions (palm plus fingers of the patient = approximately 1% BSA) in each of 12 areas of the body, 
multiplying the sum of the BSA of each lesion by a weighting factor (patch=1, plaque =2, and tumor = 3 
or 4) and generating a sum of the subtotals of each lesions. 
i. This is mandatory at sites where a PET scanner is available. For all patients, if the screening FDG-
PET scan is non-avid, the second interim FDG-PET scan will not be performed.  
j. Subjects will be followed for survival disease status every 3 months till the study closure. 
 
 


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TABLE OF CONTENTS 
STUDY OVERVIEW DIAGRAM ................................................................................................ 5 
SCHEDULE OF EVENTS ............................................................................................................ 6 
LIST OF TABLES ......................................................................................................................... 9 
1 
BACKGROUND AND STUDY RATIONALE .............................................................. 16 
1.1 
Scientific Background .......................................................................................... 16 
1.1.1    Disease Under Treatment ......................................................................... 16 
1.1.2    Study Drug ............................................................................................... 16 
1.2 
Preclinical Experience .......................................................................................... 17 
1.3 
Pharmacology and Drug Metabolism in Humans ................................................ 17 
Pharmacokinetic properties .................................................................................. 17 
1.4    
Clinical Experience .............................................................................................. 18 
1.5 
Study Rationale and Selection of Study Drug Doses ........................................... 21 
1.6    Potential Risks of brentuximab vedotin .................................................................. 22 
2 
STUDY OBJECTIVES .................................................................................................... 25 
2.1 
Primary Objectives ............................................................................................... 25 
2.2 
Secondary Objectives ........................................................................................... 25 
2.3 
Exploratory Objectives......................................................................................... 25 
3 
STUDY ENDPOINTS ..................................................................................................... 26 
3.1 
Primary Endpoints ................................................................................................ 26 
3.2 
Secondary Endpoints ............................................................................................ 26 
3.3 
Exploratory Endpoints ......................................................................................... 26 
4 
STUDY DESIGN ............................................................................................................. 27 
4.1 
Overview of Study Design ................................................................................... 27 
4.2 
Number of Patients ............................................................................................... 27 
4.3 
Duration of Study ................................................................................................. 27 
5 
STUDY POPULATION .................................................................................................. 28 
5.1 
Inclusion Criteria .................................................................................................. 28 
5.2 
Exclusion Criteria................................................................................................. 29 
6 
STUDY DRUG ................................................................................................................ 30 
6.1 
Brentuximab Vedotin Administration .................................................................. 30 
6.2   
Dose Modification Guidelines ............................................................................. 31 
6.3 
Excluded Concomitant Medications and Procedures ........................................... 32 
6.4 
Permitted Concomitant Medications and Procedures .......................................... 33 
6.5 
Precautions and Restrictions ................................................................................ 33 
6.6 
Management of Clinical Events ........................................................................... 34 
6.7 
Description of Investigational Agents .................................................................. 37 
6.8 
Preparation, Reconstitution and Dispensing ........................................................ 38 
6.9 
Packaging and Labeling ....................................................................................... 38 
6.10 
Storage, Handling and Accountability ................................................................. 38 
6.11 Study Compliance .................................................................................................... 39 
6.12 Termination of Treatment and/or Study Participation ............................................. 39 


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7 
STATISTICAL AND QUANTITATIVE ANALYSES .................................................. 40 
7.1 
Statistical Methods ............................................................................................... 40 
7.1.1 
Determination of Sample Size ................................................................. 40 
7.1.2 
Randomization and Stratification ............................................................. 40 
7.1.3 
Populations for Analyses ......................................................................... 40 
7.1.4 
Procedures for handling Missing, Unused, and Spurious Data ................ 40 
7.1.5 
Demographic and Baseline Characteristics .............................................. 41 
7.1.6 
Efficacy Analysis ..................................................................................... 41 
7.1.7 
Biomarkers ............................................................................................... 41 
7.1.8 
Safety Analysis ........................................................................................ 41 
7.1.9 
Interim Analysis ....................................................................................... 42 
8 
ADVERSE EVENTS ....................................................................................................... 43 
8.1 
Definitions ............................................................................................................ 43 
8.1.1 
Adverse Drug Reaction (ADR) ................................................................ 43 
8.1.2 
Adverse Event Definition ......................................................................... 43 
8.1.3 
Serious Adverse Event Definition ............................................................ 43 
8.2 
Procedures for Reporting Serious Adverse Events .............................................. 44 
8.3 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events .. 45 
9 
ADMINISTRATIVE REQUIREMENTS ........................................................................ 47 
9.1 
Good Clinical Practice ......................................................................................... 47 
9.2 
Ethical Considerations ......................................................................................... 47 
9.3 
Patient Information and Informed Consent .......................................................... 47 
9.4 
Patient Confidentiality ......................................................................................... 47 
9.5 
Investigator Compliance ...................................................................................... 47 
9.6 
On-site Audits ...................................................................................................... 48 
9.7 
Investigator and site Responsibility for Drug Accountability.............................. 48 
9.8 
Product Complaints .............................................................................................. 48 
9.9 
Closure of the Study ............................................................................................. 49 
9.10 
Record Retention .................................................................................................. 49 
10 
USE OF INFORMATION ............................................................................................... 50 
11 
REFERENCES ................................................................................................................. 51 
12 
APPENDICES ................................................................................................................. 52 
12.1 
Common Terminology Criteria for Adverse Events Version 4.03(4) ................... 53 
12.2 
New York Heart Association Classification of Cardiac Disease(5) ...................... 54 
12.3 
Revised response criteria for malignant lymphoma ............................................. 55 
12.4 
Modified SWAT criteria for skin lesions ............................................................. 58 
 
LIST OF TABLES 
Table 6-1    
Recommended brentuximab vedotin Dose Modifications for Treatment-
Associated Toxicity Excluding Neuropathy ...................................................... 310 
Table 6-2    
Dosing Recommendations for Treatment-Emergent or Worsening Peripheral 
Sensory or Motor Neuropathy ............................................................................ 321 


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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Abbreviation 
Definition 
A+AVD 
brentuximab vedotin (ADCETRISTM) plus doxorubicin 
(Adriamycin), vinblastine, dacarbazine 
ABVD 
doxorubicin (Adriamycin), bleomycin, vinblastine, and 
dacarbazine 
ADC 
antibody-drug conjugate 
AE 
adverse event 
ALCL 
anaplastic large cell lymphoma 
ALK 
anaplastic lymphoma kinase 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
ATA 
antitherapeutic antibody 
AUC 
area under the plasma concentration versus time curve 
AVD 
doxorubicin (Adriamycin), vinblastine, and dacarbazine  
BEACOPP 
bleomycin, etoposide, doxorubicin (Adriamycin), 
cyclophosphamide, vincristine, procarbazine, and prednisone 
hCG
beta-human chorionic gonadotropin 
BPT 
bleomycin pulmonary toxicity 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CHOP 
cyclophosphamide, doxorubicin (hydroxydaunorubicin), 
vincristine (Oncovin®), prednisone 
CI 
confidence interval 
CL 
clearance, IV dosing 
Cmax 
single-dose maximum (peak) concentration 
CO2 
carbon dioxide 
COPD 
chronic Obstructive Pulmonary Disease 
CR 
complete remission 
CR(u) 
unconfirmed complete response 
CSF 
cerebral spinal fluid 


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CT 
computed tomography 
CTACK 
cutaneous T-cell-attracting chemokine 
CTCL 
CYP 
cutaneous T-cell lymphoma 
cytochrome P450 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOCR 
duration of complete remission 
DOR 
duration of response 
DTIC 
dacarbazine 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EORTC 
European Organisation for Research and Treatment of Cancer  
EOS 
End of Study (visit) 
EOT 
End of Treatment (visit) 
ESMO 
European Society for Medical Oncology 
EU 
European Union 
FDA 
United States Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
FLAIR 
GCP 
fluid-attenuated inversion recovery 
Good Clinical Practice 
G-CSF 
granulocyte colony stimulating factor 
GGT 
gamma glutamyl transferase 
GHSG 
German Hodgkin Study Group 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practices 
GM-CSF 
granulocyte macrophage-colony stimulating factor 
GMP 
Good Manufacturing Practice 
Hb 
Hemoglobin 
Hct 
Hematocrit 
HDPE 
high-density polyethylene 
HIV 
human immunodeficiency virus 
HL 
HNSTD 
Hodgkin lymphoma 
highest nonseverely toxic dose 


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HR 
heart rate 
HRQoL 
health-related quality of life 
HRS 
Hodgkin Reed-Sternberg 
IB 
Investigator’s Brochure 
IC50 
concentration producing 50% inhibition 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IgG1 
immunoglobulin G1 
IL-6 
interleukin-6 
INN 
International Nonproprietary Name 
IPS 
(Hasenclever) International Prognostic Score 
IRB 
institutional review board 
IRF 
independent review facility 
IRR 
infusion-related reaction 
ITT 
intent-to-treat 
IV 
intravenous; intravenously 
IVRS 
interactive voice response system 
JCV 
John Cunningham virus 
LDH 
lactate dehydrogenase 
LFT 
liver function test(s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
Millennium 
Millennium Pharmaceuticals, Inc., and its affiliates 
MMAE 
monomethyl auristatin E 
mPFS 
modified progression-free survival 
MRI 
magnetic resonance imaging 
MRU 
medical resource utilization 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NOAEL 
no-observed-adverse-effect level 
NYHA 
New York Heart Association 
ORR 
objective response rate 


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OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease (disease progression) 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PML 
progressive multifocal leukoencephalopathy 
PN 
peripheral neuropathy 
PR 
partial response 
PRO 
patient-reported outcome 
q3wk 
every 3 weeks 
QALY 
quality-adjusted life year 
QOL 
quality of life 
QTc 
rate-corrected QT interval (millisec) of electrocardiograph 
QTcF 
Fridericia’s corrected QT interval 
RBC 
red blood cell 
SAE 
serious adverse event 
SCT 
stem cell transplant 
SD 
stable disease 
SJS 
Stevens-Johnson syndrome 
SmPC 
Summary of Product Characteristics 
SMQ 
Standardised MedDRA query 
SPD 
sum of the product of the (tumor) diameters 
t1/2 
terminal disposition half-life 
Tab 
total antibody 
TARC 
thymus- and activation-regulated chemokine 
TGD 
tumor growth delay 
TGI 
tumor growth inhibition 
TK 
toxicokinetics 
TLS 
tumor lysis syndrome 
Tmax 
single-dose first time of occurrence of maximum (peak) 
concentration 
TNF-R 
tumor necrosis factor-receptor 
UK 
United Kingdom 
ULN 
upper limit of the normal range 


