Conditions: Hodgkin Lymphoma Peripheral T Cell Lymphoma Anaplastic Large Cell Lymphoma
Keywords: CD30-expression sALCL PTCL cHL Seattle Genetics
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 12
Healthy volunteers: no

Brief summary:
This study will look at whether brentuximab vedotin works and is safe in the re-treatment setting. To be in this study, patients must have already received brentuximab vedotin as treatment and have cancer that progressed (got worse) after stopping treatment.

Detailed description:
This is a study to determine the safety and efficacy of brentuximab vedotin in subjects with classic Hodgkin lymphoma (cHL) and systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T cell lymphoma (PTCL) who experienced complete response (CR) or partial response (PR) with a brentuximab vedotin-containing regimen and subsequently experienced disease progression or relapse.

Arms:
arm 1: None

Interventions: intervention 1: brentuximab vedotin
Intervention descriptions: intervention 1: 1.8 mg/kg given intravenously (IV)

Protocol document:
SAP_002.pdf: 
 
 
 
Part or all of the information in this statistical analysis plan may be unpublished material. Accordingly, this 
document is to be treated as confidential and restricted to its intended use. This material is the property of 
Seattle Genetics, Inc. and must not be disclosed or used except as authorized in writing by Seattle Genetics, Inc. 
STATISTICAL ANALYSIS PLAN 
 
Protocol Number: 
SGN35-028 
Version: 
Amendment 3; 4-May-2020 
Protocol Title: 
A phase 2, multicenter, single-arm study of retreatment with 
brentuximab vedotin in subjects with relapsed or refractory 
classic Hodgkin lymphoma (cHL) or CD30-expressing 
peripheral T cell lymphoma (PTCL) 
Sponsor: 
Seattle Genetics, Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
 


Study SGN35-028 
Statistical Analysis Plan 
Version date: 9-Sept-2020 
Brentuximab vedotin 
Seattle Genetics, Inc. - Confidential 
Page 2 of 24 
APPROVAL SIGNATURES 
Product: 
SGN35-28 (brentuximab vedotin) 
Protocol Number: 
SGN35-028 
SAP Version: 
1 
Version Date: 
9-September-2020 
 
The individuals signing below have reviewed and approve this statistical analysis plan. 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
  
 
Date 


Study SGN35-028 
Statistical Analysis Plan 
Version date: 9-Sept-2020 
Brentuximab vedotin 
Seattle Genetics, Inc. - Confidential 
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TABLE OF CONTENTS 
 
STATISTICAL ANALYSIS PLAN ....................................................................................................................... 1 
LIST OF ABBREVIATIONS ................................................................................................................................ 4 
1 
INTRODUCTION ........................................................................................................................................... 5 
2 
STUDY OBJECTIVES ................................................................................................................................... 5 
2.1 
Primary Objectives ................................................................................................................................ 5 
2.2 
Secondary Objectives ............................................................................................................................ 5 
2.3 
Additional Objectives ............................................................................................................................ 5 
3 
STUDY ENDPOINTS .................................................................................................................................... 6 
3.1 
Primary Endpoints ................................................................................................................................. 6 
3.2 
Secondary Endpoints ............................................................................................................................. 6 
3.3 
Additional Endpoints ............................................................................................................................. 6 
4 
STUDY DESIGN ............................................................................................................................................ 6 
5 
ANALYSIS SETS ........................................................................................................................................... 7 
5.1 
Full Analysis Set (FAS) ........................................................................................................................ 7 
6 
STATISTICAL CONSIDERATIONS ............................................................................................................ 7 
6.1 
General Principles ................................................................................................................................. 7 
6.2 
Determination of Sample Size ............................................................................................................... 8 
6.3 
Randomization and Blinding ................................................................................................................. 8 
6.4 
Data Transformations and Derivations .................................................................................................. 8 
6.5 
Handling of Dropouts and Missing Data ............................................................................................... 9 
6.6 
Multicenter Studies ............................................................................................................................... 9 
6.7 
Multiple Comparison/Multiplicity......................................................................................................... 9 
6.8 
Examination of Subgroups .................................................................................................................... 9 
6.9 
Covariates .............................................................................................................................................. 9 
6.10 Timing of Analyses ............................................................................................................................. 10 
7 
PLANNED ANALYSES .............................................................................................................................. 10 
7.1 
Disposition .......................................................................................................................................... 10 
7.2 
Demographic and Baseline Characteristics ......................................................................................... 10 
7.3 
Important Protocol Deviations ............................................................................................................ 11 
7.4 
Treatment Administration ................................................................................................................... 11 
7.5 
Efficacy Analyses ................................................................................................................................ 12 
7.5.1 
Efficacy Endpoints ................................................................................................................. 12 
7.5.2 
Pharmacokinetics and Immunogenicity Endpoints ................................................................. 15 
7.6 
Safety Analyses ................................................................................................................................... 15 
7.6.1 
Adverse Events ....................................................................................................................... 15 
7.6.2 
Clinical Laboratory Parameters .............................................................................................. 17 
7.6.3 
ECOG Performance Status ..................................................................................................... 18 
7.6.4 
Concomitant Medications ....................................................................................................... 18 
7.6.5 
Deaths ..................................................................................................................................... 18 
8 
INTERIM ANALYSIS.................................................................................................................................. 18 
9 
CHANGES FROM PLANNED ANALYSES .............................................................................................. 18 
9.1 
Changes from the Original Protocol .................................................................................................... 18 
9.2 
Changes from the Original SAP .......................................................................................................... 18 
10 REFERENCES .............................................................................................................................................. 19 
11 APPENDICES ............................................................................................................................................... 20 
Appendix A 
Imputation of Partially Unknown Adverse Event Dates ...................................................... 20 
Appendix B 
Definition of the Term “Treatment-Emergent” with Respect to AE Classification ............. 22 
Appendix C 
Integrated PET and CT Response According to Modified Lugano Criteria and Original 
Lugano Criteria .................................................................................................................... 24 


