Clinical trial NCT02533570
Conditions: Systemic Lupus Erythematosus
Keywords: Lupus
Sponsor: Seagen Inc.
Start date: 2015-07-01; Completion date: 2017-06-05
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and tolerability of brentuximab vedotin in adults with active systemic lupus erythematosus (SLE).

Detailed description:
Systemic lupus erythematosus (SLE) is a chronic, multisystem, disabling autoimmune condition, which predominantly affects women of childbearing years. Treatment options for SLE remain relatively limited. Regardless of the specific therapy chosen, the majority of patients continue to require long term immunomodulatory or cytotoxic therapy, resulting in long-term morbidity and mortality. Brentuximab vedotin is an antibody-drug conjugate (ADC) consisting of: 1) the chimeric immunoglobulin (Ig) G1 antibody cAC10, specific for human CD30, 2) the microtubule disrupting agent monomethyl auristatin E (MMAE), and 3) a protease-cleavable linker that covalently attaches MMAE to cAC10. Since CD30 and/or CD30-expressing immune cells may play significant key roles in the pathogenesis of SLE, brentuximab vedotin may be an efficacious therapy. This study intends to explore the potential for brentuximab vedotin as a therapy for SLE.

Arms: arm 1: 4 dose groups arm 2: Matching placebo
Interventions: intervention 1: Brentuximab vedotin intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 










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TABLE OF CONTENTS 
1.0 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................10 
2.0 
INTRODUCTION......................................................................................................13 
2.1 
Background ....................................................................................................13 
2.2 
CD30 and Systemic Lupus Erythematosus .................................................13 
2.3 
Brentuximab Vedotin ....................................................................................14 
2.4 
Rationale for the Study ..................................................................................15 
2.5 
Discussion of Study Design and Dose Selection ...........................................15 
2.6 
Risk Assessment .............................................................................................16 
3.0 
STUDY OBJECTIVES ..............................................................................................19 
3.1 
Primary Objective ..........................................................................................19 
3.2 
Secondary Objectives.....................................................................................19 
4.0 
INVESTIGATIONAL PLAN ...................................................................................20 
4.1 
Summary of Study Design .............................................................................20 
4.2 
Discussion of Study Design ............................................................................21 
4.3 
Study Periods ..................................................................................................21 
4.3.1 
Screening (Days -28 to -14) ..............................................................21 
4.3.2 
Treatment Period (Days 1 to 71) .......................................................22 
4.3.2.1 
Baseline (Day 1) ..............................................................22 
4.3.2.2 
Treatment .........................................................................24 
4.3.2.3 
Observation ......................................................................27 
4.3.3 
Follow-up or Early Discontinuation (±7 days) ..................................28 
4.4 
Selection of Study Population .......................................................................28 
4.4.1 
Inclusion Criteria ...............................................................................28 
4.4.2 
Exclusion Criteria ..............................................................................30 
4.4.3 
Disease Diagnostic Criteria ...............................................................33 
4.4.4 
Subject Withdrawal ...........................................................................33 
4.5 
Safety Monitoring Committee ......................................................................34 
5.0 
STUDY TREATMENTS ...........................................................................................36 
5.1 
Treatments Administered .............................................................................36 
5.2 
Identity of Investigational Product...............................................................36 
5.3 
Method of Assigning Subjects to Treatment Group ...................................37 
5.4 
Selection of Doses in the Study .....................................................................37 
5.5 
Selection and Timing of Dose for Each Subject ..........................................37 
5.6 
Blinding ...........................................................................................................37 
5.7 
Prior and Concomitant Treatments .............................................................38 


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5.7.1 
Excluded Medications .......................................................................38 
5.7.2 
Allowed Medications .........................................................................39 
5.8 
Treatment Compliance ..................................................................................40 
5.9 
Study Drug Accountability............................................................................40 
6.0 
EFFICACY, SAFETY, PHARMACOKINETICS, AND 
PHARMACODYNAMICS........................................................................................41 
6.1 
Schedule of Events .........................................................................................41 
6.2 
Efficacy Measures ..........................................................................................41 
6.2.1 
Response Assessments ......................................................................41 
6.2.2 
Response Definitions .........................................................................42 
6.2.3 
Efficacy Endpoints ............................................................................44 
6.2.3.1 
Primary ............................................................................44 
6.2.3.2 
Secondary ........................................................................44 
6.2.3.3 
Exploratory ......................................................................44 
6.3 
Safety Assessments .........................................................................................46 
6.3.1 
Adverse Events ..................................................................................46 
6.3.1.1 
Definitions .......................................................................46 
6.3.1.2 
Procedures for Eliciting and Recording 
Adverse Events ................................................................49 
6.3.1.3 
Reporting Periods for Adverse Events and 
Serious Adverse Events ...................................................50 
6.3.1.4 
Serious Adverse Events Require Immediate 
Reporting .........................................................................51 
6.3.1.5 
Emergency Medical Contacts ..........................................51 
6.3.1.6 
Sponsor Safety Reporting to Regulatory 
Authorities .......................................................................52 
6.3.2 
Management of Infusion Reactions ...................................................52 
6.3.3 
Progressive Multifocal Leukoencephalopathy 
Assessment ........................................................................................52 
6.3.4 
Anaphylaxis .......................................................................................53 
6.3.5 
Clinical Laboratory Evaluations ........................................................53 
6.3.6 
Vital Signs, Physical Findings, and Other Safety 
Assessments .......................................................................................55 
6.4 
Pharmacokinetic Measurements ..................................................................55 
6.4.1 
Plasma Concentrations ......................................................................55 
6.4.2 
Antitherapeutic Antibodies ................................................................56 
6.5 
Pharmacodynamic Measures ........................................................................56 
6.6 
Pharmacogenetic Sampling ...........................................................................57 
6.7 
Appropriateness of Measurements ...............................................................57 
7.0 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................58 
7.1 
Monitoring ......................................................................................................58 
7.2 
Data Management/Coding ............................................................................59 


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7.3 
Quality Assurance Audit ...............................................................................59 
8.0 
STATISTICS ..............................................................................................................60 
8.1 
Determination of Sample Size .......................................................................60 
8.2 
Statistical Methods .........................................................................................60 
8.2.1 
Analysis Populations .........................................................................60 
8.2.2 
Missing Data ......................................................................................61 
8.3 
Subject Disposition.........................................................................................61 
8.4 
Subject Characteristics ..................................................................................61 
8.5 
Efficacy Analyses ...........................................................................................62 
8.5.1 
Primary Analyses ...............................................................................62 
8.5.2 
Secondary Analyses ...........................................................................62 
8.5.3 
Exploratory Efficacy Endpoints ........................................................62 
8.5.4 
Subgroup Analysis .............................................................................62 
8.6 
Safety ...............................................................................................................63 
8.6.1 
Adverse Events ..................................................................................63 
8.6.2 
Clinical Laboratory Tests ..................................................................63 
8.6.3 
Vital Signs, Physical Findings, and Other Safety 
Evaluations ........................................................................................64 
8.7 
Pharmacokinetic Analyses ............................................................................64 
8.8 
Pharmacodynamic Analyses .........................................................................64 
8.9 
Interim Analyses ............................................................................................65 
9.0 
ETHICS ......................................................................................................................66 
9.1 
Institutional Review Board or Independent Ethics Committee ................66 
9.2 
Ethical Conduct of the Study ........................................................................66 
9.3 
Subject Information and Informed Consent ...............................................66 
10.0 
STUDY ADMINISTRATION...................................................................................67 
10.1 
Administrative Structure ..............................................................................67 
10.2 
Data Handling and Record Keeping ............................................................67 
10.3 
Direct Access to Source Data/Documents ....................................................67 
10.4 
Investigator Information ...............................................................................68 
10.4.1 
Investigator Obligations ....................................................................68 
10.4.2 
Protocol Signatures ............................................................................68 
11.0 
REFERENCES ...........................................................................................................69 
12.0 
APPENDICES ............................................................................................................73 
 


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LIST OF TABLES 
Table 1 
Clinical Criteria for Diagnosing Anaphylaxis .................................................53 
Table 2 
Study Administration Structure .......................................................................67 
Table 3 
Schedule of Events ...........................................................................................76 
 
LIST OF FIGURES 
Figure 1 
Flowchart of Study Design for Protocol SGN35-022 ......................................21 
 
 


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1.0 LIST OF ABBREVIATIONS AND DEFINITIONS OF 
TERMS 
Abbreviation 
Definition 
ACR 
American College of Rheumatology 
ADC 
antibody-drug conjugate 
AE 
adverse event 
ALCL 
anaplastic large cell lymphoma 
ALT 
alanine aminotransferase 
ANA 
antinuclear antibody 
ANCOVA 
analysis of covariance 
anti-dsDNA 
anti-double-stranded deoxyribonucleic acid 
anti-RNP 
anti-ribonucleoprotein antibodies 
anti-Sm 
anti-Smith antibodies 
anti-SSA 
anti-Sjögren’s Syndrome A antibodies 
anti-SSB 
anti-Sjögren’s Syndrome B antibodies 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BAFF 
B cell activating factor 
BICLA 
BILAG-based Combined Lupus Assessment 
BILAG 
British Isles Lupus Assessment Group 
CBC 
complete blood count 
Ceoi 
observed concentration at end of infusion 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL 
clearance 
CLASI 
Cutaneous Lupus Erythematosus Disease Area and Severity Index 
Cmax 
maximum observed concentration 
CNS 
central nervous system 
CRF 
case report form 
CT 
computed tomography 
Ctrough 
observed concentration at the end of the dosing interval 
CYP3A4 
cytochrome P450 enzyme 3A4 
ECG 
electrocardiogram 


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eGFR 
estimated glomerular filtration rate 
ERB 
Ethical Review Board 
ESR 
erythrocyte sedimentation rate 
FACIT-F 
Functional Assessment of Chronic Illness Therapy-Fatigue 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
HAQ-DI 
Health Assessment Questionnaire-Disability Index 
HbA1c 
glycosylated hemoglobin 
HIV 
human immunodeficiency virus 
HL 
Hodgkin’s lymphoma 
hpf 
high-power field 
HRT 
hormone replacement therapy 
hsCRP 
high-sensitivity C-reactive protein 
IC50 
half-maximal inhibitory concentration 
ICH 
International Council for Harmonization 
IFN 
interferon 
Ig 
immunoglobulin 
IL 
interleukin 
IND 
Investigational New Drug (application) 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
intravenous(ly) 
IWRS 
Interactive Web Response System 
JAK 
Janus kinase 
JCV 
John Cunningham virus 
LupusQoL 
Lupus Quality of Life 
MCS 
Mental Component Summary 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMAE 
monomethyl auristatin E 
NCI-CTCAE 
National Cancer Institute’s Common Terminology Criteria for Adverse 
Events 
NSAID 
nonsteroidal anti-inflammatory drug 
PCS 
Physical Component Summary 
PD 
pharmacodynamic(s) 


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P-gp 
P-glycoprotein 
PhGA 
Physician’s Global Assessment of Disease Activity 
PK 
pharmacokinetic(s) 
PML 
progressive multifocal leukoencephalopathy 
PP 
Per-Protocol 
PtGA 
Patient’s Global Assessment of Disease Activity 
PtGP 
Patient’s Global Assessment of Pain 
RBC 
red blood cell 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
sCD153 
soluble CD153 
sCD30 
soluble CD30 
SELENA 
Safety of Estrogens in Lupus Erythematosus National Assessment 
SF-36 
Short Form-36 
SJC 
swollen joint count 
SLE 
systemic lupus erythematosus 
SLEDAI 
Systemic Lupus Erythematosus Disease Activity Index 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedures 
SRI 
SLE Responder Index 
t1/2 
half-life 
TAb 
total antibodies 
Th 
T helper 
TJC 
tender joint count 
TNF 
tumor necrosis factor 
TWEAK 
cytokine TNF-like weak inducer of apoptosis 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 


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2.0 INTRODUCTION 
2.1 
Background 
Systemic lupus erythematosus (SLE) is a chronic, multisystem, disabling autoimmune 
condition, which predominantly affects women of childbearing years.  Its prevalence in the 
United States (US) is estimated to be approximately 52.2/100,000, with the highest incidence 
between 15 to 44 years of age at a female-to-male ratio as high as 12:1.1-4  Clinical 
manifestations can involve multiple organ systems, including rash and alopecia, renal 
disease, inflammatory arthritis, serositis, vasculitis, autoimmune cytopenias, cognitive 
dysfunction and other central nervous system (CNS) involvement, and constitutional 
symptoms, all leading to significant morbidity including reduced physical function, 
employment loss, lower health-related quality of life, and reduced lifespan.5-7 
Treatment options for SLE remain relatively limited.  Some, particularly milder, cases of 
SLE may respond to treatment with oral antimalarial agents such as hydroxychloroquine8,9, 
but moderate-to-severe disease, particularly involving critical systems such as renal or CNS, 
often involves immunosuppressive therapies, including oral immunosuppressants such as 
mycophenolate mofetil or azathioprine, as well as cyclophosphamide, calcineurin inhibitors, 
and B cell depleting therapy with rituximab.10  The anti-B lymphocyte stimulator therapy, 
belimumab, may be particularly helpful in patients with mucocutaneous and/or 
musculoskeletal manifestations, but the treatment effect remains relatively small.11  
Regardless of the specific therapy chosen, the majority of patients continue to require 
long-term corticosteroid therapy, resulting in long-term morbidity and mortality.6,12  Novel 
therapeutic options, therefore, are urgently needed. 
2.2 
CD30 and Systemic Lupus Erythematosus 
CD30 (TNFRSF8) is a 120kD type I membrane glycoprotein of the tumor necrosis factor 
(TNF) receptor superfamily whose expression is largely restricted to activated T, B, and NK 
cells, in contrast to its ligand CD30 ligand (TNFSF8, CD153), which is expressed on many 
hematopoietic cells, including myeloid-derived cells, megakaryocytes, and erythroid 
precursors, as well as activated T cells.  Signaling through CD30 may result in cellular 
proliferation, activation, differentiation, or apoptosis, depending on the cell type and 
biological context, influencing T cell tolerance, immune response contraction, and activation 
phenotype.13  CD30 may play a particular role in T cell costimulation, such as during the 
generation and effector phases of helper T cell function14, including T helper (Th) type 1 
(Th1), Th2, and Th17 responses, and may also play a role in effector B cell differentiation, 


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such as during the development of plasmablasts and plasma cells – all of which have been 
implicated in the pathogenesis of SLE.15-22 
Indeed, increased soluble CD30 (sCD30) levels and/or CD30+ T cells have been observed in 
SLE, correlating with disease activity as assessed by indices such as the European Consensus 
Lupus Activity Measurement.23-27  In addition, CD30 ligand directed therapy with either a 
neutralizing or neutralizing and depleting antibody against CD30 ligand has been 
demonstrated to reduce renal disease and autoantibody production in lupus-prone NZB/W F1 
mice, as well as T-dependent class-switched antibody responses.28-30  CD30 and/or CD30 
ligand expression may therefore identify a subset of pathogenic lymphocytes in SLE, and 
intervention upon the CD30 pathway and/or CD30+ cells may be of therapeutic benefit. 
2.3 
Brentuximab Vedotin 
Brentuximab vedotin is an antibody-drug conjugate (ADC) consisting of:  1) the chimeric 
immunoglobulin (Ig) G1 antibody cAC10, specific for human CD30, 2) the 
microtubule-disrupting agent monomethyl auristatin E (MMAE), and 3) a protease-cleavable 
linker that covalently attaches MMAE to cAC10.  Upon binding to the surface of 
CD30-expressince cells, the ADC-CD30 complex is internalized, leading via proteolytic 
cleavage to the release of MMAE, whose binding to tubulin disrupts the microtubule network 
within the cell.  Brentuximab vedotin has been extensively studied and used in multiple 
oncology settings, particularly relapsed or refractory Hodgkin lymphoma (HL) and systemic 
anaplastic large cell lymphoma (ALCL), where CD30 is prominently expressed, and for 
which brentuximab vedotin is currently indicated for therapeutic use in the US, Europe, and 
other countries.  In the Phase 2 (pivotal) studies, objective responses (complete or partial 
remissions) were seen in 75% of HL and 86% of ALCL.  Nearly all patients (> 90%) in both 
studies experienced a reduction in tumor volume.  Treatment-emergent adverse events (AEs) 
occurring in ≥ 20% of HL and systemic ALCL patients in the Phase 2 studies were peripheral 
sensory neuropathy (45%), fatigue (43%), nausea (41%), diarrhea (34%), pyrexia (31%), 
upper respiratory tract infection (31%), neutropenia (21%), and vomiting (20%).  These 
events were primarily Grade 1 or 2, with the exception of neutropenia, for which Grade 3 and 
4 events were reported for 13% and 7% of patients, respectively.  Similar patterns and 
incidences of AEs were generally observed for HL and ALCL patients.31 
Additional information on the nonclinical and clinical studies conducted may be found in the 
Investigator’s Brochure. 


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2.4 
Rationale for the Study 
Since CD30 and/or CD30-expressing immune cells appear to play key roles in the 
pathogenesis of SLE, brentuximab vedotin may be an efficacious therapy.  At the time of 
writing this protocol, no prior studies have formally evaluated brentuximab vedotin in 
patients with SLE.  However, prior to this study, the Sponsor received reports of several 
patients with SLE whose pre-existing autoimmune disease activity improved significantly, in 
the opinion of the treating rheumatologist, during brentuximab vedotin therapy administered 
for HL or ALCL.  Therefore, this study intends to explore the potential for brentuximab 
vedotin as a therapy for SLE. 
This first study in SLE will include patients with active disease irrespective of specific organ 
involvement, because it remains unclear if CD30-related immune functions play particular 
roles in specific end-organ manifestations.  Studies in the NZB/NZW F1 lupus-prone mouse 
model demonstrated efficacy of intervention upon CD30 ligand upon renal endpoints28-30, but 
pathogenic autoantibody production was also reduced in general.  In addition, the clinical 
anecdotes received by the Sponsor have indicated improvement in several organ systems, 
including mucocutaneous and musculoskeletal.  As such, there may be a more global, 
systemic potential for benefit.  The preliminary findings from this study may help guide 
subsequent studies, which may focus on end organ-specific manifestations, such as nephritis. 
2.5 
Discussion of Study Design and Dose Selection 
This will be a randomized, blinded, placebo-controlled, multiple-ascending-dose study of 
brentuximab vedotin in patients with SLE who have moderate to severe disease and who 
have failed at least one conventional therapy.   
A multiple-ascending-dose design has been selected because the optimal dose regimen of 
brentuximab vedotin has not been determined in patients with SLE.  The current standard 
dose regimen of brentuximab vedotin given for HL and ALCL is 1.8 mg/kg intravenously 
(IV) every 3 weeks, continued until disease progression or unacceptable toxicity.  The 
tolerability of this regimen is well-understood in the oncology population and the most 
common adverse effects warranting treatment withdrawal or dose reduction are peripheral 
sensory neuropathy (45%) and neutropenia (21%).   
However, partial and complete responses have been observed with brentuximab vedotin at 
0.6 and 1.2 mg/kg every 3 weeks, respectively, where clinically significant peripheral 
neuropathy and neutropenia were not observed.32  As such, doses of brentuximab vedotin 
lower than the current oncology dose of 1.8 mg/kg may prove efficacious in SLE, with less 
or no toxicity.  Furthermore, the risks of such complications may be lower in the SLE 


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population due to a reduced number of prior and/or ongoing myelosuppressive and/or 
neuropathic medications.  Simulations based on a population pharmacokinetics (PK) model 
developed using data from oncology patients predict that the first proposed dose level of 
0.3 mg/kg will achieve serum brentuximab vedotin ADC observed concentration at the end 
of the dosing interval (Ctrough) levels greater than the in vitro half-maximal inhibitory 
concentration (IC50) against Th1 cells with 94% probability, but is expected to achieve a 
Ctrough greater than the in vitro IC50 against Th17 cells with only 11% probability, which may 
be insufficient to induce remission consistently in SLE.  The fourth doses of 0.3, 0.6, 1.2, and 
1.8 mg/kg given every 3 weeks are expected to achieve Ctrough greater than the in vitro IC50 
against Th17 cells with 22%, 48%, 72%, and 83% probability, respectively, the latter of 
which may be sufficient, in addition to Th1 inhibition, to translate into disease remission.  
Therefore, 4 doses of up to 1.8 mg/kg may be appropriate to achieve sufficient brentuximab 
vedotin exposures in patients with SLE.  As such, this study will be the first to explore the 
effects and tolerability of escalating doses of brentuximab vedotin in SLE; it is anticipated 
that the results of this study will inform the design of a longer-term, efficacy-focused Phase 2 
study, since SLE often requires chronic, maintenance therapy.  
In oncology patients, the median time to onset of neuropathy with brentuximab vedotin was 
12.4 (HL) to 15.0 (ALCL) weeks, and the majority of neutropenia (82%) occurred within the 
first 4 treatment cycles, during a 1.8 mg/kg every 3 weeks dosing regimen.  Given this 
experience, the present study proposes to examine the tolerability of a 12-week course of 
brentuximab vedotin (4 doses when given every 3 weeks) in patients with SLE. 
Since the efficacy and tolerability of brentuximab vedotin in SLE is unknown, and many of 
the AEs observed with brentuximab vedotin in the oncology population may coincide with 
disease manifestations of SLE (eg, neuropathy or leukopenia), this study will involve a 
placebo comparator in a randomized, double-blind fashion.  The randomization scheme 
proposed is anticipated to produce a cohort of placebo-treated patients comparable in size 
with the brentuximab vedotin cohorts, analogous to previously executed studies in SLE.33-34 
2.6 
Risk Assessment 
In 2011, brentuximab vedotin (ADCETRIS®) was approved for marketing in the US for the 
treatment of patients with HL and ALCL, and in 2012, the product label was revised to 
include a Boxed Warning for progressive multifocal leukoencephalopathy (PML) and a 
contraindication for concomitant use of brentuximab vedotin and bleomycin.  The product 
label dated March 2016 may be found in Appendix 4.  Should the product label be updated 
during conduct of the current study, a revised version will be provided to the Investigators. 


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Primary safety concerns with brentuximab vedotin include peripheral neuropathy and 
neutropenia.  In the pivotal trials in HL and ALCL, neutropenia of Grade 3 or higher 
developed after a median of 2 doses administered at 1.8 mg/kg every 3 weeks, while the 
median time to Grade 3 neuropathy was 36.1 to 38.0 weeks.  Therefore, neutropenia appears 
to be a more sensitive measure of serious toxicity, and should be evident by 6 weeks in the 
majority of treated subjects. 
A Safety Monitoring Committee (SMC) will review and evaluate unblinded interim safety 
data after the final subject of each cohort has been evaluated at the Day 43 (Week 6) visit.  
Initiation of enrollment at the next dose level will only commence after endorsement of the 
SMC.  When available from each full cohort, the SMC will review all Day 85 safety data and 
may recommend that an already enrolled succeeding dose cohort be discontinued, or its 
treatment regimen truncated. 
The peripheral neuropathy associated with brentuximab vedotin is predominantly sensory; 
however, cases of peripheral motor neuropathy have also been reported.  Collective data 
suggest that peripheral neuropathy is an effect of cumulative exposure to brentuximab 
vedotin.  In the pivotal trials in HL and ALCL, neuropathy of Grade 3 or higher developed in 
13% of patients after a median of 36.1 to 38.0 weeks of brentuximab vedotin administered at 
1.8 mg/kg every 3 weeks, and resolved and/or improved after a median of 16 weeks.  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 were highest in later cycles.  Subjects 
in the current study will be limited to exposures of brentuximab vedotin < 12 weeks, but 
nonetheless will be monitored for symptoms of neuropathy, such as hypoesthesia, 
hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. 
Neutropenia was the most common hematological AE reported in the pivotal trials in HL and 
ALCL, where Grade 3 or higher neutropenia developed in 20% of patients after a median of 
2 doses administered at 1.8 mg/kg every 3 weeks, and lasted a median of 1 week.  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.  Febrile neutropenia has 
been reported with brentuximab vedotin treatment.  In the current study, subjects will be 
monitored throughout for cytopenias through routine laboratory testing.  
Some cases of PML have been reported during treatment with brentuximab vedotin in the 
oncology setting, but a causal relationship remains unclear.  As of 18 August 2014, a total of 
7 cases of PML had been reported out of 14,614 patients treated, of which 3 were confirmed 
as PML by an independent adjudication committee, 2 were confirmed as not PML, and 


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2 were unable to be adjudicated.  This corresponds to a rate (0.048%) not higher than the 
published background rate of PML in patients with lymphoproliferative disorders treated 
with chemotherapy (0.07% to 0.52%).35-37  Studies on the risk of PML with other therapies, 
specifically natalizumab, indicate that the risk of PML is primarily increased in patients 
treated continuously for prolonged periods, ie, more than 12 months38, and in subjects known 
to be seropositive for John Cunningham virus (JCV) antibody.39  The present study is limited 
to 4 doses of brentuximab vedotin administered over 12 weeks, and will test all subjects for 
JCV seropositivity at screening.  These results will be available to the Investigator and 
subject before randomization to facilitate an informed decision to proceed in the study.  
During the study, a clinical monitoring plan for PML, including neurological examinations, 
will be implemented to monitor closely for signs and symptoms suggestive of PML, which 
may include altered mental status, motor deficits such as hemiparesis or ataxia, visual 
disturbances, or higher cortical dysfunction such as dysphasia or agnosia, or seizures, which 
may occur over weeks to months. 
Other warnings and precautions for the use of brentuximab vedotin, which are pertinent to a 
population of patients with SLE, include infusion-related reactions (including anaphylaxis), 
serious and opportunistic infections, Stevens-Johnson syndrome, and embryo-fetal toxicity.  
All doses of study drug will be administered in the clinic by appropriately trained personnel 
and women who are pregnant are not allowed to participate in the study.  In this study, 
subjects will be closely monitored throughout the study for the emergence of signs or 
symptoms suggestive of infection or other conditions of concern. 


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3.0 STUDY OBJECTIVES 
3.1 
Primary Objective  
The primary objective of the study is to evaluate the safety and tolerability of brentuximab 
vedotin in adults with active SLE. 
3.2 
Secondary Objectives 
The secondary objectives of the study are: 
• 
to explore the PK and pharmacodynamics (PD) of brentuximab vedotin in adults with 
active SLE; and 
• 
to explore the efficacy of brentuximab vedotin in adults with active SLE. 


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4.0 INVESTIGATIONAL PLAN 
4.1 
Summary of Study Design 
This is a multicenter, randomized, placebo-controlled, double-blind, multiple-ascending-dose 
study to evaluate the safety and tolerability of brentuximab vedotin in subjects with active 
SLE.  Approximately 40 subjects in 4 dosing cohorts (10 subjects per cohort) are planned for 
study participation at approximately 20 study sites in the US.  Subjects who meet inclusion 
and exclusion criteria will be randomly assigned in a 4:1 ratio within each dosing cohort to 
receive IV brentuximab vedotin or placebo every 3 weeks (Days 1, 22, 43, and 64) for a total 
of 4 doses.  The following doses are planned for each ascending dose cohort: 
• 
0.3 mg/kg IV every 3 weeks for 4 doses; 
• 
0.6 mg/kg IV every 3 weeks for 4 doses; 
• 
1.2 mg/kg IV every 3 weeks for 4 doses; and 
• 
1.8 mg/kg IV every 3 weeks for 4 doses. 
There will be a total of 10 subjects in each dose cohort with 8 subjects randomly assigned to 
each of the 4 brentuximab vedotin doses and 2 subjects to placebo (for a total of 8 placebo 
subjects overall).  Initiation of enrollment at the next dose level will only commence after the 
final subject of each cohort has been evaluated at the Day 43 visit, and upon endorsement of 
the SMC following review of the safety data.  Depending on the findings, the SMC may 
recommend additional enrollment of subjects at specific dose levels to better characterize the 
safety of a particular dose, or may recommend different dose regimens based on the 
emerging safety data.  When available from each full cohort, the SMC will review all Day 85 
safety data and may recommend that an already enrolled succeeding dose cohort be 
discontinued, or its treatment regimen truncated.  Doses are not to exceed 1.8 mg/kg IV every 
3 weeks or equivalent.  Up to 20 subjects total may be enrolled via additional 
SMC-recommended cohorts for a total of up to 60 subjects. 
Assessments for safety (including PML monitoring, see Section 6.3.3), efficacy, PK, and PD 
will be performed at the times indicated in the schedule of events (see Table 3).  Following 
the last dose of study drug, there will be a 6-week observation period (through Day 106) and 
a follow-up visit will take place at Day 127.  
A flowchart of the study design is presented in Figure 1. 