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URTI 
upper respiratory tract infection 
US 
United States 
USAN 
United States Adopted Name 
USP 
United States Pharmacopeia 
Vss 
steady state volume of distribution 
WBC 
white blood cell 
WFI 
water for injection 
WHO 
World Health Organization 


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1 BACKGROUND AND STUDY RATIONALE 
1.1 
    
Scientific Background 
1.1.1    
Disease Under Treatment 
Epstein-Barr virus (EBV), a member of the herpes virus family has been implicated in the 
development of B-cell or T/NK cell lymphoproliferative disorders.3 EBV-associated lymphomas 
expressed various latent genes including EBNA-1, EBERs, LMP-1, and LMP-2 (latency I, II, 
and III).4 According to the International T-Cell Lymphoma Project, virus-associated lymphomas 
generally pursue a grave prognosis: 5-year overall survival (OS), 14% and 42% for adult T-cell 
leukemia/lymphoma and extranodal NK/T-cell lymphoma, nasal type (NTCL), respectively.5 
Especially, EBV has been detected virtually in all NTCL cases and patients with NTCL showed 
clinical heterogeneity and poor survival outcomes (5-year OS 38%) in a national survey of the 
Korean Cancer Study Group.6 In general, EBV-associated lymphomas showed poorer outcomes 
compared with EBV-negative ones in Hodgkin lymphoma,7 peripheral T-cell lymphoma,8 and 
diffuse large B-cell lymphoma.9 
1.1.2    
Study Drug 
Brentuximab vedotin is an antibody-drug conjugate (ADC) composed of the anti-CD30 chimeric 
immunoglobulin G1 (IgG1) monoclonal antibody cAC10 and the potent antimicrotubule drug 
monomethyl auristatin E connected by a protease-cleavable linker.  cAC10 binds to the CD30 
antigen, which has a very low expression on normal cells but is found on some tumor cells. 
ADCETRIS was granted accelerated approval by the U.S. Food and Drug Administration (FDA) 
in August 2011 for two indications: (1) the treatment of patients with Hodgkin lymphoma after 
failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent 
chemotherapy regimens in patients who are not ASCT candidates, and (2) the treatment of 
patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen. 
ADCETRIS was granted conditional marketing authorization by the European Commission in 
October 2012 for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin 
lymphoma (HL): (1) following autologous stem cell transplant (ASCT), or (2) following at least 
two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option. 
ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory systemic 
anaplastic large cell lymphoma (sALCL). 
ADCETRIS has also been approved or submitted for approval in multiple other countries. 


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Brentuximab vedotin is contraindicated for hypersensitivity to the active substance or to 
any of the excipients. Combined use of bleomycin and brentuximab vedotin causes 
pulmonary toxicity. 
1.2    Preclinical Experience 
Detailed information regarding the nonclinical pharmacology and toxicology of brentuximab 
vedotin may be found in the Investigators Brochure (IB). 
1.3    Pharmacology and Drug Metabolism in Humans 
Further detailed information regarding the pharmacology and drug metabolism may be found in 
the European Summary of Product Characteristics (SmPC) and Investigators Brochure (IB). 
Pharmacokinetic properties 
The pharmacokinetics of brentuximab vedotin were evaluated in phase 1 studies and in a 
population pharmacokinetic analysis of data from 314 patients.  In all clinical trials, brentuximab 
vedotin was administered as an intravenous infusion. Further detailed information regarding the 
pharmacokinetic properties of brentuximab vedotin may be found in the European Summary of 
Product Characteristics (SmPC) and Investigators Brochure (IB). 
Distribution, Metabolism, and Elimination 
In vitro, the binding of MMAE to human serum plasma proteins ranged from 68-82%. MMAE is 
not likely to displace or to be displaced by highly protein-bound medicines.  The ADC is 
expected to be catabolized as a protein with component amino acids recycled or eliminated. 
MMAE did not induce any major CYP450 enzymes in primary cultures of human hepatocytes. 
The ADC is eliminated by catabolism with a typical estimated CL and half life of 1.457 l/day 
and 4-6 days respectively. The elimination of MMAE was limited by its rate of release from 
ADC, typical apparent CL and half life of MMAE was 19.99 l/day and 3-4 days respectively. 
Detailed information regarding distribution, metabolism and elimination may be found in the 
European Summary of Product Characteristics (SmPC) and Investigators Brochure (IB). 
Pharmacokinetics in Special Populations 
Detailed information regarding hepatic impairment, renal impairment, elderly patients and 
pediatric population may be found in the European Summary of Product Characteristics (SmPC). 
Drug-Drug Interaction, Cardiac electrophysiology, Immunogenicity 
Co-administration of brentuximab vedotin with ketoconazole, a strong CYP3A4 and P-gp 
inhibitor, increased the exposure to the antimicrotubule agent MMAE by approximately 73% and 


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did not alter the plasma exposure to brentuximab vedotin.  Therefore, co-administration of 
brentuximab vedotin with strong CYP3A4 and P-gp inhibitors may increase the incidence of 
neutropenia.  Co-administration of brentuximab vedotin with rifampicin, a strong CYP3A4 
inducer, did not alter the plasma exposure to brentuximab vedotin; however, it reduced exposure 
to MMAE by approximately 31%.  Co-administration of midazolam, a CYP3A4 substrate, with 
brentuximab vedotin did not alter the metabolism of midazolam. 
Forty-six (46) patients with CD30-expressing hematologic malignancies were evaluable of the 
52 patients who received 1.8 mg/kg of brentuximab vedotin every 3 weeks as part of a phase 1, 
single-arm, open-label, multicenter cardiac safety study. The upper 90% confidence interval (CI) 
around the mean effect on QTc was <10 msec at each of the Cycle 1 and Cycle 3 post-baseline 
time points. These data indicate the absence of clinically relevant QT prolongation due to 
brentuximab vedotin administered at a dose of 1.8 mg/kg every 3 weeks in patients with 
CD30-expressing malignancies. 
Patients with relapsed or refractory HL or sALCL in two phase 2 studies were tested for 
antibodies to brentuximab vedotin every 3 weeks using a sensitive electrochemiluminescent 
immunoassay.  Approximately 35% of patients in these studies developed antibodies to 
brentuximab vedotin.  The presence of antibodies to brentuximab vedotin did not correlate with a 
clinically meaningful reduction in serum brentuximab vedotin levels and did not result in a 
decrease in the efficacy of brentuximab vedotin. 
Detailed information regarding drug-drug interaction, cardiac electrophysiology and 
immunogenicity may be found in the European Summary of Product Characteristics (SmPC) and 
Investigators Brochure (IB). 
1.4    Clinical Experience 
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 
(Younes et. al. N Engl J Med. 2010 Nov 4; 363(19):1812-21).  In Study SG035-0002, a total of 
44 patients with CD30-positive hematologic malignancies (including 38 with HL) were treated 
with brentuximab vedotin at dose levels of 0.4 to 1.4 mg/kg administered IV weekly for 3 of 
4 weeks (Fanale et. al. Clin Cancer Res. 2012 Jan 1;18(1):248-55). 
Following Phase I experience, SG035-0003, a phase 2, single-arm, open-label study in patients 
with relapsed or refractory HL after ASCT, and SG035-0004, a phase 2 trial conducted in 


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patients with relapsed or refractory sALCL, brentuximab vedotin was administered at a dose of 
1.8 mg/kg every 3 weeks.  One hundred two patients with relapsed and refractory HL and 
58 patients with relapsed and refractory sALCL were exposed for a median duration of 
approximately 27 weeks (9 cycles) and 20 weeks (6 cycles), respectively.  Most patients (89%) 
in the 2 phase 2 studies were between the ages of 18 and 65 years.  The primary endpoint of both 
studies was overall response rate (ORR) as assessed by an independent review facility (IRF).  
Key secondary endpoints included duration of response, CR rate per IRF, OS, and progression 
free survival (PFS).  The key efficacy results in HL (SG035-0003) include ORR per IRF (75% 
[95% confidence interval (CI): 64.9-82.6%]), CR rate per IRF (33% (34 of 102 patients in ITT 
set), B symptom resolution rate (77%), and duration of response (DOR; 6.7 months).  After 
approximately 3 years of follow-up (median observation time from first dose = 32.7 months, 
range, 1.8 to 48.3 months), the median PFS was 5.6 months (95% CI: 
5.0, 9.0 months [range, 1.2 to 44.4+ months]) and the median OS was 40.5 months (95% CI: 
28.7, – months [range, 1.8 to 48.3+ mos]). The estimated 36-month survival rate was 54% 
(95% CI: 44%, 64%).  Key efficacy endpoints in sALCL (SG035-0004) include ORR per IRF 
(88% [95% CI: 74.6-93.9%]), CR rate per IRF (59% (34 of 58 patients in ITT set), and B 
symptom resolution rate (82%).  Patients have been followed for approximately 3 years (median 
observation time from first dose = 33.4 months, range, 0.8 to 45.6 months). The estimated 36-
month survival rate was 63% (95% CI: 51%, 76%) and the median PFS was 14.6 months (95% 
CI: 6.9, 20.6 months [range, 0.8 to 40.4+ months]). The median OS has not yet been reached (95% 
CI: 21.3, – months [range, 0.8 to 45.6+ months]). 
 