Study SGN35-028 
Statistical Analysis Plan 
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Seattle Genetics, Inc. - Confidential 
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LIST OF ABBREVIATIONS 
ADI 
absolute dose intensity 
AE 
adverse event 
ATA 
anti-therapeutic antibodies 
BICR 
blinded independent central review 
BV 
brentuximab vedotin 
cHL 
classical Hodgkin lymphoma 
CI 
confidence interval 
CR 
complete response 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
Duration of response 
ECOG 
Eastern Cooperative Oncology Group 
EOS 
end of study 
EOT 
end of treatment 
FAS 
full analysis set 
GCP 
good clinical practices 
ICF 
informed consent form 
IDI 
intended dose intensity 
IV 
intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities  
MMAE 
monomethyl auristatin E 
NCI 
National Cancer Institute 
ORR 
objective response rate 
OS 
overall survival 
PFS 
progression-free survival 
PK 
Pharmacokinetic 
PR 
partial response 
PT 
preferred term 
PTCL 
peripheral t cell lymphoma 
RDI 
relative dose intensity 
RECIL 
Response Evaluation Criteria in Lymphoma 
sALCL 
systemic anaplastic large cell lymphoma 
SAP 
statistical analysis plan 
SAE 
serious adverse event 
SCT 
stem cell transplant 
SMQ 
standardized MedDRA query 
SOC 
system organ class 
SPD 
sum of the products of diameters 
WHO 
World Health Organization 
 


Study SGN35-028 
Statistical Analysis Plan 
Version date: 9-Sept-2020 
Brentuximab vedotin 
Seattle Genetics, Inc. - Confidential 
Page 5 of 24 
1 
INTRODUCTION 
Protocol SGN35-028 amendment 3, entitled “A phase 2, multicenter, single-arm study of 
retreatment with brentuximab vedotin (BV) in subjects with relapsed or refractory classic 
Hodgkin lymphoma (cHL) or CD30-expressing peripheral T cell lymphoma (PTCL)”, has 
two cohorts and will evaluate the safety and efficacy of BV in subjects with cHL and 
systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing PTCL who 
experienced complete response (CR) or partial response (PR) with a brentuximab vedotin-
containing regimen and subsequently experienced disease progression or relapse. This 
document outlines the statistical analysis methods to be implemented in this study. Results of 
the proposed analyses of the primary objectives will become the basis for the clinical study 
report (CSR) of this protocol.  
The purpose of this plan is to provide specific guidelines from which the analysis will 
proceed. All planned analyses specified in this document will be performed. Any changes to 
this plan, in the form of “post hoc” or “data driven” analyses will be identified as such in the 
CSR. Any changes will either be reflected in amendments (to this plan) before the database 
lock or specifically documented in the CSR.  
2 
STUDY OBJECTIVES 
2.1 Primary Objectives 
● To assess the antitumor response by blinded independent central review (BICR) of 
BV retreatment 
● To assess the safety and tolerability of retreatment with BV 
2.2 Secondary Objectives 
● To assess duration of tumor control, including duration of response (DOR) as 
determined by BICR 
● To assess progression-free survival (PFS) of retreatment with BV as determined by 
BICR 
● To assess overall survival (OS) 
● To assess complete response (CR) rate per BICR  
● To assess antitumor response per investigator of BV retreatment  
● To assess DOR per investigator assessment 
● To assess PFS per investigator assessment 
● To assess CR rate per investigator assessment 
● To assess ORR as determined by BICR 
2.3 Additional Objectives 
● To assess the Pharmacokinetic (PK) and immunogenicity of brentuximab vedotin 
● To assess ORR as determined by BICR per Response Evaluation Criteria in 
Lymphoma (RECIL) 