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Figure 1 
Flowchart of Study Design for Protocol SGN35-022 
BV 0.3 mg/kg IV 
or Placebo (4:1)
Days 1, 22, 43, 
and 64
Screening
Days -28 to -14
BV 0.6 mg/kg IV 
or Placebo (4:1)
Days 1, 22, 43, 
and 64
BV 1.2 mg/kg IV 
or Placebo (4:1)
Days 1, 22, 43, 
and 64
BV 1.8 mg/kg IV 
or Placebo (4:1)
Days 1, 22, 43, 
and 64
6-week 
Observation
(through 
Day 106)
Follow-up
(Day 127)
SMC
SMC
SMC
Treatment Period
(Days 1 through 64)
 
BV = brentuximab vedotin; IV = intravenous; SMC = Safety Monitoring Committee. 
Randomization will occur on Day 1 prior to the first dose. 
An SMC will review and evaluate blinded interim safety data after the final subject of each cohort has been 
evaluated at the Day 43 visit.  Initiation of enrollment at the next dose level will only commence after 
endorsement of the SMC and Sponsor. 
4.2 
Discussion of Study Design 
A discussion of the study design may be found in Section 2.5. 
4.3 
Study Periods 
All study assessments will be performed at the times indicated in the Schedule of Events in 
Table 3. 
4.3.1 
Screening (Days -28 to -14) 
After providing written informed consent, subjects will be screened for study participation 
between 28 and 14 days prior to study start, to allow for results of laboratory testing to be 
available prior to study enrollment.  Subjects who fail the initial screening assessments may 
be rescreened, as judged appropriate by the Medical Monitor.  Individual assessments 
(ie, clinical laboratory tests) may be repeated within the initial screening window.  If the 


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initial screening window has passed, a full rescreening may be conducted at a later date, with 
agreement from the Medical Monitor.  Screening assessments will include the following: 
• 
review of inclusion and exclusion criteria (see Section 4.4); 
• 
demographics; 
• 
medical history; 
• 
concomitant medications, including previously failed or intolerated SLE therapy; 
• 
British Isles Lupus Assessment Group (BILAG), SLE disease activity index (SLEDAI), 
Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), swollen 
joint count (SJC)/tender joint count (TJC), Patient’s Global Assessment of Pain (PtGP), 
Patient’s Global Assessment of Disease Activity (PtGA), and Physician’s Global 
Assessment of Disease Activity (PhGA) assessments (to be performed prior to other 
study procedures);  
• 
chest x-ray or chest computed tomography (CT) (if not performed and documented 
within the last 3 months); 
• 
physical and neurological examinations; 
• 
height; 
• 
measurement of vital signs (blood pressure, pulse rate, respiratory rate, temperature, and 
weight); 
• 
clinical laboratory assessments (complete blood count [CBC] with differential, chemistry 
panel, glycosylated hemoglobin [HbA1c], B cell [CD19+] count [if applicable], 
urinalysis, viral serologies [including sample for JCV testing], tuberculosis testing, and 
serum pregnancy test for women of childbearing potential [WOCBP] only); 
• 
collection of blood samples for flow cytometry, antinuclear antibodies (ANA), 
anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibodies, autoantibody panel, 
complement studies, cytokines, and ribonucleic acid (RNA) analysis; and 
• 
recording of AEs/serious AEs (SAEs). 
4.3.2 
Treatment Period (Days 1 to 71) 
4.3.2.1 
Baseline (Day 1) 
Prior to study drug administration on Day 1, subjects will be assessed to confirm that no new 
criteria have been met since the screening visit that would exclude the subject from entering 


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the study.  Eligible subjects will be randomly assigned to treatment (see Section 5.3) and the 
following baseline assessments will be performed prior to dosing: 
• 
BILAG, SLEDAI, CLASI, SJC/TJC, PtGP, PtGA, PhGA, Health Assessment 
Questionnaire-Disability Index (HAQ-DI), Short Form-36 (SF-36), Functional 
Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and Lupus Quality of Life 
(LupusQoL) assessments (to be performed prior to other study procedures);  
• 
physical and neurological (PML assessment) examinations; 
• 
measurement of vital signs (blood pressure, pulse rate, respiratory rate, temperature, and 
weight); 
• 
clinical laboratory assessments (CBC with differential, chemistry panel, B cell [CD19+] 
count [if applicable], fasting lipid panel, urinalysis, and urine pregnancy test for WOCBP 
only); 
(Note:  The results of the CBC must be available prior to dosing and testing may be done 
by a local laboratory to facilitate availability of the results.  In addition, a separate CBC 
sample for central laboratory testing should also be collected.  Urine pregnancy testing 
will be performed locally only and results must be available prior to dosing.) 
• 
12-lead electrocardiogram (ECG);  
• 
collection of blood samples for PK analysis (predose and end of infusion) and 
antitherapeutic antibodies (predose only); 
• 
collection of blood samples for flow cytometry, inflammatory markers, ANA, anti-
dsDNA antibodies, autoantibody panel, complement studies, cytokines, and RNA 
analysis; 
• 
collection of pharmacogenetic sample (if applicable); 
• 
optional lymph node or tonsil biopsy; and 
• 
recording of AEs/SAEs and concomitant medication use. 
Following completion of predose procedures, subjects will receive either brentuximab 
vedotin or matching placebo as an IV infusion over approximately 30 minutes.  Blood 
samples for PK analysis will be collected prior to and at the end of the infusion; samples for 
antitherapeutic antibodies will be collected prior to dosing only. 


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4.3.2.2 
Treatment 
4.3.2.2.1 
Days 2 and 3 
On Days 2 and 3, blood samples for PK analysis, flow cytometry, anti-dsDNA antibodies, 
and RNA analysis will be collected.  Adverse events and concomitant medication use will be 
recorded. 
4.3.2.2.2 
Day 8 (±1 day) 
On Day 8 (±1 day), blood samples for PK analysis, flow cytometry, inflammatory markers, 
anti-dsDNA antibodies, complement studies, cytokines, and RNA analysis will be collected.   
In addition, blood samples for clinical laboratory assessments (CBC with differential and 
chemistry panel) will be collected.  Adverse events and concomitant medication use will be 
recorded. 
4.3.2.2.3 
Day 15 (±2 days) 
On Day 15 (±2 days), blood samples for PK analysis, flow cytometry, inflammatory markers, 
anti-dsDNA antibodies, complement studies, and RNA analysis will be collected.  In 
addition, blood samples for clinical laboratory assessments (CBC with differential and 
chemistry panel) will be collected.  Adverse events and concomitant medication use will be 
recorded. 
4.3.2.2.4 
Day 22 (±2 days) 
On Day 22 (±2 days) prior to study drug administration, the following assessments will be 
performed: 
• 
BILAG, SLEDAI, CLASI, SJC/TJC, PtGP, PtGA, and PhGA assessments;  
• 
physical and neurological (PML assessment) examinations; 
• 
measurement of vital signs (blood pressure, pulse rate, respiratory rate, temperature, and 
weight); 
• 
clinical laboratory assessments (CBC with differential, chemistry panel, fasting lipid 
panel, urinalysis, and urine pregnancy test for WOCBP only); 
(Note:  The results of the CBC must be available prior to dosing and testing may be done 
by a local laboratory to facilitate availability of the results.  In addition, a separate CBC 
sample for central laboratory testing should also be collected.  Urine pregnancy testing 
will be performed locally only and results must be available prior to dosing.) 


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• 
collection of blood samples for PK analysis (predose and end of infusion) and 
antitherapeutic antibodies (predose only); 
• 
collection of blood samples for flow cytometry, inflammatory markers, ANA, 
anti-dsDNA antibodies, complement studies, cytokines, direct Coombs test, and RNA 
analysis; and 
• 
recording of AEs/SAEs and concomitant medication use. 
Following completion of predose procedures, subjects will receive either brentuximab 
vedotin or matching placebo as an IV infusion over approximately 30 minutes.  Blood 
samples for PK analysis will be collected prior to and at the end of the infusion; samples for 
antitherapeutic antibodies will be collected prior to dosing only. 
4.3.2.2.5 
Day 29 (±2 days) 
Approximately 1 week following the administration of study drug (Day 29 ±2 days), blood 
samples for clinical laboratory assessments (CBC with differential and chemistry panel) will 
be collected. 
4.3.2.2.6 
Day 43 (±2 days) 
On Day 43 (±2 days) prior to study drug administration, the following assessments will be 
performed: 
• 
BILAG, SLEDAI, CLASI, SJC/TJC, PtGP, PtGA, PhGA, HAQ-DI, SF-36, FACIT-F, 
and LupusQoL assessments;  
• 
physical and neurological (PML assessment) examinations; 
• 
measurement of vital signs (blood pressure, pulse rate, respiratory rate, temperature, and 
weight); 
• 
clinical laboratory assessments (CBC with differential, chemistry panel, fasting lipid 
panel, urinalysis, and urine pregnancy test for WOCBP only); 
(Note:  The results of the CBC must be available prior to dosing and testing may be done 
by a local laboratory to facilitate availability of the results.  In addition, a separate CBC 
sample for central laboratory testing should also be collected.  Urine pregnancy testing 
will be performed locally only and results must be available prior to dosing.) 
• 
ECG; 
• 
collection of blood samples for PK analysis (predose and end of infusion) and 
antitherapeutic antibodies (predose only); 


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• 
collection of blood samples for flow cytometry, inflammatory markers, ANA, 
anti-dsDNA antibodies, autoantibody panel, complement studies, and RNA analysis; and 
• 
recording of AEs/SAEs and concomitant medication use. 
Following completion of predose procedures, subjects will receive either brentuximab 
vedotin or matching placebo as an IV infusion over approximately 30 minutes.  Blood 
samples for PK analysis will be collected prior to and at the end of the infusion; samples for 
antitherapeutic antibodies will be collected prior to dosing only. 
4.3.2.2.7 
Day 50 (±2 days) 
Approximately 1 week following the administration of study drug (Day 50 ±2 days), blood 
samples for clinical laboratory assessments (CBC with differential and chemistry panel) will 
be collected. 
4.3.2.2.8 
Day 64 (±2 days) 
On Day 64 (±2 days) prior to study drug administration, the following assessments will be 
performed: 
• 
BILAG, SLEDAI, CLASI, SJC/TJC, PtGP, PtGA, and PhGA assessments;  
• 
physical and neurological (PML assessment) examinations; 
• 
measurement of vital signs (blood pressure, pulse rate, respiratory rate, temperature, and 
weight); 
• 
clinical laboratory assessments (CBC with differential, chemistry panel, fasting lipid 
panel, urinalysis, and urine pregnancy test for WOCBP only); 
(Note:  The results of the CBC must be available prior to dosing and testing may be done 
by a local laboratory to facilitate availability of the results.  In addition, a separate CBC 
sample for central laboratory testing should also be collected.  Urine pregnancy testing 
will be performed locally only and results must be available prior to dosing.) 
• 
collection of blood samples for PK analysis (predose and end of infusion) and 
antitherapeutic antibodies (predose only); 
• 
collection of blood samples for flow cytometry, inflammatory markers, ANA, 
anti-dsDNA antibodies, complement studies, cytokines, direct Coombs test, and RNA 
analysis; and 
• 
recording of AEs/SAEs and concomitant medication use. 


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Following completion of predose procedures, subjects will receive either brentuximab 
vedotin or matching placebo as an IV infusion over approximately 30 minutes.  Blood 
samples for PK analysis will be collected prior to and at the end of the infusion; samples for 
antitherapeutic antibodies will be collected prior to dosing only. 
4.3.2.2.9 
Day 71 (±2 days) 
Approximately 1 week following the administration of study drug (Day 71 ±2 days), blood 
samples for clinical laboratory assessments (CBC with differential and chemistry panel) will 
be collected. 
4.3.2.3 
Observation 
4.3.2.3.1 
Day 85 (±2 days) 
On Day 85 (±2 days), the following assessments will be performed: 
• 
BILAG, SLEDAI, CLASI, SJC/TJC, PtGP, PtGA, PhGA, HAQ-DI, SF-36, FACIT-F, 
and LupusQoL assessments;  
• 
physical and neurological (PML assessment) examinations; 
• 
measurement of vital signs (blood pressure, pulse rate, respiratory rate, temperature, and 
weight); 
• 
clinical laboratory assessments (CBC with differential, chemistry panel, fasting lipid 
panel, urinalysis, and urine pregnancy test for WOCBP only); 
• 
ECG; 
• 
collection of blood samples for PK analysis and antitherapeutic antibodies; 
• 
collection of blood samples for flow cytometry, inflammatory markers, ANA, 
anti-dsDNA antibodies, autoantibody panel, complement studies, cytokines, and RNA 
analysis; 
• 
optional lymph node or tonsil biopsy; and 
• 
recording of AEs/SAEs and concomitant medication use. 
4.3.2.3.2 
Day 106 (±2 days) 
On Day 106 (±2 days), the following assessments will be performed: 
• 
BILAG, SLEDAI, CLASI, SJC/TJC, PtGP, PtGA, and PhGA assessments;  
• 
physical and neurological (PML assessment) examination; 


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• 
measurement of vital signs (blood pressure, pulse rate, respiratory rate, temperature, and 
weight); 
• 
clinical laboratory assessments (CBC with differential, chemistry panel, fasting lipid 
panel, and urinalysis); 
• 
collection of blood samples for PK analysis and antitherapeutic antibodies; 
• 
collection of blood samples for flow cytometry, inflammatory markers, ANA, 
anti-dsDNA antibodies, complement studies, direct Coombs test, and RNA analysis; and 
• 
recording of AEs/SAEs and concomitant medication use. 
4.3.3 
Follow-up or Early Discontinuation (±7 days) 
The final study visit will be conducted 3 weeks (Day 127 ±7 days) following the last 
observation visit or at early study termination.  The following assessments will be performed: 
• 
BILAG, SLEDAI, CLASI, SJC/TJC, PtGP, PtGA, PhGA, HAQ-DI, SF-36, FACIT-F, 
and LupusQoL assessments;  
• 
physical and neurological (PML assessment) examinations; 
• 
measurement of vital signs (blood pressure, pulse rate, respiratory rate, temperature, and 
weight); 
• 
clinical laboratory assessments (CBC with differential, HbA1c, chemistry panel, and 
urinalysis); 
• 
collection of blood samples for PK analysis and antitherapeutic antibodies; 
• 
collection of blood samples for flow cytometry, inflammatory markers, ANA, 
anti-dsDNA antibodies, autoantibody panel, complement studies, cytokines, and RNA 
analysis; and 
• 
recording of AEs/SAEs and concomitant medication use. 
4.4 
Selection of Study Population 
4.4.1 
Inclusion Criteria 
Subjects may be entered in the study only if they meet all of the following criteria: 
1. Subject is able to provide written, informed consent. 


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2. Subject is an adult, aged ≥ 18 years. 
3. Women of childbearing potential or male subjects with a WOCBP partner, will use 
2 forms of highly-effective contraception method during the study through 6 months 
following the last dose of study drug.  Women of childbearing potential includes any 
female who has experienced menarche and who has not undergone successful surgical 
sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not 
postmenopausal.  Postmenopausal is defined as amenorrhea ≥ 12 consecutive months 
without another cause, or documented follicle-stimulating hormone level > 35 mIU/mL 
for women with irregular menstrual periods and on hormone replacement therapy (HRT).  
Acceptable forms of effective contraception include:  established use of oral, injected, or 
implanted hormonal methods of contraception; placement of an intrauterine device or 
intrauterine system; barrier methods of contraception (condom or occlusive cap) with 
spermicidal foam/gel/film/cream/suppository; male sterilization; and true abstinence.  
Women of childbearing potential taking concomitant mycophenolate and oral 
contraceptives must use a barrier method of contraception along with their oral 
contraceptives. 
4. If subject is a WOCBP, a serum pregnancy test result at screening and urine pregnancy 
test result at baseline must be negative. 
5. Subjects must have a documented diagnosis of SLE for at least 6 months prior to 
screening according to both of the following: 
a. 
fulfills at least 4 of 11 of the 1997 Update of the 1982 American College of 
Rheumatology (ACR) Revised Criteria for Classification of SLE; and 
b. 
has a history of positive ANA (≥ 1:80) or anti-dsDNA (≥ 30 IU/mL) test prior to 
screening.  
6. Subjects must have a positive ANA (≥ 1:80) or anti-dsDNA (≥ 30 IU/mL) test at 
screening (a single rescreening of previously positive subjects who were negative at 
screening will be allowed). 
7. Subjects must demonstrate active SLE as indicated by a SLEDAI score ≥ 4 points at 
screening and at baseline. 
8. Subject has failed (defined as inadequate response, such as worsening or continued 
disease activity while on treatment) at least one of the following treatments for SLE after 
a trial of at least 3 months: 


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a. 
mycophenolate mofetil or mycophenolic acid, azathioprine, methotrexate, 
leflunomide, 6-mercaptopurine, calcineurin inhibitors, cyclophosphamide; 
b. 
belimumab, other B cell activating factor (BAFF) pathway antagonists, or abatacept; 
or 
c. 
antimalarials, such as hydroxychloroquine, in combination with prednisone of at 
least 10 mg/day or equivalent. 
9. If taking the following medications, the subject must be on a stable dose prior to the 
baseline visit for at least the durations indicated and be willing and able to continue at 
stable doses throughout the study, unless otherwise allowed by this protocol: 
a. 
corticosteroids (up to 40 mg/day prednisone or equivalent):  4 weeks; 
b. 
hydroxychloroquine or other antimalarials:  3 months;  
c. 
mycophenolate mofetil or mycophenolic acid, azathioprine, methotrexate, 
leflunomide, or 6-mercaptopurine:  3 months; or 
d. 
nonsteroidal anti-inflammatory drugs (NSAIDS) or COX-2 inhibitors at or below the 
maximum approved dose:  2 weeks. 
4.4.2 
Exclusion Criteria 
Subjects will not be entered in the study for any of the following reasons: 
1. The subject has any serious health condition, which, in the opinion of the Investigator, 
would place the subject at undue risk from the study, including: 
a. uncompensated congestive heart failure (New York Heart Association Class III or 
IV); 
b. clinically significant active cardiac disease (eg, unstable angina or acute myocardial 
infarction within 3 months); 
c. recently active cerebrovascular disease (eg, stroke or transient ischemic attack within 
3 months); 
d. uncontrolled hypertension, unless attributable to SLE disease activity; 
e. uncontrolled diabetes; 


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f. pancreatitis within the past 14 days prior to screening, unless attributable to SLE 
disease activity; if recent pancreatitis, must have normal amylase and lipase for 
7 days prior to screening; 
g. known clinically significant immunodeficiency; 
h. substance abuse, such as alcoholism or drug abuse;  
i. history of a known peripheral neuropathy, such as mononeuritis multiplex, acute or 
chronic inflammatory demyelinating polyneuropathy, axonal sensorimotor 
neuropathies, drug-related neuropathy or neuritis, or diabetic neuropathy; 
2. Subject has had recent serious or ongoing infection, or risk for serious infection, 
including: 
a. active or latent tuberculosis, as suggested by chest x-ray or CT scan within the 
3 months prior to screening and/or QuantiFERON-TB Gold/tuberculin purified 
protein derivative testing at screening (subjects with a history of latent tuberculosis 
with documented completed treatment by a Centers for Disease Control-
recommended regimen are allowed); 
b. known history of chronic hepatitis B or hepatitis C, as suggested by serological 
testing; 
c. seropositivity for human immunodeficiency virus (HIV); 
d. history of PML; 
e. use of antibiotics within 2 weeks of baseline; or 
f. live vaccinations within 8 weeks of baseline. 
3. Subject has screening laboratory abnormalities of any of the following criteria: 
a. hemoglobin < 10.0 g/dL; 
b. absolute neutrophil count < 1500/µL (< 1.5 ×109/L); 
c. platelet count < 100,000/µL (< 100 ×109/L); 
d. alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5x upper 
limit of normal (ULN); 
e. serum total bilirubin > 1.5x ULN, or > 3x ULN for patients with Gilbert’s syndrome; 


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f. serum creatinine > 1.5x ULN or estimated glomerular filtration rate (eGFR) 
< 60 mL/min/1.73m2; or 
g. serum amylase or lipase > 1.5x ULN. 
4. Subject has a history of new or recurrent malignancy within the past 5 years, except basal 
cell carcinoma of the skin, squamous cell skin cancer, or in situ carcinoma that has been 
adequately treated with no evidence of recurrent disease for 12 months. 
5. The subject is pregnant and/or breastfeeding. 
6. The subject is unable or unwilling to complete the study protocol. 
7. The subject fulfills diagnostic criteria for another rheumatic (overlap) disease that may 
confound clinical assessments in the study.  Secondary sicca or Sjögren’s syndrome, 
antiphospholipid antibody syndrome, and overlap with rheumatoid arthritis (“rhupus”) 
are allowed. 
8. The subject is receiving treatment with any of the following within the timeframes 
indicated before baseline, if not otherwise previously dosed longer term according to 
Inclusion Criterion 9: 
a. corticosteroids:  2 weeks; 
b. cyclosporin, tacrolimus, methotrexate, leflunomide, azathioprine, 6-mercaptopurine, 
cyclophosphamide, tofacitinib, or other Janus kinase (JAK) inhibitors:  4 weeks; 
c. biologic therapies, including belimumab, abatacept, interleukin (IL)-6, and TNF-α 
(eg, infliximab, adalimumab, certolizumab pegol, or golimumab) antagonists:  
8 weeks; 
d. rituximab or other B cell depleting therapies:  6 months (subjects who have been 
exposed to B cell depleting therapies must have a normal peripheral B cell count at 
baseline, if not demonstrated before); or 
e. other drugs or biologics, including investigational products:  8 weeks or 5 half-lives, 
whichever is longer. 
9. The subject has urgent, severe SLE disease activity, which, in the opinion of the 
Investigator, warrants immediate immunosuppressive therapy and would not be 
appropriate for the study (eg, severely active neuropsychiatric SLE warranting immediate 
pulse corticosteroids and/or immunosuppressants such as cyclophosphamide, which 
makes the possibility of receiving placebo an inappropriate risk). 


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10. The subject has ongoing participation in another therapeutic clinical trial. 
11. The subject has a known hypersensitivity to brentuximab vedotin, component thereof, or 
excipient contained in the drug formulation. 
4.4.3 
Disease Diagnostic Criteria 
For participation in the study, subjects must: 
• 
have a documented diagnosis of SLE for at least 6 months prior to screening according 
Inclusion Criterion 5; 
• 
must demonstrate active SLE at screening and at baseline, as indicated in Inclusion 
Criterion 7; and 
• 
have failed at least one of the treatments for SLE as listed in Inclusion Criterion 8. 
4.4.4 
Subject Withdrawal 
All subjects are free to withdraw from participation in the study at any time, for any reason, 
specified or unspecified, and without prejudice to further treatment.  The criteria for 
enrollment are to be followed explicitly.  If a subject who does not meet enrollment criteria is 
inadvertently enrolled, that subject should be withdrawn from the study, and the Sponsor and 
Quintiles must be contacted.   
In addition, subjects will be withdrawn from study drug and from the study in the following 
circumstances: 
• 
The Investigator decides that the subject should be withdrawn.  If this decision is made 
because of an intolerable AE or a clinically significant laboratory value, the study drug is 
to be discontinued and appropriate measures are to be taken.  The Sponsor and Quintiles 
are to be notified immediately.   
• 
The subject experiences a clinically significant worsening of SLE warranting a 
significant change in therapy according to the Investigator.  The Sponsor and Quintiles 
are to be notified immediately. 
• 
The subject experiences signs or symptoms suggestive of PML. 
• 
The subject experiences any Grade 3 or higher infection. 
• 
The subject experiences any Grade 3 (according to the National Cancer Institute’s 
Common Terminology Criteria for Adverse Events [NCI-CTCAE]) or higher neutropenia 
(ie, absolute neutrophil count < 1.0 ×109/L), thrombocytopenia (ie, platelet count 


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< 50 ×109/L), anemia (ie, hemoglobin < 8.0 g/dL or transfusion indicated), or liver 
function test abnormal (ie, ALT or AST > 5x ULN) that does not correct to Grade 1 or 
better before the next scheduled dose of brentuximab vedotin. 
• 
The subject experiences any Grade 3 or higher neuropathy.  Dosing will be withheld for 
any subject who experiences Grade 2 neuropathy, but decisions to resume dosing will be 
made on a case-by-case basis in consultation with the Medical Monitor (see Section 5.1). 
• 
The subject has missed more than 1 dose. 
• 
The subject is unwilling to continue in the study.  
• 
The subject exhibits a lack of compliance with protocol. 
• 
The Investigator or the Sponsor, for any reason, stops the study.  
Subjects who discontinue the study early will have early termination procedures performed 
as shown in the schedule of events (Table 3).  Subjects who are withdrawn from the study 
will not be replaced. 
4.5 
Safety Monitoring Committee 
An SMC consisting of Sponsor representatives as well as members independent from the 
Sponsor will be established.  The membership should include at least 1 Sponsor 
representative, 1 member independent from the Sponsor, and 1 rheumatologist.  The SMC 
will review and evaluate the blinded interim safety data after the final subject of each cohort 
has been evaluated at the Day 43 visit.  Initiation of enrollment at the next dose level will 
only commence after endorsement of the SMC and Sponsor.  In addition, the SMC will 
review neurological AEs and other safety events during the study as considered necessary.  
When available from each full cohort, the SMC will review all Day 85 safety data and may 
recommend that an already enrolled succeeding dose cohort be discontinued, or its treatment 
regimen truncated. 
The SMC will be responsible for making recommendations as to whether it is scientifically 
and ethically appropriate to continue enrollment, discontinue treatment groups, or 
discontinue the study.  Only the SMC is authorized to evaluate unblinded interim efficacy 
and safety analyses prior to the completion of each dosing cohort, if appropriate.  Study sites 
will receive information about interim results ONLY if they need to know for the safety of 
their subjects. 


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Details of the SMC and interim analyses will be documented in an SMC charter and SMC 
analysis plan.  All Investigators and subjects will remain blinded to the original treatment 
assignments before final database lock. 


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5.0 STUDY TREATMENTS 
5.1 
Treatments Administered 
Eligible subjects will receive 4 doses of either brentuximab vedotin 0.3, 0.6, 1.2, or 
1.8 mg/kg IV or matching placebo, given every 3 weeks (Days 1, 22, 43, and 64) during the 
treatment period.   
Individual doses are based on subject weight (see Section 5.5) and will be administered as an 
IV infusion over approximately 30 minutes.  The study drug cannot be mixed with other 
medications. 
Dose reductions are not permitted; however, dosing will be withheld if a subject experiences 
Grade 2 neuropathy.  Resumption of dosing will be decided on a case-by-case basis by the 
Medical Monitor.  Subjects who experience Grade 3 or higher neuropathy or who miss more 
than a single dose will be withdrawn from the study (see Section 4.4.4). 
Further instructions on the dose preparation and administration will be provided in the 
Pharmacy Manual. 
5.2 
Identity of Investigational Product 
Study drug will be provided by the Sponsor in individual kits containing four 50-mg vials.  
Each vial of active study drug contains 55 mg for injection (brentuximab vedotin), trehalose, 
sodium citrate, and polysorbate 80.  The 5-mg overfill in each vial is to ensure that the 
labeled quantity of 50 mg may be withdrawn.  Vials containing placebo are identical in 
appearance.  The vials will be reconstituted with the appropriate amount of Sterile Water for 
Injection.  The pH of reconstituted product is approximately 6.6.  Vials and reconstituted 
study drug should be stored at 2° to 8°C.  Brentuximab vedotin does not contain 
preservatives; therefore, opened and reconstituted vials of brentuximab vedotin should be 
used as soon as possible.  If not used immediately, the in-use storage should not be longer 
than 24 hours.  It is recommended that brentuximab vedotin vials and solutions be protected 
from direct sunlight until time of use.  Reconstituted vials and solutions must not be shaken. 
Additional information on the storage, handling, and destruction of study drug will be 
provided in the Pharmacy Manual. 


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5.3 
Method of Assigning Subjects to Treatment Group 
Once the subject meets inclusion and exclusion criteria and has provided written informed 
consent, the study site will request the study medication assignment using the Interactive 
Web Response System (IWRS). 
A total of 10 subjects in each dose cohort will be randomly assigned in a 4:1 ratio, resulting 
in 8 subjects assigned to each of the 4 brentuximab vedotin dose cohorts and a total of 
8 subjects assigned to placebo (2 per cohort).   
To randomly assign a subject to treatment, the study site will use the internet to access the 
IWRS.  Subjects will be assigned their 6-digit subject number, starting with a 3-digit site 
number followed by a hyphen and a 3-digit sequential number (eg, 101-001).  The IWRS will 
provide the study drug kit number(s) of the blinded study drug to be dispensed.   
5.4 
Selection of Doses in the Study 
The doses selected for administration in this study are at or below those used for the standard 
regimen of brentuximab vedotin when given for HL and ALCL.  See Section 2.5 for 
additional discussion of the dose selection. 
5.5 
Selection and Timing of Dose for Each Subject 
Dosing is based on subject weight at baseline; however, doses will be adjusted for subjects 
who experience a ≥ 10% change in weight from baseline.  Actual weights will be used except 
for subjects weighing > 100 kg; the dose for these subjects will be calculated based on 100 
kg.  Rounding is permissible within 5% of the nominal dose. 
Subjects will receive 4 doses of study drug (either brentuximab vedotin or placebo according 
to the randomized treatment) given 3 weeks apart during the treatment period (Days 1, 22, 
43, and 64). 
5.6 
Blinding 
This is a randomized, double-blind, placebo-controlled study with limited access to the 
randomization code.  Brentuximab vedotin and placebo solutions for IV administration will 
be identical in physical appearance.  The treatment each subject will receive during the 
treatment period will not be disclosed to the Investigator, study site personnel, subject, 
Sponsor, or Quintiles.  Upon request, treatment assignments will be revealed to the 
Investigators when the clinical study report is final.  The SMC will review and evaluate 
blinded interim safety data after the final subject of each cohort has been evaluated at the 


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Day 43 visit.  The data for a given cohort may be unblinded for preliminary data analyses 
after completion of all subjects for the cohort (Day 85 and/or Day 127). 
The process for breaking the blind will be handled through the IWRS.  Investigators are 
strongly discouraged from requesting the blind be broken for an individual subject, unless 
there is a subject safety issue that requires unblinding and would change subject 
management.  Any site that breaks the blind under inappropriate circumstances may be asked 
to discontinue its participation in the study.  If the blind is broken, it may be broken for only 
the subject in question and the subject must be withdrawn from the study.  
The Sponsor and Quintiles must be notified immediately if a subject and/or Investigator is 
unblinded during the course of the study.  Pertinent information regarding the circumstances 
of unblinding of a subject’s treatment code must be documented in the subject’s source 
documents and case report forms (CRFs). 
5.7 
Prior and Concomitant Treatments 
A concomitant treatment is any drug or substance administered from the time of the subject’s 
written informed consent until the subject’s last study visit, including over-the-counter 
medications, herbal medications, vitamins, NSAIDS, and mineral supplements.  The use of 
all concomitant treatments during the study, including the start and stop dates, must be 
recorded on the subject’s CRF, according to instructions for CRF completion.   
If there are changes to a concomitant medication or if the subject requires concomitant 
therapy for an AE, it must be reported on the appropriate CRF page and in the source medical 
records. 
Previously failed or intolerated treatments for SLE will be recorded in the subject’s CRF as a 
prior medication. 
5.7.1 
Excluded Medications 
Treatment with any of the following within the timeframes indicated before baseline (if not 
otherwise previously dosed longer term according to Section 5.7.2) are not allowed: 
• 
colchicine or corticosteroids:  2 weeks; 
• 
cyclosporin, tacrolimus, methotrexate, leflunomide, azathioprine, 6-mercaptopurine, 
cyclophosphamide, tofacitinib, or other JAK inhibitors:  4 weeks; 
• 
biologic therapies, including belimumab, abatacept, IL-6, and TNF-α (eg, infliximab, 
adalimumab, certolizumab pegol, or golimumab) antagonists:  8 weeks; 


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• 
rituximab or other B cell depleting therapies:  6 months (subjects who have been exposed 
to B cell depleting therapies must have a normal peripheral B cell count at baseline, if not 
demonstrated before);  
• 
other drugs or biologics, including investigational products:  8 weeks or 5 half-lives, 
whichever is longer; 
• 
antibiotics:  2 weeks; or 
• 
live vaccinations:  8 weeks. 
Concomitant use of brentuximab vedotin and bleomycin is contraindicated due to pulmonary 
toxicity (see Appendix 4); therefore, the administration of bleomycin is not allowed during 
this study. 
5.7.2 
Allowed Medications 
If taking the following medications, the subject must be on a stable dose prior to the baseline 
visit for at least the durations indicated and be willing and able to continue at stable doses 
throughout the study: 
• 
corticosteroids (up to 40 mg/day prednisone or equivalent):  4 weeks; 
• 
hydroxychloroquine or other antimalarials:  3 months;  
• 
mycophenolate mofetil, mycophenolic acid, azathioprine, methotrexate, leflunomide, or 
6-mercaptopurine:  3 months;  
• 
NSAIDS and COX-2 inhibitors at or below the maximum approved dose:  2 weeks; or 
• 
Oral, injected, or implanted hormonal methods of contraception, as well as HRT:  
3 months. 
Temporary increases in corticosteroid dosage (“bursts”) are permissible during the study as 
follows. 
• 
The maximum duration of a burst is limited to 14 days duration on no more than 
2 occasions. 
• 
The corticosteroid dose must return to the preburst dose or lower at least 1 week before 
the 12-week assessments. 
• 
The maximum dosage during a burst is up to 0.5 mg/kg prednisone, or equivalent, 
including any other steroids being given. 