Summary of the safety profile 
Brentuximab vedotin was studied as monotherapy in 160 patients in two pivotal phase 2 studies 
(SG035-0003 and SG035-0004) (see section 5.1 of SmPC). Serious infections and opportunistic 
infections have been reported in patients treated with this medicine (see section 4.4 of SmPC). In 
the phase 2 population, 16% of patients experienced treatment-related infections. Serious adverse 
drug reactions were: neutropenia, thrombocytopenia, constipation, diarrhea, vomiting, pyrexia, 
peripheral motor neuropathy and peripheral sensory neuropathy, hyperglycemia, demyelinating 
polyneuropathy, tumor lysis syndrome and Stevens-Johnson syndrome. 
The most frequently observed adverse reactions in patients receiving this treatment were: 
peripheral sensory neuropathy, fatigue, nausea, diarrhea, neutropenia, vomiting, pyrexia, and 
upper respiratory tract infection.  Overall, 20% of HL patients and 28% of systemic ALCL 
patients in the pivotal studies (Studies SG035-0003 and SG035-0004) discontinued treatment 


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because of AEs. AEs that led to the treatment discontinuation of ≥2 HL or sALCL patients were 
peripheral sensory neuropathy and peripheral motor neuropathy. 
The safety data reported from the phase 1 dose escalation and clinical pharmacology studies 
(n=15 patients) and from the Named Patient Program (NPP; n= 26 patients), in patients with 
relapsed or refractory HL who had not received an autologous stem cell transplant (see section 
5.1 of SmPC), and were treated with the recommended dose of 1.8 mg/kg every three weeks, 
were consistent with the safety profile of the pivotal clinical studies.  
Description of selected adverse reactions 
Doses were reduced in patients for peripheral sensory neuropathy, which was the only AE 
that led to the dose reduction of more than 1 patient in either of the phase 2 studies. Adverse 
events that led to dose delays in the most patients were neutropenia, peripheral sensory 
neuropathy, and thrombocytopenia; the total percentage of doses delayed in HL patients was 
8% (80 of 985 doses) and the total percentage of doses delayed in sALCL patients was 10% 
(47 of 476 doses). A total of 13 patients had an interruption or early stoppage to the infusion 
due to an AE.  
Thirty-four patients (21%) in SG035-0003 and SG035-0004 had a treatment-emergent AE of 
neutropenia; for 20% of patients, neutropenia was ≥Grade 3 (13% at Grade 3 and 7% at Grade 4). 
The first onset of neutropenia (any grade) occurred within the first 4 cycles of treatment for most 
patients (82%), suggesting that neutropenia is not cumulative. Neutropenia ≥Grade 3 tended to 
develop after a median of 2 doses and last a median of approximately 1 week. Of the 7% of 
patients with Grade 4 neutropenia, 3 had neutropenia that lasted ≥7 days. No treatment-emergent 
AEs of febrile neutropenia were reported in the pivotal studies and no patient discontinued 
treatment because of neutropenia. In the pivotal studies (Studies SG035-0003 and SG035-0004), 
89 patients (56%) had at least 1 treatment-emergent AE within the PN SMQ (56 patients [55%] 
in SG035-0003 and 33 patients [57%] in SG035-0004). The peripheral neuropathy symptoms 
that occurred in ≥5% of HL or ALCL patients were peripheral sensory neuropathy (47% HL, 41% 
ALCL), peripheral motor neuropathy (12% HL, 5% ALCL), paraesthesia (9% ALCL), and 
neuralgia (5% ALCL).  
The median time to onset of any grade PN SMQ event was approximately 12.4 (HL) to 
15.0 (ALCL) weeks. Peripheral neuropathy tended to worsen with longer treatment 
exposure. Median time to onset of Grade 2 neuropathy was 27.3 weeks for HL patients and 
17.0 weeks for ALCL patients. Median time to onset of Grade 3 neuropathy was 38.0 weeks 
for HL patients and 36.1 weeks for ALCL patients. 
PML has been reported in patients treated with brentuximab vedotin and has been fatal in 


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some cases. (see section 4.4 of SmPC).  Acute pancreatitis has been reported in patients treated 
with brentuximab vedotin and has contributed to fatal outcomes in some cases. Onset typically 
occurred after 1 to 2 doses of brentuximab vedotin. Early symptoms included severe abdominal 
pain, nausea, and vomiting. The estimated incidence of acute pancreatitis in patients treated with 
brentuximab vedotin is≤0.5%. Approximately 1% of patients treated with brentuximab vedotin 
in the commercial or investigational setting have had an AE that was suggestive of a 
hepatobiliary disorder. The majority of events occurred after 1 to 2 treatment cycles and were 
characterized by asymptomatic mild to moderate transient elevation in aspartate 
aminotransferase and alanine aminotransferase. Elevated liver enzymes were observed upon 
rechallenge for some patients. Serious hepatobiliary disorders have been reported, but were 
confounded by comorbidities and/or concomitant medications with known hepatotoxic potential. 
Anaphylaxis has been reported outside of the pivotal phase 2 clinical trials discussed in this 
section.  Symptoms of anaphylaxis may include, but are not limited to, urticaria, angioedema, 
hypotension and bronchospasm. Febrile neutropenia has been reported outside of the pivotal 
phase 2 clinical trials described in this section (see section 4.2).  A patient enrolled in a phase 1 
dose escalation trial experienced Grade 5 febrile neutropenia after receiving a single dose of 3.6 
mg/kg of brentuximab vedotin. 
Further details on these and other ongoing studies are provided in the Investigators Brochure (IB) 
and SmPC. 
1.5 Study Rationale and Selection of Study Drug Doses 
Although anthracycline-based regimen such as CHOP (cyclophosphamide, doxorubicin, 
vincristine, and prednisolone) has been the standard treatment of aggressive non-Hodgkin’s 
lymphomas,10  patients with EBV-positive lymphomas might relapse more frequently than those 
with EBV-negative lymphomas. Because CD30 is frequently expressed in EBV-infected 
lymphoid cells,11  it is a druggable target at EBV- and CD30-positive lymphomas. In addition, 
CD30 is overexpressed in EBV-positive lymphomas: extranodal NK/T-cell lymphoma, nasal 
type, 72%12; EBV-positive peripheral T-cell lymphoma, 43%13; and EBV-positive diffuse large 
B-cell lymphoma (DLBCL) of the elderly, 70%.14 
The high CR rate and ORR obtained with brentuximab vedotin in 2 single-arm phase 2 studies in 
relapsed or refractory HL (SG035-0003) and relapsed or refractory sALCL(SG035-0004) 
suggest that single-agent brentuximab vedotin may be active against CD30-positive lymphomas 
other than HL and sALCL. Single-agent brentuximab vedotin showed antitumor activity against 
refractory B-cell lymphomas with variable CD30 expression (0-100%): ORR 40% (CR 16%) and 
median duration of response 36 weeks (range, 0.1-62.3 weeks) for DLBCL; and ORR 22% and 


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median duration of response 21.7 weeks (range, 6.1-37.1 weeks) for other B-cell lymphomas.15 
Similarly, brentuximab vedotin is active against CD30-positive cutaneous T-cell lymphomas and 
lymphoproliferative disorders: ORRs 50% and 100% for Mycosis Fungoides and primary 
cutaneous ALCL/lymphomatoid papulosis, respectively.16 However, it is unknown whether 
single-agent brentuximab vedotin is active against EBV- and CD30-positive lymphomas. 
Brentuximab vedotin monotherapy has previously been shown to be reasonably well tolerated in 
a phase 1 study and a phase 2 pivotal trial at 1.8 mg/kg in every 3 week dosing. Therefore, 
brentuximab vedotin at 1.8 mg/kg in every 3 week will be delivered in this study. 
1.6    Potential Risks of brentuximab vedotin 
As detailed in the Clinical Experience Section 1.4, brentuximab vedotin monotherapy has 
demonstrated therapeutic activity in CD30+ hematological malignancies. 
Brentuximab vedotin treatment causes a peripheral neuropathy that is predominantly sensory.  
Cases of peripheral motor neuropathy have also been reported.  Monitoring patients for 
symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning 
sensation, neuropathic pain or weakness is required. Patients experiencing new or worsening 
peripheral neuropathy may require brentuximab vedotin dose modifications, including a dose 
delay (see Section 5.2 Dose Modification Guidelines). 
Infusion-related reactions, including anaphylaxis, have occurred with brentuximab vedotin.17  
Monitoring of patients during infusion is required.  If anaphylaxis occurs, the administration of 
brentuximab vedotin should be immediately and permanently discontinued and appropriate 
medical therapy administered.  If an infusion-related reaction occurs, the infusion should be 
interrupted and appropriate medical management instituted.  Patients who have experienced a 
prior infusion-related reaction should be premedicated according to institutional guidelines for 
subsequent infusions.  Premedication may include acetaminophen, an antihistamine and a 
corticosteroid. 
Clinically significant laboratory abnormalities were to be reported as adverse events per the 
phase 2 study protocols.  The clinical laboratory parameters for which the most patients had new 
or worsening shifts to  Grade 3 were low neutrophils (11%), lymphocytes (11%), platelets (6%), 
leukocytes (5%), and high glucose (6%).  Only 1 patient in the phase 2 studies had Grade 3 ALT 
and AST. 


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Any treatment that can decrease immune function may contribute to malignancy and infections; 
patients are to be monitored for these events during the treatment period and up to and including 
30 days after the last dose of frontline therapy. 
Complete blood counts should be monitored prior to each dose of brentuximab vedotin and more 
frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia.  Prolonged 
(≥ 1 week) severe neutropenia can occur.  If Grade 3 or 4 neutropenia develops, manage by dose 
delays, reductions, or discontinuations (see Section 5.2 Dose Modification Guidelines). 
Tumor lysis syndrome may occur.  Patients with rapidly proliferating tumor and high tumor 
burden are at risk of tumor lysis syndrome and should be closely monitored.  If tumor lysis 
syndrome occurs, take medically appropriate measures. 
Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with brentuximab 
vedotin. Fatal outcomes have been reported.  If Stevens-Johnson syndrome or toxic epidermal 
necrolysis occur, brentuximab vedotin must be discontinued and the appropriate medical therapy 
administered. 
Progressive multifocal leukoencephalopathy (PML) has been reported with brentuximab vedotin 
use.  PML is a rare demyelinating disease of the brain that is caused by the John Cunningham 
virus (JCV).  If PML is suspected, a diagnostic work-up should be performed, as described in 
Section 5.6 Management of Clinical Events. 
Acute pancreatitis has been observed in patients treated with brentuximab vedotin. Fatal 
outcomes have been reported. Patients should be closely monitored for new or worsening 
abdominal pain, which may be suggestive of acute pancreatitis.  
 
Cases of pulmonary toxicity have been reported in patients receiving brentuximab vedotin. 
Although a causal association with brentuximab vedotin has not been established, the risk of 
pulmonary toxicity cannot be ruled out.  
 
Hepatotoxicity,  predominantly in the form of asymptomatic, mild to moderate transient 
elevations in ALT/AST, has been observed during use of brentuximab vedotin. 
 
Monomethyl auristatin E (MMAE) is primarily metabolized by CYP3A.  Co-administration of 
brentuximab vedotin with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to 
MMAE by approximately 34%.  Patients who are receiving strong CYP3A4 inhibitors 
concomitantly with brentuximab vedotin should be closely monitored for adverse reactions.  Co-
administration of brentuximab vedotin with rifampicin, a potent CYP3A4 inducer, reduced 
exposure to MMAE by approximately 46%. 