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3 
STUDY ENDPOINTS 
3.1 Primary Endpoints 
● BICR reporting of objective response rate (ORR) per modified Lugano response 
criteria (Cheson 2014) 
● Type, incidence, severity, seriousness, and relatedness of adverse events (AEs)  
● Type, incidence, and severity of laboratory abnormalities 
3.2 Secondary Endpoints 
● BICR reporting of DOR per modified Lugano response criteria (Cheson 2014) 
● BICR reporting of PFS per modified Lugano response criteria (Cheson 2014) 
● OS 
● Rate of CR per BICR per modified Lugano response criteria (Cheson 2014) 
● Investigator reporting of ORR per modified Lugano response criteria (Cheson 2014) 
● Investigator reporting of DOR per modified Lugano response criteria (Cheson 2014) 
● Investigator reporting of PFS per modified Lugano response criteria (Cheson 2014) 
● Rate of CR per investigator per modified Lugano response criteria (Cheson 2014) 
● BICR reporting of ORR per Lugano response criteria (Cheson 2014) 
3.3 Additional Endpoints 
● Brentuximab vedotin PK concentrations and incidence of anti-therapeutic antibodies 
(ATA) to brentuximab vedotin 
● BICR reporting of ORR per RECIL (Younes 2017) 
4 
STUDY DESIGN 
This is a phase 2, multicenter, single-arm study to determine the safety and efficacy of BV in 
subjects with cHL, sALCL, or other CD30-expressing PTCL who demonstrated an objective 
response to a prior brentuximab vedotin-containing treatment regimen and subsequently 
experienced disease progression or relapse. It is anticipated that approximately 80 subjects 
will enroll in this study: approximately 40 subjects with cHL and approximately 40 subjects 
with CD30-expressing PTCL. In the PTCL cohort, subjects with sALCL and subjects with 
other CD30-expressing PTCL will both have an estimated enrollment cap of approximately 
50%. Subjects will be administered 1.8 mg/kg BV intravenously (IV), up to a maximum of 
180 mg, over 30 minutes once per 21-day cycle. Subjects who previously required a dose 
reduction due to AEs will start BV at a dose of 1.2 mg/kg and will not escalate to 1.8 mg/kg. 
Safety of treatment will be monitored throughout the trial via laboratory values and AE 
collection (Figure 1).  
Subjects may continue on treatment for unlimited cycles until any of the following occur: 
disease progression, unacceptable toxicity, pregnancy, investigator or subject’s decision, 
study closure, or other non-AE reason.  


Study SGN35-028 
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Seattle Genetics, Inc. - Confidential 
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Figure 1: 
Study design 
 
 
5 
ANALYSIS SETS 
5.1 Full Analysis Set (FAS) 
The FAS includes all subjects who receive at least 1 dose of BV on this study. The full 
analysis set will be used for efficacy analyses and safety analyses. Demographics and 
baseline disease characteristics will be summarized based on FAS, unless specified 
otherwise.  
6 
STATISTICAL CONSIDERATIONS 
6.1 General Principles 
Unless otherwise specified, all summary and analyses will be provided by cohort. The 
summary with two cohorts combined may be presented as appropriate. Descriptive statistics 
(mean, median, standard deviation, minimum, and maximum) will be used to describe 
continuous variables. Frequencies and percentages will be used to describe categorical 
variables. Confidence intervals (CIs) may be presented to describe precision of estimates.  
Unless otherwise specified, all CIs will be performed using a two-sided alpha of 0.05. No 
multiple comparisons are planned and no alpha adjustment is needed because no formal 
hypotheses are being tested.  
All statistical tables, listings and figures will be produced using SAS®, version 9.4 or more 
recent.  