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• 
The specific dose and taper schedule is at the discretion of the Investigator. 
No increases in corticosteroid dosage outside of bursts are permitted.  Decreases in the 
maintenance corticosteroid dose are allowed. 
MMAE is primarily metabolized by cytochrome P450 enzyme 3A4 (CYP3A4), and is a 
substrate of P-glycoprotein (P-gp).  Caution should be used in co-administering drugs which 
strongly inhibit CYP3A4 or P-gp, since increased MMAE exposures may result. 
Required Premedication and Postmedication 
Medication should not be administered for the prevention of infusion-related reactions prior 
to the first dose of brentuximab vedotin.  However, subjects who experience a Grade 1 or 
Grade 2 infusion-related reaction may receive subsequent brentuximab vedotin infusions 
with premedication as described in Section 6.3.2.  
5.8 
Treatment Compliance  
All doses of study drug (including placebo) will be administered in the clinic under the 
supervision of the Investigator or designee and recorded in the CRFs.  Therefore, no 
assessment of treatment compliance is planned. 
The prescribed dosage, timing, and mode of administration may not be changed.  Any 
departures from the intended regimen must be recorded in the CRFs.  
5.9 
Study Drug Accountability 
The Investigator, a member of the study site staff, or a hospital pharmacist must maintain an 
adequate record of the receipt and distribution of all study drug using the Drug 
Accountability Form.  These forms must be available for inspection at any time. 


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6.0 EFFICACY, SAFETY, PHARMACOKINETICS, AND 
PHARMACODYNAMICS 
6.1 
Schedule of Events 
A schedule of events is presented in Table 3. 
6.2 
Efficacy Measures 
6.2.1 
Response Assessments 
The following response assessments will be performed at the time points indicated in the 
schedule of events (Table 3): 
• 
BILAG 2004; 
• 
SLEDAI-2K; 
• 
CLASI40; 
• 
SJC – 66 joints; 
• 
TJC – 68 joints; 
• 
PtGP; 
• 
PtGA; 
• 
PhGA; 
• 
HAQ-DI; 
• 
SF-36; 
• 
FACIT-F; 
• 
LupusQoL; and 
• 
high-sensitivity C-reactive protein (hsCRP) and erythrocyte sedimentation rate (ESR). 
Details of these scales and assessments will be provided in the study reference manual. 


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6.2.2 
Response Definitions 
The following definitions will be used to evaluate the response assessments. 
• 
BILAG Clinical Response is defined as (must meet both criteria): 
− BILAG C scores or better in all organ domains; and  
− no new BILAG A or B scores in any organ domain. 
• 
Systemic Lupus Erythematosus Responder Index (SRI) definition of response 
includes: 
− reduction in Safety of Estrogens in Lupus Erythematosus National Assessment 
(SELENA)-SLEDAI of at least 4 points; 
− no new BILAG A organ domain scores and no more than 1 new BILAG B score; and 
− no worsening (increase of < 0.3) in PhGA versus baseline. 
• 
BILAG-based Combined Lupus Assessment (BICLA) definition of response includes: 
− BILAG-2004 improvement (all A scores at baseline improved to B/C/D, and all 
B scores improved to C or D); 
− no worsening in disease activity (no new BILAG-2004 A scores and ≤ 1 new 
B score); 
− no worsening of total SLEDAI-2K score from baseline; 
− no significant deterioration (< 10% worsening) in 100 mm visual analogue PhGA; 
and 
− no treatment failure (defined as nonprotocol treatment [ie, new or increased 
immunosuppressives or antimalarials or increased or parenteral corticosteroids] or 
premature discontinuation from study treatment). 
• 
Active renal disease is defined as either: 
− both of urinary protein:creatinine ratio ≥ 0.5 and active urinary sediment as defined 
by at least one of the following (in the absence of urinary tract infection): 
o more than 5 red blood cells (RBCs)/high power field (hpf) (or above the reference 
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o  more than 5 white blood cells (WBCs)/hpf (or above the reference range for the 
laboratory), or 
o presence of cellular casts (RBC or WBC); or 
− isolated severe proteinuria without active sediment (eg, ≥ 3.5 grams/day or 
equivalent). 
• 
SELENA SLE flare definitions include: 
− SELENA mild/moderate flare: 
o a change in SLEDAI ≥ 3 points,  
o new/worse skin, stomatitis, serositis, arthritis, or fever,  
o increased prednisone < 0.5 mg/kg/day,  
o added NSAID/hydroxychloroquine, or 
o ≥ 1.0 increase in PhGA (on a 0 to 3 scale); 
− SELENA severe flare: 
o change in SLEDAI > 12,  
o new/worse CNS-SLE, vasculitis, nephritis, myositis, platelet count < 60,000/µL, 
hemolytic anemia with hemoglobin < 7 mg/dL, requiring doubling or 
> 0.5 mg/kg/day prednisone, 
o hospitalization for SLE,  
o prednisone > 0.5 mg/kg/day,  
o new immunosuppressive, or 
o increased PhGA to > 2.5. 
• 
BILAG SLE flare definitions include: 
− BILAG flare: 
o development of any new BILAG A domain score, or 
o ≥ 2 new BILAG B domain scores; 
− BILAG severe flare:  development of any new BILAG A domain score. 


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• 
Renal flare is defined as any of these 3 events: 
− increased proteinuria, as defined by: 
o a urinary protein:creatinine ratio > 0.5, provided the 24-hour urine protein (if 
done) contains a total of at least 500 mg of protein, OR 
o a reproducible increase in 24-hour urine protein levels to:  
− > 1,000 mg if the baseline value was < 200 mg,  
− > 2,000 mg if the baseline value was between 200 and 1,000 mg, or  
− more than twice the value at baseline if the baseline value was > 1,000; 
− impaired renal function, as defined by a reproducible decrease in eGFR of > 20%, 
accompanied by proteinuria (> 1,000 mg/24 hours), hematuria (≥ 4 RBCs/hpf or 
above the reference range for the laboratory), and/or cellular (RBC and WBC) casts; 
or 
− new hematuria, as defined by a new, reproducible hematuria (≥ 11 to 20 RBCs/hpf) or 
a reproducible increase in hematuria by 2 grades compared with baseline, associated 
with > 25% dysmorphic RBCs, glomerular in origin, exclusive of menses, 
accompanied by either an 800 mg increase in 24-hour urinary protein levels or new 
RBC casts. 
6.2.3 
Efficacy Endpoints 
6.2.3.1 
Primary  
Not applicable to this study. 
6.2.3.2 
Secondary 
The secondary endpoint is the proportion of subjects achieving an SRI response at Day 85. 
6.2.3.3 
Exploratory 
Exploratory efficacy outcomes include the following: 
• 
proportion of subjects achieving a BICLA response at Day 85; 
• 
proportion of subjects achieving a BILAG clinical response at Day 85  
• 
proportion of subjects achieving a BILAG partial clinical response at Day 85, defined as 
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• 
proportion of subjects achieving a BILAG partial clinical response at Day 85, defined as 
a maximum of 1 BILAG B score or better; 
• 
proportion of subjects achieving a SLEDAI clinical response at Day 85, defined by a ≥ 4 
point improvement from baseline; 
• 
proportion of subjects achieving organ-specific BILAG clinical response and partial 
clinical responses at Day 85 as determined by organ domain-specific scores; 
• 
proportion of subjects achieving 20%, 50%, 70%, and n% (ACR20, ACR50, ACR70, and 
ACRn, respectively) improvement in SJC and TJC at Days 22, 43, 64, 85, 106, and 127; 
• 
mean and median of observed and percentage change from baseline in SLEDAI, CLASI, 
TJC, SJC, PtGP, PtGA, PhGA, hsCRP, and ESR at Days 22, 43, 64, 85, 106, and 127; 
• 
mean and median of observed and percentage change from baseline in organ domain-
specific SLEDAI scores at Days 22, 43, 64, 85, 106, and 127; 
• 
mean and median of observed and percentage change from baseline in HAQ-DI, SF-36, 
SF-36 Physical Component Summary (PCS), SF-36 Mental Component Summary 
(MCS), and FACIT-F at Days 43, 85, and 127; 
• 
mean and median of observed and percentage change from baseline in urinary sediment 
(cellular casts, pyuria, hematuria), proteinuria (protein/creatinine ratio), and eGFR at 
Days 22, 43, 64, 85, 106, and 127; and 
• 
mean and median of observed and percentage change from baseline in urinary sediment 
(cellular casts, pyuria, hematuria), proteinuria (protein/creatinine ratio), and eGFR at 
Days 22, 43, 64, 85, 106, and 127 in subjects with active renal disease at baseline. 
Additional possible exploratory efficacy outcomes include the following: 
• 
median time to treatment failure as defined by: 
− death or need for additional immunosuppressive therapy, or 
− death, end-stage renal disease, doubling of serum creatinine, or SLE or renal flare; 
• 
incidence at Days 22, 43, 64, 85, 106, and 127 of SLE flares using the SELENA and 
BILAG definitions; 
• 
median time to first mild/moderate and severe SLE flares using SELENA and BILAG 
definitions; 
• 
incidence at Days 22, 43, 64, 85, 106, and 127 of renal flares; 


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• 
median time to first renal flare; 
• 
mean and median of observed and percentage change from Day 85 in SLEDAI, CLASI, 
TJC, SJC, PtGP, PtGA, PhGA, hsCRP, and ESR to Days 106 and 127; 
• 
mean and median of observed and percentage change from Day 85 in HAQ-DI, SF-36, 
SF-36 PCS, SF-36 MCS, and FACIT-F to Day 127; 
• 
mean and median of observed and percentage change from Day 85 in urinary sediment 
(cellular casts, pyuria, hematuria), proteinuria (protein/creatinine ratio), and eGFR to 
Days 106 and 127; and 
• 
mean and median of observed and percentage change from Day 85 in urinary sediment 
(cellular casts, pyuria, hematuria), proteinuria (protein/creatinine ratio), and eGFR to 
Days 106 and 127 in subjects with active renal disease at baseline. 
6.3 
Safety Assessments  
The assessment of safety during the course of this study will consist of the surveillance and 
recording of AEs, including SAEs; recording of concomitant medications; physical and 
neurological examination findings; ECG recordings; and measurements of vital signs and 
protocol-specified laboratory tests.  In addition, subjects will be closely monitored for signs 
and symptoms suggestive of neuropathy or PML.   
6.3.1 
Adverse Events 
6.3.1.1 
Definitions 
Adverse Event 
According to the International Council for Harmonization (ICH) E2A guideline Definitions 
and Standards for Expedited Reporting, and 21 Code of Federal Regulations (CFR) 312.32, 
Investigational New Drug (IND) Safety Reporting, an AE is any untoward medical 
occurrence in a patient or clinical investigational subject administered a medicinal product 
and which does not necessarily have a causal relationship with this treatment. 
The following information should be considered when determining whether or not to record a 
test result, medical condition, or other incident on the Adverse Events and Pre-existing 
Conditions CRF. 
• 
All AEs and SAEs, including AEs of special interest (eg, new-onset neuropathy or 
suspected cases of PML), that occur from the time of informed consent through the 
follow-up visit should be recorded. 


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• 
Changes in medical conditions and AEs, including changes in severity, frequency, or 
character, during the safety reporting period should be recorded. 
• 
In general, an abnormal laboratory value should not be recorded as an AE unless it is 
associated with clinical signs or symptoms, requires an intervention, results in an SAE, or 
results in study termination or interruption/discontinuation of study treatment.  When 
recording an AE resulting from a laboratory abnormality, the resulting medical condition 
rather than the abnormality itself should be recorded (eg, record “anemia” rather than 
“low hemoglobin”). 
Adverse Events of Special Interest 
For this study, AEs of special interest include any treatment-emergent neuropathy and 
suspected cases of PML (see Section 6.3.1.3 for reporting of AEs).  These events will be 
followed until significant changes return to baseline, the event stabilizes or is no longer 
considered clinically significant by the Investigator, the subject dies or withdraws consent, or 
the study is closed.   
Subjects who experience a Grade 2 neuropathy will have dosing withheld (see Section 5.1); 
subjects with Grade 3 or higher neuropathy will be withdrawn from the study (see 
Section 4.4.4). 
See Section 6.3.3 for additional information on PML monitoring and Section 6.3.2 for 
management of infusion reactions. 
Serious Adverse Event 
An AE should be classified as an SAE if it meets one of the following criteria: 
• 
Fatal: 
The AE resulted in death. 
• 
Life-threatening: 
The AEs placed the subject at immediate risk of death.  This 
classification does not apply to an AE that hypothetically might 
cause death if it were more severe. 
• 
Hospitalization: 
The AE required or prolonged an existing inpatient 
hospitalization.  Hospitalizations for elective medical or surgical 
procedures or treatments planned before the signing of informed 
consent in the study or routine check-ups are not SAEs by this 
criterion.  Admission to a palliative unit or hospice care facility is 
not considered to be a hospitalization.  Hospitalizations or 
prolonged hospitalizations for scheduled therapy of the 


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underlying study target disease need not be captured as SAEs. 
• 
Disabling/ 
incapacitating: 
The AE resulted in a persistent or significant incapacity or 
substantial disruption of the subject’s ability to conduct normal 
life functions. 
• 
Congenital anomaly 
or birth defect: 
The AE was an adverse outcome in a child or fetus of a subject 
exposed to the molecule or study treatment regimen before 
conception or during pregnancy. 
• 
Medically significant: The AE did not meet any of the above criteria, but could have 
jeopardized the subject and might have required medical or 
surgical intervention to prevent one of the outcomes listed above 
or involves suspected transmission via a medicinal product of an 
infectious agent. 
 
Adverse Event Severity 
Adverse event severity should be graded using the NCI-CTCAE, version 4.03.  These criteria 
will be provided in the study manual. 
The AE severity and seriousness are assessed independently.  ‘Severity’ characterizes the 
intensity of an AE.  ‘Serious’ is a regulatory definition and serves as a guide to the Sponsor 
for defining regulatory reporting obligations (see definition for Serious Adverse Event). 
Relationship of the Adverse Event to Study Treatment 
The relationship of each AE to brentuximab vedotin should be evaluated by the Investigator 
using the following criteria: 
• 
Related: 
There is evidence to suggest a causal relationship between the study drug 
and the AE, such as: 
− 
an event that is uncommon and known to be strongly associated with 
drug exposure (eg, angioedema, hepatic injury, or Stevens-Johnson 
syndrome); or 
− 
an event that is not commonly associated with study drug exposure, 
but is otherwise uncommon in the population exposed to the drug (eg, 
tendon rupture). 
• 
Unrelated: 
Another cause of the AE is more plausible (eg, due to underlying disease 


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or occurs commonly in the study population), or a temporal sequence 
cannot be established with the onset of the AE and administration of the 
study drug, or a causal relationship is considered biologically implausible. 
 
6.3.1.2 
Procedures for Eliciting and Recording Adverse Events 
Investigator and study personnel will report all AEs and SAEs whether elicited during 
subject questioning, discovered during physical examination, laboratory testing, and/or other 
means by recording them on the CRF and/or SAE Form, as appropriate. 
Eliciting Adverse Events 
An open-ended or nondirected method of questioning should be used at each study visit to 
elicit the reporting of AEs. 
Recording Adverse Events 
The following information should be recorded on the Adverse Events and Pre-existing 
Conditions CRF: 
• 
description, including onset and resolution dates; 
• 
whether it met serious criteria; 
• 
severity; 
• 
relationship to study treatment or other causality; and 
• 
outcome. 
Diagnosis Versus Signs or Symptoms 
In general, the use of a unifying diagnosis is preferred to the listing out of individual 
symptoms.  Grouping of symptoms into a diagnosis should only be done if each component 
sign and/or symptom is a medically confirmed component of a diagnosis as evidenced by 
standard medical textbooks.  If any aspect of a sign or symptom does not fit into a classic 
pattern of the diagnosis, report the individual symptom as a separate AE. 
Important exceptions for this study are adverse reactions associated with the infusion of 
study drug.  For infusion-related reactions, do not use the NCI-CTCAE terms of ‘cytokine 
release syndrome,’ ‘acute infusion reaction,’ or ‘allergic or hypersensitivity reaction.’  
Instead, record each sign or symptom as an individual AE.  If multiple signs or symptoms 


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occur with a given infusion-related event, each sign or symptom should be recorded 
separately with its level of severity. 
Recording Serious Adverse Events 
For SAEs, record the event(s) on both the CRF and the SAE Form. 
The following should be considered when recording SAEs: 
• 
Death is an outcome of an event.  The event that resulted in the death should be recorded 
and reported on both an SAE Form and CRF. 
• 
For hospitalizations, surgical, or diagnostic procedures, the illness leading to the surgical 
or diagnostic procedure should be recorded as the SAE, not the procedure itself.  The 
procedure should be captured in the narrative as part of the action taken in response to the 
illness. 
Pregnancy 
Notification to Drug Safety:  Complete a Pregnancy Report Form for all pregnancies that 
occur from the time of first study drug dose until 6 months after the last dose of study 
drug(s), including any pregnancies that occur in the partner of a male study subject.  Only 
report pregnancies that occur in a male subject’s partner if the estimated date of conception is 
after the male subject’s first study drug dose.  Fax to the Sponsor’s Drug Safety Department 
within 48 hours of becoming aware of a pregnancy.  All pregnancies will be monitored for 
the full duration; all perinatal and neonatal outcomes should be reported.  Infants should be 
followed for a minimum of 8 weeks. 
Collection of data on the CRF:   All pregnancies (as described above) that occur within 
28 days of the last dose of study drug(s), will also be recorded on the Adverse Events and 
Pre-existing Conditions CRF. 
Abortion, whether accidental, therapeutic, or spontaneous, should be reported as an SAE.  
Congenital anomalies or birth defects, as defined by the ‘serious’ criterion above (see 
definitions in Section 6.3.1.1) should be reported as SAEs. 
6.3.1.3 
Reporting Periods for Adverse Events and Serious Adverse Events 
The safety reporting period for all AEs and SAEs is from date of consent through the 
follow-up visit.  All SAEs that occur after the safety reporting period and are considered 
study treatment-related in the opinion of the Investigator should also be reported to the 
Sponsor.  In addition, new-onset neuropathy, suspected PML, or other AEs/SAEs of interest 
will be reported until the end of the follow-up period. 


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Serious AEs will be followed until significant changes return to baseline, the event stabilizes 
(recovering/resolving) or is no longer considered clinically significant by the Investigator, or 
the subject dies or withdraws consent.  All nonserious AEs will be followed through the 
safety reporting period.  Certain nonserious AEs of special interest may be followed until 
resolution, return to baseline, the event stabilizes or is no longer considered clinically 
significant by the Investigator, the subject dies or withdraws consent, or study closure. 
6.3.1.4 
Serious Adverse Events Require Immediate Reporting 
Within 24 hours of observing or learning of an SAE or suspected case of PML, Investigators 
are to report the event to the Sponsor at the fax number below, regardless of the relationship 
of the event to the study treatment regimen. 
SAE Fax: 
+1 (425) 527-4308 
For initial SAE reports, available case details are to be recorded on an SAE Form.  At a 
minimum, the following should be included: 
• 
subject number; 
• 
date of event onset; 
• 
description of the event; and 
• 
study treatment, if known. 
The completed SAE Form and SAE Fax Cover Sheet are to be faxed to the Sponsor’s Drug 
Safety Department within 24 hours (see fax number above and as specified on the SAE 
report form). 
Relevant follow-up information is to be submitted to the Sponsor as soon as it becomes 
available. 
6.3.1.5 
Emergency Medical Contacts 
To ensure the safety of study subjects, an Emergency Medical Call Center Help Desk will 
access the Quintiles Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the Investigator with a Quintiles Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  A primary global contact number and 
additional back up number for the Help Desk and Medical Monitor contact information will 
be distributed to all Investigators. 


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Primary: 
 
Secondary: 
 
6.3.1.6 
Sponsor Safety Reporting to Regulatory Authorities 
Investigators are required to report all SAEs, including anticipated SAEs, to the Sponsor (see 
Section 6.3.1.4). 
The Sponsor will report all SAEs to regulatory authorities as required per local regulatory 
reporting requirements.   
6.3.2 
Management of Infusion Reactions 
Infusion-related reactions may occur during the infusion of study treatment.  The infusion 
should be administered at a site properly equipped and staffed to manage anaphylaxis should 
it occur.  All supportive measures consistent with optimal subject care should be given 
throughout the study according to institutional standards.  Supportive measures may include 
administering medications for infusion-related reactions. 
Subjects who have experienced a Grade 1 or Grade 2 infusion-related reaction should be 
premedicated for subsequent infusions.  Premedication may include acetaminophen and an 
antihistamine administered 30 to 60 minutes prior to each brentuximab vedotin infusion or 
according to institutional standards. 
If anaphylaxis occurs, brentuximab vedotin administration should be immediately and 
permanently discontinued. 
6.3.3 
Progressive Multifocal Leukoencephalopathy Assessment 
Study site personnel and subjects will be educated regarding the signs and symptoms of 
PML.  Close monitoring during the course of the study for any new symptoms or signs 
suggestive of PML will be performed, with regular neurologic examinations (including 
evaluation of cranial nerves, motor and sensory function, coordination, and mental status).  
The PML assessment will be conducted by a qualified individual and will be performed at 
screening and as indicated on the schedule of events (see Table 3).   
If a subject has a positive finding on the PML assessment or if there is strong clinical 
suspicion for PML, the event should be expeditiously reported as an AE of special interest 
within 24 hours (see Section 6.3.1.4).  If PML is suspected, dosing with study drug for that 
subject will be suspended and the subject should be promptly referred to a neurologist.  
Following formal evaluation by a neurologist, further work up will include brain magnetic 
resonance imaging performed with and without contrast.  If PML cannot be ruled out, a 


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lumbar puncture with cerebrospinal fluid analysis for JCV by polymerase chain reaction may 
be performed.  If JCV is detected, the subject should be treated as a PML case, permanently 
discontinue study drug, and transfer to safety follow-up.  Dosing with study drug can only be 
resumed in subjects where PML has been ruled out.   
6.3.4 
Anaphylaxis 
Anaphylaxis will be defined by the criteria discussed in the statement paper from the Second 
Symposium on the Definition and Management of Anaphylaxis41 and reproduced in Table 1. 
Table 1 
Clinical Criteria for Diagnosing Anaphylaxis 
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, 
or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING 
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia) 
b. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], 
syncope, incontinence) 
2.  Two or more of the following that occur rapidly after exposure to a likely allergen for that patient 
(minutes to several hours): 
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-tongue-
uvula) 
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia) 
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence) 
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours): 
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in systolic 
BP* 
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s 
baseline 
BP = blood pressure; PEF = peak expiratory flow. 
* 
Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 1 year, less than 
(70 mm Hg + [2 × age]) from 1 to 10 years, and less than 90 mm Hg from 11 to 17 years. 
 
6.3.5 
Clinical Laboratory Evaluations 
Samples will be drawn for both central and local laboratories.  Local laboratory testing will 
include institutional standard tests for evaluating safety and making clinical decisions. 


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The following laboratory assessments will be performed by the central laboratory (unless 
otherwise specified) to evaluate safety at scheduled time points (see Table 3) during the 
course of the study: 
• 
CBC with differential:  hemoglobin, hematocrit, RBC count, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, red 
cell distribution width, WBC count with 5-part differential (neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils), and platelet count; 
Note:  The results of the CBC must be available prior to administration of each dose; 
therefore, testing at these time points may be done by a local laboratory to facilitate 
availability of the results.  In addition, separate CBC samples at all specified time points 
should be collected for central laboratory testing.   
• 
B cell count as quantified by CD19+ cells on flow cytometry, if applicable (for subjects 
with prior B cell depletion therapy, see Table 3); 
• 
HbA1c; 
• 
chemistry panel:  sodium, potassium, chloride, bicarbonate, blood urea nitrogen, 
creatinine, uric acid, albumin, eGFR, glucose, total bilirubin, direct bilirubin, AST, ALT, 
alkaline phosphatase, lactate dehydrogenase, amylase, lipase, and creatine 
phosphokinase; 
• 
eight-hour fasting lipid panel:  total cholesterol, triglycerides, high-density lipoprotein, 
and low-density lipoprotein; 
• 
urinalysis:  dipstick urinalysis, spot urinary protein and creatinine, and microscopic 
examination of the urinary sediment; and 
• 
pregnancy test for WOCBP (Note:  testing will be performed locally only and results will 
be available prior to dosing). 
In addition, viral serology (HIV, hepatitis B surface antigen, anti-hepatitis B surface 
antibody, anti-hepatitis B core antibody, hepatitis C, and JCV) and tuberculosis 
(QuantiFERON-TB Gold or tuberculin purified protein derivative) tests will be performed at 
screening only.   
Clinical laboratory tests will be reviewed for results of potential clinical significance at all 
time points throughout the study.  The Investigator will evaluate any change in laboratory 
values.  If the Investigator determines a laboratory abnormality to be clinically significant, it 
is considered a laboratory AE; however, if the laboratory value abnormality is consistent with 
a current diagnosis, it may be documented accordingly. 


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6.3.6 
Vital Signs, Physical Findings, and Other Safety Assessments 
Measurement of vital signs, physical examinations, and 12-lead ECG recordings will be 
performed at the time points indicated in the schedule of events (see Table 3) and recorded in 
the subject’s medical records and CRF.  New or worsened abnormalities from baseline 
should be reported as AEs, as appropriate. 
Vital signs will include systolic and diastolic blood pressure, pulse rate, respiratory rate, and 
temperature after the subject has been seated for 5 minutes.  Weight in kilograms will be 
measured in indoor clothing without shoes; height in centimeters is measured at screening 
only. 
Complete physical examinations should include, but are not limited to, an assessment of 
head, eye, ear, nose, and throat, and cardiovascular, respiratory, gastrointestinal, 
musculoskeletal, dermatological, and neurological systems.  See Section 6.3.3 for additional 
information on PML monitoring and neurological examinations. 
Standard 12-lead ECGs will be recorded after the subject has rested in a supine position for at 
least 10 minutes and should be obtained from the same machine whenever possible.  The 
Investigator or designee should review, sign, and date the ECG tracings.  Paper copies will be 
filed in the subject’s records at the site. 
6.4 
Pharmacokinetic Measurements  
6.4.1 
Plasma Concentrations 
Sensitive, qualified assays will be used to measure drug analytes, including brentuximab 
vedotin (ADC), total antibody (TAb), and MMAE concentrations in serum or plasma.  These 
assays will include enzyme-linked immunosorbent assays and liquid chromatography/tandem 
mass spectrometry assays, as well as other assays if further characterization is required. 
Samples for PK analysis will be collected within 30 minutes prior to study drug 
administration and at the end of infusion (within 5 minutes) on study drug administration 
days (Days 1, 22, 43, and 64).  Samples will also be collected between the first and second 
doses on Days 2, 3, 8, and 15 at approximately the same time of day as the end-of-infusion 
sample on Day 1, if possible.  Additional samples will be collected any time on the day of 
collection during the observation period (Days 85 and 106) and at the follow-up visit on 
Day 127.   
Up to approximately 700 mL of whole blood will be obtained from each subject for PK, PD, 
and safety assessments during the study. 