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Further detailed information regarding the potential risks and benefits of brentuximab vedotin 
may be found in the European Summary of Product Characteristics (SmPC) and Investigators 
Brochure (IB).  
The effects of brentuximab vedotin on embryogenesis, reproduction, and spermatogenesis in 
humans are unknown.  In addition, data about the effects of brentuximab vedotin in pregnant 
women are unavailable.  Please see Section 5.5 Precautions and Restrictions for appropriate 
precautions triggered by the administration of study medication. 
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 (ABVD), the rate of noninfectious pulmonary toxicity was higher than the 
historical incidence reported with ABVD. Two events of pulmonary toxicity led to death. 
Monotherapy with brentuximab vedotin has not been associated with a clinically meaningful risk 
of pulmonary toxicity. 
 


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2 STUDY OBJECTIVES 
2.1 Primary Objectives 
To evaluate the overall response rate (ORR) of brentuximab vedotin in relapsed or refractory 
EBV- and CD30-positive lymphomas  
2.2 Secondary Objectives 
The key secondary objective is  
  To evaluate the safety profile of brentuximab vedotin using CTCAE version 4.03 
Other secondary objectives include: 
- 
To calculate progression-free survival (PFS) time  
- 
To calculate the duration of response  
- 
To calculate overall survival (OS) time  
2.3 Exploratory Objectives 
     The exploratory objectives include: 
- 
To determine the CD30-positive rate of EBV-positive lymphomas  
- 
To compare ORR according to the CD30 expression level  
- 
To compare ORR according to the soluble CD30 level  
- 
To compare ORR according to the EBV copy number  


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3 STUDY ENDPOINTS 
3.1 Primary Endpoints 
The primary endpoint is 
  ORR using the revised response criteria for malignant lymphoma or modified SWAT criteria 
 
3.2 Secondary Endpoints 
The key secondary endpoint is 
   AEs, SAEs, and assessments of clinical laboratory values 
Other secondary endpoints include: 
- 
PFS 
- 
Duration of response 
- 
CR rate 
- 
The rate of interim PET-negativity 
- 
OS 
 
3.3 Exploratory Endpoints 
Exploratory endpoints include: 
- 
CD30-positivity 
- 
Qualitative and semi-quantitative measures of CD30 expression 
- 
Serum concentrations of soluble CD30 receptor 
- 
Serum concentrations of EBV titer 


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4 STUDY DESIGN 
4.1 Overview of Study Design 
 This is an open-label, non-randomized, multi-center, phase II trial of brentuximab vedotin to 
evaluate ORR primarily in patients with EBV- and CD30-positive lymphomas. The ORR will be 
evaluated based on the revised Cheson’s criteria1 or modified SWAT criteria2 in case of 
cutaneous EBV- and CD30-positive lymphomas. Patients may receive up to 16 cycles of 
brentuximab vedotin. 
Tumor measurements will be assessed (CT and PET scans) at screening, after completion of 
cycle 2 (Cycle 2 Day 21 ± 7 day), and at 4 to 8 weeks after the last dose of brentuximab vedotin. 
CT scans only will be used for the disease assessment follow-up every 3 months until the study 
closure. 
Safety will be evaluated according to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE), Version 4.03, as well as by measuring changes from baseline 
in the patient’s vital signs, ECOG performance status, electrocardiogram (ECG), and clinical 
laboratory results.  
Patients may discontinue therapy at any time. Patients will attend the EOT visit 30 (±7) days 
after completion of their last dose of brentuximab vedotin.  
4.2 Number of Patients 
 Based on the optimal Simon’s two-stage design, at least 3 responders among stage 1 patients 
(N=10) are required to enter into a stage 2. The stage 2 will be delayed until the completion of ≥4 
cycles of study medication in the last patient in stage 1, so-called interim analysis of stage 1. A 
total of 25 patients with EBV- and CD30-positive lymphomas will be enrolled.  
4.3 Duration of Study 
This study will last approximately 30 months to reach the final analyses of the ORR and PFS (24 
months of enrollment plus 6 months of additional follow-up after the last patient-in). 


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5     STUDY POPULATION 
5.1 Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
 
1. Male or female patients 18 years or older  
2. Patients with relapsed or refractory EBV- and CD30-positive lymphomas 
a. EBV-positivity determined by EBV in situ hydridization at participating centers 
i. Extranodal NK/T-cell lymphoma, nasal type 
ii. EBV-positive peripheral T-cell lymphoma, not otherwise specified 
iii. EBV-positive diffuse large B-cell lymphoma of the elderly 
iv. Plasmablastic lymphoma 
v. Lymphomatoid granulomatosis 
vi. Hydroa vacciniform-like T-cell lymphoma 
vii. Other EBV-positive lymphoproliferative disorders 
b. CD30-positivity determined by a specialized hemato-pathologist. CD30 positivity 
defined as 10% or greater tumor cells expressing CD30 at any intensity greater than or 
equal to 1+ with any cellular distribution pattern. 
c. Relapsed or refractory disease that fails to at least one and maximum four regimens 
including anthracycline-based chemotherapy; if anthracycline-based regimen is not 
standard treatment of certain subtypes (e.g. hydroa vacciniforme-like T-cell lymphoma 
or EBV-positive lymphoproliferative disorder, etc), a prior chemotherapy is acceptable. 
3. ECOG Performance status 0-2 
4. At least one measurable lesion based on revised Cheson’s or modified SWAT criteria 
5. Provision archival tumor tissues (4 μm thickness x 5 unstained slides) and blood samples  
6. Adequate hematologic function: absolute neutrophil count (ANC) ≥1,500/µL, platelet 
count ≥ 75,000/µL, and hemoglobin ≥8.0 g/dL  unless there is known hematologic tumor 
marrow involvement (ANC ≥ 1,000/µL and platelet count ≥ 50,000/µL if there is known 
bone marrow involvement)  
7. Adequate liver function: total bilirubin < 1.5 x the upper limit of the normal (ULN) 
unless the elevation is known to be due to Gilbert syndrome and ALT or AST  < 3 x ULN 
(AST and AST < 5 x ULN if their elevation can be reasonably ascribed to the presence of 
hematologic tumor in liver) 
8. Adequate renal function: serum creatinine < 2.0 mg/dL and/or creatinine clearance or 
calculated creatinine clearance > 40 mL/minute.  
9. Expected survival > 3 months  
10. Voluntary written informed consent must be given before performance of any study-
related procedure not part of standard medical care, with the understanding that consent 
may be withdrawn by the patient at any time without prejudice to future medical care. 


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5.2 Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study. 
 
1. Female patient who are both lactating and breast-feeding or have a positive serum pregnancy 
test during the screening period or a positive pregnancy test on Day 1 before first dose of 
study drug  
2. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially 
interfere with the completion of treatment according to the protocol. 
3. Known cerebral or meningeal disease (EBV- and CD30-positive lymphoma or any other 
etiology), including signs or symptoms of PML 
4. Symptomatic neurologic disease compromising normal activities of daily living or requiring 
medications 
5. Any sensory or motor peripheral neuropathy greater than or equal to Grade 2 
6. Known history of any of the following cardiovascular conditions 
a. 
Myocardial infarction within 1 year of study enrollment 
b. 
New York Heart Association (NYHA) Class III or IV heart failure (see 
Appendix 12.2) 
c. 
Evidence of current uncontrolled cardiovascular conditions, including cardiac 
arrhythmias, congestive heart failure (CHF), angina, or electrocardiographic 
evidence of acute ischemia or active conduction system abnormalities 
d. 
Recent evidence (within 6 months before first dose of study drug) of a left-
ventricular ejection fraction <50%  
 
7. Any active systemic viral, bacterial, or fungal infection requiring systemic antibiotics within 
2 weeks prior to first study drug dose 
8. Patients that have not completed any prior treatment chemotherapy and/or other 
investigational agents within at least 5 half-lives of last dose of that prior treatment  
9. Known hypersensitivity to recombinant proteins, murine proteins, or to any excipient 
contained in the drug formulation of brentuximab vedotin. 
10. Known human immunodeficiency virus (HIV) positive 
11. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C 
infection  
12. Diagnosed or treated for another malignancy within 3 years before the first dose or 
previously diagnosed with another malignancy and have evidence of residual disease.  
Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if 
they have undergone complete resection. 
 


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6 STUDY DRUG 
6.1 Brentuximab Vedotin Administration 
Study drug will be administered only to eligible patients under the supervision of the investigator 
or identified subinvestigator(s). 
Brentuximab vedotin must not be administered as an IV push or bolus.  Study treatment will be 
administered by IV infusion given over approximately 30 minutes on Day 1 of each 21-day cycle.  
In the absence of infusion toxicities, the infusion rate for all patients must be calculated in order 
to achieve a 30-minute (approximate) infusion period.   Brentuximab vedotin will be 
administered through a dedicated IV line and cannot be mixed with other medications. 
The dose of brentuximab vedotin is 1.8 mg/kg. Dosing is based on patients’ weight according to 
the institutional standard; however, doses will be adjusted for patients who experience a ≥ 10% 
change in weight from baseline.  Actual weight will be used except for patients weighing greater 
than 100 kg; dose will be calculated based on 100 kg for these individuals.  The dose will be 
rounded to the nearest whole number of milligrams. 
Infusion-related reactions may occur during the infusion of brentuximab vedotin.  The infusion 
should be administered at a site properly equipped and staffed to manage anaphylaxis should it 
occur.  The patient should be observed for 60 minutes following the first infusion of brentuximab 
vedotin. 
During this observation period, the IV line should remain open for at least 1 hour to allow 
administration of IV drugs if necessary.  All supportive measures consistent with optimal patient 
care will be given throughout the study according to 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.  The 
routine use of steroids as premedication is discouraged. 
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 as per institutional guidelines. 


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6.2   Dose Modification Guidelines  
Brentuximab vedotin dose modifications may change depending on the disease and combination 
with other drug(s).  
Table 6-1 and Table 6-2 detail the recommended brentuximab vedotin dose modifications to be 
enacted in the event of treatment-associated toxicity. 
Table 6-1    
Recommended brentuximab vedotin Dose Modifications for Treatment-
Associated Toxicity Excluding Neuropathy 
Toxicity  
≤Grade 2  
Grade 3  
Grade 4  
Non-hematologic 
(excluding neuropathy)  
Continue at same dose 
level.   
 
Withhold dose until 
toxicity is  
≤ Grade 1 or baseline, 
then resume treatment at 
the same dose and 
schedule a. 
Withhold dose until 
toxicity is ≤ Grade 1 or 
has returned to 
baseline, then reduce 
dose to 1.2 mg/kg and  
resume treatment, or 
discontinue at the 
discretion of the 
investigator.a     
Hematologic  
Continue at same dose 
level.   
 