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6.2 Determination of Sample Size 
It is anticipated that approximately 40 cHL and 40 CD30-expressing PTCL subjects will be 
enrolled in this study. This sample size was chosen to allow adequate precision of estimates 
of response rates.  
For the cHL cohort, if 24 responses are observed, the estimated ORR would be 60%, and the 
associated 2-sided 95% CI using the Clopper-Pearson method (Clopper 1934) would be 
(43.3%, 75.1%).  
For the CD30-expressing PTCL cohort, if 20 responses are observed, the estimated ORR 
would be 50%, and the associated 2-sided 95% CI using the Clopper-Pearson method 
(Clopper 1934) would be (33.8%, 66.2%). The 50% ORR for the PTCL cohort was 
calculated based on a weighted average of subjects with sALCL and other CD30-expressing 
PTCL, where subjects with sALCL have an ORR of 60% and an estimated enrollment cap of 
approximately 50%, and subjects with other CD30-expressing PTCL have an ORR of 40% 
and an estimated enrollment cap of approximately 50%.  
6.3 Randomization and Blinding 
Not applicable; this is an open-label, single-arm study.  
6.4 Data Transformations and Derivations 
Age in years will be calculated using informed consent date and birth date as (informed 
consent date - birth date)/365.25 truncated to the whole number.  
Study Day will be calculated as Date–First Dose Date + 1 for dates on or after the first dose 
date. For dates prior to the first dose date, Study Day will be calculated as Date–First Dose 
Date. For all calculations of Study Day, the First Dose Date will be the earliest date of 
treatment administration of brentuximab vedotin.  
Other time variables based on two dates, e.g., start date and end date, will be calculated as 
(End Date–Start Date + 1) (in days) unless otherwise specified in the planned analysis 
section.  
The following unit conversion will be implemented unless otherwise specified:  
Months = Days/30.4375 
Years = Days/365.25 
The end-of-treatment (EOT) date will be the date the EOT visit is performed; if an EOT visit 
is not performed then the EOT date will be either the EOS date or 30 days after the last dose 
of study drug, whichever is earlier.  
Baseline values will be the most recent non-missing measurement prior to the first dose of 
BV on this study.  


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Seattle Genetics, Inc. - Confidential 
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The change from baseline is the post-baseline value minus the baseline value:  
(Post-baseline Value – Baseline Value) 
For efficacy assessments, the date of response will be the latest of all radiologic scan dates 
for the given restage assessment. The date of progression will be the earliest of all radiologic 
scan dates for the given restage assessment.  
6.5 Handling of Dropouts and Missing Data 
With the exceptions noted below, missing data will not be imputed.  
AE start dates will be imputed for the purpose of calculating duration of events and 
treatment-emergent status (see Appendix A for AE partial date imputation and Appendix B 
for treatment-emergent definition). Censoring for time-to-event endpoints (eg. PFS and 
DOR) will be described in Section 7 with each planned analysis, as applicable. Subjects 
whose disease response cannot be assessed will be scored as non-responders for calculating 
the CR rate and ORR.  
6.6 Multicenter Studies 
Site-to-site variation will not be adjusted in the analysis. Although there are multiple sites in 
this study, it is not anticipated that any site will accrue enough subjects to warrant an analysis 
by site.  
6.7 Multiple Comparison/Multiplicity 
No multiple comparisons are planned, and no alpha adjustment is needed because no formal 
hypotheses are being tested.  
6.8 Examination of Subgroups 
As exploratory analyses, subgroup analyses may be performed for primary efficacy endpoint 
and selected secondary endpoints, where the sizes of subgroups are not too small (eg. at least 
10 subjects in each subgroup per cohort). Subgroups may include, but are not limited to, the 
following:  
● Age (< median,  median) 
● Sex (male, female) 
● Eastern Cooperative Oncology Group (ECOG) performance status at baseline (0, 1) 
● Best tumor response achieved with the most recent prior treatment of BV or BV-
containing regimen (CR, vs non-CR) 
6.9 Covariates 
This is a phase 2, open-label study. Covariates are not considered for adjustment in the 
analyses.  