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The following information will be captured for blood sample collection in each subject’s 
CRF: 
1. subject’s number and initial; 
2. time and date of dose administration; and 
3. time and date of each blood sample collected for PK analysis. 
Please refer to the Laboratory Manual for sample collection and storage procedures. 
6.4.2 
Antitherapeutic Antibodies 
Serum samples will be collected for the detection and characterization of antibodies against 
brentuximab vedotin in all subjects at the time points indicated in the schedule of events (see 
Table 3).  Samples will be analyzed using validated assays.   
6.5 
Pharmacodynamic Measures 
Pharmacodynamic assessments will be performed as specified in the schedule of events 
(Table 3) and include the following: 
• 
flow cytometry for specific lymphocyte populations that may include, but are not limited 
to, the following: 
− naïve T, TEM, TCM: CD4, CD30, CD45RA, CD153, CD3, CD197, and CD8; 
− Treg/Th1/Th2/Th17: CD4, CD30, CD127, CD183, CD153, CD25, CD3, CD196, 
CD8, and CD194; 
− naïve B, plasmablasts, plasma cells, memory B: CD19, CD30, CD38, IgD, CD153, 
CD10, CD27, CD138, and CD20;  
− macrophages, NK cells DCs: CD30/CD19, CD30, HLA-DR, CD16, CD153, CD11c, 
CD7, CD123, CD56, and CD14; and 
• 
inflammatory markers, including:  ESR, hsCRP, sCD30, and soluble CD153 (sCD153); 
• 
autoantibody assays including, but not limited to: 
− ANA, as assessed by indirect immunofluorescence titer; 
− anti-dsDNA; 
− anti-C1q; 


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− anti-Smith antibodies (anti-Sm), anti-ribonucleoprotein (anti-RNP), anti-Sjögren’s 
Syndrome A antibodies (anti-SSA), and anti-Sjögren’s Syndrome B antibodies (anti-
SSB); 
− anticardiolipin, anti-β-2-glycoprotein I, lupus anticoagulant; 
− direct Coombs test; and 
− quantitative IgG, IgM, IgA, and IgE; 
• 
complement studies:  C1q, C3, C4, and CH50; 
• 
lymph node or tonsil biopsies (optional): 
− T cell subpopulations such as, but not limited to: 
o CD4+ and CD4+CD30+, and subpopulations of each, such as: CD25+ or Foxp3+, 
interferon (IFN)γ+ or CXCR3+, IL-4+ or CCR4+, and IL-17+ or CCR7+; 
o CD8+ and CD8+CD30+; 
− B cell subpopulations such as, but not limited to, naïve and memory, plasmablasts and 
plasma cells; and 
− germinal center structure. 
In addition, a serum sample will be collected for possible future testing of SLE-related 
cytokines, such as, but not necessarily limited to, IFN-α, BAFF, and cytokine TNF-like weak 
inducer of apoptosis (TWEAK). 
Also, RNA sampling as specified in the schedule of events (Table 3) will consist of retention 
of a peripheral blood RNA sample for possible future testing of genome-wide SLE-related 
inflammatory gene expression patterns, such as via microarray or RNA-seq. 
6.6 
Pharmacogenetic Sampling 
For subjects who provide additional consent, a de-identified blood sample will be collected at 
baseline for potential future research. 
6.7 
Appropriateness of Measurements 
All efficacy, safety, PK, and PD assessments used in this study are widely used and generally 
recognized as reliable, accurate, and relevant. 


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7.0 QUALITY CONTROL AND QUALITY ASSURANCE 
According to the Guidelines of Good Clinical Practice (GCP) (CPMP/ICH/135/95), the 
Sponsor is responsible for implementing and maintaining quality assurance and quality 
control systems with written Standard Operating Procedures (SOPs).  
Quality control will be applied to each stage of data handling.  
The following steps will be taken to ensure the accuracy, consistency, completeness, and 
reliability of the data: 
• 
Investigator meeting(s); 
• 
central laboratories for clinical laboratory parameters and ECGs; 
• 
site initiation visit; 
• 
early site visits post enrollment; 
• 
routine site monitoring; 
• 
ongoing site communication and training; 
• 
data management quality control checks; 
• 
continuous data acquisition and cleaning; 
• 
internal review of data; and 
• 
quality control check of the final clinical study report. 
In addition, the Sponsor and/or Quintiles Clinical Quality Assurance Department may 
conduct periodic audits of the study processes including, but not limited to, study site, site 
visits, central laboratories, vendors, clinical database, and final clinical study report.  When 
audits are conducted, access must be authorized for all study-related documents including 
medical history and concomitant medication documentation to authorized Sponsor’s 
representatives and regulatory authorities. 
7.1 
Monitoring 
The Sponsor has engaged the services of a contract research organization, Quintiles, to 
perform all monitoring functions within this clinical study.  Quintiles’ monitors will work in 
accordance with Sponsor or Quintiles’ SOPs and have the same rights and responsibilities as 


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monitors from the Sponsor organization.  Monitors will establish and maintain regular 
contact between the Investigator and the Sponsor. 
Monitors will evaluate the competence of each study site, informing the Sponsor about any 
problems relating to facilities, technical equipment, or medical staff.  During the study, 
monitors will check that written informed consent has been obtained from all subjects 
correctly and that data are recorded correctly and completely.  Monitors are also entitled to 
compare entries in CRFs with corresponding source data and to inform the Investigator of 
any errors or omissions.  Monitors will also control adherence to the protocol at the study 
site.  They will arrange for the supply of study drug and ensure appropriate storage 
conditions are maintained. 
Monitoring visits will be conducted according to the United States CFR Title 21 parts 50, 56, 
and 312 and ICH Guideline for GCP.  Monitoring visits will be made to each site while 
subjects are enrolled in the study.  The monitor will make written reports to the Sponsor on 
each occasion contact with the Investigator is made, regardless of whether it is by phone or in 
person. 
During monitoring visits, entries in the CRFs will be compared with the original source 
documents (source data verification).  For all items, this check will be 100%. 
7.2 
Data Management/Coding 
Data generated within this clinical study will be handled according to the relevant SOPs of 
the data management and biostatistics departments of Quintiles.  The data will be inspected 
for inconsistencies by performing validation checks. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Concomitant medications will be coded using the World Health Organization 
(WHO) drug dictionary.  Concomitant diseases will be coded using MedDRA. 
7.3 
Quality Assurance Audit 
Study sites, the study database, and study documentation may be subject to a Quality 
Assurance audit during the course of the study by the Sponsor or Quintiles on behalf of the 
Sponsor.  In addition, inspections may be conducted by regulatory bodies at their discretion.  


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8.0 STATISTICS 
8.1 
Determination of Sample Size 
Since no prior studies in SLE have been conducted with brentuximab vedotin, the primary 
objective of this study is to evaluate the safety and tolerability of brentuximab vedotin in this 
patient population.  As such, the number of subjects planned has been based on clinical 
judgment, to provide sufficient experience upon which to design a larger efficacy (Phase 2) 
study.  Study measurements of efficacy, safety, PK, and PD will be listed and summarized by 
dose and treatment group.  Comparisons between brentuximab vedotin-treated subjects and 
placebo-treated controls will be performed, where applicable. 
8.2 
Statistical Methods 
Data will be analyzed by Quintiles Inc. biostatistical staff.   All details regarding the 
statistical analysis and the preparation of tables, listings, and figures will be described in the 
Statistical Analysis Plan prepared by Quintiles and approved by the Sponsor before database 
lock.  
Summaries for safety and efficacy data collected will be presented for each treatment group, 
ie, for brentuximab vedotin 0.3, 0.6, 1.2, or 1.8 mg/kg IV every 3 weeks and placebo at each 
scheduled visit/assessment.  Placebo subjects across cohorts will be aggregated for analysis.  
Subjects will be evaluated according to the treatment received. 
For qualitative parameters, the population size (N for sample size and n for available data) 
and the percentage (of available data) for each class of parameters will be presented.  
Quantitative parameters will be summarized by the population size (N for sample size and n 
for available data), the mean, the standard deviation, the median, 25th percentile, 
75th percentile, the minimum, and the maximum values.  Geometric means and coefficients 
of variation will be included as deemed relevant. 
A nominal significance level of 5% will be used for exploratory inference testing. 
8.2.1 
Analysis Populations 
Assignment of subjects into the Safety, Per-Protocol (PP), Intent-to-Treat (ITT), and 
Pharmacokinetic Populations will be conducted prior to the database lock.  
Full Analysis Set (FAS):  The FAS (ITT Population) includes all randomized subjects.  
Subjects will be analyzed according to the treatment assigned. 


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Per-Protocol:  The PP Population includes all randomized subjects who have received at 
least 1 dose of study drug, have both the baseline and Day 85 SRI and have no protocol 
violations.  Subjects will be analyzed according to the actual treatment received.   
Safety:  The Safety Population includes all subjects who received at least 1 dose of study 
drug. 
Pharmacokinetic:  The Pharmacokinetic Population will include all subjects who 
received at least 1 dose of brentuximab vedotin and for whom at least 1 plasma or serum 
sample was obtained for PK analysis. 
Analyses of secondary efficacy endpoints will be performed on the ITT Population.  
Supportive analyses may be repeated using the PP Population.  The PD endpoints (see 
Section 6.2.3 for a description of the endpoints) may be analyzed using the ITT population 
only.  All safety analyses will be based on the Safety Population.  All PK analyses will be 
based on the Pharmacokinetic Population. 
8.2.2 
Missing Data 
No imputation will be performed on any missing assessments. 
8.3 
Subject Disposition 
The numbers of subjects who receive each treatment and the duration of exposure will be 
summarized for the Safety Population. 
Prior and concomitant therapies will be listed.  The frequency and percentage of subjects 
who used prior or concomitant medication will be summarized by Anatomic, Therapeutic, 
and Chemical classification (WHO Drug) and treatment.  Concomitant medications will also 
be checked for protocol deviations. 
Subjects who took prohibited concomitant medications will be noted in the summary of 
protocol deviations. 
8.4 
Subject Characteristics 
Subject demographics will include (but are not limited to) age, sex, race, ethnicity, height, 
weight, and body mass index.  
Continuous variables will be presented with mean, median, 25th percentile, 75th percentile, 
standard deviation, minimum, maximum, and (if appropriate) the number of nonmissing 
observations. 


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Categorical data will be displayed via absolute and relative frequencies for each category 
(including a category labeled as ‘missing’ when appropriate). 
Furthermore, all protocol deviations will be summarized with the number (%) of subjects by 
deviation and listed by subject. 
8.5 
Efficacy Analyses 
8.5.1 
Primary Analyses 
Not applicable to this study. 
8.5.2 
Secondary Analyses 
The number and percentage of subjects achieving SRI response will be presented with 95% 
exact binomial confidence intervals (CIs).  Comparisons between the active treatments and 
placebo will be performed through a Fisher’s exact test.  The nominal p-value and 95% CI 
for the treatment effect will be presented. 
8.5.3 
Exploratory Efficacy Endpoints 
For each continuous endpoint based on change from baseline, descriptive statistics (number, 
mean, median, standard deviation, minimum, maximum, and 95% CI) will be generated for 
each treatment group. 
The difference in the changes from baseline between the active and placebo treatments will 
be tested using an analysis of covariance (ANCOVA) model controlling for baseline.  The 
treatment effect will be estimated by the difference in least-squares means (brentuximab 
vedotin at each dose level and overall minus placebo) from the ANCOVA model described 
above.  If the assumptions underlying the ANCOVA model are not met, then a nonparametric 
ANCOVA or a Wilcoxon Mann-Whitney test will be performed as a supplemental analysis 
of the parametric ANCOVA model.  The nominal p-value and 95% CI for the treatment 
effect will be presented. 
For each binary endpoint based on proportion, the number of subjects as well as the 
percentage within each group will be presented.  Comparisons between treatments will be 
performed through a Fisher’s exact test. 
8.5.4 
Subgroup Analysis 
Given the small sample size in this study, no subgroup analyses will be performed. 


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8.6 
Safety 
The assessment of safety will be based on the analyses of AEs, vital signs, physical 
examinations, ECGs, and clinical laboratory evaluations.   
8.6.1 
Adverse Events 
Adverse events will be coded using the MedDRA dictionary and will be summarized by 
presenting the number and percentage of subjects having any AE, having an AE in each 
system organ class, and having each individual AE as reported by preferred term.  
Furthermore, a summary for SAEs and summaries by severity (according to the 
NCI-CTCAE, version 4.03) and relationship to study drug will be presented.  Most frequent 
AEs and drug-related AEs will also be provided.  In addition, AEs of special interest will be 
summarized. 
All percentages will be based on the number of patients in the Safety Population. 
In the summaries, AEs will be counted only once per subject.  If a subject reports the same 
AE more than once, it will be counted with its worst severity and closest relationship to study 
drug.  Only those AEs that began between start and end of the study will be summarized.  
Adverse events will also be listed by subject and treatment. 
Subject death due to any cause and subjects with AEs leading to study drug discontinuation 
will be listed and summarized. 
The proportion of subjects who discontinue study drug or dose interruption due to AEs will 
be summarized by treatment. 
8.6.2 
Clinical Laboratory Tests 
Proportions of subjects who develop laboratory abnormalities of interest will be summarized 
by treatment. 
Summary statistics over time will be presented for the continuous laboratory parameters.  
Descriptive statistics of changes from baseline by study visits will also be presented. 
A frequency table of results of categorical laboratory parameters will be produced.  
Furthermore, laboratory abnormalities will be analyzed by shift tables where each subject 
will be counted only once with the worst grade in the summary tables.  
All laboratory data will be listed with abnormal values flagged. 


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8.6.3 
Vital Signs, Physical Findings, and Other Safety Evaluations 
Observed and change-from-baseline vital signs will be listed and summarized over time by 
treatment.  Changes from baseline will also be summarized.  Notable values and changes will 
be tabulated. 
Electrocardiogram evaluations will be summarized by treatment and visit.  
Descriptive statistics (n, mean, standard deviation, median, minimum, and maximum values) 
of the continuous ECG parameters will be presented by treatment group and overall at each 
assessment visit for the raw data and change from baseline data.  Frequency counts will be 
presented per treatment for both change and absolute values. 
Individual listings presenting subjects with flags will be created for both change and absolute 
values. 
Physical and neurological examination findings will be displayed in a descriptive manner for 
each subject. 
8.7 
Pharmacokinetic Analyses 
Pharmacokinetic endpoints include the following (when determinable): 
• 
PK parameters for brentuximab vedotin (ADC), eg, maximum observed concentration 
(Cmax) (concentration at the end of infusion [Ceoi]), area under the concentration-time 
curve (AUC), clearance (CL), and half-life (t1/2);  
• 
PK parameters for TAb, eg, Cmax (Ceoi), AUC, CL, and t1/2;  
• 
PK parameters for MMAE, eg, Cmax, AUC, and t1/2; and 
• 
the incidence of antitherapeutic antibodies. 
8.8 
Pharmacodynamic Analyses 
Observed, change from baseline, and percentage change from baseline for all PD assessments 
will be listed and summarized over time by treatment.  Corresponding figures for summary 
measures over time will be presented as relevant. 
The incidence of positivity for the following will also be summarized: ANA, anti-dsDNA, 
anti-Sm, anti-RNP, anti-SSA, anti-SSB, anticardiolipin, anti-β-2-glycoprotein I, lupus 
anticoagulant, anti-C1q, and direct Coombs test. 


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8.9 
Interim Analyses 
An SMC will review and evaluate blinded interim safety data after the final subject of each 
cohort has been evaluated at the Day 43 visit (see Section 4.5).  The data from a given cohort 
may be unblinded for preliminary data analyses after completion of all subjects for the cohort 
(Day 85 and/or Day 127). 


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9.0 ETHICS 
9.1 
Institutional Review Board or Independent Ethics Committee 
The Investigator will provide the Sponsor or Quintiles with documentation of Institutional 
Review Board (IRB)/Ethical Review Board (ERB) approval of the protocol and informed 
consent before the study may begin at the study sites.  The Investigator will supply 
documentation to the Sponsor or Quintiles of required IRB/ERB’s annual renewal of the 
protocol, and any approvals of revisions to the informed consent document or amendments to 
the protocol.  
The Investigator will report promptly to the IRB/ERB, any new information that may 
adversely affect the safety of subjects or the conduct of the study.  Similarly, the Investigator 
will submit written summaries of the study status to the IRB/ERB annually, or more 
frequently if requested by the IRB/ERB.  Upon completion of the study, the Investigator will 
provide the ethics committee with a brief report of the outcome of the study, if required. 
9.2 
Ethical Conduct of the Study 
This study will be conducted and the informed consent will be obtained according to the 
ethical principles stated in the Declaration of Helsinki (2013), the applicable guidelines for 
GCP, or the applicable drug and data protection laws and regulations of the countries where 
the study will be conducted. 
9.3 
Subject Information and Informed Consent 
The informed consent form will be used to explain the risks and benefits of study 
participation to the subject in simple terms before the subject will be entered into the study.  
The informed consent form contains a statement that the consent is freely given, that the 
subject is aware of the risks and benefits of entering the study, and that the subject is free to 
withdraw from the study at any time.  Written consent must be given by the subject and/or 
legal representative, after the receipt of detailed information on the study. 
The Investigator is responsible for ensuring that informed consent is obtained from each 
subject or legal representative and for obtaining the appropriate signatures and dates on the 
informed consent document prior to the performance of any protocol procedures and prior to 
the administration of study drug.  The Investigator will provide each subject with a copy of 
the signed and dated consent form and will document in the subject’s source notes that 
informed consent was given.  




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The Investigator will allow the Sponsor, Quintiles, and authorized regulatory authorities to 
have direct access to all documents pertaining to the study. 
10.4 Investigator Information 
10.4.1 
Investigator Obligations 
This study will be conducted in accordance with the ICH Harmonized Tripartite Guideline 
for GCP (1997); the United States CFR Title 21 parts 50, 56, and 312; and European 
Legislation; and the ethical principles that have their origin in the Declaration of Helsinki.  
A summary of Investigator obligations is provided in Appendix 3. 
10.4.2 
Protocol Signatures 
The Investigator must sign the Investigator Signature Page of the Protocol (Appendix 1).  By 
signing the protocol, the Investigator confirms in writing that he/she has read, understands, 
and will strictly adhere to the study protocol and will conduct the study in accordance with 
ICH Tripartite Guidelines for GCP and applicable regulatory requirements.  The study will 
not be able to start at any site where the Investigator has not signed the protocol. 


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11.0 REFERENCES 
1. Siegel M, Lee SL. The epidemiology of systemic lupus erythematosus. Semin Arthritis 
Rheum. 1973;3(1):1-54. 
2. Cooper GS, Dooley MA, Treadwell EL, St Clair EW, Parks CG, Gilkeson GS. Hormonal, 
environmental, and infectious risk factors for developing systemic lupus erythematosus. 
Arthritis Rheum. 1998 Oct;41(10):1714-24. 
3. Lahita RG. Emerging concepts for sexual predilection in the disease systemic lupus 
erythematosus. Ann N Y Acad Sci. 1999 Jun 22;876:64-9; discussion 69-70. 
4. Danchenko N, Satia JA, Anthony MS. Epidemiology of systemic lupus erythematosus: a 
comparison of worldwide disease burden. Lupus. 2006;15(5):308-18. 
5. Dobkin PL, Da Costa D, Dritsa M, et al. Quality of life in systemic lupus erythematosus 
patients during more and less active disease states: differential contributors to mental and 
physical health. Arthritis Care Res. 1999 Dec;12(6):401-10. 
6. Petri M. Long-term outcomes in lupus. Am J Manag Care. 2001 Oct;7(16 Suppl): 
S480-5. 
7. Bernatsky S, Boivin JF, Joseph L, et al. Mortality in systemic lupus erythematosus. 
Arthritis Rheum. 2006 Aug;54(8):2550-7. 
8. Costedoat-Chalumeau N, Galicier L, Aumaître O, et al. Hydroxychloroquine in systemic 
lupus erythematosus: results of a French multicentre controlled trial (PLUS Study). Ann 
Rheum Dis. 2013 Nov;72(11):1786-92.  
9. The Canadian Hydroxychloroquine Study Group. A randomized study of the effect of 
withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. N Engl J Med. 
1991 Jan 17;324(3):150-4. 
10. Hahn BH, McMahon MA, Wilkinson A, et al. American College of Rheumatology 
guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care 
Res (Hoboken). 2012 Jun;64(6):797-808. 
11. Hahn BH. Belimumab for systemic lupus erythematosus. N Engl J Med. 2013 Apr 
18;368(16):1528-35.  


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12. Urowitz MB, Bookman AA, Koehler BE, Gordon DA, Smythe HA, Ogryzlo MA. The 
bimodal mortality pattern of systemic lupus erythematosus. Am J Med. 1976 
Feb;60(2):221-5. 
13. Opat S, Gaston JS. CD30: CD30 ligand interactions in the immune response. 
Autoimmunity. 2000;33(1):45-60. 
14. Kim MY, Gaspal FM, Wiggett HE, et al. CD4(+)CD3(-) accessory cells costimulate 
primed CD4 T cells through OX40 and CD30 at sites where T cells collaborate with B 
cells. Immunity. 2003 May;18(5):643-54. 
15. Tang C, Yamada H, Shibata K, et al. A novel role of CD30L/CD30 signaling by T-T cell 
interaction in Th1 response against mycobacterial infection. J Immunol. 2008 Nov 
1;181(9):6316-27. 
16. Pellegrini P, Berghella AM, Contasta I, Adorno D. CD30 antigen: not a physiological 
marker for TH2 cells but an important costimulator molecule in the regulation of the 
balance between TH1/TH2 response. Transpl Immunol. 2003 Oct-Nov;12(1):49-61. 
17. Harlin H, Podack E, Boothby M, Alegre ML. TCR-independent CD30 signaling 
selectively induces IL-13 production via a TNF receptor-associated factor/p38 mitogen-
activated protein kinase-dependent mechanism. J Immunol. 2002 Sep 1;169(5):2451-9. 
18. Del Prete G, De Carli M, D'Elios MM, et al. CD30-mediated signaling promotes the 
development of human T helper type 2-like T cells. J Exp Med. 1995 Dec 1;182(6):1655-
61. 
19. Sun X, Yamada H, Shibata K, et al. CD30 ligand/CD30 plays a critical role in Th17 
differentiation in mice. J Immunol. 2010 Aug 15;185(4):2222-30.  
20. Jourdan M, Caraux A, Caron G, et al. Characterization of a transitional preplasmablast 
population in the process of human B cell to plasma cell differentiation. J Immunol. 2011 
Oct 15;187(8):3931-41. 
21. Odendahl M, Jacobi A, Hansen A, et al. Disturbed peripheral B lymphocyte homeostasis 
in systemic lupus erythematosus. J Immunol. 2000 Nov 15;165(10):5970-9. 
22. Martin JC, Baeten DL, Josien R. Emerging role of IL-17 and Th17 cells in systemic lupus 
erythematosus. Clin Immunol. 2014 Sep;154(1):1-12. 
23. Caligaris-Cappio F, Bertero MT, Converso M, et al. Circulating levels of soluble CD30, a 
marker of cells producing Th2-type cytokines, are increased in patients with systemic 


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lupus erythematosus and correlate with disease activity. Clin Exp Rheumatol. 1995 May-
Jun;13(3):339-43. 
24. Ichikawa Y, Yoshida M, Yamada C, Horiki T, Hoshina Y, Uchiyama M. Circulating 
soluble CD30 levels in primary Sjögren's syndrome, SLE and rheumatoid arthritis. Clin 
Exp Rheumatol. 1998 Nov-Dec;16(6):759-60. 
25. Ciferská H, Horák P, Hermanová Z, et al. The levels of sCD30 and of sCD40L in a group 
of patients with systemic lupus erythematodes and their diagnostic value. Clin 
Rheumatol. 2007 May;26(5):723-8. 
26. Dong L, Hu S, Chen F, et al. Increased expression of ganglioside GM1 in peripheral 
CD4+ T cells correlates soluble form of CD30 in Systemic Lupus Erythematosus 
patients. J Biomed Biotechnol. 2010;2010:569053.  
27. Cabrera CM, Urra JM, Carreño A, Zamorano J. Differential expression of CD30 on CD3 
T lymphocytes in patients with systemic lupus erythematosus. Scand J Immunol. 2013 
Sep;78(3):306-12.  
28. Rottman JB, Hu YL, Willis C. Blockade of the CD30/CD30L pathway inhibits renal 
disease in young, SLE-prone NZB/W F1 mice. J Immunol. 2009;182:50.41. 
29. Willis CR, Hu Y, Leith A, Bailey KL, Rottman JB. Treatment with anti-CD30 ligand 
prevents disease progression in murine systemic lupus erythematosus. Ann Rheum Dis. 
2008;67(Suppl II):101. 
30. Willis CR, Hu YL, Leith A, Rottman JB. CD30/CD30L interactions promote 
class-switched antibody responses to T-dependent antigens. J Immunol. 2009;182:34.3.  
31. Brentuximab vedotin [package insert]. Bothell, WA:  Seattle Genetics, Inc.; 2013. 
32. Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed 
CD30-positive lymphomas. N Engl J Med. 2010 Nov 4;363(19):1812-21. 
33. Illei GG, Shirota Y, Yarboro CH, et al. Tocilizumab in systemic lupus erythematosus: 
data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-
label phase I dosage-escalation study. Arthritis Rheum. 2010 Feb;62(2):542-52. 
34. Merrill JT, Wallace DJ, Petri M, et al. Lupus Interferon Skin Activity (LISA) Study 
Investigators. Safety profile and clinical activity of sifalimumab, a fully human anti-
interferon α monoclonal antibody, in systemic lupus erythematosus: a phase I, 
multicentre, double-blind randomised study. Ann Rheum Dis. 2011 Nov;70(11):1905-13. 


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35. Power C, Gladden JG, Halliday W, et al. AIDS- and non-AIDS-related PML association 
with distinct p53 polymorphism. Neurology. 2000 Feb 8;54(3):743-6. 
36. García-Suárez J, de Miguel D, Krsnik I, Bañas H, Arribas I, Burgaleta C. Changes in the 
natural history of progressive multifocal leukoencephalopathy in HIV-negative 
lymphoproliferative disorders: impact of novel therapies. Am J Hematol. 2005 
Dec;80(4):271-81. 
37. Bellizzi A, Nardis C, Anzivino E, et al. Human polyomavirus JC reactivation and 
pathogenetic mechanisms of progressive multifocal leukoencephalopathy and cancer in 
the era of monoclonal antibody therapies. J Neurovirol. 2012 Feb;18(1):1-11). 
38. Bloomgren et al. Bloomgren G1, Richman S, Hotermans C, et al. Risk of natalizumab-
associated progressive multifocal leukoencephalopathy. N Engl J Med, 2012, 366:1870. 
39. Gorelik L, Lerner M, Bixler S, et al. Anti-JC virus antibodies: implications for PML risk 
stratification. Ann Neurol. 2010 Sep;68(3):295-303. 
40. Albrecht J, Taylor L, Berlin JA, et al. The CLASI (Cutaneous Lupus Erythematosus 
Disease Area and Severity Index): an outcome instrument for cutaneous lupus 
erythematosus. J Invest Dermatol. 2005 Nov;125(5):889-94. 
41. Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the 
definition and management of anaphylaxis: summary report--Second National Institute of 
Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium.  J 
Allergy Clin Immunol.  2006 Feb;117(2):391-7. 




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SIGNATURE OF INVESTIGATOR 
PROTOCOL TITLE:  A Multi-center, Randomized, Double-blinded, Placebo-controlled, 
Multiple-ascending-dose Study of Brentuximab Vedotin in Adults With Active Systemic 
Lupus Erythematosus 
PROTOCOL NO: 
SGN35-022 
This protocol is a confidential communication of Seattle Genetics, Inc.  I confirm that I have 
read this protocol, I understand it, and I will work according to this protocol.  I will also work 
consistently with the ethical principles that have their origin in the Declaration of Helsinki 
and that are consistent with good clinical practices and the applicable laws and regulations.  
Acceptance of this document constitutes my agreement that no unpublished information 
contained herein will be published or disclosed without prior written approval from Seattle 
Genetics, Inc. 
Instructions to the Investigator:  Please SIGN and DATE both copies of this signature page.  PRINT your name, 
title, and the name of the center/address in which the study will be conducted on both copies.  Return one of the 
signed copies to Seattle Genetics, Inc., and retain the second signed copy for the study files. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature Principal Investigator:     __________________________            Date:  ________ 
Printed Name:                                 ___________________________ 
Investigator Title:                           ___________________________ 
 
Name/Address of Center:              ____________________________ 
 
 
 
 
      ____________________________ 
 
 
 
 
      ____________________________ 


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SIGNATURE OF INVESTIGATOR 
PROTOCOL TITLE:  A Multi-center, Randomized, Double-blinded, Placebo-controlled, 
Multiple-ascending-dose Study of Brentuximab Vedotin in Adults With Active Systemic 
Lupus Erythematosus 
PROTOCOL NO: 
SGN35-022 
This protocol is a confidential communication of Seattle Genetics, Inc.  I confirm that I have 
read this protocol, I understand it, and I will work according to this protocol.  I will also work 
consistently with the ethical principles that have their origin in the Declaration of Helsinki 
and that are consistent with good clinical practices and the applicable laws and regulations. 
Acceptance of this document constitutes my agreement that no unpublished information 
contained herein will be published or disclosed without prior written approval from Seattle 
Genetics, Inc. 
Instructions to the Investigator:  Please SIGN and DATE both copies of this signature page.  PRINT your name, 
title, and the name of the center/address in which the study will be conducted on both copies.  Return one of the 
signed copies to Seattle Genetics, Inc., and retain the second signed copy for the study files. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature Principal Investigator:     __________________________            Date:  ________ 
Printed Name:                                 ___________________________ 
Investigator Title:                           ___________________________ 
 
Name/Address of Center:              ____________________________ 
 
 
 
 
      ____________________________ 
 
 
 
 
      ____________________________ 
 


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APPENDIX 2:  SCHEDULE OF EVENTS 
Table 3 
Schedule of Events 
 
 
Screening 
Baseline 
Treatment 
Obser-
vation 
Follow-up/ 
Early 
Term 
 
Day(s) 
-28 to -14 
1 (1) 
2 
3 
8 
15 
22 
29 
43 
50 
64 
71 
85 
106 
127 
 
Visit Window 
 
 
 
 
±1d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±7d 
General 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physician present 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Clinic visit 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Home or clinic visit 
 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
Safety 
Assessments 
Physical 
examination 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
PML assessment 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Vital signsb 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with 
differentialc 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
B cell (CD19+) 
countd 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Chemistry panele 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting lipid profilef 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Viral serologiesg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis 
testingh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinary studiesi 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 


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Table 3 
Schedule of Events 
 
 
Screening 
Baseline 
Treatment 
Obser-
vation 
Follow-up/ 
Early 
Term 
 
Day(s) 
-28 to -14 
1 (1) 
2 
3 
8 
15 
22 
29 
43 
50 
64 
71 
85 
106 
127 
 
Visit Window 
 
 
 
 
±1d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±7d 
 
Pregnancy test 
(WOCBP)j 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
Chest x-rayk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
PK/PD 
Pharmacokinetic 
sampleError  Reference 
source not found. 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Antitherapeutic 
antibodiesm 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Flow cytometryn 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Inflammatory 
markerso 
 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
ANAp 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Anti-dsDNA 
antibodies 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Autoantibody 
panelq 
X 
X 
 
 
 
 
Xr 
 
X 
 
Xr 
 
X 
Xr 
X 
Complement 
studiess 
X 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Cytokinest 
X 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
RNA sampleu 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Lymph node or 
tonsil biopsyv 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Pharmaco-
genetic 
DNA samplew 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy 
Assessmentsx 
BILAG 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
SLEDAI 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
CLASI 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 


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Table 3 
Schedule of Events 
 
 
Screening 
Baseline 
Treatment 
Obser-
vation 
Follow-up/ 
Early 
Term 
 
Day(s) 
-28 to -14 
1 (1) 
2 
3 
8 
15 
22 
29 
43 
50 
64 
71 
85 
106 
127 
 
Visit Window 
 
 
 