Withhold dose until 
toxicity is ≤ Grade 2, or 
baseline, then resume 
treatment at the same 
dose levelb.  Consider 
growth factor support (G-
CSF or GM-CSF) in 
subsequent cycles. b 
Withhold dose until 
toxicity is ≤ Grade 2 or 
baseline, then resume 
treatment at the same 
dose and schedule.  
Consider growth factor 
support (G-CSF or 
GM-CSF) in 
subsequent cycles for 
patients who develop 
Grade 3 or Grade 4 
neutropenia .b  
NOTE:  Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) v. 4.03 
a Patients who develop Grade 3 or 4 electrolyte laboratory abnormalities may continue study treatment 
without interruption.  Brentuximab vedotin will be held for clinically meaningful Grade 3 or 4 electrolyte 
abnormalities. 
b Patients who develop Grade 3 or 4 lymphopenia may continue study treatment without interruption. 
 


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Table 6-2    
Dosing Recommendations for Treatment-Emergent or Worsening 
Peripheral Sensory or Motor Neuropathy 
Severity of Peripheral Sensory or Motor 
Neuropathy (Signs and Symptoms [abbreviated 
description of CTCAE]) 
Modification of Dose and Schedule 
Grade 1(Asymptomatic; clinical or diagnostic 
observations only; intervention not indicated; 
paresthesia and/or loss of deep tendon reflexes) 
Continue with the same dose and schedule 
Grade 2 (Moderate symptoms; limiting instrumental 
activities of daily living) 
 
Grade 3 ( Severe symptoms; limiting self care activities 
of daily living) 
Withhold dose until toxicity returns to ≤ Grade 1 
or baseline, then restart treatment at a reduced 
dose of 1.2 mg/kg every 3 weeks 
Grade 4 (life-threatening consequences; urgent 
intervention indicated) 
Discontinue treatment 
Grade 5 (Death) 
 
NOTE:  Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) v. 4.03; see neuropathy; peripheral motor neuropathy; peripheral sensory neuropathy. 
 
6.3 Excluded Concomitant Medications and Procedures   
The following medications and procedures are prohibited during the study: 
Bleomycin:  The concomitant use of brentuximab vedotin and bleomycin has resulted in 
increased pulmonary toxicity versus bleomycin alone.  Co-administration of brentuximab 
vedotin and bleomycin is a contraindication. 
Use of the following medications and procedures should be considered with caution: 
Interaction with medicinal products metabolized through CYP3A4 route:  
CYP3A4 Inhibitors: Co-administration of brentuximab vedotin with 
ketoconazole, a strong CYP3A4/P-gp inhibitor, increased the exposure to 
the antimicrotubule agent MMAE by approximately 73%, and did not alter 
the plasma exposure to brentuximab vedotin. Therefore, co-administration 
of brentuximab vedotin with strong CYP3A4 and P-gp inhibitors may 
increase the incidence of neutropenia.  If neutropenia develops, refer to 
Table 6-1 Recommended brentuximab vedotin Dose Modifications for 
Treatment Associated Toxicity Excluding Neuropathy 
CYP3A4 Inducers: Co-administration of brentuximab vedotin with 
rifampicin, a strong CYP3A4/P-gp inhibitor inducer, did not alter the 
plasma exposure to brentuximab vedotin; however it reduced exposure to 
MMAE by approximately 31 
CYP3A4 Substrates: Co-administration of midazolam, a CYP3A4 
substrate, with brentuximab vedotin did not alter the metabolism of 
midazolam; therefore brentuximab vedotin is not expected to alter the 
exposure to medicines that are metabolized by CYP3A4 enzymes. 
 


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6.4 
Permitted Concomitant Medications and Procedures 
The following medications and procedures are allowed during the study: 
 The use of topical, inhalational and ophthalmic steroids is permitted.  Corticosteroids are 
permitted as part of a chemotherapy premedication regimen or for the treatment of study 
disease per institutional standards. 
 The use of platelet and/or red blood cell supportive growth factors or transfusions when 
applicable is allowed. 
 The use of colony stimulating factors for the treatment of neutropenia per institutional 
practice is permitted during therapy. 
 
6.5 
Precautions and Restrictions  
Infusion-Related Reactions 
All infusions should be administered at a site properly equipped and staffed for anaphylaxis 
should it occur.  Medications for treatment of hypersensitivity reactions, such as epinephrine, 
antihistamines and steroids, should be available for immediate use in the event of a reaction 
during administration and also during the observation period following the first brentuximab 
vedotin infusion. 
Pregnancy 
It is not known what effects brentuximab vedotin has on human pregnancy or development of the 
embryo or fetus.  Therefore, female patients participating in this study should avoid becoming 
pregnant, and male patients should avoid impregnating a female partner.  Non-sterilized female 
patients of reproductive age group and male patients should use effective methods of 
contraception through defined periods during and after study treatment as specified below: 
Female patients must meet 1 of the following: 
 Postmenopausal for at least 1 year before the screening visit, or 
 Surgically sterile, or 
 If they are of childbearing potential, agree to practice 2 effective methods of 
contraception from the time of signing the informed consent form through 6 months after 
the last dose of study drug, or agree to completely abstain from heterosexual intercourse.   
Male patients, even if surgically sterilized (i.e., status post-vasectomy) must agree to one 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 completely abstain from 
heterosexual intercourse. 
 


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6.6 
Management of Clinical Events 
Peripheral Neuropathy 
Collectively, the data support that peripheral neuropathy is an effect of cumulative exposure to 
brentuximab vedotin.  The first onset of any grade peripheral neuropathy increased incrementally 
with increasing numbers of cycles, and a trend toward increased incidence of first onset of Grade 
3 peripheral neuropathy and peripheral motor neuropathy in later cycles was apparent.  In line 
with these observations, the incidences of peripheral neuropathy (any SMQ event, Grade 3 event, 
and/or motor event) were highest in later cycles. 
Neuropathy associated with brentuximab vedotin was managed using a combination of dose 
delay and reduction to 1.2 mg/kg.  Dose delay and reduction appeared to mitigate worsening of 
neuropathy.  For new or worsening Grade 2 or 3 neuropathy, dosing should be held until 
neuropathy improves to Grade 1 or baseline and then restarted at the 1.2 mg/kg dose level (or as 
specified in individual protocols).  For Grade 4 peripheral neuropathy, brentuximab vedotin 
should be discontinued. 
Hematological Toxicities 
The hematological AEs of thrombocytopenia, anemia, and neutropenia were reported in the 
pivotal studies. Neutropenia was the most common hematological AE (21%) and was not 
unexpected based on the toxicology results from the sponsor’s nonclinical program and 
phase 1 safety and clinical pharmacology studies. Although neutropenia was a common 
treatment-emergent AE in the pivotal studies, it appeared to be well managed with the 
protocol-specified recommendations for hematologic toxicity (i.e., dose delay, growth factor 
support). The median duration of Grade 3 or Grade 4 neutropenia was limited (1 week); 
3 patients had Grade 4 neutropenia that lasted ≥7 days. Less than half of the patients with 
Grade 3 or 4 neutropenia had temporally associated infections, and the majority of 
temporally associated infections were Grade 1 or 2.  Although not reported in the pivotal studies, 
febrile neutropenia has been reported in  additional completed studies with brentuximab vedotin.  
Patients should be monitored for cytopenias.  
For new or worsening Grade 3 or 4 neutropenia, dosing should be held until neutropenia 
improves to ≤ Grade 2 or baseline and then restarted at the same dose level (or as specified in 
individual protocols).  Growth factor support (G-CSF or GM-CSF) should be considered for 
subsequent cycles (refer to Dose Modification Section 6.2). 
Infusion-Related Reactions 
Brentuximab vedotin is administered via IV infusion.  Infusion of proteins can result in 
hypersensitivity reactions that may be fatal if not rapidly and appropriately managed.  Infusion 


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interruption for IRR treatment generally led to the successful completion of the dose and 
continued treatment with brentuximab vedotin with or without IRR prophylaxis, according to the 
clinical judgment of the investigator. 
Although the experience with IRRs related to brentuximab vedotin is limited, in part due to the 
low incidence observed to date, data support brentuximab vedotin administration by 
appropriately trained personnel without the need for routine prophylaxis.  If IRR symptoms 
develop, the infusion should be interrupted and appropriate medical management instituted.  The 
infusion may be restarted at a slower rate after symptom resolution.  Premedication should be 
administered for subsequent infusions in patients who have experienced a prior IRR.  If 
anaphylaxis occurs, brentuximab vedotin should be immediately and permanently discontinued 
and appropriate medical management instituted. 
Infections 
Serious and opportunistic infections have been reported for patients treated with brentuximab 
vedotin.  Monitor patients for the emergence of possible bacterial, fungal, or viral infections.  
Although infections were observed in 61% of patients in the completed phase 2 studies (Studies 
SG035-0003 and SG035-0004), the majority of infections were Grade 1 to 2 and occurred with 
an incidence comparable to that reported in similar populations.  While serious infections were 
reported in 10% of patients, the majority of infections were not considered by the investigator to 
be related to brentuximab vedotin.  Infection led to dose delay in 14% of HL patients and 7% of 
ALCL patients.  No patient discontinued treatment because of infection.  The infection with the 
highest incidence was Grade 1 or 2 URTI, which occurred in more HL than ALCL patients.  
Grade 3 or 4 infections occurred in 7% of HL patients and 12% of ALCL patients.  No Grade 5 
infections were reported.  HL patients had a higher incidence of infections, largely reflective of 
the higher incidence of Grade 1 to 2 URTI (37%).  Several factors may have contributed to this 
higher incidence, including the high frequency of respiratory tract infections in HL patients post-
transplant, the lower median age of the HL patients compared with systemic ALCL patients, and 
differences in exposure to respiratory viruses.  These URTIs, while frequent, led to dose delay in 
only 3 patients.  Importantly, the rate of pneumonia was low, which is indicative of a low rate of 
progression from URTI to pneumonia, and the incidence was lower than that reported in the 
literature for comparable populations.   
Stevens-Johnson Syndrome 
Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with brentuximab 
vedotin. Fatal outcomes have been reported.  If Stevens-Johnson syndrome or toxic epidermal 
necrolysis occur, brentuximab vedotin must be discontinued and the appropriate medical therapy 
administered. 


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Tumor Lysis Syndrome 
Tumor lysis syndrome (TLS) is typically reported in patients with acute leukemias and high-
grade non-Hodgkin lymphomas after the initiation of cytotoxic therapy. 
 