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6.10 Timing of Analyses 
No formal interim analyses are planned for this study.  
The primary analysis will be conducted when all treated subjects have been followed for at 
least 6 months, discontinued from study, or had 30 days of safety follow-up after progressive 
disease (PD), whichever comes first.  
7 
PLANNED ANALYSES 
7.1 Disposition 
An accounting of study subjects by disposition will be tabulated by cohort and total using all 
enrolled subjects. Subjects who withdraw from the study will be summarized by primary 
reason for withdrawal and will be listed with the timing and reason for withdrawal. Subjects 
who have entered and are still in long term follow-up will also be summarized. A listing of 
disposition data will be provided for all enrolled subjects.  
The number of subjects who signed informed consent, the number of subjects in the FAS, 
and the number of subjects enrolled at each site and country will be summarized for all 
enrolled subjects.  
7.2 Demographic and Baseline Characteristics 
Demographics and baseline characteristics (including age, gender, ethnicity, race, baseline 
weight, and ECOG score) will be summarized by cohort using the FAS.  
Disease specific characteristics will be summarized by cohort using the FAS. These 
characteristics include, but are not limited to, the following: disease diagnosis, time from 
diagnosis to the first dose of study drug on this study, time from the most recent disease 
progression to the first dose of study drug on this study, time from completion of previous 
treatment with BV to the first dose of study drug on this study, best response to most recent 
prior therapy, best response to most recent prior BV therapy, baseline B symptoms, baseline 
sum of the products of the largest diameters (SPD).  
Subsequent cancer-related therapies received after the end of the re-treatment of BV will be 
summarized using the FAS. These summaries include, but are not limited to, the following: 
use of subsequent palliative cancer-related radiotherapy, systemic therapy for progressive 
disease, systemic therapy for relapsed disease, maintenance, consolidative radiotherapy, 
systemic therapy for secondary malignancy, autologous hematopoietic stem cell transplant 
(SCT), allogeneic hematopoietic SCT, syngeneic stem cell transplant, number of subsequent 
cancer-related therapies.  
Listings of demographics, baseline disease characteristics, and subsequent cancer-related 
therapies will be provided.  


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7.3 Important Protocol Deviations 
Important Protocol deviations (defined as protocol violations by Seattle Genetics) are those that 
represent a divergence from the protocol that could have a significant effect on the integrity of 
the study data, or on the subject’s rights, safety, or welfare.  Important Protocol deviations also 
include exemptions to the study inclusion/exclusion criteria and will be summarized by category. 
A list of subjects with important protocol deviations will be presented. Protocol deviations that 
may affect the study results will be reviewed prior to the database lock.  
7.4 Treatment Administration 
Treatment administration will be summarized by cohort using the FAS. Summary statistics 
will be presented for duration of treatment (months), and number of cycles. Additionally, 
number and percent for the number of doses received will be presented. Cumulative dose and 
average dose per cycle will be summarized in mg and mg/kg for intended dose intensity 
(IDI), absolute dose intensity (ADI), and relative dose intensity (RDI). The number and 
percentage of subjects whose dose was ever modified will be summarized by modification 
type, cycle and overall.  
Duration of treatment (except when calculating exposure) is defined as time from the first 
dose of BV on the study to 21 days after the last dose of the current study [(last dose date 
+21) – first dose date]. If death occurs less than 21 days after the last study dose, duration of 
treatment is defined as [date of death – first dose date +1].  
IDI is defined as the intended dose of drug (mg/kg) per unit of time. For subjects whose 
intended dose is 1.8 mg/kg, this is 1.8 mg/kg/3 weeks = 0.6. For subjects whose intended 
dose is 1.2 mg/kg, this is 1.2 mg/kg/3 weeks = 0.4.  
ADI is defined as the actual dose (mg/kg) per unit of time that the subject received over the 
entire treatment period. For the purpose of the ADI calculation, the duration of treatment is to 
be used is [(last dose date +21) – first dose date], including for those whose death date may 
be less than 21 days after the last study dose.  
Example: 
Consider a subject with an intended dose of 1.8 mg/kg who is treated for three cycles 
(i.e., 9 weeks) where the weight in the electronic case report form used for calculating the 
dose of infusion was 50 kg. For the last treatment, the infusion was not completed and the 
subject received less than the full dose, as represented in the following table:  
Visit 
Intended Dose Regimen (mg/kg) 
Intended Dose (mg) 
Actual Dose (mg) 
C1D1 
1.8 
90 
90 
C2D1 
1.8 
90 
90 
C3D1 
1.8 
90 
45 
 