 
±1d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±7d 
SJC/TJC 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
PtGP, PtGA, PhGA 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
HAQ-DI, SF-36, 
FACIT-F, 
LupusQoL 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
General 
Monitoring 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Treatment 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug 
administrationError  
Reference source not 
found.,y 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
ALT = alanine aminotransferase; ANA = antinuclear antibodies; anti-dsDNA = anti-double-stranded deoxyribonucleic acid; anti-RNP = anti-r bonucleoprotein; anti-Sm = anti-Smith 
ant body; anti-SSA = anti-Sjögren’s Syndrome A antibodies; anti-SSB = anti-Sjögren’s Syndrome B antibodies; AST = aspartate aminotransferase; BAFF = B cell activating factor; 
BILAG = British Isles Lupus Assessment Group; CBC = complete blood count; CLASI = Cutaneous Lupus Erythematosus Disease Area and Severity Index; 
DNA = deoxyribonucleic acid; eGFR = estimated glomerular filtration rate; ESR = erythrocyte sedimentation rate; FACIT-F = Functional Assessment of Chronic Illness 
Therapy-Fatigue; HAQ-DI = Health Assessment Questionnaire-Disability Index; HbA1c = glycosylated hemoglobin; HIV = human immunodeficiency virus; hsCRP = high-sensitivity 
C-reactive protein; IFN = interferon; Ig = immunoglobulin; JCV = John Cunningham virus; LupusQoL = Lupus Quality of Life; PD = pharmacodynamic; PhGA = Physician’s Global 
Assessment of Disease Activity; PK = pharmacokinetic; PML = progressive multifocal leukoencephalopathy; PtGA = Patient’s Global Assessment of Disease Activity; 
PtGP = Patient’s Global Assessment of Pain; RBC = red blood cell; RNA = r bonucleic acid; sCD153 = soluble CD153; sCD30 = soluble CD30; SF-36 = Short Form-36; SJC = 
swollen joint count; SLE = systemic lupus erythematosus; SLEDAI = Systemic Lupus Erythematosus Disease Activity Index; TJC = tender joint count; TNF = tumor necrosis factor; 
TWEAK = cytokine TNF-l ke weak inducer of apoptosis; WBC = white blood cell; WOCBP = women of childbearing potential. 
a 
Continuing study eligibility will be confirmed at the Baseline Visit. 
b 
Vital signs include blood pressure, pulse rate, respiratory rate, temperature, and weight. 
c 
Complete blood count with differential to include hemoglobin, hematocrit, RBC count, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean 
corpuscular volume, red cell distr bution width, WBC count with 5-part differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), and platelet count.  
Results must be available prior to dosing; therefore, an additional sample may be collected for local laboratory testing on Days 1, 22, 43, and 64.  The predose sample on 
these days should still be collected for central laboratory testing. 
d 
B cell count for subjects with prior B cell depletion therapy, such as rituximab.  Baseline testing may be omitted for subjects with normal counts at screening. 
e 
Chemistry panel includes:  sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, a bumin, eGFR, glucose, total and direct bilirubin, ALT, AST, a kaline 


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Table 3 
Schedule of Events 
 
 
Screening 
Baseline 
Treatment 
Obser-
vation 
Follow-up/ 
Early 
Term 
 
Day(s) 
-28 to -14 
1 (1) 
2 
3 
8 
15 
22 
29 
43 
50 
64 
71 
85 
106 
127 
 
Visit Window 
 
 
 
 
±1d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±7d 
phosphatase, lactate dehydrogenase, uric acid, amylase, lipase, and creatine phosphokinase. 
f 
Eight-hour fasting lipid profile includes total cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein. 
g 
Viral serologies include tests for HIV, hepatitis B (surface antigen, surface antibody, and core antibody), hepatitis C, and JCV. 
h 
Tuberculosis testing involves QuantiFERON-TB Gold or tuberculin purified protein derivative. 
i 
Urinary studies include dipstick urinalysis, spot urinary protein and creatinine, and microscopic examination.  Urine samples will be collected and stored for future exploratory 
analysis. 
j 
Urine pregnancy tests will be performed by the local laboratory only. 
k 
Chest x-ray or CT scan at screening, unless documented within the last 3 months. 
l 
Pharmacokinetic samples will be collected within 30 minutes prior to dosing and within 5 minutes after the end of infusion on study drug administration days (Days 1, 22, 43, 
and 64).  On Days 2, 3, 8, and 15, PK samples will be collected at approximately the same time of day as the end of infusion sample on Day 1, if possible.  On Days 85, 106, 
and 127, PK samples may be collected at any time of day. 
m 
Samples for antitherapeutic antibodies are collected prior to dosing only. 
n 
Flow cytometry includes assessments for lymphocyte populations.  A separate peripheral blood mononuclear cell sample will be retained for future exploratory analysis.   
o 
Inflammatory markers include ESR, hsCRP, sCD30, and sCD153.  A replicate serum sample will be retained for future exploratory analysis. 
p 
Antinuclear antibodies consists of immunofluorescence testing.  A replicate serum sample will be retained for future exploratory analysis. 
q 
Autoantibody panel includes anti-Sm, anti-RNP, anti-SSA, anti-SSB, lupus anticoagulant, anti-β-2-glycoprotein I, anticardiolipin, anti-C1q, direct Coombs test, and quantitative 
IgG, IgM, IgA, and IgE. 
r 
Direct Coombs test only. 
s 
Complement studies include C3, C4, CH50, and C1q. 
t 
Cytokines indicates retention of a serum sample for poss ble future testing of SLE-related cytokines, such as IFN-α, BAFF, or TWEAK. 
u 
Sample consists of retention of a peripheral blood RNA sample for possible future testing of genome-wide SLE-related inflammatory gene expression patterns, such as via 
microarray or RNA-seq.   
v 
Optional.  For each subject, location of this tissue collection should remain consistent throughout the study.  May include analyses of CD30+ T and B cell populations and 
germinal center structure. 
w 
Optional sample for subjects who have provided separate informed consent.  The sample will be collected in a Vacutainer™ tube containing ethylenediaminetetraacetic acid as 
an anticoagulant and stored frozen until use. 
x 
Quality of life questionnaires should be completed prior to other study assessments scheduled for the same visit. 
y 
Randomization occurs prior to study drug administration. 
 


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APPENDIX 3:  INVESTIGATOR RESPONSIBILITIES 
Per Good Clinical Practices 21CFR312.53 
The Investigator: 
• 
Will conduct the study in accordance with the relevant, current protocol and will only 
make changes in the protocol after notifying the Sponsor, except when necessary to 
protect the safety, the rights, or welfare of subjects; 
• 
Will comply with all requirements regarding the obligations of clinical Investigators and 
all other pertinent requirements; 
• 
Will personally conduct or supervise the described investigation; 
• 
Will inform any potential subjects that the drugs are being used for investigational 
purposes and will ensure that the requirements relating to obtaining informed consent and 
Institutional Review Board (IRB) review and approval are met. 
• 
Will report to the Sponsor adverse experiences that occur in the course of the 
investigation in accordance with Section 312.64; 
• 
Has read and understands the information in the Investigator’s Brochure, including the 
potential risks and side effects of the drug; and 
• 
Will ensure that all associates, colleagues, and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments. 
Per Good Clinical Practices 21CFR312.60 
General Responsibilities of Investigators: 
An Investigator is responsible for ensuring that an investigation is conducted according to the 
signed Investigator statement, the investigational plan, and applicable regulations; for 
protecting the rights, safety, and welfare of subjects under the Investigator’s care; and for the 
control of drugs under investigation.  An Investigator shall, in accordance with the provisions 
of part 50, obtain the informed consent of each human subject to whom the drug is 
administered, except as provided in CFR50.23. 


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Obligations of the Investigator 
The Investigator Shall: 
• 
Maintain IRB approval to conduct the clinical trial and report to the IRB as required.  The 
IRB must assume continued responsibility for the study and review the research on at 
least an annual basis; 
• 
Maintain a file of all communications with the IRB on issues related to the clinical trial; 
• 
Complete, sign, and return to Quintiles a Food and Drug Administration (FDA) 
Form 1572 including a current curricula vitae (CV) for the Principal Investigator and 
Sub-Investigator(s), if listed; 
• 
Conduct the study in strict adherence to the protocol; 
• 
Supervise the use of the study drug as outlined in the protocol.  The study drug may only 
be provided by staff working under the supervision of the Investigator; 
• 
Store the study drug in a secure and locked area with limited access.  The storage and 
custody of the study drug are the responsibilities of the Investigator; 
• 
Maintain adequate records of the receipt and disposition of all study drug (including 
dates, quantities, and use by study subjects); 
• 
Inform each subject of the risks and benefits of participating in the study and obtain a 
properly signed, dated, and witnessed (if applicable) informed consent form for each 
subject before he or she begins any study-related procedures; 
• 
Document all adverse events on the case report forms (CRFs); document all serious 
adverse events (SAEs) on the SAE Form and immediately notify Sponsor and Quintiles 
via phone and fax; 
• 
Report all SAEs to the IRB; 
• 
Maintain a master log of all subjects screened for the study and establish a system to alert 
clinic staff of scheduled follow-up visits; provide clinic staff with a system for contacting 
study subjects who do not return for scheduled follow-up; 
• 
Document and maintain accurate CRFs for all subjects.  As required, sign forms 
ascertaining the accuracy of data recorded.  Storage and custody of all study-related 
records are the responsibility of the Investigator; 
• 
Retain the copies of the CRFs, the original informed consent forms, and all study-related 
documentation at the study site for a period of fifteen (15) years after termination of the 


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study unless Quintiles authorizes, in writing, earlier destruction.  Notify Quintiles before 
destroying any study records after the required retention period.  It is the responsibility of 
the Sponsor to inform the Investigator/institution as to when these documents no longer 
need to be retained; 
• 
Make available all study subjects’ records to staff and representatives from Quintiles, 
Sponsor and FDA or other Regulatory Agency personnel; 
• 
Return to Sponsor or their agent, study materials (which may include unused study 
supplies) following completion, discontinuation, or suspension of the study; 
• 
Be thoroughly familiar with the properties of the investigational agent as described in the 
Clinical Investigator Brochure; 
• 
Ensure that sufficient time is allotted to conduct and complete the study; ensure adequate 
staff and facilities are available for the duration of the study; and ensure that other studies 
do not divert essential subjects or facilities from the study at hand; 
• 
Provide information to all staff members involved with the study or with other elements 
of the subject’s management; 
• 
Notify Quintiles and Sponsor in the event the blind is broken; and 
• 
Ensure that the confidentiality of all information about subjects and the information 
supplied by Quintiles and Sponsor is respected by all persons. 


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APPENDIX 4:  ADCETRIS (BRENTUXIMAB VEDOTIN) 
PRESCRIBING INFORMATION 
 