TLS has been reported with brentuximab vedotin. Patients with rapidly proliferating tumor and 
high tumor burden are at risk of tumor lysis syndrome. These patients 
Should be monitored closely and managed according to best medical practice. Management of 
TLS may include aggressive hydration, monitoring of renal function, correction of electrolyte 
abnormalities, anti-hyperuricaemic therapy, and supportive care.  
Progressive Multifocal Leukoencephalopathy 
PML can occur in patients receiving brentuximab vedotin.  PML is a rare demyelinating disease 
of the brain that is caused by the John Cunningham virus (JCV).  It typically occurs in 
immunocompromised individuals and can be fatal.   Presenting features may include altered 
mental status, motor deficits such as hemiparesis or ataxia, visual disturbances, or higher cortical 
dysfunction such as dysphasia or agnosia.  Seizures have also been reported in PML patients 
(approximately 20%).  The onset of neurological deficits may occur over weeks to months. 
Cognitive decline without accompanying deficits in motor or sensory function is uncommon.  
Optic nerve involvement, fever, and spinal cord disease are not typically associated with PML.  
In addition, peripheral neuropathy, which has been reported with brentuximab vedotin treatment, 
is not commonly reported with PML.   
If PML is suspected, a diagnostic work-up should be performed.  The work-up 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 non-enhancing and do not have 
mass effect. 
• PCR analysis: JCV DNA detectable in CSF or there is evidence of JCV in a brain biopsy 
• Neurology consultation 
Brentuximab vedotin dosing should be held if PML is suspected.  If PML is confirmed, 
brentuximab vedotin should be permanently discontinued. 
Pulmonary Toxicity in Combination with Bleomycin 
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 (ABVD), the rate of noninfectious pulmonary toxicity was higher than the 


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historical incidence reported with ABVD.  Monotherapy with brentuximab vedotin has not been 
associated with a clinically meaningful risk of pulmonary toxicity.  In the event of new or 
worsening pulmonary symptoms (e.g., cough, dyspnoea), a prompt diagnostic evaluation should 
be performed and patients should be treated appropriately. 
 
Acute Pancreatitis 
 
Acute pancreatitis has been reported for patients treated with brentuximab vedotin. 
Patients should be monitored for signs of new or worsening acute abdominal pain and, if 
observed, a diagnostic workup for pancreatitis should be considered.  A diagnostic workup may 
include physical examination, laboratory evaluation for serum amylase and serum lipase, and 
abdominal imaging, such as ultrasound and other appropriate diagnostic measures. Brentuximab 
vedotin should be held for any suspected case of acute pancreatitis. Brentuximab vedotin should 
be discontinued if a diagnosis of acute pancreatitis is confirmed. 
 
Hepatotoxicity 
 
Hepatotoxicity, predominately in the form of asymptomatic mild to moderate transient 
elevations in AST and/or ALT, has been reported for patients treated with brentuximab 
vedotin.  Patients should be monitored for elevated liver enzymes. 
 
Embryogenesis, Reproduction, and Spermatogenesis 
 
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. Therefore, women of childbearing potential and fertile men should 
be advised to use adequate and effective contraception during and after treatment with 
brentuximab vedotin.  
 
6.7 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 50 mg of useable brentuximab vedotin, 
trehalose, sodium citrate, and polysorbate 80.  The lyophilized product, after reconstitution with 
10.5 mL sterile Water for Injection, USP, yields 11 mL of brentuximab vedotin solution (5 
mg/mL concentration after reconstitution). 


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6.8 Preparation, Reconstitution and Dispensing 
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.  
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 150 to 250 mL infusion bag containing 0.9% Sodium Chloride Injection, USP. 
There are no known incompatibilities between study treatment and polypropylene (PP),  
polyvinyl chloride (PVC), ethyl vinyl acetate (EVA), polyolefin, or polyethylene (PE) bags.  The 
bag should be gently inverted to mix the solution.  The bag must not be shaken; excess 
agitation may cause aggregate formation.  Prior to administration, the reconstituted and diluted 
drug product should be inspected visually for any particulate matter and discoloration.   
The formulation contains no preservative and is intended for single use only; infusion solutions 
should be prepared and transferred using aseptic technique in a bio-safety hood. 
6.9 Packaging and Labeling 
Vials of study treatment will be packaged as one single-use vial per carton (kit).  Vials and kits 
will be labeled to meet country-specific regulatory requirements.    
6.10 Storage, Handling and Accountability 
Vials containing brentuximab vedotin must be refrigerated at 2oC to 8oC in a secure location 
(e.g., locked room) accessible only to the pharmacist, the investigator, or a duly designated 
person. 
Brentuximab vedotin does not contain preservatives; therefore, opened and reconstituted vials of 
study treatment must be used within 24 hours when stored under refrigeration at 2oC to 8oC.  
Reconstituted brentuximab vedotin should not be stored at room temperature.  It is recommended 
that brentuximab vedotin vials and solutions be protected from direct sunlight until the time of 
use.  Reconstituted vials must not be shaken. 
A study drug accountability log must be completed for all brentuximab vedotin dispensed and 
administered to study patients. 


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6.11 Study Compliance  
Study drug will be administered or dispensed only to eligible patients under the supervision of 
the investigator or identified sub-investigator(s).  The appropriate study personnel will maintain 
records of study drug receipt and dispensing. 
6.12 Termination of Treatment and/or Study Participation 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care.  The investigator also has the right to withdraw 
patients from the study for any of the following reasons: 
 Adverse event 
 Protocol violation 
 Lost to follow-up 
 Progressive disease  
 Study terminated 
 Other 
Patients who are withdrawn from the study will not be replaced.                                                                         
At the time of withdrawal, all study procedures outlined for the End of Study visit should be 
completed.  The primary reason for a patient’s withdrawal from the study is to be recorded in the 
source documents and CRF. 


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7  
STATISTICAL AND QUANTITATIVE ANALYSES 
7.1  Statistical Methods 
In general, summary tabulations will display the number of observations, mean, standard 
deviation, median, minimum, and maximum for continuous variables, and the number and 
percent per category for categorical data. Kaplan-Meier survival curves will be provided along 
with their 2-sided 95% CIs for time-to-event data. 
 
7.1.1  Determination of Sample Size 
Optimal Simon’s two-stage design 
- 
α=0.05, β=0.20 
- 
P0=0.20, P1=0.45 
- 
Stage 1: 2/10 (≥3 responders are required to move to stage 2)  
- 
Stage 2: 7/22 (8 or more responses are required to reject the null hypothesis) 
- 
Total patients: 22 + 3 (10% drop-out rate) = 25 patients 
7.1.2 Randomization and Stratification 
Not applicable 
7.1.3 Populations for Analyses 
 The populations used for analysis will include the following: 
Safety population: patients who receive at least 1 dose of study drug will be used for all safety 
analyses. All patients in the safety population will be analyzed according to the actual 
treatment received. 
Intent-to-Treat (ITT) population: all patients randomized to treatment. All patients in the ITT 
population will be analyzed according to the treatment they were randomized to receive and 
not according to what they actually received, if different. 
Per-Protocol (PP) population: a subset of ITT patients who do not have a major protocol 
violation as determined by the project clinician. All decisions to exclude patients from the PP 
population will be made prior to database lock. 
Response-Evaluable population: all patients with diagnosis as confirmed by an independent 
pathology review facility, with measurable disease at baseline, who receive at least 1 dose of 
study drug, and have at least 1 postbaseline response assessment.  
 
7.1.4  Procedures for handling Missing, Unused, and Spurious Data 
   All available efficacy and safety data will be included in data listings and tabulations. The 
relevance of missing sample data will be assessed. Data that are potentially spurious or 
erroneous will be examined according to standard data management operating procedures.  
 


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7.1.5 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized, including gender, age, weight, 
height, BSA, primary diagnosis, and other parameters as appropriate. No inferential statistics 
will be carried out. 
 
7.1.6 Efficacy Analysis 
   All efficacy evaluations will be conducted using the ITT population unless otherwise specified. 
ORR will be used for the primary efficacy analysis using revised response criteria for malignant 
lymphoma (Appendix 12.3) or modified SWAT (Appendix 12.4) criteria. Duration of response 
in subjects with confirmed response is the time between first documentation of response and 
disease progression.  
PFS and OS will be analyzed based on the ITT population using a stratified log-rank test. PFS 
is defined as the time from the date of randomization to the date of the first of (1) 
documentation of PD; (2) death due to any cause; (3) for patients who are confirmed non-
complete responders, receipt of anticancer chemotherapy or radiotherapy for EBV- and CD30-
positive lymphoma after completion of brentuximab vedotin. OS is defined as the time from the 
date of study enrollment to the date of death. Patients without documented death at the time of 
analysis will be censored at the date last known to be alive. Stratified log-rank testing will be 
used to compare OS between the groups. The hazard ratios along with the 95% CIs will be 
estimated using a stratified Cox regression model. The Kaplan-Meier method will be used to 
estimate the distribution of the OS endpoint. Median survival times (if estimable), along with 
the 2-sided 95% CIs will be presented. Analysis of OS will be performed based on the ITT 
population. 
 
7.1.7 Biomarkers 
 Baseline value of circulating biomarkers will be summarized by time point using descriptive 
statistics, as applicable. Descriptive statistics (eg, number of patients, mean, standard deviation, 
median, minimum, maximum) will also be provided to summarize the levels of soluble CD30 
receptor and qualitative and semiquantitative measures of CD30 expression. 
 
7.1.8 Safety Analysis 
 Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes from 
baseline in the patient’s vital signs, weight, and clinical laboratory results using the safety 
population. Exposure to frontline therapy and reasons for discontinuation will be tabulated. 
Treatment-emergent AEs that occur after administration of the first dose of study drug and 
through 30 days after the last dose of brentuximab vedotin will be tabulated. 
AEs will be tabulated according to the Medical Dictionary for Regulatory Activities 
(MedDRA) and will include the following categories: 


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- 
Treatment-emergent AEs 
- 
Drug-related treatment-emergent AEs 
- 
Grade 3 or higher treatment-emergent AEs 
- 
Grade 3 or higher drug-related treatment-emergent AEs 
- 
The most commonly reported treatment-emergent AEs (ie, those events reported by  
        10% of all patients) 
- 
SAEs  
 
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. 
  
7.1.9 Interim Analysis 
Not applicable 


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8 ADVERSE EVENTS     
8.1 Definitions 
8.1.1 Adverse Drug Reaction (ADR) 
An adverse reaction (ADR) is a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. This includes adverse reactions 
which arise from: use of a medicinal product within the terms of the marketing authorization; use 
outside the terms of the marketing authorization, including overdose, misuse, abuse and 
medication errors; and occupational exposure*. 
 