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ADI = (1.8 + 1.8 + ((45/90) *1.8)) mg/kg / 9 weeks 
≈ .5 mg/kg per week 
RDI is defined as the absolute dose intensity over the intended dose intensity. 
ADI/IDI * 100. 
A listing of BV administration on study will be provided.  
7.5 Efficacy Analyses 
All efficacy analyses will be presented by cohort using the full analysis set. Analyses may 
also be performed using the subgroups listed in Section 6.8.  
7.5.1 Efficacy Endpoints 
7.5.1.1 Objective Response Rate  
The primary endpoint is objective response rate (ORR) by BICR, according to the Modified 
Lugano Criteria for Response Assessment (Cheson 2007) (See Appendix C for details on 
response assessment according to the Modified Lugano Criteria). ORR is defined as the 
proportion of subjects with CR or PR. Subjects whose response to treatment cannot be 
adequately assessed according to the specified criteria will be classified as non-responders 
for the purpose of calculating ORR. The ORR will be summarized by cohort and an exact 
two-sided 95% CI will be calculated, using the Clopper-Pearson method (Clopper 1934).  
The ORR will also be evaluated by investigator per modified Lugano criteria (Cheson 2014) 
as a secondary endpoint. In addition, ORR will also be assessed according to Lugano Criteria 
for Response Assessment (Cheson 2014) (See Appendix C for details on response assessment 
according to the Lugano Criteria) per BICR and the ORR will also be assessed according to 
RECIL (Younes 2017) per BICR. The ORRs based on these criteria will be summarized 
similarly.  
Up to 6 of the largest dominant nodes or nodal masses will be quantitatively identified at 
baseline based on the product of diameters (Cheson 2007). The nodes or nodal masses being 
followed for response assessment will also be quantitatively assessed at each pre-specified 
time point. SPD of these nodes or nodal masses is defined as the sum of the products of 
diameters from those nodes or nodal masses being followed for response assessment. The 
SPD changes from baseline, as well as the SPD change from the previous response 
assessment (as applicable), at each assessment visit for each subject will be derived. Baseline 
SPD and the number of subjects with SPD reduction from baseline will be summarized. The 
maximum percent reduction in SPD from baseline (or minimum percent increase if there is 
no reduction), will also be summarized and graphically displayed for each subject (e.g., using 
a waterfall plot).  


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Up to 3 target lesions will be quantitatively identified at baseline based on the longest 
diameters (Younes 2017).  Sum of the longest diameters of these nodes or nodal masses will 
be summarized and graphically displayed by cohort similarly to SPD.  
Listings for tumor evaluation and response data will be provided.  
7.5.1.2 Duration of Response  
Duration of response is defined as the time from start of the first documentation of objective 
tumor response (CR or PR), according to the Modified Lugano Criteria for Response 
Assessment (Cheson 2007), to the first documentation of objective tumor progression or to 
death due to any cause, whichever comes first.  
Duration of response data will be censored as described below:  
● Subjects who do not have objective tumor progression and are still on study at the 
time of an analysis will be censored on the day following the date of the last 
radiological disease assessment of measured lesions documenting absence of PD.  
● Subjects who are given antitumor treatment other than the study treatment or SCT 
(includes donor lymphocyte infusion) prior to documentation of disease progression will 
be censored on the day following the date of the last radiological disease assessment prior 
to the start of new therapy.  
● Subjects who are removed from study prior to documentation of objective tumor 
progression will be censored on the day following the date of the last radiological 
disease assessment of measured lesions documenting absence of PD.  
● Subjects who have disease progression or death after missing two or more 
consecutive radiologic tumor assessments will be censored at the date of last visit 
with adequate tumor assessment prior to missed scans.  
 
Duration of response will be estimated using Kaplan-Meier methodology and Kaplan-Meier 
plots will be provided by cohort. The median duration of response and its two-sided 95% CI 
using the log-log transformation method (Collett 1994) will be calculated. Duration of 
responses by BICR and DOR by investigator are to be summarized by cohort.  
Duration of response will also be calculated for the subgroup of subjects with CR.  
7.5.1.3 Progression-Free Survival  
PFS is defined as the time from start of study treatment to first documentation of objective 
tumor progression according to the Modified Lugano Criteria for Response Assessment 
(Cheson 2007) or to death due to any cause, whichever comes first.  
Specifically,  
PFS = Date of first documented PD or death – Date of first dose of study treatment + 1.  
PFS data will be censored as described below:  


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● Subjects who do not have objective tumor progression and are still on study at the 
time of an analysis will be censored on the day following the date of the last 
radiological disease assessment of measured lesions documenting absence of PD.  
● Subjects who are given antitumor treatment other than the study treatment or SCT 
(includes donor lymphocyte infusion) will be censored on the day following the date 
of the last radiological disease assessment of measured lesions documenting absence 
of PD prior to the start of antitumor treatment.  
● Subjects who are removed from study prior to documentation of objective tumor 
progression will be censored on the day following the date of the last radiological 
disease assessment of measured lesions documenting absence of PD.  
● Subjects lacking an evaluation of tumor response after their first dose will have their 
event time censored at Day 1.  
● Subjects who have disease progression or death after missing two or more 
consecutive radiologic tumor assessments will be censored at the date of last visit 
with adequate tumor assessment prior to missed scans.  
 