ADCETRIS® (brentuximab vedotin)
1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use 
ADCETRIS safely and effectively. See full prescribing information for 
ADCETRIS.
ADCETRIS® (brentuximab vedotin) for injection, for intravenous use
Initial U.S. approval: 2011
RECENT MAJOR CHANGES
Indications and Usage (1.2)
08/2015
Dosage and Administration (2.1)
08/2015
Warnings and Precautions (5)
03/2016
INDICATIONS AND USAGE
ADCETRIS is a CD30-directed antibody-drug conjugate indicated for
treatment of patients with:
•
Classical Hodgkin lymphoma (HL) after failure of autologous 
hematopoietic stem cell transplantation (auto-HSCT) or after failure of 
at least two prior multi-agent chemotherapy regimens in patients who 
are not auto-HSCT candidates (1.1).
•
Classical HL at high risk of relapse or progression as post-auto-HSCT 
consolidation (1.2).
•
Systemic anaplastic large cell lymphoma (sALCL) after failure of at 
least one prior multi-agent chemotherapy regimen (1.3).
Accelerated approval was granted for the sALCL indication based on 
overall response rate. Continued approval for this indication may be 
contingent upon verification and description of clinical benefit in 
confirmatory trials.
DOSAGE AND ADMINISTRATION
•
Administer only as an intravenous infusion over 30 minutes every 
3 weeks.
•
The recommended dose is 1.8 mg/kg (2).
•
Reduce dose in patients with mild hepatic impairment (2).
DOSAGE FORMS AND STRENGTHS
For injection: 50 mg lyophilized powder in a single-use vial (3).
CONTRAINDICATIONS
Concomitant use with bleomycin due to pulmonary toxicity (4).
WARNINGS AND PRECAUTIONS
•
Peripheral neuropathy: Monitor patients for neuropathy and institute 
dose modifications accordingly (5.1).
•
Anaphylaxis and infusion reactions: If an infusion reaction occurs, 
interrupt the infusion. If anaphylaxis occurs, immediately 
discontinue the infusion (5.2).
•
Hematologic toxicities: Monitor complete blood counts prior to each 
dose of ADCETRIS. Closely monitor patients for fever. If Grade 3 
or 4 neutropenia develops, consider dose delays, reductions,
discontinuation, or G-CSF prophylaxis with subsequent doses (5.3).
•
Serious infections and opportunistic infections: Closely monitor
patients for the emergence of bacterial, fungal or viral infections
(5.4).
•
Tumor lysis syndrome: Closely monitor patients with rapidly 
proliferating tumor or high tumor burden (5.5).
•
Hepatotoxicity: Monitor liver enzymes and bilirubin (5.8).
•
Pulmonary toxicity: Monitor patients for new or worsening 
symptoms (5.10).
•
Serious dermatologic reactions: Discontinue if Stevens-Johnson 
syndrome or toxic epidermal necrolysis occurs (5.11).
•
Gastrointestinal complications: Monitor patients for new or 
worsening symptoms (5.12).
•
Embryo-Fetal toxicity: Can cause fetal harm. Advise females of 
reproductive potential of the potential risk to a fetus and to avoid 
pregnancy (5.13).
ADVERSE REACTIONS
The most common adverse reactions  were: 
•
Relapsed classical HL and relapsed sALCL: neutropenia, 
peripheral sensory neuropathy, fatigue, nausea, anemia, upper 
respiratory tract infection, diarrhea, pyrexia, rash, 
thrombocytopenia, cough, and vomiting (6.1).
•
Classical HL post-auto-HSCT consolidation: neutropenia, 
peripheral sensory neuropathy, thrombocytopenia, anemia, upper 
respiratory tract infection, fatigue, peripheral motor neuropathy, 
nausea, cough, and diarrhea (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Seattle 
Genetics, Inc. at 1-855-473-2436 or FDA at 1-800-FDA-1088 or 
www.fda.gov/medwatch.
DRUG INTERACTIONS
Concomitant use of strong CYP3A4 inhibitors or inducers, or P-gp
inhibitors, has the potential to affect the exposure to monomethyl 
auristatin E (MMAE) (7.1).
USE IN SPECIFIC POPULATIONS
Moderate or severe hepatic impairment or severe renal impairment: 
MMAE exposure and adverse reactions are increased. Avoid use (5.6,
5.7, 8.6, 8.7).
Lactation:  Breastfeeding not recommended (8.2).
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 03/2016
WARNING: PROGRESSIVE MULTIFOCAL 
LEUKOENCEPHALOPATHY (PML)
See full prescribing information for complete boxed warning.
JC virus infection resulting in PML and death can occur in patients 
receiving ADCETRIS (5.9, 6.1).
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FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: PROGRESSIVE MULTIFOCAL 
LEUKOENCEPHALOPATHY (PML) 
1 
INDICATIONS AND USAGE 
1.1 
Classical Hodgkin Lymphoma (HL) 
1.2 
Classical Hodgkin Lymphoma (HL) Post-auto-HSCT 
Consolidation 
1.3 
Systemic Anaplastic Large Cell Lymphoma (sALCL) 
2 
DOSAGE AND ADMINISTRATION 
2.1 
Dosage Recommendations 
2.2 
Dose Modification 
2.3 
Instructions for Preparation and Administration 
3 
DOSAGE FORMS AND STRENGTHS 
4 
CONTRAINDICATIONS 
5 
WARNINGS AND PRECAUTIONS 
5.1 
Peripheral Neuropathy 
5.2 
Anaphylaxis and Infusion Reactions 
5.3 
Hematologic Toxicities 
5.4 
Serious Infections and Opportunistic Infections 
5.5 
Tumor Lysis Syndrome 
5.6 
Increased Toxicity in the Presence of Severe Renal 
Impairment 
5.7 
Increased Toxicity in the Presence of Moderate or 
Severe Hepatic Impairment 
5.8 
Hepatotoxicity 
5.9 
Progressive Multifocal Leukoencephalopathy 
5.10 
Pulmonary Toxicity 
5.11 
Serious Dermatologic Reactions 
5.12 
Gastrointestinal Complications 
5.13 
Embryo-Fetal Toxicity 
6 
ADVERSE REACTIONS 
6.1 
Clinical Trial Experience 
6.2 
Post Marketing Experience 
6.3 
Immunogenicity 
7 
DRUG INTERACTIONS 
7.1 
Effect of Other Drugs on ADCETRIS 
7.2 
Effect of ADCETRIS on Other Drugs 
8 
USE IN SPECIFIC POPULATIONS 
8.1 
Pregnancy 
8.2 
Lacta ion 
8.3 
Females and Males of Reproductive Potential 
8.4 
Pediatric Use 
8.5 
Geriatric Use 
8.6 
Renal Impairment 
8.7 
Hepatic Impairment 
10 
OVERDOSAGE 
11 
DESCRIPTION 
12 
CLINICAL PHARMACOLOGY 
12.1 
Mechanism of Action 
12.2 
Pharmacodynamics 
12.3 
Pharmacokinetics 
13 
NONCLINICAL TOXICOLOGY 
13.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
14 
CLINICAL STUDIES 
14.1 
Classical Hodgkin Lymphoma 
14.2 
Systemic Anaplastic Large Cell Lymphoma 
15 
REFERENCES 
16 
HOW SUPPLIED/STORAGE AND HANDLING 
16.1 
How Supplied 
16.2 
Storage 
16.3 
Special Handling 
17 
PATIENT COUNSELING INFORMATION 
*Sections or subsections omitted from the full prescribing information are not 
listed.
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FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Classical Hodgkin Lymphoma (HL)
ADCETRIS is indicated for treatment of patients with classical HL after failure of autologous
hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least two prior multi-
agent chemotherapy regimens in patients who are not auto-HSCT candidates.
1.2
Classical Hodgkin Lymphoma (HL) Post-auto-HSCT Consolidation
ADCETRIS is indicated for the treatment of patients with classical HL at high risk of relapse or 
progression as post-auto-HSCT consolidation [see Clinical Studies (14.1)].
1.3
Systemic Anaplastic Large Cell Lymphoma (sALCL)
ADCETRIS is indicated for treatment of patients with sALCL after failure of at least one prior 
multi-agent chemotherapy regimen.
The sALCL indication is approved under accelerated approval based on overall response rate
[see Clinical Studies (14.2)]. Continued approval for this indication may be contingent upon 
verification and description of clinical benefit in confirmatory trials.
2
DOSAGE AND ADMINISTRATION
2.1
Dosage Recommendations 
Administer ADCETRIS as an intravenous infusion over 30 minutes every 3 weeks until disease 
progression or unacceptable toxicity. See Table 1 for the recommended starting dosage.
For classical HL post-auto-HSCT consolidation treatment, initiate ADCETRIS treatment within 
4–6 weeks post-auto-HSCT or upon recovery from auto-HSCT. These patients should continue 
treatment until a maximum of 16 cycles, disease progression, or unacceptable toxicity.
WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)
JC virus infection resulting in PML and death can occur in patients receiving 
ADCETRIS [see Warnings and Precautions (5.9), Adverse Reactions (6.1)].
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Table 1:
Recommended ADCETRIS Dosage
Recommended Starting Dosage
Normal renal and hepatic function
1.8 mg/kg up to 180 mg
Renal impairment
Mild (creatinine clearance >50–80 mL/min) or 
moderate (creatinine clearance 30–50 mL/min)
1.8 mg/kg up to 180 mg
Severe (creatinine clearance less than 30 mL/min)
Avoid use 
[see Warnings and Precautions (5.6)]
Hepatic impairment
Mild (Child-Pugh A)
1.2 mg/kg up to 120 mg
Moderate (Child-Pugh B) or severe (Child-Pugh C)
Avoid use 
[see Warnings and Precautions (5.7)]
2.2
Dose Modification
Peripheral 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 1.2 mg/kg. For 
Grade 4 peripheral neuropathy, ADCETRIS should be discontinued.
Neutropenia:  The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until 
resolution to baseline or Grade 2 or lower. Consider G-CSF prophylaxis for subsequent cycles 
in patients who experience Grade 3 or 4 neutropenia in the previous cycle. In patients with 
recurrent Grade 4 neutropenia despite the use of G-CSF prophylaxis, consider discontinuation 
or dose reduction of ADCETRIS to 1.2 mg/kg.
2.3
Instructions for Preparation and Administration
Administration
•
Administer ADCETRIS as an intravenous infusion only.
•
Do not mix ADCETRIS with, or administer as an infusion with, other medicinal 
products.
Reconstitution
•
Follow procedures for proper handling and disposal of anticancer drugs [see References 
(15)].
•
Use appropriate aseptic technique for reconstitution and preparation of dosing solutions.
•
Determine the number of 50 mg vials needed based on the patient’s weight and the 
prescribed dose [see Dosage and Administration (2.1)].
•
Reconstitute each 50 mg vial of ADCETRIS with 10.5 mL of Sterile Water for Injection, 
USP, to yield a single-use solution containing 5 mg/mL brentuximab vedotin.
•
Direct the stream toward the wall of vial and not directly at the cake or powder.
•
Gently swirl the vial to aid dissolution. DO NOT SHAKE.
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•
Inspect the reconstituted solution for particulates and discoloration. The reconstituted 
solution should be clear to slightly opalescent, colorless, and free of visible particulates.
•
Following reconstitution, dilute immediately into an infusion bag. If not diluted 
immediately, store the solution at 2–8°C (36–46°F) and use within 24 hours of 
reconstitution. DO NOT FREEZE.
•
Discard any unused portion left in the vial.
Dilution
•
Calculate the required volume of 5 mg/mL reconstituted ADCETRIS solution needed.
•
Withdraw this amount from the vial and immediately add it to an infusion bag containing 
a minimum volume of 100 mL of 0.9% Sodium Chloride Injection, 5% Dextrose Injection 
or Lactated Ringer's Injection to achieve a final concentration of 0.4 mg/mL to 1.8 mg/mL 
brentuximab vedotin.
•
Gently invert the bag to mix the solution.
•
Following dilution, infuse the ADCETRIS solution immediately. If not used immediately,
store the solution at 2–8°C (36–46°F) and use within 24 hours of reconstitution. DO 
NOT FREEZE.
3
DOSAGE FORMS AND STRENGTHS
For injection: 50 mg of brentuximab vedotin as a sterile, white to off-white lyophilized,
preservative-free cake or powder in a single-use vial for reconstitution.
4
CONTRAINDICATIONS
ADCETRIS is contraindicated with concomitant bleomycin due to pulmonary toxicity
(e.g., interstitial infiltration and/or inflammation) [see Adverse Reactions (6.1)].
5
WARNINGS AND PRECAUTIONS
5.1
Peripheral Neuropathy
ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of 
peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral 
neuropathy is cumulative. In the relapsed classical HL and sALCL clinical trials, 54% of patients 
experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% 
had partial improvement, and 20% had no improvement. Of the patients who reported 
neuropathy, 51% had residual neuropathy at the time of their last evaluation. Monitor patients
for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a 
burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening 
peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS
[see Dosage and Administration (2.2) and Adverse Reactions (6.1)].
5.2
Anaphylaxis and Infusion Reactions
Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor 
patients during infusion. If anaphylaxis occurs, immediately and permanently discontinue 
administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related 
reaction occurs, the infusion should be interrupted and appropriate medical management 
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instituted. Patients who have experienced a prior infusion-related reaction should be 
premedicated for subsequent infusions. Premedication may include acetaminophen, an 
antihistamine, and a corticosteroid.
5.3
Hematologic Toxicities
PURORQJHG  ZHHN VHYHUH QHXWURSHQLD and Grade 3 or Grade 4 thrombocytopenia or anemia
can occur with ADCETRIS. Febrile neutropenia has been reported with treatment with 
ADCETRIS. Complete blood counts should be monitored prior to each dose of ADCETRIS and
more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia.
Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays,
reductions, discontinuation, or G-CSF prophylaxis with subsequent ADCETRIS doses [see 
Dosage and Administration (2.2)].
5.4
Serious Infections and Opportunistic Infections
Serious infections and opportunistic infections such as pneumonia, bacteremia, and sepsis or 
septic shock (including fatal outcomes) have been reported in patients treated with ADCETRIS.
Patients should be closely monitored during treatment for the emergence of possible bacterial, 
fungal, or viral infections.
5.5
Tumor Lysis Syndrome
Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of 
tumor lysis syndrome. Monitor closely and take appropriate measures.
5.6
Increased Toxicity in the Presence of Severe Renal Impairment
The frequency of Grade 3 adverse reactions and deaths was greater in patients with severe 
renal impairment compared to patients with normal renal function. Due to higher MMAE 
exposure, Grade 3 adverse reactions may be more frequent in patients with severe renal 
impairment compared to patients with normal renal function.  Avoid the use of ADCETRIS in 
patients with severe renal impairment [creatinine clearance (CLcr) <30 mL/min] [see Use in 
Specific Populations (8.6)].
5.7
Increased Toxicity in the Presence of Moderate or Severe Hepatic Impairment
The frequency of Grade 3 adverse reactions and deaths was greater in patients with moderate 
and severe hepatic impairment compared to patients with normal hepatic function. Avoid the use of 
ADCETRIS in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic
impairment [see Use in Specific Populations (8.7)].
5.8
Hepatotoxicity
Serious cases of hepatotoxicity, including fatal outcomes, have occurred in patients receiving 
ADCETRIS. Cases were consistent with hepatocellular injury, including elevations of 
transaminases and/or bilirubin. Cases have occurred after the first dose of ADCETRIS or after 
ADCETRIS rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and 
concomitant medications may also increase the risk. Monitor liver enzymes and bilirubin.
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Patients experiencing new, worsening, or recurrent hepatotoxicity may require a delay, change 
in dose, or discontinuation of ADCETRIS.
5.9
Progressive Multifocal Leukoencephalopathy
JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients.
First onset of symptoms occurred at various times from initiation of ADCETRIS therapy, with 
some cases occurring within 3 months of initial exposure.  In addition to ADCETRIS therapy, 
other possible contributory factors include prior therapies and underlying disease that may 
cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-
onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS dosing 
for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is 
confirmed.
5.10
Pulmonary Toxicity
Events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and 
acute respiratory distress syndrome (ARDS), some with fatal outcomes, have been reported.  
Monitor patients for signs and symptoms of pulmonary toxicity, including cough and dyspnea.  In 
the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation 
and until symptomatic improvement.
5.11
Serious Dermatologic Reactions
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal 
outcomes, have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS
and administer appropriate medical therapy.
5.12
Gastrointestinal Complications
Fatal and serious gastrointestinal (GI) complications including perforation, hemorrhage, erosion, 
ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus have been reported in 
ADCETRIS-treated patients. Lymphoma with preexisting GI involvement may increase the risk 
of perforation.  In the event of new or worsening GI symptoms, perform a prompt diagnostic 
evaluation and treat appropriately.
5.13
Embryo-Fetal Toxicity
Based on the mechanism of action and findings in animals, ADCETRIS can cause fetal harm 
when administered to a pregnant woman. There are no adequate and well-controlled studies of 
ADCETRIS in pregnant women. Brentuximab vedotin caused embryo-fetal toxicities, including 
significantly decreased embryo viability and fetal malformations, in animals at maternal 
exposures that were similar to the clinical dose of 1.8 mg/kg every three weeks.
Advise females of reproductive potential to avoid pregnancy during ADCETRIS treatment and 
for at least 6 months after the final dose of ADCETRIS. If ADCETRIS is used during pregnancy 
or if the patient becomes pregnant during ADCETRIS treatment, the patient should be apprised 
of the potential risk to the fetus [see Use in Specific Populations (8.1, 8.3)].
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6
ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the 
prescribing information:
•
Peripheral Neuropathy [see Warnings and Precautions (5.1)]
•
Anaphylaxis and Infusion Reactions [see Warnings and Precautions (5.2)]
•
Hematologic Toxicities [see Warnings and Precautions (5.3)]
•
Serious Infections and Opportunistic Infections [see Warnings and Precautions (5.4)]
•
Tumor Lysis Syndrome [see Warnings and Precautions (5.5)]
•
Increased Toxicity in the Presence of Severe Renal Impairment [see Warnings and 
Precautions (5.6)]
•
Increased Toxicity in the Presence of Moderate or Severe Hepatic Impairment [see 
Warnings and Precautions (5.7)]
•
Hepatotoxicity [see Warnings and Precautions (5.8)]
•
Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.9)]
•
Pulmonary Toxicity [see Warnings and Precautions (5.10)]
•
Serious Dermatologic Reactions [see Warnings and Precautions (5.11)]
•
Gastrointestinal Complications [see Warnings and Precautions (5.12)]
6.1
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates 
observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of 
another drug and may not reflect the rates observed in practice.
The data below reflect exposure to ADCETRIS as monotherapy in 327 patients with classical 
Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL), including 160 
patients in two uncontrolled single-arm trials (Studies 1 and 2) and 167 patients in one placebo-
controlled randomized trial (Study 3).
In Studies 1 and 2, the most common adverse reactions , regardless of causality, were 
neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract 
infection, diarrhea, pyrexia, rash, thrombocytopenia, cough, and vomiting. The most common 
adverse reactions occurring in at least 10% of patients in either Study 1 or 2, regardless of 
causality, using the NCI Common Toxicity Criteria (CTC) Version 3.0, are shown in Table 2.
In Study 3, the PRVW FRPPRQ DGYHUVH UHDFWLRQV  LQ WKH $'&(75,6-treatment arm, 
regardless of causality, were neutropenia, peripheral sensory neuropathy, thrombocytopenia, 
anemia, upper respiratory tract infection, fatigue, peripheral motor neuropathy, nausea, cough, 
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and diarrhea. The most common adverse reactions occurring in at least 10% of patients, using 
the NCI CTC Version 4, are shown in Table 3.
Experience in Classical Hodgkin Lymphoma
Summary of Clinical Trial Experience in Relapsed Classical HL (Study 1)
ADCETRIS was studied in 102 patients with classical HL in a single arm clinical trial in which 
the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks.
Median duration of treatment was 9 cycles (range, 1–16) [see Clinical Studies (14.1)].
The most common adverse reactions , regardless of causality, were neutropenia, 
peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, 
anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting.
Summary of Clinical Trial Experience in Classical HL Post-auto-HSCT Consolidation 
(Study 3)
ADCETRIS was studied in 329 patients with classical HL at high risk of relapse or progression 
post-auto-HSCT in a randomized, double-blind, placebo-controlled clinical trial in which the 
recommended starting dose and schedule was 1.8 mg/kg of ADCETRIS administered 
intravenously over 30 minutes every 3 weeks or placebo for up to 16 cycles. Of the 
329 enrolled patients, 327 (167 brentuximab vedotin, 160 placebo) received at least one dose of 
study treatment. The median number of treatment cycles in each study arm was 15 (range, 
1–16) and 80 patients (48%) in the ADCETRIS-treatment arm received 16 cycles [see Clinical 
Studies (14.1)].
Standard international guidelines were followed for infection prophylaxis for herpes simplex 
virus (HSV), varicella-zoster virus (VZV), and Pneumocystis jiroveci pneumonia (PCP) post-
auto-HSCT.  Overall, 312 patients (95%) received HSV and VZV prophylaxis with a median 
duration of 11.1 months (range, 0–20) and 319 patients (98%) received PCP prophylaxis with a 
median duration of 6.5 months (range, 0–20).
Experience in Systemic Anaplastic Large Cell Lymphoma
Summary of Clinical Trial Experience in Relapsed sALCL (Study 2)
ADCETRIS was studied in 58 patients with sALCL in a single arm clinical trial in which the 
recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median 
duration of treatment was 7 cycles (range, 1–16) [see Clinical Studies (14.2)].
The most common adverse reactions  UHJDUGOHVV RI FDXVDOLW\ ZHUH neutropenia, 
anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, diarrhea, and pain.
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Table 2:
0RVW &RPPRQO\ 5HSRUWHG  $GYHUVe Reactions in Studies 1 and 2
Classical HL
sALCL
Total N = 102
% of patients
Total N = 58
% of patients
Adverse Reaction
Any 
Grade
Grade 
3
Grade 
4
Any 
Grade
Grade 
3
Grade 
4
Blood and lymphatic system disorders
Neutropenia* 
54
15
6
55
12
9
Anemia*
33
8
2
52
2
-
Thrombocytopenia*
28
7
2
16
5
5
Lymphadenopathy
11
-
-
10
-
-
Nervous system disorders
Peripheral sensory neuropathy
52
8
-
53
10
-
Peripheral motor neuropathy
16
4
-
7
3
-
Headache
19
-
-
16
2
-
Dizziness
11
-
-
16
-
-
General disorders and administration 
site conditions
   Fatigue
49
3
-
41
2
2
   Pyrexia
29
2
-
38
2
-
   Chills
13
-
-
12
-
-
   Pain
7
-
-
28
-
5
   Edema peripheral
4
-
-
16
-
-
Infections and infestations
   Upper respiratory tract infection
47
-
-
12
-
-
Gastrointestinal disorders
   Nausea
42
-
-
38
2
-
   Diarrhea
36
1
-
29
3
-
   Abdominal pain
25
2
1
9
2
-
   Vomiting
22
-
-
17
3
-
   Constipation
16
-
-
19
2
-
Skin and subcutaneous tissue 
disorders
Rash
27
-
-
31
-
-
Pruritus
17
-
-
19
-
-
Alopecia
13
-
-
14
-
-
Night sweats
12
-
-
9
-
-
Dry skin
4
-
-
10
-
-
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Classical HL
sALCL
Total N = 102
% of patients
Total N = 58
% of patients
Adverse Reaction
Any 
Grade
Grade 
3
Grade 
4
Any 
Grade
Grade 
3
Grade 
4
Respiratory, thoracic and mediastinal 
disorders
Cough
25
-
-
17
-
-
Dyspnea
13
1
-
19
2
-
Oropharyngeal pain
11
-
-
9
-
-
Musculoskeletal and connective tissue 
disorders
Arthralgia
19
-
-
9
-
-
Myalgia
17
-
-
16
2
-
Back pain
14
-
-
10
2
-
Pain in extremity
10
-
-
10
2
2
Muscle spasms
9
-
-
10
2
-
Psychiatric disorders
Insomnia
14
-
-
16
-
-
Anxiety
11
2
-
7
-
-
Metabolism and nutrition disorders
Decreased appetite
11
-
-
16
2
-
Investigations
Weight decreased
6
-
-
12
3
-
*Derived from laboratory values and adverse reaction data
Table 3:
0RVW &RPPRQO\ 5HSRUWHG  LQ WKH $'&(75,6 DUP $GYHUVH 5HDFWLRQV LQ 6WXG\ 
ADCETRIS
Total N = 167
% of patients
Placebo
Total N = 160
% of patients
Adverse Reaction
Any
Grade
Grade 3 Grade 4
Any
Grade
Grade 3 Grade 4
Blood and lymphatic system disorders
Neutropenia*
78
30
9
34
6
4
Thrombocytopenia*
41
2
4
20
3
2
Anemia*
27
4
-
19
2
-
Nervous system disorders
Peripheral sensory neuropathy
56
10
-
16
1
-
Peripheral motor neuropathy
23
6
-
2
1
-
Headache
11
2
-
8
1
-
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ADCETRIS
Total N = 167
% of patients
Placebo
Total N = 160
% of patients
Adverse Reaction
Any
Grade
Grade 3 Grade 4
Any
Grade
Grade 3 Grade 4
Infections and infestations
Upper respiratory tract infection
26
-
-
23
1
-
General disorders and administration site 
conditions
Fatigue
24
2
-
18
3
-
Pyrexia
19
2
-
16
-
-
Chills
10
-
-
5
-
-
Gastrointestinal disorders
Nausea
22
3
-
8
-
-
Diarrhea
20
2
-
10
1
-
Vomiting
16
2
-
7
-
-
Abdominal pain
14
2
-
3
-
-
Constipation
13
2
-
3
-
-
Respiratory, thoracic and mediastinal 
disorders
Cough
21
-
-
16
-
-
Dyspnea
13
-
-
6
-
1
Investigations
Weight decreased
19
1
-
6
-
-
Musculoskeletal and connective tissue 
disorders
Arthralgia
18
1
-
9
-
-
Muscle spasms
11
-
-
6
-
-
Myalgia
11
1
-
4
-
-
Skin and subcutaneous tissue disorders
Pruritus
12
1
-
8
-
-
Metabolism and nutrition disorders
Decreased appetite
12
1
-
6
-
-
*Derived from laboratory values and adverse reaction data
Additional Important Adverse Reactions
Peripheral neuropathy
In Studies 1 and 2, 54% of patients experienced any grade of neuropathy. Of these patients, 
49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of 
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the patients who reported neuropathy, 51% had residual neuropathy at the time of their last 
evaluation. 
In Study 3, 67% of patients treated with ADCETRIS experienced any grade of neuropathy. The
median time to first onset of any grade was 14 weeks (range, 0.1–47), of Grade 2 was 27 weeks 
(range, 0.4–52) and of Grade 3 was 34 weeks (range, 7–106). The median time from onset to 
resolution or improvement of any grade was 23 weeks (range, 0.1–138), of Grade 2 was 
24 weeks (range, 1–108), and of Grade 3 was 25 weeks (range, 2–98). Of the patients who 
reported neuropathy, 59% had complete resolution and 41% had residual neuropathy 
(26% partial improvement, 15% no improvement) at the time of their last evaluation.
Infusion reactions
Two cases of anaphylaxis were reported in the dose-finding trials. There were no Grade 3 or 4 
infusion-related reactions reported in Studies 1 and 2; however, Grade 1 or 2 infusion-related 
reactions were reported for 19 patients (12%). In Studies 1 and 2, the most common adverse 
reactions  DVVRFLDWHG ZLWK LQIXVLRQ-related reactions were chills (4%), nausea (3%), 
dyspnea (3%), pruritus (3%), pyrexia (2%), and cough (2%).
In Study 3, infusion-related reactions were reported in 25 patients (15%) in the ADCETRIS-
treated arm and 3 patients (2%) in the placebo arm.  Grade 3 events were reported in 3 of the 
25 patients treated with ADCETRIS who experienced infusion-related reactions.  No Grade 4 
infusion-related reactions were reported. 7KH PRVW FRPPRQ DGYHUVH UHDFWLRQV 
associated with infusion-related reactions were nausea (4%), chills (4%), dyspnea (2%), 
headache (2%), pruritus (2%), rash (2%), back pain (2%), and vomiting (2%).
Pulmonary Toxicity
In a trial in patients with classical HL that studied ADCETRIS with bleomycin as part of a
combination regimen, the rate of non-infectious pulmonary toxicity was higher than the historical 
incidence reported with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients 
typically reported cough and dyspnea. Interstitial infiltration and/or inflammation were observed 
on radiographs and computed tomographic imaging of the chest. Most patients responded to 
corticosteroids. The concomitant use of ADCETRIS with bleomycin is contraindicated [see 
Contraindications (4)].
Cases of pulmonary toxicity have also been reported in patients receiving ADCETRIS. In Study 
3, pulmonary toxicity was reported in 8 patients (5%) in the ADCETRIS-treated arm and 
5 patients (3%) in the placebo arm. A causal association with single-agent ADCETRIS has not 
been established.
Serious adverse reactions
In Studies 1 and 2, serious adverse reactions, regardless of causality, were reported in 31% of 
patients receiving ADCETRIS. The most common serious adverse reactions experienced by
patients with classical HL include peripheral motor neuropathy (4%), abdominal pain (3%),
pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and 
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pyrexia (2%). The most common serious adverse reactions experienced by patients with 
sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and 
urinary tract infection (3%). Other important serious adverse reactions reported include PML,
Stevens-Johnson syndrome, and tumor lysis syndrome.
In Study 3, serious adverse reactions, regardless of causality, were reported in 25% of
ADCETRIS-treated patients.  The most common serious adverse reactions were pneumonia 
(4%), pyrexia (4%), vomiting (3%), nausea (2%), hepatotoxicity (2%), and peripheral sensory 
neuropathy (2%).
Dose modifications
Adverse reactions that led to dose delays in more than 5% of patients in Studies 1 and 2 were 
neutropenia (14%) and peripheral sensory neuropathy (11%) [see Dosage and Administration
(2.2)].
Adverse reactions that led to dose delays in more than 5% of ADCETRIS-treated patients in 
Study 3 were neutropenia (22%), peripheral sensory neuropathy (16%), upper respiratory tract 
infection (6%), and peripheral motor neuropathy (6%) [see Dosage and Administration (2.2)].
Discontinuations
Adverse reactions led to treatment discontinuation in 21% of patients in Studies 1 and 2.
Adverse reactions that led to treatment discontinuation in 2 or more patients with classical HL or 
sALCL were peripheral sensory neuropathy (8%) and peripheral motor neuropathy (3%).
Adverse reactions led to treatment discontinuation in 32% of ADCETRIS-treated patients in 
Study 3. Adverse reactions that led to treatment discontinuation in 2 or more patients were 
peripheral sensory neuropathy (14%), peripheral motor neuropathy (7%), acute respiratory 
distress syndrome (1%), paraesthesia (1%), and vomiting (1%).
6.2
Post Marketing Experience
The following adverse reactions have been identified during post-approval use of ADCETRIS.
Because these reactions are reported voluntarily from a population of uncertain size, it is not 
always possible to reliably estimate their frequency or establish a causal relationship to drug 
exposure.
Blood and lymphatic system disorders: febrile neutropenia [see Warnings and Precautions 
(5.3)].
Gastrointestinal disorders:
•
Pancreatitis (including fatal outcomes).  Consider the diagnosis of pancreatitis for 
patients presenting with severe abdominal pain.
•
Gastrointestinal complications (including fatal outcomes) [see Warnings and Precautions 
(5.12)].
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Hepatobiliary disorders: hepatotoxicity [see Warnings and Precautions (5.8)].
Infections: PML [see Boxed Warning, Warnings and Precautions (5.9)], serious infections and 
opportunistic infections [see Warnings and Precautions (5.4)].
Metabolism and nutrition disorders: hyperglycemia.
Respiratory, thoracic and mediastinal disorders: noninfectious pulmonary toxicity including 
pneumonitis, interstitial lung disease, and ARDS (some with fatal outcomes) [see Warnings and 
Precautions (5.10) and Adverse Reactions (6.1)].
Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, including fatal outcomes 
[see Warnings and Precautions (5.11)].
6.3
Immunogenicity
Patients with classical HL and sALCL in Studies 1 and 2 [see Clinical Studies (14)] were tested 
for antibodies to brentuximab vedotin every 3 weeks using a sensitive electrochemiluminescent 
immunoassay. Approximately 7% of patients in these trials developed persistently positive 
antibodies (positive test at more than 2 timepoints) and 30% developed transiently positive 
antibodies (positive in 1 or 2 post-baseline timepoints). The anti-brentuximab antibodies were 
directed against the antibody component of brentuximab vedotin in all patients with transiently 
or persistently positive antibodies. Two of the patients (1%) with persistently positive antibodies 
experienced adverse reactions consistent with infusion reactions that led to discontinuation of 
treatment. Overall, a higher incidence of infusion related reactions was observed in patients 
who developed persistently positive antibodies.
A total of 58 patient samples that were either transiently or persistently positive for anti-
brentuximab vedotin antibodies were tested for the presence of neutralizing antibodies. Sixty-
two percent of these patients had at least one sample that was positive for the presence of 
neutralizing antibodies. The effect of anti-brentuximab vedotin antibodies on safety and efficacy 
is not known.
Immunogenicity assay results are highly dependent on several factors including assay 
sensitivity and specificity, assay methodology, sample handling, timing of sample collection, 
concomitant medications, and underlying disease. For these reasons, comparison of incidence 
of antibodies to ADCETRIS with the incidence of antibodies to other products may be 
misleading.
7
DRUG INTERACTIONS
In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of 
CYP3A4/5. In vitro data indicate that MMAE is also a substrate of the efflux transporter 
P-glycoprotein (P-gp).
7.1
Effect of Other Drugs on ADCETRIS
CYP3A4 Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A [see Clinical 
Pharmacology (12.3)]. Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 
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inhibitor, increased exposure to MMAE by approximately 34%. Patients who are receiving 
strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for 
adverse reactions. Co-administration of ADCETRIS with rifampin, a potent CYP3A4 inducer, 
reduced exposure to MMAE by approximately 46%.
P-gp Inhibitors: Co-administration of ADCETRIS with P-gp inhibitors may increase exposure to 
MMAE. Patients who are receiving P-gp inhibitors concomitantly with ADCETRIS should be 
closely monitored for adverse reactions.
7.2
Effect of ADCETRIS on Other Drugs
Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate.
MMAE does not inhibit other CYP enzymes at relevant clinical concentrations [see Clinical 
Pharmacology (12.3)]. ADCETRIS is not expected to alter the exposure to drugs that are 
metabolized by CYP3A4 enzymes.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
ADCETRIS can cause fetal harm based on the findings from animal studies and the drug’s 
mechanism of action [see Clinical Pharmacology (12.1)]. In animal reproduction studies, 
administration of brentuximab vedotin to pregnant rats during organogenesis at doses similar to 
the clinical dose of 1.8 mg/kg every three weeks caused embryo-fetal toxicities, including 
congenital malformations [see Data]. Consider the benefits and risks of ADCETRIS and 
possible risks to the fetus when prescribing ADCETRIS to a pregnant woman. 
In the U.S. general population, the estimated background risk of major birth defects and 
miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Data
Animal Data
In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, 
or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy 
Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 
3 DQG  PJNJ RI WKH GUXJ DQG LQFOXGHG LQFUHDVHG HDUO\ UHVRUSWLRQ  SRVW-implantation 
ORVV  decreased numbers of live fetuses, and external malformations (i.e., umbilical 
hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin 
dose of 3 mg/kg is approximately the same exposure in patients with classical HL or sALCL who 
received the recommended dose of 1.8 mg/kg every three weeks.
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8.2
Lactation
Risk Summary
There is no information regarding the presence of brentuximab vedotin in human milk, the 
effects on the breastfed infant, or the effects on milk production. Because of the potential for 
serious adverse reactions in a breastfed infant from ADCETRIS, including cytopenias and 
neurologic or gastrointestinal toxicities, advise patients that breastfeeding is not recommended
during ADCETRIS treatment.
8.3
Females and Males of Reproductive Potential
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating ADCETRIS 
therapy. 
Contraception
Females
Advise females of reproductive potential to avoid pregnancy during ADCETRIS treatment and 
for at least 6 months after the final dose of ADCETRIS.  Advise females to immediately report 
pregnancy [see Use in Specific Populations (8.1)].
Males
ADCETRIS may damage spermatozoa and testicular tissue, resulting in possible genetic 
abnormalities.  Males with female sexual partners of reproductive potential should use effective 
contraception during ADCETRIS treatment and for at least 6 months after the final dose of 
ADCETRIS [see Nonclinical Toxicology (13.1)].
Infertility
Males
Based on findings in rats, male fertility may be compromised by treatment with ADCETRIS [see 
Nonclinical Toxicology (13.1)].
8.4
Pediatric Use
Safety and effectiveness of ADCETRIS have not been established in pediatric patients.
8.5
Geriatric Use
Clinical trials of ADCETRIS did not include sufficient numbers of patients aged 65 and over to
determine whether they respond differently from younger patients.
8.6
Renal Impairment
Avoid the use of ADCETRIS in patients with severe renal impairment (CLcr <30 mL/min) [See 
Warnings and Precautions (5.6)].
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The kidney is a route of excretion for monomethyl auristatin E (MMAE). The pharmacokinetics 
and safety of brentuximab vedotin and MMAE were evaluated after the administration of 
1.2 mg/kg of ADCETRIS to patients with mild (CLcr >50–80 mL/min; n=4), moderate 
(CLcr 30–50 mL/min; n=3) and severe (CLcr <30 mL/min; n=3) renal impairment. In patients 
with severe renal impairment, the rate of Grade 3 or worse adverse reactions was 3/3 (100%) 
compared to 3/8 (38%) in patients with normal renal function. Additionally, the AUC of MMAE 
(component of ADCETRIS) was approximately 2-fold higher in patients with severe renal 
impairment compared to patients with normal renal function. Due to higher MMAE exposure, 
Grade 3 adverse reactions may be more frequent in patients with severe renal impairment 
compared to patients with normal renal function.
8.7
Hepatic Impairment
Avoid the use of ADCETRIS in patients with moderate or severe hepatic impairment [See 
Warnings and Precautions (5.7)].
The liver is a route of clearance for MMAE. The pharmacokinetics and safety of brentuximab 
vedotin and MMAE were evaluated after the administration of 1.2 mg/kg of ADCETRIS to 
patients with mild (Child-Pugh A; n=1), moderate (Child-Pugh B; n=5) and severe (Child-Pugh 
C; n=1) hepatic impairment. In patients with moderate and severe hepatic impairment, the rate 
of Grade 3 adverse reactions was 6/6 (100%) compared to 3/8 (38%) in patients with normal 
hepatic function. Additionally, the AUC of MMAE was approximately 2.2-fold higher in patients 
with hepatic impairment compared to patients with normal hepatic function.
10
OVERDOSAGE
There is no known antidote for overdosage of ADCETRIS. In case of overdosage, the patient 
should be closely monitored for adverse reactions, particularly neutropenia, and supportive 
treatment should be administered.
11
DESCRIPTION
ADCETRIS (brentuximab vedotin) is a CD30-directed antibody-drug conjugate (ADC) consisting 
of three components: 1) the chimeric IgG1 antibody cAC10, specific for human CD30, 2) the 
microtubule disrupting agent MMAE, and 3) a protease-cleavable linker that covalently attaches 
MMAE to cAC10.
Brentuximab vedotin has an approximate molecular weight of 153 kDa. Approximately 
4 molecules of MMAE are attached to each antibody molecule. Brentuximab vedotin is 
produced by chemical conjugation of the antibody and small molecule components. The 
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antibody is produced by mammalian (Chinese hamster ovary) cells, and the small molecule 
components are produced by chemical synthesis.
ADCETRIS (brentuximab vedotin) for Injection is supplied as a sterile, white to off-white,
preservative-free lyophilized cake or powder in single-use vials. Following reconstitution with 
10.5 mL Sterile Water for Injection, USP, a solution containing 5 mg/mL brentuximab vedotin is 
produced. The reconstituted product contains 70 mg/mL trehalose dihydrate, 5.6 mg/mL 
sodium citrate dihydrate, 0.21 mg/mL citric acid monohydrate, and 0.20 mg/mL polysorbate 80
and water for injection. The pH is approximately 6.6.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Brentuximab vedotin is an ADC. The antibody is a chimeric IgG1 directed against CD30. The 
small molecule, MMAE, is a microtubule disrupting agent. MMAE is covalently attached to the 
antibody via a linker. Nonclinical data suggest that the anticancer activity of ADCETRIS is due 
to the binding of the ADC to CD30-expressing cells, followed by internalization of the 
ADC-CD30 complex, and the release of MMAE via proteolytic cleavage. Binding of MMAE to 
tubulin disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest 
and apoptotic death of the cells.
12.2
Pharmacodynamics
QT/QTc Prolongation Potential
The effect of brentuximab vedotin (1.8 mg/kg) on the QTc interval was evaluated in an open-
label, single-arm study in 46 evaluable patients with CD30-expressing hematologic 
malignancies. Administration of brentuximab vedotin did not prolong the mean QTc interval 
>10 ms from baseline. Small increases in the mean QTc interval (<10 ms) cannot be excluded 
because this study did not include a placebo arm and a positive control arm.
12.3
Pharmacokinetics
The pharmacokinetics of brentuximab vedotin were evaluated in early development trials, 
including dose-finding trials, and in a population pharmacokinetic analysis of data from 
314 patients. The pharmacokinetics of three analytes were determined: the ADC, MMAE, and 
total antibody. Total antibody had the greatest exposure and had a similar PK profile as the 
ADC. Hence, data on the PK of the ADC and MMAE have been summarized.
Absorption
Maximum concentrations of ADC were typically observed close to the end of infusion. A
multiexponential decline in ADC serum concentrations was observed with a terminal half-life of 
approximately 4 to 6 days. Exposures were approximately dose proportional from 1.2 to 
2.7 mg/kg. Steady-state of the ADC was achieved within 21 days with every 3-week dosing of 
ADCETRIS, consistent with the terminal half-life estimate. Minimal to no accumulation of ADC 
was observed with multiple doses at the every 3-week schedule.
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The time to maximum concentration for MMAE ranged from approximately 1 to 3 days. Similar 
to the ADC, steady-state of MMAE was achieved within 21 days with every 3 week dosing of 
ADCETRIS. MMAE exposures decreased with continued administration of ADCETRIS with 
approximately 50% to 80% of the exposure of the first dose being observed at subsequent 
doses.
Distribution
In vitro, the binding of MMAE to human plasma proteins ranged from 68–82%. MMAE is not 
likely to displace or to be displaced by highly protein-bound drugs. In vitro, MMAE was a 
substrate of P-gp and was not a potent inhibitor of P-gp.
In humans, the mean steady state volume of distribution was approximately 6–10 L for ADC.
Metabolism
In vivo data in animals and humans suggest that only a small fraction of MMAE released from 
brentuximab vedotin is metabolized. In vitro data indicate that the MMAE metabolism that 
occurs is primarily via oxidation by CYP3A4/5. In vitro studies using human liver microsomes 
indicate that MMAE inhibits CYP3A4/5 but not other CYP isoforms. MMAE did not induce any 
major CYP450 enzymes in primary cultures of human hepatocytes.
Elimination
MMAE appeared to follow metabolite kinetics, with the elimination of MMAE appearing to be 
limited by its rate of release from ADC. An excretion study was undertaken in patients who 
received a dose of 1.8 mg/kg of ADCETRIS. Approximately 24% of the total MMAE 
administered as part of the ADC during an ADCETRIS infusion was recovered in both urine and 
feces over a 1-week period. Of the recovered MMAE, approximately 72% was recovered in the 
feces and the majority of the excreted MMAE was unchanged.
Specific Populations
Renal Impairment: [see Use in Specific Populations (8.6)].
Hepatic Impairment: [see Use in Specific Populations (8.7)].
Effects of Gender, Age, and Race: Based on the population pharmacokinetic analysis;
gender, age, and race do not have a meaningful effect on the pharmacokinetics of 
brentuximab vedotin.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies with brentuximab vedotin or the small molecule (MMAE) have not been 
conducted.
MMAE was genotoxic in the rat bone marrow micronucleus study through an aneugenic 
mechanism. This effect is consistent with the pharmacological effect of MMAE as a microtubule
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disrupting agent. MMAE was not mutagenic in the bacterial reverse mutation assay (Ames test) 
or the L5178Y mouse lymphoma forward mutation assay.
Fertility studies with brentuximab vedotin or MMAE have not been conducted. However, results 
of repeat-dose toxicity studies in rats indicate the potential for brentuximab vedotin to impair 
male reproductive function and fertility. In a 4-week repeat-dose toxicity study in rats with 
weekly dosing at 0.5, 5, or 10 mg/kg brentuximab vedotin, seminiferous tubule degeneration, 
Sertoli cell vacuolation, reduced spermatogenesis, and aspermia were observed. Effects in 
animals were seen mainly at 5 and 10 mg/kg of brentuximab vedotin. These doses are 
approximately 3 and 6-fold the human recommended dose of 1.8 mg/kg, respectively, based on 
body weight.
14
CLINICAL STUDIES
14.1
Classical Hodgkin Lymphoma
Clinical Trial in Relapsed Classical HL (Study 1)
The efficacy of ADCETRIS in patients with classical HL who relapsed after autologous 
hematopoietic stem cell transplantation was evaluated in one open-label, single-arm, 
multicenter trial. One hundred two patients were treated with 1.8 mg/kg of ADCETRIS
intravenously over 30 minutes every 3 weeks. An independent review facility (IRF) performed 
efficacy evaluations which included overall response rate (ORR = complete remission [CR] +
partial remission [PR]) and duration of response as defined by clinical and radiographic 
measures including computed tomography (CT) and positron-emission tomography (PET) as 
defined in the 2007 Revised Response Criteria for Malignant Lymphoma (modified).
The 102 patients ranged in age from 15–77 years (median, 31 years) and most were female 
(53%) and white (87%). Patients had received a median of 5 prior therapies including
autologous hematopoietic stem cell transplantation.
The efficacy results are summarized in Table 4. Duration of response is calculated from date of
first response to date of progression or data cutoff date.
Table 4:
Efficacy Results in Patients with Classical Hodgkin Lymphoma (Study 1)
N=102
Percent (95% CI)
Duration of Response, in months
Median (95% CI)
Range
CR
32 (23, 42)
20.5 (12.0, NE*)
1.4 to 21.9+
PR
40 (32, 49)
3.5 (2.2, 4.1)
1.3 to 18.7
ORR
73 (65, 83)
6.7 (4.0, 14.8)
1.3 to 21.9+
*Not estimable
+Follow up was ongoing at the time of data submission.
Seattle Genetics, Inc. 
SGN35-022 
Brentuximab Vedotin
104 
 
25 July 2016 (Version 3)
                                             


ADCETRIS® (brentuximab vedotin)
22
Randomized Placebo-controlled Clinical Trial in Classical HL Post-auto-HSCT 
Consolidation (Study 3)
The efficacy of ADCETRIS in patients with classical HL at high risk of relapse or disease 
progression post-auto-HSCT was studied in a randomized, double-blind, placebo-controlled 
clinical trial. Three hundred twenty-nine patients were randomized 1:1 to receive placebo or 
ADCETRIS 1.8 mg/kg intravenously over 30 minutes every 3 weeks for up to 16 cycles,
beginning 30–45 days post-auto-HSCT. Patients in the placebo arm with progressive disease 
per investigator could receive ADCETRIS as part of a separate trial.  The primary endpoint was 
progression-free survival (PFS) determined by IRF. Standard international guidelines were 
followed for infection prophylaxis for HSV, VZV, and PCP post-auto-HSCT [see Clinical Trial 
Experience (6.1)].
High risk of post-auto-HSCT relapse or progression was defined according to status following 
frontline therapy: refractory, relapsH ZLWKLQ  PRQWKV RU UHODSVH  PRQWKV ZLWK H[WUDQRGDO
disease. Patients were required to have obtained a CR, PR, or stable disease (SD) to most 
recent pre-auto-HSCT salvage therapy.
A total of 329 patients were enrolled and randomized (165 ADCETRIS, 164 placebo); 
327 patients received study treatment. Patient demographics and baseline characteristics were 
generally balanced between treatment arms.  The 329 patients ranged in age from 18–76 years 
(median, 32 years) and most were male (53%) and white (94%). Patients had received a 
median of 2 prior systemic therapies (range, 2–8) excluding autologous hematopoietic stem cell 
transplantation.
The efficacy results are summarized in Table 5. PFS is calculated from randomization to date 
of disease progression or death (due to any cause). The median PFS follow-up time from 
randomization was 22 months (range, 0–49).  Study 3 demonstrated a statistically significant 
improvement in IRF-assessed PFS and increase in median PFS in the ADCETRIS arm 
compared with the placebo arm. At the time of the PFS analysis, an interim overall survival 
analysis demonstrated no difference.
Table 5:
Efficacy Results in Patients with Classical HL Post-auto-HSCT Consolidation (Study 3)
Progression-free Survival
ADCETRIS
N=165
Placebo
N=164
Independent Review Facility
Number of events (%)
60 (36)
75 (46)
Median months (95% CI)
42.9+ (30.4, 42.9+)
24.1 (11.5, NE*)
Stratified Hazard Ratio (95% CI)
0.57 (0.40, 0.81)
Stratified Log-Rank Test P-value
P=0.001
* Not estimable
+ Estimates are unreliable
Seattle Genetics, Inc. 
SGN35-022 
Brentuximab Vedotin
105 
 