* This corresponds to the exposure to a medicinal product for human use as a result of one’s 
occupation, such as nurses who may handle products routinely in their occupational setting. 
8.1.2 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. 
8.1.3 Serious Adverse Event Definition 
Serious adverse event (SAE) means any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening (refers to an AE in which the patient was at risk of death at the time of 
the event.  It does not refer to an event which hypothetically might have caused death if it 
were more severe). 
• Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph below on planned hospitalizations). 
• Results in persistent or significant disability or incapacity.  (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect. 
• Is a medically important event.  This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 


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when, based on appropriate medical judgment, may jeopardize the patient, require 
medical or surgical intervention to prevent one of the outcomes listed above, or involves 
suspected transmission via a medicinal product of an infectious agent.   Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse; any 
organism, virus, or infectious particle (e.g., prion protein transmitting Transmissible 
Spongiform Encephalopathy), whether pathogenic or non-pathogenic, is considered an 
infectious agent.   
Clarification should be made between a serious AE (SAE) and an AE that is considered severe in 
intensity (Grade 3 or 4), because the terms serious and severe are NOT synonymous.  The 
general term severe is often used to describe the intensity (severity) of a specific event; the event 
itself, however, may be of relatively minor medical significance (such as a Grade 3 headache).  
This is NOT the same as serious, which is based on patient/event outcome or action criteria 
described above, and is usually associated with events that pose a threat to a patient’s life or 
ability to function.  A severe AE (Grade 3 or 4) does not necessarily need to be considered 
serious.  For example, a white blood cell count of 1000/mm3 to less than 2000 is considered 
Grade 3 (severe) but may not be considered serious.  Seriousness (not intensity) serves as a guide 
for defining regulatory reporting obligations. 
8.2 Procedures for Reporting Serious Adverse Events  
AEs may be 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.  
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 one comprehensive event.  AEs which are serious must be reported 
to Millennium/Takeda Pharmacovigilance (or designee) from the first dose of brentuximab 
vedotin up to and including 30 days after administration of the last dose of brentuximab vedotin.  
Any SAE that occurs at any time after completion of brentuximab vedotin treatment or after the 
designated follow-up period that the sponsor-investigator and/or sub-investigator considers to be 
related to any study drug must be reported to Millennium/Takeda Pharmacovigilance (or 
designee).  Planned hospital admissions or surgical procedures for an illness or disease that 
existed before the patient was enrolled in the trial are not to be considered AEs unless the 
condition deteriorated in an unexpected manner during the trial (e.g., surgery was performed 
earlier or later than planned).  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). 
Since this is an investigator-initiated study, the principal investigator, Tae Min Kim, also referred 
to as the sponsor-investigator, is responsible for reporting serious adverse events (SAEs) to any 
regulatory agency and to the sponsor- investigator’s EC or IRB.   Regardless of expectedness or 
causality, all SAEs must also be reported to Millennium/Takeda Pharmacovigilance (or designee) 
within 24 hours of the sponsor-investigator’s observation or awareness of the event (contact 
information provided below).     


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The sponsor-investigator should fax the SAE Form within 24 hours after becoming aware of the 
event.  A sample of an SAE Form will be provided.  Follow-up information on the SAE may be 
requested by Millennium/Takeda.  The SAE report must include event term(s), serious criteria, 
and the sponsor-investigator’s or sub-investigator’s determination of both the intensity of the 
event(s) and the causality of the event(s) in relationship to study drug administration.  Intensity 
for each SAE, including any lab abnormalities, will be determined by using the NCI CTCAE 
version used at your institution, as a guideline, whenever possible.  The criteria are available 
online at http://ctep.cancer.gov/reporting/ctc.html. 
In the event that this is a multisite study, the sponsor-investigator is responsible to ensure that the 
SAE reports are sent to Millennium/Takeda Pharmacovigilance (or designee) from all sites 
participating in the study.  Sub-investigators must report all SAEs to the sponsor-investigator so 
that the sponsor-investigator can meet his/her foregoing reporting obligations to the required 
regulatory agencies and to Millennium/Takeda Pharmacovigilance, unless otherwise agreed 
between the sponsor-investigator and sub-investigator(s).   
Relationship to all study drugs for each SAE will be determined by the sponsor-investigator or 
sub-investigator by responding yes or no to the question: Is there a reasonable possibility that the 
AE is associated with the study drug(s)? 
Sponsor-investigator must also provide Millennium/Takeda Pharmacovigilance with a copy of 
all communications with applicable regulatory authorities related to the study or study drug(s), as 
soon as possible but no later than 4 calendar days of such communication. 
Millennium/Takeda Pharmacovigilance 
SAE and Pregnancy Reporting Contact Information 
US and Canada 
Toll-Free Fax #: 1-800-963-6290 
E-mail: takedaoncocases@cognizant.com 
 
All other countries (Rest of World) 
Fax #: 1 202 315-3560 
E-mail: takedaoncocases@cognizant.com 
 
8.3 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, 
she must inform the investigator immediately and permanently discontinue study drug.  All 
pregnancies and suspected pregnancies must be reported to Millennium/Takeda 
Pharmacovigilance (or designee) immediately (see Section 8.2 for contact information).  The 
pregnancy must be followed for the final pregnancy outcome (i.e., delivery, still birth, 
miscarriage) and Millennium/Takeda Pharmacovigilance will request this information from the 
sponsor-investigator. 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, this must be reported to Millennium/Takeda Pharmacovigilance or designee 


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immediately (see Section 8.2 for contact information).  Every effort should be made to follow the 
pregnancy for the final pregnancy outcome. 
 


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9 ADMINISTRATIVE REQUIREMENTS 
9.1 Good Clinical Practice 
The study will be conducted in accordance with the International Conference on Harmonisation 
(ICH) for Good Clinical Practice (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 Investigator’s Brochure.  Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected.  Master files should 
be established at the beginning of the study, maintained for the duration of the study and retained 
according to the appropriate regulations.   
9.2 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 in order 
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, Investigator’s Brochure, 
informed consent form, 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.  Millennium requests that 
informed consent documents be reviewed by Millennium or designee prior to IRB/IEC 
submission.   
9.3 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 requirement(s). 
9.4 Patient Confidentiality 
In order to maintain patient privacy, all data capture records, drug accountability records, study 
reports and communications will identify the patient by initials and the assigned patient number.  
If requested, the investigator will grant monitor(s) and auditor(s) from Millennium or its 
designees and regulatory authority(ies) access to the patient’s original medical records for 
verification of data gathered on the data capture records and to audit the data collection process.  
The patient’s confidentiality will be maintained and will not be made publicly available to the 
extent permitted by the applicable laws and regulations. 
9.5 Investigator Compliance 
The investigator will conduct the study in compliance with the protocol given approval/favorable 
opinion by the IRB/IEC and the appropriate regulatory authority(ies).  Changes to the protocol 
will require approval from Millennium and written IRB/IEC approval/favorable opinion prior to 
implementation, except when the modification is needed to eliminate an immediate hazard(s) to 
patients.  The IRB/IEC may provide, if applicable regulatory authority(ies) permit, expedited 
review and approval/favorable opinion for minor change(s) in ongoing studies that have the 


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approval /favorable opinion of the IRB/IEC.  The investigator will submit all protocol 
modifications to Millennium and the regulatory authority(ies) in accordance with the governing 
regulations.  
Any departures from the protocol must be fully documented in the source documents.   
9.6 On-site Audits 
Regulatory authorities, the IEC/IRB and/or Millennium may request access to all source 
documents, data capture records, and other study documentation for on-site audit or inspection.  
Direct access to these documents must be guaranteed by the investigator, who must provide 
support at all times for these activities. 
9.7 Investigator and site Responsibility for Drug Accountability 
Accountability for the study drug at all study sites is the responsibility of the principal 
investigator.  The investigator will ensure that the drug is used only in accordance with this 
protocol.  Drug accountability records indicating the drug’s delivery date to the site, inventory at 
the site, use by each patient, and amount returned to Millennium or a designee or disposal of the 
drug (if applicable and if approved by Millennium) will be maintained by the clinical site.  
Accountability records will include dates, quantities, lot numbers, expiration dates (if applicable), 
and patient numbers.   
9.8 Product Complaints    
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product.  Individuals who 
identify a potential product complaint situation should immediately contact MedComm Solutions 
(see below) and report the event.  Whenever possible, the associated product should be 
maintained in accordance with the label instructions pending further guidance from a 
Millennium/Takeda Quality representative. 
 
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm.  While overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not.  
Individuals who identify a potential medication error situation should immediately contact 
MedComm Solutions (see below) and report the event. 
For Product Complaints or Medication Errors, 
call MedComm Solutions at 
(US and International) 
877-674-3784 
  
Product complaints and medication errors in and of themselves are not AEs.  If a product 
complaint or medication error results in an SAE, an SAE form should be completed and sent to 
Millennium/Takeda (refer to Section 8.2). 
 


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9.9 Closure of the Study 
This study may be prematurely terminated, if in the opinion of the investigator or 
Millennium/Takeda, there is sufficient reasonable cause.  Written notification documenting the 
reason for study termination will be provided to the investigator or Millennium/Takeda by the 
terminating party.   
 
Circumstances that may warrant termination include, but are not limited to: 
 Determination of unexpected, significant, or unacceptable risk to patients 
 Failure to enter patients at an acceptable rate 
 Insufficient adherence to protocol requirements 
 Insufficient, incomplete and/or unevaluable data 
 Determination of efficacy based on interim analysis 
 Plans to modify, suspend or discontinue the development of the drug 
 
Should the study be closed prematurely, all study materials must be returned to 
Millennium/Takeda. 
 
9.10 Record Retention 
The investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s).   
 


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10 USE OF INFORMATION 
All information regarding brentuximab vedotin supplied by Millennium/Takeda to the 
investigator is privileged and confidential information.  The investigator agrees to use this 
information to accomplish the study and will not use it for other purposes without consent from 
Millennium/Takeda.  It is understood that there is an obligation to provide Millennium/Takeda 
with complete data obtained during the study.  The information obtained from the clinical study 
will be used toward the development of brentuximab vedotin and may be disclosed to regulatory 
authority(ies), other investigators, corporate partners, or consultants as required. 
Upon completion of the clinical study and evaluation of results by Millennium/Takeda, the 
hospital or institution and/or investigator may publish or disclose the clinical trial results 
pursuant to the terms contained in the applicable Clinical Trial Agreement. 