PFS will be analyzed using Kaplan-Meier methodology and Kaplan-Meier plots will be 
provided by cohort. The median PFS and its two-sided 95% CI using the complementary 
log-log transformation method (Collett 1994) will be calculated. PFS by BICR and PFS by 
investigator are to be summarized by cohort.  
7.5.1.4 Complete Response Rate  
CR rate is defined as the proportion of subjects with CR according to the Modified Lugano 
Criteria for Response Assessment (Cheson 2014). Subjects whose disease response cannot be 
assessed will be scored as non-responders for calculating the CR rate. CR by BICR and CR 
by investigator will be summarized by cohort.  
CR rate will be summarized using descriptive statistics and an exact two-sided 95% CI will 
be calculated using the using the Clopper-Pearson method (Clopper 1934).  
7.5.1.5 Overall Survival 
OS is defined as the time from date of enrollment to date of death due to any cause. 
Specifically,  
OS=Date of death – Date of enrollment + 1. 
In the absence of confirmation of death, overall survival time will be censored at the last date 
the subject is known to be alive (i.e., date of last contact). The last contact date will be 
derived based on data points including, but not limited to, start/end dates from subsequent 
cancer-related therapy, last date subject known to be alive from Long-term follow-up 
assessment, and end of study date. Subjects lacking data beyond the date of first dose will 
have their overall survival time censored to 1 day.  


Study SGN35-028 
Statistical Analysis Plan 
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OS will be analyzed using Kaplan-Meier methodology and Kaplan-Meier plots will be 
provided by cohort. The median OS and its two-sided 95% CI using the log-log 
transformation method (Collett 1994) will be calculated if the median is reached.  
7.5.2  Pharmacokinetics and Immunogenicity Endpoints 
7.5.2.1 Pharmacokinetics 
Brentuximab vedotin ADC and MMAE concentrations in serum or plasma will be measured 
using sensitive, qualified assays. Select PK parameters, including trough concentration 
(Ctrough) and concentration and the end of infusion (Ceoi), will be summarized and reported by 
cohort using the full analysis set with available data. Brentuximab vedotin ADC and MMAE 
concentrations will be reported by subject at each PK sampling time point.  
7.5.2.2 Antitherapeutic Antibody Incidence Rate 
The ATA incidence rate is defined as the proportion of subjects free of confirmed ATA at 
enrollment in the current study that develop ATA at any time during the retreatment period. 
Overall ATA incidence will be summarized by cohort using the FAS.  
Additionally, the incidence of ATA will be summarized at each collection time point.  
7.6 Safety Analyses 
The FAS will be used to summarize all safety endpoints.  AEs will be classified by system 
organ class (SOC) and preferred term (PT) using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 22.0 or higher and graded using the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0.  
Laboratory values will be graded using NCI CTCAE, Version 5.0 or higher.  
Concomitant medications will be coded using WHODrug Global version 2020MarB3.  
7.6.1 Adverse Events 
AEs will be summarized by descending frequency of MedDRA preferred term unless 
otherwise specified.  For incidence reporting, if a subject reports more than one AE that was 
coded to the same SOC or PT, the subject will be counted only once for that specific SOC or 
PT. For summaries by maximum severity, multiple occurrences of events at each SOC or PT 
within a subject are counted only once at the highest severity.  
A treatment-emergent AE (TEAE) is defined as a newly occurring or worsening AE after the 
first dose of BV on the current study. Unless documented as a pre-existing condition, AEs 
with unknown start date will be counted as treatment-emergent.  
TEAEs are defined as TEAEs that are determined by the investigator to be related to the BV 
treatment on study.  
A summary of AEs will be provided by cohort for the following:  
● Pre-existing AEs 


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● All TEAEs 
● TEAEs related to brentuximab vedotin 
● Treatment-emergent serious adverse events (SAEs) 
● Treatment-emergent SAEs related to brentuximab vedotin 
● TEAEs leading to dose delay 
● TEAEs leading to dose modification 
● TEAEs leading to dose elimination 
● TEAEs leading to treatment discontinuation 
● TEAEs by SOC and PT 
● TEAEs by SOC, PT, and maximum severity  
● Grade 3 - 5 TEAEs 
● Infusion related reactions by preferred term 
● Summary of TEAEs of peripheral neuropathy (standardized MedDRA query [SMQ]) 
● Summary of onset of treatment emergent peripheral neuropathy (SMQ) 
● Summary of improvement and resolution of treatment-emergent peripheral 
neuropathy (SMQ) 
Listings will be presented for all AEs, SAEs, AEs leading to treatment discontinuation, and 
AEs leading to death.  
7.6.1.1 Peripheral neuropathy 
Peripheral Neuropathy (PN) is defined by the PN MedDRA SMQ broad search. The 
incidence of PN at baseline will be summarized. The incidence of treatment-emergent and 
treatment-related PN will each be summarized by PT and severity. The incidence of PN 
leading to treatment discontinuation or requiring dose modification will be summarized. 
Time to onset, resolution, and improvement of PN events will be summarized.  
Subjects with any event of treatment-emergent PN will be categorized into groups according 
to the following criteria: 
● Resolution of all events 
● At least 1 event resolved, but all other PN events did not improve 
● Improvement of at least 1 event 
○ 
All events either improved or resolved 
○ 
Some events improved, some events resolved and some events neither improved 
nor resolved 
○ 
Some events improved but no events resolved 
● No improvement or resolution of any events 
 