25 July 2016 (Version 3)
                                             




ADCETRIS® (brentuximab vedotin)
24
Table 6:
Efficacy Results in Patients with Systemic Anaplastic Large Cell Lymphoma (Study 2)
N=58
Percent (95% CI)
Duration of Response, in months
Median (95% CI)
Range
CR
57 (44, 70)
13.2 (10.8, NE*)
0.7 to 15.9+
PR
29 (18, 41)
2.1 (1.3, 5.7)
0.1 to 15.8+
ORR
86 (77, 95)
12.6 (5.7, NE*)
0.1 to 15.9+
*Not estimable
+ Follow up was ongoing at the time of data submission.
15
REFERENCES
1.
OSHA Hazardous Drugs. OSHA. [Accessed on 30 July 2013, from
http://www.osha.gov/SLTC/hazardousdrugs/index.html]
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
ADCETRIS (brentuximab vedotin) for Injection is supplied as a sterile, white to off-white 
preservative-free lyophilized cake or powder in individually-boxed single-use vials:
•
NDC (51144-050-01), 50 mg brentuximab vedotin.
16.2
Storage
Store vial at 2–8°C (36–46°F) in the original carton to protect from light.
16.3
Special Handling
ADCETRIS is an antineoplastic product. Follow special handling and disposal procedures1.
17
PATIENT COUNSELING INFORMATION
• Peripheral neuropathy
Advise patients that ADCETRIS can cause a peripheral neuropathy. They should be advised to 
report to their health care provider any numbness or tingling of the hands or feet or any muscle 
weakness [see Warnings and Precautions (5.1)].
• Fever/Neutropenia
Advise patients to contact their health care provider if a fever of 100.5°F or greater or other 
evidence of potential infection such as chills, cough, or pain on urination develops [see 
Warnings and Precautions (5.3)].
• Infusion reactions
Advise patients to contact their health care provider if they experience signs and symptoms of 
infusion reactions including fever, chills, rash, or breathing problems within 24 hours of infusion 
[see Warnings and Precautions (5.2)].
Seattle Genetics, Inc. 
SGN35-022 
Brentuximab Vedotin
107 
 
25 July 2016 (Version 3)
                                             


ADCETRIS® (brentuximab vedotin)
25
• Hepatotoxicity
Advise patients to report symptoms that may indicate liver injury, including fatigue, anorexia, 
right upper abdominal discomfort, dark urine, or jaundice [see Warnings and Precautions (5.8)].
• Progressive multifocal leukoencephalopathy
Instruct patients receiving ADCETRIS to immediately report if they have any of the following 
neurological, cognitive, or behavioral signs and symptoms or if anyone close to them notices 
these signs and symptoms [see Boxed Warning, Warnings and Precautions (5.9)]:
• changes in mood or usual behavior
• confusion, thinking problems, loss of memory
• changes in vision, speech, or walking 
• decreased strength or weakness on one side of the body
• Pulmonary Toxicity
Instruct patients to report symptoms that may indicate pulmonary toxicity, including cough or 
shortness of breath [see Warnings and Precautions (5.10)].
• Pancreatitis
Advise patients to contact their health care provider if they develop severe abdominal pain [see 
Adverse Reactions (6.2)].
• Gastrointestinal Complications
Advise patients to contact their health care provider if they develop severe abdominal pain, 
chills, fever, nausea, vomiting, or diarrhea [see Warnings and Precautions (5.12)].
• Females and Males of Reproductive Potential
ADCETRIS can cause fetal harm. Advise women receiving ADCETRIS to avoid pregnancy
during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.
Advise males with female sexual partners of reproductive potential to use effective 
contraception during ADCETRIS treatment and for at least 6 months after the final dose of 
ADCETRIS [see Use in Specific Populations (8.3)].
Advise patients to report pregnancy immediately [see Warnings and Precautions (5.13)].
• Lactation
Advise patients to avoid breastfeeding while receiving ADCETRIS [see Use in Specific 
Populations (8.2)].
Manufactured by:
Seattle Genetics, Inc.
Seattle Genetics, Inc. 
SGN35-022 
Brentuximab Vedotin
108 
 
25 July 2016 (Version 3)
                                             


ADCETRIS® (brentuximab vedotin)
26
Bothell, WA 98021
1-855-473-2436
U.S. License 1853
ADCETRIS, Seattle Genetics and
are US registered trademarks of Seattle Genetics, Inc.
Seattle Genetics, Inc. 
SGN35-022 
Brentuximab Vedotin
109 
 
25 July 2016 (Version 3)
                                             

SAP_001.pdf: 
 
Document: 
SGN35-022 SAP v1 V0.3 
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Page 1 of 39 
 
STATISTICAL ANALYSIS PLAN 
 
 
SGN35-022 
A MULTI-CENTER, RANDOMIZED, DOUBLE-BLINDED, PLACEBO-CONTROLLED, 
MULTIPLE-ASCENDING-DOSE STUDY OF BRENTUXIMAB VEDOTIN IN ADULTS WITH 
ACTIVE SYSTEMIC LUPUS ERYTHEMATOSUS. 
 
STUDY PHASE: PHASE 2A 
PRODUCT: BRENTUXIMAB VEDOTIN 
AUTHOR: 
 
VERSION NUMBER AND DATE: 1.0, 31 JANUARY 2017 
 
 


 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE - AUTHORS 
 
 
Name 
Signature 
Date 
Author: 
 
 
 
 
Position: 
 
 
Company: 
Quintiles 
 


 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE - APPROVAL 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, authorizing 
that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date 
Approved By: 
 
 
 
 
Position: 
 
 
Company: 
Seattle Genetics 
 
Approved By: 
 
 
 
 
Position: 
 
 
Company: 
Seattle Genetics 
 


 
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MODIFICATION HISTORY 
 
Listed below are modifications made to the SAP after the signed approval(s).  
 
Unique 
Identifier 
for this 
Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
1.0 
 
 
Not Applicable – First Version 
 
 
 
 
 


 
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TABLE OF CONTENTS 
1. 
INTRODUCTION...................................................................................................................... 10 
2. 
STUDY OBJECTIVES ............................................................................................................... 10 
2.1. 
Primary Objective................................................................................................................................... 10 
2.2. 
Secondary Objectives ............................................................................................................................. 10 
3. 
STUDY DESIGN ........................................................................................................................ 10 
3.1. 
General Description ................................................................................................................................ 10 
3.1.1. 
Sample Size ...............................................................................................................................................11 
3.1.2. 
Blinding .....................................................................................................................................................11 
3.2. 
Method of Treatment Assignment .......................................................................................................... 11 
3.3. 
Schedule of Events ................................................................................................................................. 11 
3.4. 
Changes to Analysis from Protocol .......................................................................................................... 12 
4. 
PLANNED ANALYSES............................................................................................................. 12 
4.1. 
Safety Monitoring Committee (SMC) ...................................................................................................... 12 
4.2. 
Interim Analysis ..................................................................................................................................... 12 
4.3. 
Final Analysis ......................................................................................................................................... 12 
5. 
ANALYSIS SETS ....................................................................................................................... 12 
5.1. 
Safety Analysis Set ................................................................................................................................. 12 
5.2. 
Full Analysis Set ..................................................................................................................................... 12 
5.3. 
Per-Protocol Analysis Set ........................................................................................................................ 12 
5.4. 
Pharmacokinetic Analysis Set ................................................................................................................. 13 
5.5. 
Pharmacodynamic Analysis Set .............................................................................................................. 13 


 
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6. 
GENERAL CONSIDERATIONS .............................................................................................. 13 
6.1. 
Summary Statistics ................................................................................................................................. 13 
6.2. 
Precision ................................................................................................................................................ 13 
6.3. 
Baseline ................................................................................................................................................. 13 
6.4. 
Retests, Unscheduled Visits and Early Termination Data ......................................................................... 14 
6.5. 
Common Calculations ............................................................................................................................. 14 
6.6. 
Software Versions .................................................................................................................................. 14 
7. 
STATISTICAL CONSIDERATIONS ...................................................................................... 14 
7.1. 
Adjustment for Covariates ...................................................................................................................... 14 
7.2. 
Multicenter Studies ................................................................................................................................ 14 
7.3. 
Missing data ........................................................................................................................................... 15 
7.4. 
Multiplicity ............................................................................................................................................ 15 
7.5. 
Subgroup Analyses ................................................................................................................................. 15 
8. 
OUTPUT PRESENTATIONS ................................................................................................. 15 
9. 
DISPOSITION AND WITHDRAWALS ................................................................................ 15 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .................................. 15 
10.1. 
Derivations ......................................................................................................................................... 16 
10.2. 
Lupus Diagnosis .................................................................................................................................. 16 
10.3. 
Chest X-Ray ........................................................................................................................................ 16 
11. 
PROTOCOL DEVIATIONS AND VIOLATIONS ................................................................. 16 
12. 
MEDICAL HISTORY ................................................................................................................ 16 
13. 
MEDICATIONS ......................................................................................................................... 16 


 
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14. 
STUDY MEDICATION EXPOSURE ...................................................................................... 17 
15. 
EFFICACY OUTCOMES........................................................................................................... 17 
15.1. 
General Methodology ......................................................................................................................... 17 
15.2. 
Secondary Efficacy .............................................................................................................................. 17 
15.2.1. 
SRI Response .............................................................................................................................................17 
15.2.1.1. 
Derivation .............................................................................................................................................18 
15.2.1.2. 
Analysis .................................................................................................................................................18 
15.3. 
Exploratory Efficacy ............................................................................................................................ 18 
15.3.1. 
BILAG 2004 ...............................................................................................................................................18 
15.3.1.1. 
Derivation .............................................................................................................................................19 
BILAG Clinical Response ............................................................................................................................................19 
BILAG Partial Clinical Response ................................................................................................................................19 
15.3.1.2. 
Analysis .................................................................................................................................................19 
15.3.2. 
BICLA Response ........................................................................................................................................19 
15.3.2.1. 
Derivation .............................................................................................................................................19 
15.3.2.2. 
Analysis .................................................................................................................................................20 
15.3.3. 
CLASI .........................................................................................................................................................20 
15.3.3.1. 
Derivations ............................................................................................................................................20 
15.3.3.2. 
Analysis .................................................................................................................................................20 
15.3.4. 
SLEDAI-2K ..................................................................................................................................................20 
15.3.4.1. 
Derivations ............................................................................................................................................20 
15.3.4.2. 
Analysis .................................................................................................................................................21 
15.3.5. 
Global Assessments: PtGP, PtGA, PhGA ...................................................................................................21 
15.3.5.1. 
Derivations ............................................................................................................................................21 
15.3.5.2. 
Analysis .................................................................................................................................................21 
15.3.6. 
Swollen and Tender Joint Counts .............................................................................................................21 
15.3.6.1. 
Derivations ............................................................................................................................................21 
15.3.6.2. 
Analysis .................................................................................................................................................21 
15.3.7. 
ACR Response ...........................................................................................................................................22 
15.3.7.1. 
Derivations ............................................................................................................................................22 
15.3.7.2. 
Analysis .................................................................................................................................................22 
15.3.8. 
SELENA SLE Flares .....................................................................................................................................22 
15.3.8.1. 
Derivations ............................................................................................................................................22 
15.3.8.2. 
Analysis .................................................................................................................................................23 
15.3.9. 
BILAG SLE Flares ........................................................................................................................................23 
15.3.9.1. 
Derivation .............................................................................................................................................23 
15.3.9.2. 
Analysis .................................................................................................................................................23 
15.3.10. 
Renal Flares ...........................................................................................................................................23 
15.3.10.1. 
Derivation .........................................................................................................................................23 
15.3.10.2. 
Analysis .............................................................................................................................................23 
15.3.11. 
Active Renal Disease .............................................................................................................................24 
15.3.11.1. 
Derivation .........................................................................................................................................24 
15.3.11.2. 
Analysis .............................................................................................................................................24 


 
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15.3.12. 
Concommitant use of Oral Corticosteroids ..........................................................................................24 
15.3.12.1. 
Derivation .........................................................................................................................................24 
15.3.12.2. 
Analysis .............................................................................................................................................24 
15.3.13. 
Treatment Failure .................................................................................................................................24 
15.3.13.1. 
Derivation .........................................................................................................................................25 
15.3.13.2. 
Analysis .............................................................................................................................................25 
15.3.14. 
HAQ-DI ..................................................................................................................................................25 
15.3.14.1. 
Derivation .........................................................................................................................................25 
15.3.14.2. 
Analysis .............................................................................................................................................25 
15.3.15. 
SF-36 .....................................................................................................................................................25 
15.3.15.1. 
Derivation .........................................................................................................................................25 
15.3.15.2. 
Analysis .............................................................................................................................................26 
15.3.16. 
FACIT-F ..................................................................................................................................................26 
15.3.16.1. 
Derivation .........................................................................................................................................26 
15.3.16.2. 
Analysis .............................................................................................................................................26 
15.3.17. 
LupusQoL ..............................................................................................................................................27 
15.3.17.1. 
Derivation .........................................................................................................................................27 
15.3.17.2. 
Analysis .............................................................................................................................................27 
15.3.18. 
Urinary Cellular Casts, Pyruira and Hematuria .....................................................................................27 
15.3.18.1. 
Derivation .........................................................................................................................................27 
15.3.18.2. 
Analysis .............................................................................................................................................27 
15.3.19. 
Protein/creatinine ratio and eGFR ........................................................................................................27 
15.3.19.1. 
Derivation .........................................................................................................................................27 
15.3.19.2. 
Analysis .............................................................................................................................................28 
16. 
PHARMACOKINETIC OUTCOMES...................................................................................... 28 
16.1. 
Pharmacokinetic Concentrations ........................................................................................................ 28 
16.2. 
Pharmacokinetic Parameters .............................................................................................................. 28 
16.3. 
Analyses ............................................................................................................................................. 28 
17. 
PHARMACODYNAMIC OUTCOMES ................................................................................... 28 
17.1. 
Pharmacodynamic Variables ............................................................................................................... 28 
17.2. 
Derivations ......................................................................................................................................... 29 
17.3. 
Analyses ............................................................................................................................................. 29 
18. 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES ........................................... 30 
19. 
SAFETY OUTCOMES .............................................................................................................. 30 


 
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19.1. 
Adverse Events ................................................................................................................................... 30 
19.1.1. 
TEAEs Leading to Discontinuation of Study Medication ...........................................................................31 
19.1.2. 
Serious Adverse Events .............................................................................................................................31 
19.1.3. 
Adverse Events of Special Interest ...........................................................................................................31 
19.1.4. 
Deaths .......................................................................................................................................................32 
19.2. 
Laboratory Evaluations ....................................................................................................................... 32 
19.2.1. 
Laboratory Reference Ranges and CTCAE Grading ...................................................................................32 
19.3. 
Vital Signs ........................................................................................................................................... 33 
19.4. 
ECG Evaluations .................................................................................................................................. 33 
19.5. 
Physical Examination .......................................................................................................................... 34 
20. 
REFERENCES ............................................................................................................................ 35 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS ........................................... 36 
Output Conventions .......................................................................................................................................... 36 
Dates & Times ................................................................................................................................................... 36 
Spelling Format ................................................................................................................................................. 36 
Presentation of Treatment Groups .................................................................................................................... 36 
Listings .............................................................................................................................................................. 36 
PARTIAL DATE CONVENTIONS ........................................................................................................ 37 
Algorithm for Treatment Emergence of Adverse Events: .................................................................................... 37 
Algorithm for Prior / Concomitant Medications: ................................................................................................ 38 
 


 
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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation of safety, pharmacokinetic, 
pharmacodynamic and efficacy data for Protocol SGN35-022. It describes the data analysis to be conducted after 
data base lock and unblinding, and is to be signed prior to those milestones.   
This statistical analysis plan (SAP) is based on protocol Amendment 2, dated 25 July 2016. 
2. STUDY OBJECTIVES 
2.1. 
PRIMARY OBJECTIVE 
To evaluate the safety and tolerability of brentuximab vedotin in adults with active systemic lupus 
erythematosus (SLE). 
2.2. 
SECONDARY OBJECTIVES 
The secondary objectives of the study are: 
• 
to explore the pharmacokinetics (PK) and pharmacodynamics (PD) of brentuximab  vedotin in adults 
with active SLE; and  
• 
to explore the efficacy of brentuximab vedotin in adults with active SLE.  
3. STUDY DESIGN 
3.1. 
GENERAL DESCRIPTION 
This is a multicenter, randomized, placebo-controlled, double-blind, multiple-ascending-dose study to evaluate the 
safety and tolerability of brentuximab vedotin in subjects with active SLE. Approximately 40 subjects in 4 dosing 
cohorts (10 subjects per cohort) are planned for study participation at approximately 20 study sites in the US. 
Subjects who meet inclusion and exclusion criteria will be randomly assigned in a 4:1 ratio within each dosing 
cohort to receive IV brentuximab vedotin or placebo every 3 weeks (Days 1, 22, 43, and 64) for a total of 4 doses. 
The following doses are planned for each ascending dose cohort: 
• 0.3 mg/kg IV every 3 weeks for 4 doses; 
• 0.6 mg/kg IV every 3 weeks for 4 doses; 


 
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• 1.2 mg/kg IV every 3 weeks for 4 doses; and 
• 1.8 mg/kg IV every 3 weeks for 4 doses. 
Individual doses are based on subject weight and will be administered as an IV infusion over approximately 30 
minutes. Dose and/or schedule adjustments are not permitted. In-line filters are permitted. However the study 
drug cannot be mixed with other medications. Further instructions on the dose preparation and administration will 
be provided in the Pharmacy Manual. 
 
Initiation of enrollment at the next dose level will only commence upon endorsement of the SMC following review 
of the safety data. Depending on the findings, the SMC may recommend additional enrollment of subjects at 
specific dose levels to better characterize the safety of a particular dose, or may recommend different dose 
regimens based on the emerging safety data. When available from each full cohort, the SMC will review all Day 85 
safety data and may recommend that an already enrolled succeeding dose cohort be discontinued, or its treatment 
regimen truncated. Doses are not to exceed 1.8 mg/kg IV every 3 weeks or equivalent. Up to 20 subjects total may 
be enrolled via additional SMC-recommended cohorts for a total of up to 60 subjects. 
3.1.1. SAMPLE SIZE 
Since no prior studies in SLE have been conducted with brentuximab vedotin, the primary objective of this study 
is to evaluate the safety and tolerability of brentuximab vedotin in this patient population. As such, the number 
of subjects planned has been based on clinical judgment, to provide sufficient experience upon which to design a 
larger efficacy (Phase 2) study.  
3.1.2. BLINDING 
This is a randomized, double-blind, placebo-controlled study with limited access to the randomization code. 
Brentuximab vedotin and placebo solutions for IV administration will be identical in physical appearance. The 
treatment each subject will receive during the treatment period will not be disclosed to the Investigator, study 
site personnel, subject, or the blinded study team.   
For more details on blinding refer section 5.6 Blinding of the protocol. 
3.2. 
METHOD OF TREATMENT ASSIGNMENT 
The subjects will be randomly assigned to the study treatment by the study site using Interactive Web Response 
System (IWRS). The IWRS will provide the study drug kit number(s) of the blinded study drug to be dispensed. 
Randomization will occur on Day 1 prior to the first dose. 
3.3. 
SCHEDULE OF EVENTS 
Schedule of events can be found in APPENDIX 2: SCHEDULE OF EVENTS of the protocol. 


 
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3.4. 
CHANGES TO ANALYSIS FROM PROTOCOL 
There are no meaningful deviations from the analyses planned in the study protocol. 
4. PLANNED ANALYSES 
4.1. 
SAFETY MONITORING COMMITTEE (SMC) 
Please refer to the SMC SAP. 
4.2. 
INTERIM ANALYSIS  
No formal interim analyses are planned. 
4.3. 
FINAL ANALYSIS  
The final analyses will be conducted after the finalization of the SAP, database lock and unblinding. 
5. ANALYSIS SETS 
5.1. 
SAFETY ANALYSIS SET 
The safety analysis set (SAF) includes all subjects who receive at least one dose of study medication.  Subjects in 
this population is used for all safety, dosing, demographic, disposition and pharmacodynamic summaries.  The 
SAF will be analyzed according to the treatment administered. 
5.2. 
FULL ANALYSIS SET 
The full analysis set (FAS) includes all randomized subjects, without regard for treatment administration.  The FAS 
will be analyzed according to the treatment assigned, and used for all efficacy analyses. 
5.3. 
PER-PROTOCOL ANALYSIS SET 
The per-protocol analysis set (PPAS) includes all randomized subjects who have received at least 1 dose of study 
medication, have both the baseline and Day 85 SRI and have no protocol violations. The PPAS will be analyzed 
according to the actual treatment received, and will be used for the secondary efficacy analysis only.  


 
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5.4. 
PHARMACOKINETIC ANALYSIS SET 
The PK analysis set (PKAS) includes all randomized subjects who have received at least 1 dose of brentuximab 
vedotin, have a post-baseline PK measurement. The PKAS will be analyzed according to the treatment 
administered. 
5.5. 
PHARMACODYNAMIC ANALYSIS SET 
The PD analysis set (PDAS) includes all randomized subjects who have received at least 1 dose of study 
medication, have a post-baseline PD measurement.  The PDAS will be analyzed according to the treatment 
administered. 
6. GENERAL CONSIDERATIONS  
Some minor modifications may be necessary to the planned design of tables, figures, and listings to 
accommodate data collected during the actual study conduct. 
6.1. 
SUMMARY STATISTICS 
For qualitative variables, the population size (N for sample size and n for available data) and the percentage (of 
available data) for each class of the variable will be presented.  Quantitative variables will be summarized using 
descriptive statistics, including N, mean, standard deviation (SD), coefficient of variation (CV%), median, 25th 
percentile, 75th percentile, minimum, and maximum values.  CV will not be presented for change from baseline 
results.  95% CI will be reported in place of CV for efficacy variables. 
In general, data will be summarized for each dose group, with all placebo subjects aggregated into a single group, 
and scheduled study day/visit.  Data for all active-treated subjects combined will also be presented when 
appropriate.  Descriptive statistics for optional tests will be suppressed if the sample size is below 3. 
6.2. 
PRECISION 
All variables, including derivations thereof, will be reported to the same precision as the source data.  
For the reporting of descriptive statistics, the mean, standard deviation, standard error and confidence intervals 
will be presented to one digit more precision than the source data.   The minimum, median, 25th percentile, 75th 
percentile and maximum will be presented to the same precision as the source data.  Coefficient of variation will 
always be reported to 1 decimal place.  P-values, if any, shall be reported to four decimal places or as <0.0001. 
6.3. 
BASELINE 
Baseline, is defined as the last scheduled non-missing measurement taken prior to dosing and will correspond to 


 
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Day 1 (predose) for clinical laboratory evaluations, physical examinations, vital signs and ECGs.  Baseline for 
efficacy and pharmacodynamics is defined as the Day 1 assessments.  However, if a subject is missing the 
planned baseline collection, the previous non-missing evaluation if available will become the baseline value.  
End of treatment (EOT) is defined as Day 85 for use in the efficacy analyses. 
6.4. 
RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
Unscheduled measurements will not be included in summary statistics, but will contribute to the assessment of 
clinical outliers.  Early termination results will be recorded as such, and included with the summaries. 
In the case of a retest of a scheduled assessment, the earliest available measurement for that scheduled time 
(i.e. the original assessment) will be used for summaries unless flagged as invalid.  
Listings will include all scheduled, unscheduled, retest and early discontinuation data. 
6.5. 
COMMON CALCULATIONS 
• 
Change from baseline (CFB)  = Observed Value (after baseline) – Baseline Value 
• 
Percent change from baseline (PCFB) = CFB / Baseline Value * 100.  
• 
Change from end of treatment (CFEOT)  = Observed Value (after treatment end) – EOT Value 
• 
Percent change from end of treatment (PCFEOT) = CFEOT / EOT Value *100. 
6.6. 
SOFTWARE VERSIONS 
All derivations, statistical analyses, summaries and listings will be generated using SAS version 9.4 or higher (SAS 
Institute, Inc., Cary, North Carolina).  Graphics may be prepared using the same version of SAS.   
7. STATISTICAL CONSIDERATIONS 
7.1. 
ADJUSTMENT FOR COVARIATES 
The baseline value for a dependent variable will be used as a continuous covariate in statistical models when 
available.  
7.2. 
MULTICENTER STUDIES 
Given the small number of subjects per study center/site, no adjustment for site effects will be considered OR 
sites will be aggregated according to geographic regions: USA (Western, Southern, Central, Northeast), Central 
America, South America, and Canada. 


 
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7.3. 
MISSING DATA 
Missing data will not be imputed.  Treatment attribution of adverse events and concomitant medications, in the 
event of missing dates, will be determined as specified in Appendix 2. 
7.4. 
MULTIPLICITY 
Given the lack of primary statistical hypotheses, small sample size, large number of endpoints, and the 
hypothesis generating nature of this study, no adjustment for multiplicity will be made for this study. 
7.5. 
SUBGROUP ANALYSES 
No subgroup analyses will be performed for this study. 
8. OUTPUT PRESENTATIONS 
Appendix 1 shows conventions for presentation of data in outputs.  
The templates provided with this SAP outline the presentations, format and content of the summary tables, 
figures and listings to be provided by Quintiles Biostatistics. 
9. DISPOSITION AND WITHDRAWALS 
All subjects who provide informed consent, are randomized and received study medication, will be accounted in 
this study. Subject disposition will be tabulated for each dose group with the number of subjects who are 
randomly assigned to treatment, complete the study, prematurely discontinue, and the reason for early 
discontinuation. A listing will present dates of completion or early withdrawal and the reason for early 
discontinuation, if applicable, for each subject.   
Listings of subject consent, screen failures, inclusion/exclusion criteria responses, study eligibility, study drug 
administration and study visits will be provided. 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic characteristics such as age, sex, race, ethnicity, height, weight, and body mass index (BMI) will be 
summarized and tabulated by dose group. Descriptive statistics will be presented for age, height, weight, and 
BMI.  Frequency counts and percent will be presented for sex, race, and ethnicity.  No statistical testing will be 
carried out for demographic or other baseline characteristics.  


 
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10.1. 
DERIVATIONS 
• 
BMI (kg/ m2) = weight (kg)/ height (m)2 
• 
Age (years) will be calculated as the number of complete years for patients’ birth date relative to date 
of consent. 
10.2. 
LUPUS DIAGNOSIS 
Current signs and symptoms for lupus will be listed along with the date and length of lupus diagnosis. 
10.3. 
CHEST X-RAY 
The date and overall interpretation of chest x-rays taken in the 3-months prior to Screening will be listed. 
11. PROTOCOL DEVIATIONS AND VIOLATIONS 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Manual of Procedure 
requirements.  The noncompliance may be either on the part of the subject, the site PI, or the study site staff. 
Any subject enrolled who does not meet eligibility criteria will be considered an enrollment deviation.  
All protocol deviations will be summarized with the number (%) of subjects by category and/or type deviation.  
Protocol violations are defined as those meriting exclusion from the PPAS.  These will be identified through 
review of the protocol deviation logs prior to database lock and unblinding.  All protocol violations and those 
meriting exclusion from the PPAS will be listed. 
12. MEDICAL HISTORY 
Medical History is collected and will be coded using MedDRA Version 18.0. Medical history will be listed and 
summarized by SOC and preferred term for each treatment group. 
13. MEDICATIONS 
Medication usage is collected and coded using the WHO Drug Dictionary 01MAR2014.  
• 
 ‘Prior’ medications are medications which started and stopped prior to providing informed consent.  
• 
  ‘Concomitant’ medications are medications which were taken during the treatment period, or 
specifically:  
o 
started after providing informed consent or  
o 
started prior to providing informed consent and ended after providing informed consent or was 
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See Appendix 2 for handling of partial dates for medications, in the case where it is not possible to define a 
medication as prior, concomitant, or post treatment, the medication will be classified by the worst case; i.e. 
concomitant. 
A subject listing of all previous and concomitant medications will be presented. The total number and percentage 
of subjects with concomitant medications will be presented by Anatomical Therapeutic Chemical (ATC) 
classification and preferred term. This summary will not include previous medication. 
Lupus specific medications will be listed separately, based on the specific eCRF panel. 
14. STUDY MEDICATION EXPOSURE 
Exposure to study medication as the number of doses administered (1, 2, 3 or 4) will be listed for each subject, 
and summarized. 
The percentage of subjects with dose interruptions due to treatment-emergent AEs will be summarized by 
treatment. 
15. EFFICACY OUTCOMES    
There is no primary efficacy endpoint defined for this study.   Secondary and exploratory efficacy analysis are 
described below. 
15.1. 
GENERAL METHODOLOGY 
If subjects are missing assessments during participation in the trial (prior to completion or withdrawal), these will 
be assumed to be non-events. The denominator used for percentages or proportions in tabulations will be the 
number of subjects in the analysis set with available data for the corresponding time point and treatment group. 
The time to a pre-defined event will be calculated in days for each subject and response/flare as the date of the 
first event minus the date of randomization.  If the date of the event is not recorded, the date of the study visit 
will be used.  When there are multiple criteria to be met, the first event date is defined as the first date on which 
all criteria are met concurrently. If no flare/event occurred prior to the end of study participation (including for 
early termination), the time to flare will be regarded as censored at termination. 
15.2. 
SECONDARY EFFICACY 
All secondary efficacy analyses will be performed using both the FAS and the PPAS.   
15.2.1. SRI RESPONSE 
Systemic Lupus Erythematosus Responder Index (SRI) response will be assessed for Study Days 22, 43, 64, 85, 
106, and 127, with Day 85 specified as the secondary endpoint for the study.  