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11 
REFERENCES    
 
 
1. 
Cheson BD, Pfistner B, Juweid ME, et al: Revised response criteria for malignant lymphoma. J 
Clin Oncol 25:579-86, 2007 
 
2. 
Olsen EA, Whittaker S, Kim YH, et al: Clinical end points and response criteria in mycosis 
fungoides and Sezary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the 
United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European 
Organisation for Research and Treatment of Cancer. J Clin Oncol 29:2598-607, 2011 
 
3. 
Carbone A, Gloghini A, Dotti G: EBV-associated lymphoproliferative disorders: classification and 
treatment. Oncologist 13:577-85, 2008 
 
4. 
Young LS, Rickinson AB: Epstein-Barr virus: 40 years on. Nat Rev Cancer 4:757-68, 2004 
 
5. 
Armitage J, Vose J, Weisenburger D: International peripheral T-cell and natural killer/T-cell 
lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 26:4124-30, 2008 
 
6. 
Kim TM, Lee SY, Jeon YK, et al: Clinical heterogeneity of extranodal NK/T-cell lymphoma, 
nasal type: a national survey of the Korean Cancer Study Group. Ann Oncol 19:1477-84, 2008 
 
7. 
Jarrett RF, Stark GL, White J, et al: Impact of tumor Epstein-Barr virus status on presenting 
features and outcome in age-defined subgroups of patients with classic Hodgkin lymphoma: a population-based 
study. Blood 106:2444-51, 2005 
 
8. 
Dupuis J, Emile JF, Mounier N, et al: Prognostic significance of Epstein-Barr virus in nodal 
peripheral T-cell lymphoma, unspecified: a Groupe d'Etude des Lymphomes de l'Adulte (GELA) study. Blood 
108:4163-9, 2006 
 
9. 
Park S, Lee J, Ko YH, et al: The impact of Epstein-Barr virus status on clinical outcome in diffuse 
large B-cell lymphoma. Blood 110:972-8, 2007 
 
10. 
Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three 
intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med 328:1002-6, 1993 
 
11. 
Katz J, Janik JE, Younes A: Brentuximab Vedotin (SGN-35). Clin Cancer Res 17:6428-36, 2011 
 
12. 
Pongpruttipan T, Sukpanichnant S, Assanasen T, et al: Extranodal NK/T-cell lymphoma, nasal 
type, includes cases of natural killer cell and alphabeta, gammadelta, and alphabeta/gammadelta T-cell origin: a 
comprehensive clinicopathologic and phenotypic study. Am J Surg Pathol 36:481-99, 2012 
 
13. 
Kagami Y, Suzuki R, Taji H, et al: Nodal cytotoxic lymphoma spectrum: a clinicopathologic study 
of 66 patients. Am J Surg Pathol 23:1184-200, 1999 
 
14. 
Shimoyama Y, Asano N, Kojima M, et al: Age-related EBV-associated B-cell lymphoproliferative 
disorders: diagnostic approach to a newly recognized clinicopathological entity. Pathol Int 59:835-43, 2009 
 
15. 
Sharman JP, Oki Y, Advani RH, et al: A Phase 2 Study Of Brentuximab Vedotin In Patients With 
Relapsed Or Refractory CD30-Positive Non-Hodgkin Lymphomas: Interim Results In Patients With DLBCL and 
Other B-Cell Lymphomas. Blood 122:848, 2013 
 
16. 
Tetzlaff M, Clos AL, Gangar P, et al: Phase II Trial Of Brentuximab Vedotin For CD30+ 
Cutaneous T-Cell Lymphomas and Lymphoproliferative Disorders. Blood 122:367, 2013 
 
17. 
Younes A, Bartlett NL, Leonard JP, et al: Brentuximab vedotin (SGN-35) for relapsed CD30-
positive lymphomas. N Engl J Med 363:1812-21, 2010 
 
                                                                                                                                                                                                
 


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12 
APPENDICES 
 


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12.1 
Common Terminology Criteria for Adverse Events Version 4.03(4) 
http://ctep.cancer.gov/reporting/ctc.html  
 
 
 
 
 


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12.2 
New York Heart Association Classification of Cardiac Disease(5) 
Class Functional Capacity 
Objective 
Assessment 
I 
Patients with cardiac disease but without resulting 
limitations of physical activity.  Ordinary physical activity 
does not cause undue fatigue, palpitation, dyspnea, or 
54angina pain. 
No objective 
evidence of 
cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation of 
physical activity.  They are comfortable at rest.  Ordinary 
physical activity results in fatigue, palpitation, dyspnea, or 
54angina pain. 
Objective evidence 
of minimal 
cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation 
of physical activity.  They are comfortable at rest.  Less 
than ordinary activity causes fatigue, palpitation, dyspnea, 
or angina pain. 
Objective evidence 
of moderately 
severe 
cardiovascular 
disease. 
IV 
Patients with cardiac disease resulting in inability to carry 
on any physical activity without discomfort.  Symptoms of 
heart failure or the 54angina syndrome may be present even 
at rest.  If any physical activity is undertaken, discomfort is 
increased. 
Objective evidence 
of severe 
cardiovascular 
disease. 
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for Diagnosis 
of Diseases of the Heart and Great Vessels.  9th Ed.  Boston, MA:  Little, Brown & Co; 1994:253-256.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12.3 Revised response criteria for malignant lymphoma 
Complete Remission (CR) 
1. Complete disappearance of all detectable clinical evidence of disease and disease-related  
symptom if present prior to therapy. 
2. The spleen and/or liver, if considered enlarged prior to therapy on the basis of a physical  
examination or CT scan, should not be palpable on physical examination and should be  
considered normal size by imaging studies, and nodules related to lymphoma should  
disappear.  
3. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have  
been cleared on repeat bone marrow biopsy and EBV should be negative by EBV in situ  
hybridization (ISH). 
4. In patients for whom FDG by PET is avid, incorporation of interim PET imaging results as  
follows: All CR requirements as described above. However, if a patient’s PET scan was  
positive before therapy, a post-treatment residual mass of any size is permitted as long as it is  
PET negative 
 
Partial Remission (PR) 
1. ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest  
dominant nodes or nodal masses.  
2. No increase in the size of the other nodes, liver, or spleen. 
3. Splenic and hepatic nodules must regress by ≥ 50% in their SPD or, for single nodules, in  
the greatest transverse diameter. 
4. With the exception of splenic and hepatic nodules, involvement of other organs is usually  
assessable and no measurable disease should be present. 
5. Bone marrow assessment is irrelevant for determination of a PR if the sample was positive  
prior to treatment. However, if positive, the EBV-positivity should be specified by EBV ISH.  
Patients who achieve a CR by the above criteria, but who have persistent morphologic or  
molecular bone marrow involvement will be considered partial responders. 
6. No new sites of disease should be observed (e.g., nodes > 1.5 cm in any axis). 
7. For patients with FDG-avidity, an interim assessment should be made. For patients whose  
PET scan was positive before therapy, the post-treatment PET scan should be positive in at  


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least one previously involved site.  
 
Stable Disease (SD) 
1. Failure to attain the criteria needed for a CR or PR, but not fulfilling those for progressive  
disease 
2. PET imaging should be positive at prior sites of disease with no new areas of involvement  
on the post-treatment PET scan.  
 
Relapsed Disease (RD; after CR) or Progressive Disease (PD; for Patients with PR or SD) 
1. Appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy,  
even if other lesions are decreasing in size. 
2. At least a 50% increase from nadir in the SPD of any previously involved nodes, or in a  
single involved node, or the size of other lesions (e.g., splenic or hepatic nodules). To be  
considered progressive disease, a lymph node with a diameter of the short axis of less than  
1.0 cm must increase by ≥50% and to a size of 1.5 × 1.5 cm or more than 1.5 cm in the long  
axis. 
3. At least a 50% increase in the longest diameter of any single previously identified node  
more than 1 cm in its short axis. 
4. If FDG-PET imaging has been obtained, PD should only be designated if the CT criteria  
for progression have been met and the lesions are PET positive for patients with PET-positive  
disease prior to therapy. FDG-PET is not mandatory for surveillance of progression. 
 
 
 
 
 
 
 
 
 
 


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Response 
Definition 
Nodal masses 
Spleen, liver 
Bone marrow 
CR 
Disappearance of all 
evidence of disease 
(a) FDG-avid or PET positive prior to 
therapy; mass of any size permitted if 
PET negative 
(b) Variably FDG-avid or PET negative; 
regression to normal size on CT 
Not palpable, nodules 
disappeared 
Infiltrate cleared 
on repeat biopsy; 
if indeterminate 
by morphology, 
IHC should be 
negative 
PR 
Regression of 
measurable disease 
and no new sites 
≥ 50% decrease in SPD of up to 6 largest 
dominant masses; no increase in size of 
other nodes 
(a) FDG-avid or PET positive prior to 
therapy; one or more PET positive at 
previously involved site 
(b) Variably FDG-avid or PET negative; 
regression on CT 
≥ 50% decrease in 
SPD of nodules (for 
single nodule in 
greatest transverse 
diameter); no increase 
in size of liver or 
spleen 
Irrelevant if 
positive prior to 
therapy; cell type 
should be 
specified 
SD 
Failure to attain 
CR/PR or PD 
(a) FDG-avid or PET positive prior to 
therapy; PET positive at prior sites of 
disease and no new sites on CT or PET 
(b) Variably FDG-avid or PET negative; 
no change in size of previous lesions on 
CT 
 
 
RD or PD 
Any new lesion or 
increase by ≥ 50% of 
previously involved 
sites from nadir 
Appearance of a new lesion(s) > 1.5 cm 
in any axis, ≥ 50% increase in SPD of 
more than one node, or ≥ 50% increase in 
longest diameter of a previously identifed 
node > 1 cm in short axis 
Lesions PET positive if FDG-avid 
lymphoma or PET positive prior to 
therapy 
> 50% increase from 
nadir in the SPD of 
any previous lesions 
New or recurrent 
involvement 
 
 
 
 
 
 
 
 
 
 
 
 


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12.4 
Modified SWAT criteria for skin lesions 
Definitions of skin lesions 
1. Patch: any size lesion without induration or significant elevation above the surrounding  
uninvolved skin: pokiloderma may be present.  
2. Plaque:  any size lesion that is elevated or indurated: crusting or poikiloderma may be  
present. 
3. Tumor:  any solid or nodular lesion ≥ 1 cm in diameter with evidence of deep infiltration in  
the skin and/or vertical growth. 
 
Modified SWAT tool 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Response in skin 
 
T1 Limited patches, papules, and/or plaques covering < 10% of the skin surface; may further  
stratify into T1a (patch only) v T1b (plaque ± patch) 
T2 Patches, papules, or plaques covering ≥ 10% of the skin surface; may further stratify into  
T2a (patch only) v T2b (plaque ± patch) 
T3 One or more tumors (≥ 1 cm diameter) 
T4 Confluence of erythema covering ≥ 80% body surface area