 
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15.2.1.1. DERIVATION 
The SRI definition of response includes meeting all of the following criteria: 
• 
Reduction from baseline in SLEDAI of at least 4 points; 
• 
no new British Isles Lupus Assessment Group (BILAG) A organ domain scores, relative to baseline 
• 
no more than 1 new BILAG B score, relative to baseline;  
• 
no worsening (increase of < 10% of scale length) in PhGA, relative to baseline. 
Assessment for response will be made using data only for the visit of interest and baseline, without regard for 
changes at prior on-treatment visits. 
15.2.1.2. ANALYSIS 
The following analyses will be performed for all study days with Day 85 specified as the secondary endpoint, and 
all other visits falling under exploratory analyses. 
The percentage of subjects demonstrating SRI Response will be presented by treatment with 95% CI using 
Wilson’s score method (SAS PROC FREQ syntax: table response/binomial (wilson)).  Comparisons between each 
active treatment group and placebo will be performed using Fisher’s exact test (two-sided).  The ratio of 
percentages (relative risk) for active to placebo will be presented for each dose level with corresponding 95% CI, 
based on the score method [Farrington]  (SAS PROC FREQ syntax: table trta*response / relrisk(method=score 
equal) ).  Percentages with Wilson 95% CI will be plotted versus study day per treatment, with all treatments 
overlain. 
Logistic regression of the log odds of SRI response on log2 dose level (mg/kg) will be performed. Placebo subjects 
will be treated as a having dose of 0 mg/kg.  Based on this model, the estimate of the slope and odds ratio (OR) 
for a doubling of dose will be presented with 95% CI (based on the profile likelihood) and two-sided p-value 
(Wald test). 
15.3. 
EXPLORATORY EFFICACY 
All efficacy variables outside SRI are defined as exploratory for this protocol. All exploratory efficacy analyses will 
be performed using the FAS only.  Analyses will be performed for all scheduled on-treatment assessments 
collected. 
15.3.1. BILAG 2004 
The BILAG disease activity index is assessed and scored by trained study investigators based the past 4 weeks of 
patient experience.  Scoring is performed for each of the following domains: constitutional, mucocutaneous, 
central nervous system, musculoskeletal, cardiovascular/respiratory, abdominal, renal, ophthalmic and 
haematological.  A total score will be derived from the nine domains by the investigator, as the maximum 
severity across the domains.   No programmatic derivation is required for the index itself.   BILAG scores are 
graded as follows: Grade A represents very active disease; Grade B represents moderate disease activity; Grade C 


 
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indicates mild stable disease; Grade D indicates no disease activity; Grade E indicates no current or previous 
disease activity. 
No numeric scores will be assigned to the grades for any analyses. 
15.3.1.1. DERIVATION 
BILAG CLINICAL RESPONSE 
BILAG Clinical Response is defined as: 
• 
BILAG C scores or better in all organ domains; which includes by definition no new BILAG A or B scores 
in any organ domain 
BILAG PARTIAL CLINICAL RESPONSE 
BILAG Partial Clinical Response is defined as: 
• 
at most 1 BILAG A or B score in any organ domain 
15.3.1.2. ANALYSIS 
BILAG domain scores will be tabulated by treatment group at each visit, plus categories for grade B or worse and 
grade C grade or better.  Shifts from baseline among the grades will be tabulated similarly.  Individual grades for 
each domain will be graphed over time, treating grade as ordinal, with one plot per subject.   
The analysis for BILAG clinical response (full and partial) will replicate that performed for SRI. 
15.3.2. BICLA RESPONSE 
15.3.2.1. DERIVATION 
The BILAG-based Combined Lupus Assessment (BICLA) definition of response includes all of the following: 
• 
BILAG-2004 improvement (all A scores at baseline improved to B/C/D, and all B scores improved to C or 
D); 
• 
no worsening in disease activity (no new BILAG-2004 A scores and ≤ 1 new B score); 
• 
no worsening of total SLEDAI-2K score from baseline (no change or reduction from baseline); 
• 
no significant deterioration (< 10% worsening) in 100 mm visual analogue PhGA; 
• 
no treatment failure (See Section 15.3.15) 
Patients’ BICLA response will be derived from the above criteria for visits on which all of the component variables 
are captured.   


 
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15.3.2.2. ANALYSIS 
The analysis for BICLA response will replicate that performed for SRI. 
15.3.3. CLASI 
The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) consists of measures of cutaneous 
disease activity and damage over 14 anatomical locations, with the scores ranging from 0-70 and 0-56, 
respectively, and higher scores indicating greater severity (Klein, 2010).  Scores are determined by trained 
investigators and are recorded on the eCRF.  
15.3.3.1. DERIVATIONS 
CFB, PCFB, CFEOT and PCFEOT will be calculated for this endpoint.  
15.3.3.2. ANALYSIS 
Observed and change values will be summarized by treatment group.  Means with 95% CI will be plotted for 
Observed and CFB values over time with treatment groups overlain. Individual values over time will be plotted 
over time per treatment group.  
An analysis of covariance model will be fit for CFB/CFEOT at each scheduled time, with a fixed effect for 
treatment group and a covariate for the baseline value.   Comparisons will be made between each dose level, 
and all active treated subjects combined versus placebo at the 5% significance level (two-sided).  Least-squares 
treatment means and mean differences will be estimated with 95% CI and two-sided p-values for the test of no 
treatment difference. 
15.3.4. SLEDAI-2K 
The Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) is numeric index based on 24 
outcomes covering 9 organs systems, each with scores ranging from 1 to 8 when the outcome is present (Yee, 
2011). The total SLEDAI-2K score is the simple sum of the scores and falls between 0 and 105, with higher scores 
representing higher disease activity.  Scores are determined by trained investigators and are recorded on the 
eCRF. 
15.3.4.1. DERIVATIONS 
CFB, PCFB, CFEOT and PCFEOT will be calculated for this endpoint and the organ systems. 
A SLEDAI clinical response is defined as an improvement (reduction) of 4 or more points, relative to baseline. 


 
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15.3.4.2. ANALYSIS 
The analyses for SLEDAI-2K scores will replicate those performed for CLASI.     
The analysis for SLEDAI clinical response will replicate those performed for SRI. 
Boxplots profiles of SLEDAI-2K through time (study day) for each dose level.  Stacked bar graphs will be 
generated for each subject with all visits included, with stacks comprised of the scoring domains, and dose levels 
comprising separate pages.   
15.3.5. GLOBAL ASSESSMENTS: PTGP, PTGA, PHGA 
Physician’s Global Assessment of Disease Activity (PhGA), Patient’s Global Assessment of Disease Activity (PtGA), 
Patient’s Global Assessment of Pain (PtGP) are assessed as visual analog scale responses ranging from 0 to 100 
mm, with higher numbers indicating greater activity/pain. 
15.3.5.1. DERIVATIONS 
CFB, PCFB, CFEOT and PCFEOT will be calculated for these endpoints. The following reductions in global scores 
will be derived: 20%, 50% and 70%, labeled as PhGA20/50/70, PtGA20/50/70, PtGP20/50/70. 
15.3.5.2. ANALYSIS 
The analyses for global assessments will replicate those performed for CLASI.  PhGA20/50/70, PtGA20/50/70, 
and PtGP20/50/70 will be tabulated by treatment. 
Grouped subject-level line (spaghetti) plots vs study day will be generated, with one plot per dose level. 
15.3.6. SWOLLEN AND TENDER JOINT COUNTS 
Swollen and tender joint counts (SJC; TJC) are measured out a total of 66 and 68 joints, respectively.  
15.3.6.1. DERIVATIONS 
CFB, PCFB, CFEOT and PCFEOT will be calculated for both joint counts.  The following reductions in PCFB joint 
counts from baseline will be derived: 20%, 50% and 70% (SJC20/50/70 and TJC20/50/70).  
15.3.6.2. ANALYSIS 
The analyses for SJC/TJC will replicate those performed for CLASI.   SJC20/50/70 and TJC20/50/70 will be 
summarized by treatment. 


 
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15.3.7. ACR RESPONSE 
The American College of Rheumatology (ACR) response criteria are standard criteria used to identify 
improvement across 7 biometrics by a specified minimum percentages of 20, 50 and 70%. 
15.3.7.1. DERIVATIONS 
ACR20, ACR50 and ACR70 responses relative to baseline will be assessed on Days 43, 85 and 127 using the 
standard definition (Felson, 1995), namely a 20/50/70% reduction in both SJC and TJC, plus a 20/50/70% 
reduction in 3 of the following 5 tests: PtGP, PtGA, PhGA, HAQ-DI and ESR.  Response will only be assessed for 
subjects for whom sufficient variables are available at the given visit, and will otherwise be regarded as a missing 
value. 
15.3.7.2. ANALYSIS 
The analysis for ACR response will replicate that performed for SRI. 
15.3.8. SELENA SLE FLARES 
Occurrence of SELENA SLE flares will be recorded on the eCRF. 
A mild/moderate flare is defined to include any of the following: 
• 
increase in SLEDAI ≥ 3 points, relative to baseline 
• 
new/worse skin, stomatitis, serositis, arthritis, or fever 
• 
increased prednisone < 0.5 mg/kg/day 
• 
added NSAID/hydroxychloroquine 
• 
increase in PhGA ≥ 1.0, relative to baseline 
A severe flare is defined to include any of the following: 
• 
increase in SLEDAI ≥ 12 points, relative to baseline 
• 
new/worse CNS-SLE, vasculitis, nephritis, myositis, platelet count < 60,000/μL, hemolytic anemia with 
hemoglobin < 7 mg/dL, requiring doubling > 0.5 mg/kg/day prednisone 
• 
hospitalization for SLE 
• 
prednisone > 0.5 mg/kg/day 
• 
new immunosuppressive increase in PhGA to > 2.5, relative to baseline 
15.3.8.1. DERIVATIONS 
Time to flare will be calculated for each severity as defined in Section 15.1.   


 
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15.3.8.2. ANALYSIS  
The analysis for incidence of flares will replicate that performed for SRI, and will be performed for each severity 
grade (mild/moderate and severe) and overall.  
The flare-free survival function will be estimated by treatment group and for all active-treated subjects combined 
using Kaplan-Meier methodology, with 95% confidence intervals based on Greenwood’s formula.  These survival 
curves will be plotted.  The KM estimates of quartiles for time to event with the corresponding 95% CIs will be 
provided for each treatment and for all active-treated subjects, when estimable, using Greenwood’s formula. 
15.3.9. BILAG SLE FLARES 
15.3.9.1. DERIVATION 
A moderate flare is defined as ≥ 2 new BILAG B domain scores, relative to baseline. A severe flare is defined as 
development of any new BILAG A domain score, relative to baseline. 
The time to first flare will be derived for each severity above, as detailed in Section 15.1. If a subject experiences 
both moderated and severe flares during the course of the study, both events will be analysed separately. 
The number of domains exhibiting a new A or B score will be determined per subject per study visit. 
15.3.9.2. ANALYSIS 
The analysis for BILAG SLE flares (moderate, severe, moderate or severe) will replicate that performed for SRI. 
Flare-free survival will be analyzed as detailed for SELENA flares (Section 15.3.8.2). The number of domains 
exhibiting a new A or B scores will be tabulated. 
15.3.10. 
RENAL FLARES 
Renal flares are defined as in Section 6.2.2 of the study protocol, and occurrences are captured on the eCRF.   
15.3.10.1. DERIVATION 
The time to first flare will be calculated in days as defined in Section 15.1.   
15.3.10.2. ANALYSIS 
The analysis for occurrence of renal flares will replicate that performed for SRI.    Flare-free survival will be 
estimated as detailed for SELENA flares (Section 15.3.8.2).  


 
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15.3.11. 
ACTIVE RENAL DISEASE 
Active Renal disease is defined as in Section 6.2.2 of the study protocol, and occurrences are captured on the 
eCRF.   
15.3.11.1. DERIVATION 
The time to first diagnosis will be calculated in days as defined in Section 15.1.   
15.3.11.2. ANALYSIS 
The analysis for occurrence of active renal disease will replicate that performed for SRI.    Flare-free survival 
endpoints will be analyzed as detailed for SELENA flares (Section 15.3.8.2).  
15.3.12. 
CONCOMMITANT USE OF ORAL CORTICOSTEROIDS 
Use of oral corticosteroids is collected continuously in the concomitant medication panel of the eCRF and will be 
identified using the WHO anatomical therapeutic class.  
15.3.12.1. DERIVATION 
Corticosteroid usage will be assessed (present vs absent) for each postdose visit, as the interval starting with the 
date following the previous visit and ending with the date of the current visit (inclusive).   
The time to first usage of oral corticosteroids will be calculated in days as defined in Section 15.1.   
15.3.12.2. ANALYSIS 
The analysis for corticosteroid usage will replicate that performed for SRI.  Corticosteroid -free survival endpoints 
will be analyzed as detailed for SELENA flares (Section 15.3.8.2). 
15.3.13. 
TREATMENT FAILURE 
Treatment failure is defined as meeting at least one of the following criteria, and will be recorded on the eCRF: 
• 
Death 
• 
Premature withdrawal from the study due to adverse events or lack of efficacy 
• 
Addition of new or increased immunosuppressive or antimalarial or increased or parenteral 
corticosteroids. 


 
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15.3.13.1. DERIVATION 
The time to treatment failure will be to the first occurrence of the above events, calculated in days as defined in 
Section 15.1.   
15.3.13.2. ANALYSIS   
The time to treatment failure will be analyzed as detailed for SELENA flares (Section 15.3.8.2). 
15.3.14. 
HAQ-DI 
The Health Assessment Questionnaire (HAQ) Disability Index (DI) assesses patient disability over the past week 
over 8 daily functions and activities on a scale of 0 to 3, with 0 indicating no difficulty and 3 indicating inability.  
Version 96.4 is being used for this study.  The independent HAQ assessments for pain and health VAS are also 
collected. 
15.3.14.1. DERIVATION 
The standard HAQ-DI will be scored according to the instructions for version 96.4 (National Institute of 
Environmental Health Sciences, 1996), including the handling of missing values.  In summary, the maximum 
severity reported for each function is averaged across all available functions for the assessment.  If an aide or 
device is used or if help is required from another individual, then the minimum score for that function is 2.  The 
HAQ-DI will be calculated to 3 decimal places. 
CFB, PCFB, CFEOT and PCFEOT will be calculated.   The following reductions in HAQ-DI score from baseline will be 
derived: 20%, 50% and 70% (HAQ20, HAQ50 and HAQ70). 
15.3.14.2. ANALYSIS 
The analyses for HAQ-DI will replicate those performed for CLASI.   HAQ20/50/70 will be summarized by treatment. 
15.3.15. 
SF-36 
The RAND 36-Item Short Form Health Survey (SF-36; Version 1.0) estimates quality of life indices over 8 
components ranging from 0 to 100, over the past four weeks, plus subjects’ perception of change in health.  
Scores represent the percentage of total possible score achieved and higher scores indicates a more favorable 
health state.  
15.3.15.1. DERIVATION 
Scoring of the SF-36 will comply with the Rand scoring instructions version 1 (Rand Corporation, 2016), including 
the handling of missing components.  Responses are coded to scores ranging from zero to 100, based on Table 1 


 
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in the instructions.  Groups of scores are then averaged to form the overall score for each component, based on 
Table 2 of the instructions. 
No normalization will be performed on the component scores, in compliance with the version 1 scoring 
instructions.  Summary scores for physical and mental health will be derived from all components of the SF-36 
using orthogonal factor scoring coefficients derived from a large sample that allow the components to be 
correlated, using the 1998 z-scores for the 8 components.  
CFB, PCFB, CFEOT and PCFEOT will be calculated for all scores.   
15.3.15.2. ANALYSIS 
The analyses for SF-36 physical and mental component scores will replicate those performed for CLASI.  Summary 
statistics for the observed scores only will be presented for the 8 SF-36 components.  
15.3.16. 
FACIT-F 
Functional Assessment of Chronic Illness Therapy (FACIT) measures subjects’ quality of life level (QOL) over the 
categories of physical, social/family, emotional and functional well-being over 27 questions using on a five-point 
Likert scale (0 to 4), with higher scores indicating better QOL.  A supplementary fatigue score is measured over 
13 additional questions using the same scale, for which a score of less than 30 indicates severe fatigue. 
15.3.16.1. DERIVATION 
The FACIT-F fatigue score, FACIT-F Trial Outcome Index (TOI), Functional Assessment of Cancer Therapy-General 
(FACT-G), and FACIT-F total score will be calculated from the Likert responses. FACIT-F Scoring Guidelines Version 
4 (Cella, 2004) will be used to derive each component score and the following indices: 
• 
FACIT-F fatigue score = weighted sum of available response scores * 13; range 0-52 
• 
FACIT-F Trial Outcome Index (TOI) = weighted sum of available physical, functional, and fatigue scores; 
range 0-108 
• 
FACT-G total score = weighted sum of available physical, social/family, emotional and functional scores; 
range 0-108 
• 
FACIT-F total score = weighted sum of available components scores (physical, social/family, emotional, 
functional, fatigue); range 0-160 
CFB, PCFB, CFEOT and PCFEOT will be calculated for all scores. 
15.3.16.2. ANALYSIS 
The analyses for all FACIT scores will replicate those performed for CLASI.  The Likert responses will be listed only. 


 
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15.3.17. 
LUPUSQOL 
The LupusQOL measures subjects’ quality of life level for the past four weeks over eight domains (physical 
health, pain, planning, intimate relationship, burden to others, emotional health, body image, fatigue) using 34 
questions using on a five-point Likert scale (0 to 4), and  yielding scores ranging from 0 to 100, with higher scores 
indicating better QOL. 
15.3.17.1. DERIVATION 
Scores for each domain will be calculated as the average of the available Likert responses/4 * 100 (McElhone, 
2007). CFB, PCFB, CFEOT and PCFEOT will be calculated for all domains. 
15.3.17.2. ANALYSIS 
The analyses for all LupusQOL scores will replicate those performed for CLASI. 
15.3.18. 
URINARY CELLULAR CASTS, PYRUIRA AND HEMATURIA 
Urinary cellular casts (RBC and WBC only), RBC and WBC in urine are recorded as ordinal categorical results by the 
clinical labs.   
15.3.18.1. DERIVATION 
No derivations are required for this analysis. 
15.3.18.2. ANALYSIS 
Shift tables will be presented, tabulating the number of subjects moving from baseline to the each of the result 
categories for these laboratory tests.  This analysis may be repeated for subjects assessed with active renal 
disease at any point during the trial, if sufficient sample size is available. 
15.3.19. 
PROTEIN/CREATININE RATIO AND EGFR 
Protein/creatinine ratio and eGFR are captured as central laboratory results. 
15.3.19.1. DERIVATION 
CFB, PCFB, CFEOT and PCFEOT will be calculated for all of these laboratory tests. 


 
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15.3.19.2. ANALYSIS 
The analyses will replicate those performed for CLASI. This analysis will be repeated for subjects assessed with 
active renal disease at any point during the trial. 
16. PHARMACOKINETIC OUTCOMES 
16.1. 
PHARMACOKINETIC CONCENTRATIONS 
Concentrations of brentuximab vedotin (ADC), total antibody (TAb), and monomethyl auristatin E (MMAE) will be 
assayed for samples collected on Days 1, 2, 3, 8, 15, 22, 43, 64, 85 and 106.  Antitherapeutic antibodies are 
measured prior to each dosing and on Days 1, 85, 106, and 127. 
16.2. 
PHARMACOKINETIC PARAMETERS 
Derivation the pharmacokinetic parameters is the responsibility of the sponsor or designee, and outside the scope 
of this SAP.  
16.3. 
ANALYSES 
A listing of PK blood sample collection times as well as derived sampling time deviations will be provided. 
Plasma concentrations will be summarized using descriptive statistics for each treatment group/dose level.  
Concentrations that are below the limit of quantitation (BLQ) will be treated as zero for the computation of 
descriptive statistics. Figures of arithmetic mean concentration-time data ±SD will be presented for each 
treatment on linear and semi-logarithmic scales.  The incidence of antitherapeutic antibodies will be tabulated. 
A subject listing of all concentration-time data for each treatment will be presented.  Individual subject 
concentration-time data will be graphically presented on linear and semi-logarithmic scales. 
Plasma parameters will be summarized using descriptive statistics for each treatment group/dose level.  Dose 
proportionality will be assessed using least-squares regression of the log-transform PK parameters on log dose.  
Slope and intercept estimates will be presented with 90% CI.   AUC and Cmax parameters will be plotted vs dose 
on the log-log scale, with the regression lines overlain.   
17. PHARMACODYNAMIC OUTCOMES 
17.1. 
PHARMACODYNAMIC VARIABLES 
The following variables are collected as PD endpoints throughout this study: 


 
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• 
flow cytometry for specific lymphocyte populations 
• 
inflammatory markers, including: ESR, hsCRP, sCD30, and soluble CD153 (sCD153) 
• 
quantitative autoantibody assays including, but not limited to: 
o 
antinuclear antibodies (ANA), as assessed by indirect immunofluorescence titer:  quantified in ratios 
such as 1:80, 1:160, 1:320.  
o 
anti-dsDNA; 
o 
anti-C1q (quantitative); 
o 
anti-Smith antibodies (anti-Sm), anti-ribonucleoprotein (anti-RNP), anti-Sjögren’s Syndrome A 
antibodies (anti-SSA), and anti-Sjögren’s Syndrome B antibodies (anti-SSB);  
o 
anti-cardiolipin IgA, IgG and IgM, anti-β-2-glycoprotein IgG and IgM, lupus anticoagulant; 
o 
direct Coombs test (Positive/Negative); and 
o 
quantitative IgG, IgM, IgA, and IgE 
• 
complement studies: C1q, C3, C4, and CH50 
• 
lymph node or tonsil biopsies (optional): T cell subpopulations, CD4+ and CD4+CD30+, and 
subpopulations of each, CD8+ and CD8+CD30+; B cell subpopulations, germinal center structure 
Note that samples collected for cytokine assessment were planned for possible future testing and therefore 
outside the scope of this SAP. 
17.2. 
DERIVATIONS 
CFB, PCFB, CFEOT and PCFEOT will be calculated for all quantitative PD tests.  The following reductions in PCFB 
from baseline will be derived for ESR only: 20%, 50% and 70% (ESR20/50/70).  
17.3. 
ANALYSES 
The analyses for all PD variables scores will replicate those performed for CLASI.  ESR20/50/70 will be tabulated 
by treatment. The incidence of positivity for the following will also be tabulated: ANA, anti-dsDNA, anti-Sm, anti-
RNP, anti-SSA, anti-SSB, anti-cardiolipin, anti-β-2-glycoprotein I, lupus anticoagulant, anti-C1q, and direct Coombs 
test. 
Assayed values reported by the labs as below limit of quantitation (BLQ: e.g. <0.3 U/mL) will be treated as that 
limit for analyses.   For summarizing incidence, BLQ values will be treated as Negative. 
The following tests will be analyzed on the log 10 scale:  anti-SSA, anti-SSB, anti-RNP70. 
For ANA values, the denominator will be used for analyses (e.g. 80, 160, 320) and log-transformed for 
quantitative analyses. 
Any results from lymph node or tonsil biopsies will be listed only. 


 
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18. PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES 
PK vs PD analyses are outside the scope of this document and may be analyzed separately. 
19. SAFETY OUTCOMES 
All analyses for safety outcomes will be based on the Safety Analysis Set.  
The assessment of safety during the course of this study will consist of the surveillance and recording of AEs, 
including SAEs; recording of concomitant medications; physical and neurological examination findings; ECG 
recordings; and measurements of vital signs and protocol-specified laboratory tests. In addition, subjects will be 
closely monitored for signs and symptoms suggestive of neuropathy or PML.  
19.1. 
ADVERSE EVENTS 
An AE is any untoward medical occurrence in a patient or clinical investigational subject administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment  
Adverse Events (AEs) will be coded using MedDRA central coding dictionary, Version 18.0. 
Treatment emergent adverse events (TEAEs) are defined as AEs that started or worsened in severity on or after 
the first dose of study medication. 
Pretreatment AEs are defined as AEs occurring prior to dosing.  These events will be presented in the listings only 
and are not included in the tabular summary of AEs. 
See Appendix 2 for handling of partial dates for AEs.  In the rare case where it is not possible to assess treatment 
emergence, the AE will be classified as treatment emergent (i.e. the worst case).  
Severity 
Adverse event severity will be graded using the NCI-CTCAE, version 4.03. TEAEs starting after the first dose of 
study medication with a missing severity will be classified as severe. If a subject reports a TEAE more than once 
within that SOC/ PT, the AE with the worst case severity grade will be used in the corresponding severity 
summaries. 
Relationship to Study Medication 
Relationship to study medication, as indicated by the Investigator, is classified as Related and Unrelated .A 
”related” TEAE is defined as a TEAE with a causal relationship between the study drug and the AE, such as: 
 
• 
an event that is uncommon and known to be strongly associated with drug exposure (eg, angioedema, 
hepatic injury, or Stevens-Johnson syndrome); or 
 
• 
an event that is not commonly associated with study drug exposure, but is otherwise uncommon in the 
population exposed to the drug (eg, tendon rupture).  
 


 
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An unrelated AE to study medication is defined as another cause of the AE is more plausible (eg, due to underlying 
disease or occurs commonly in the study population), or a temporal sequence cannot be established with the onset 
of the AE and administration of the study drug, or a causal relationship is considered biologically implausible. 
 
TEAEs with a missing relationship to study medication will be regarded as “related” to study medication. If a 
subject reports the same AE more than once within a particular SOC/ PT, the AE with the highest level of 
relationship to study medication will be used in the corresponding relationship summaries. 
All AE tabulations will be performed by treatment group and active-treated overall, and will include the number 
and percentage of subjects. All percentages will be based on the number of patients in the Safety Population. 
Incidence of TEAEs will be tabulated by the following: 
• 
Across all System Organ Class (SOC) and Preferred Term (PT), By Severity Grade, by Relationship, by 
Leading to Discontinuation, and by Seriousness  
• 
By System Organ Class (SOC) and Preferred Term (PT)  
• 
By System Organ Class (SOC), Preferred Term (PT) and Severity Grade 
• 
By System Organ Class (SOC), Preferred Term (PT) for AEs Related to study medication only 
19.1.1. TEAES LEADING TO DISCONTINUATION OF STUDY MEDICATION 
TEAEs leading to permanent discontinuation of study medication or dose interruption will be identified by using the 
variable pertaining to outcome on the Adverse Events page of the CRF, and listed. 
19.1.2. SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as ”Serious” on the Adverse Events page of the CRF, and 
will be summarized and listed. 
 
Incidence of serious TEAEs will be tabulated by the following: 
• 
By System Organ Class (SOC) and Preferred Term (PT)  
• 
By System Organ Class (SOC), Preferred Term (PT) and Severity Grade 
• 
By System Organ Class (SOC), Preferred Term (PT) and Severity Grade for SAEs Related to study 
medication only 
19.1.3. ADVERSE EVENTS OF SPECIAL INTEREST 
AEs of special interest (AEOSI) are defined as those related to peripheral neuropathy (including PML) and infusion 
site reactions (eg, pain, irritation, itching), and will be identified using the corresponding standardized MedDRA 
query.  AEOSI will be separately listed and summarized by SOC/PT and overall.   


 
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19.1.4. DEATHS 
If any subjects die during the study, as recorded on the adverse events page of the eCRF, the information will be 
presented in a data listing.  
19.2. 
LABORATORY EVALUATIONS 
Serology screening, results from tuberculosis screening, urine pregnancy tests, will be listed. 
Central laboratory results will be included in the reporting of this study. A list of laboratory assessments to be 
included in the outputs is included in Schedule of events and the protocol, Section 6.3.4.  Presentations will use 
SI Units, as provided by the labs.   
Protocol-specified clinical laboratory tests will be summarized using descriptive statistics.  Clinical laboratory data 
collected during study conduct, which were not required per protocol, such as for special testing to evaluate an 
AE, will be listed separately and not summarized. 
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of quantification (BLQ), or 
“> X”, i.e. above the upper limit of quantification (ULQ), will be converted to X for the purpose of quantitative 
summaries, but will be presented as recorded, i.e. as “< X” or “> X” in the listings. 
The following summaries will be provided for laboratory data: 
• 
Actual and change from baseline by visit (for quantitative measurements) 
• 
Shift from baseline according to normal range criteria (for quantitative measurements and categorical 
measurements) for all on-treatment and follow-up visits.  
• 
Shift from baseline according to CTCAE severity grading for all on-treatment and follow-up visits. 
• 
Tabulation of categorical/qualitative results  
• 
Listing of lab results outside the normal range/abnormal (high or low)  
• 
Listing of lab results with CTCAE severity grading of 1 or above  
19.2.1. LABORATORY REFERENCE RANGES AND CTCAE GRADING 
Quantitative laboratory measurements will be compared with the relevant laboratory reference ranges by the 
lab vendors and categorized as: 
• 
Low: Below the lower limit of the laboratory reference range.  
• 
Normal: Within the laboratory reference range (upper and lower limit included). 
• 
High: Above the upper limit of the laboratory reference range. 
Clinical laboratory reference/normal ranges will be listed.   
In addition, safety laboratory assessments will also be categorized for severity in accordance with the National 
Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) criteria, version 4.03.   




 
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T-wave, U-wave and overall assessment of ECG (Investigator’s judgment are recorded as following: 
• 
Normal 
• 
Abnormal, Not Clinically Significant (ANCS) 
• 
Abnormal, Clinically Significant (ACS) 
Electrocardiogram evaluations will be tabulated by visit.   
19.5. 
PHYSICAL EXAMINATION  
Physical examination results will be listed and abnormal physical examination findings summarized by body 
system.  Any clinically significant abnormalities will be recorded as adverse events.  


 
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20. REFERENCES 
Felson, D. (1995). Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum, 38, 727-35. 
Klein, R. S. (2010). Cutaneous Lupus and the CLASI Instrument. Rheum Dis Clin North Am, 36(1), 33-51. 
doi:10.1016/j.rdc.2009.12.001 
McElhone, K. (2007). Development and Validation of a Disease-Specific Health-Related Quality of Life Measure, the 
LupusQoL, for Adults With Systemic Lupus Erythematosus. Arthritis & Rheumatism, 57(6), 972–979. 
doi:10.1002/art.22881 
Yee, C.-S. (2011). The use of Systemic Lupus Erythematosus Disease Activity Index-2000 to define active disease and 
minimal clinically meaningful change based on data from a large cohort of systemic lupus erythematosus 
patients. Rheumatology, 50(5), 982-988. doi:doi:10.1093 
 
 


 
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APPENDIX 1. Programming Conventions for Outputs 
OUTPUT CONVENTIONS 
Outputs will be presented according to the following Quintiles Global Biostatistics Standard Output Conventions, 
which is available upon request. 
DATES & TIMES 
Depending on data available, dates and times will take the format DDMONYYYY; times will take the format 
HH:MM:SS. 
SPELLING FORMAT 
English US  
PRESENTATION OF TREATMENT GROUPS 
For outputs, treatment groups will be represented as follows and in this order: 
Treatment Group 
For Tables, Listing and Graphs 
 Placebo 
Placebo  
X.X mg/kg IV for each 
dose level 
X.X mg/kg 
All active dose levels 
combined 
≥0.3 mg/kg 
LISTINGS 
All listings will be ordered by the following (unless otherwise indicated in the template): Subject identifier, date 
(where available), study day