The number of subjects will be summarized for the categories defined as above.  
Motor neuropathy will be defined as PN events meeting any of the criteria below:  


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● Coded to a MedDRA PT of either ‘peripheral motor neuropathy’ or ‘peripheral 
sensorimotor neuropathy’, ‘peroneal nerve palsy’ 
● Verbatim AE term contains “motor”, “weakness”, or “palsy” 
The incidence of treatment-emergent motor neuropathy will be summarized by PT and 
severity. Time to resolution and improvement of motor neuropathy events will be 
summarized.  
Resolution of selected AEs will be defined as event status of recovered/resolved or 
recovered/resolved with sequelae; or return to baseline or lower severity as of the latest 
assessment for pre-existing events. The date of resolution is defined as follows: for events 
with an onset after the first dose date, if event outcome is “recovered/resolved” or 
“recovered/resolved with sequelae”, then the date of resolution is the event end date; for 
events ongoing at baseline, if event severity returns to baseline severity or lower as of the last 
recorded severity, then the date of resolution is the date of severity change to baseline or 
lower severity.  
For events that are not resolved, improvement is defined as decrease by at least one grade 
from worst grade as of the latest assessment. The date of improvement is defined as follows: 
for events that did not resolve and decrease by one grade or more from the worst 
post-baseline severity as of the last recorded severity (i.e., severity did not subsequently 
worsen), then the date of improvement is the start date when the post-baseline grade becomes 
lower than the worst grade for the first time without any subsequent grade(s) equal to the 
worst grade.  
Time to resolution is computed from start date of first treatment emergent episode of the 
event or start date of newly onset event after first dose of treatment drug to date of resolution. 
Time to improvement is computed from start date of the worst grade of the event. Time to 
resolution /improvement will be summarized at the event level.  
For summaries of events or summaries of subjects with events ongoing at EOT, EOT is 
defined as the EOT visit or 30 days after the last dose of the study drug, whichever occurred 
later.  
Time to onset of TEAEs is defined as time from the date of first dose to start date of first 
treatment emergent episode of the event or start date of newly onset event after first dose of 
treatment drug. In the analyses of time to onset by grade, the events should be excluded 
where the specified grade only occurs after a higher grade.  
7.6.2 Clinical Laboratory Parameters 
Clinical laboratory data (CBC with differential and serum chemistry panel) will be 
summarized by cohort. Both observed data and changes from baseline will be summarized 
with descriptive statistics. In addition, laboratory data will be summarized by the worst 
post-baseline grade, by NCI CTCAE v5.0 or higher for each parameter. 


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Laboratory results and NCI CTCAE grades will be presented in data listings. All laboratory 
results through the end of treatment visit will be presented in standardized units.  
7.6.3 ECOG Performance Status 
ECOG data will be listed by subject.  
7.6.4 Concomitant Medications 
Concomitant medications will be summarized by the WHO Drug substance name and listed 
by subject. The number and percentage of subjects taking concomitant medications from 
screening through the end of the on-study period will be tabulated by cohort.  
7.6.5 Deaths 
The total number of deaths, deaths that occur within 30 days of last study treatment, deaths 
that occur more than 30 days after last study treatment, and relationship to disease will be 
summarized by cohort and total. Death information will be listed by subject.  
8 
INTERIM ANALYSIS 
No formal interim analyses are planned.  
9 
CHANGES FROM PLANNED ANALYSES 
9.1 Changes from the Original Protocol 
Not applicable  
9.2 Changes from the Original SAP 
Not applicable 


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10 REFERENCES 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response 
assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 
2014;32(27):3059-68. 
 
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 
2007;25(5):579-86. 
 
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the binomial. 
Biometrika. 1934;26(4):404-13. 
 
Collett D. Interval-censored survival data. Modelling survival data in medical research. London, Chapman & 
Hall. 1994:237-51. 
 
Younes A, Hilden P, Coiffier B, et al. International Working Group consensus response evaluation criteria in 
lymphoma (RECIL 2017). Ann Oncol. 2017;28(7):1436-47. 
 
 
 


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11 APPENDICES 
Appendix A 
Imputation of Partially Unknown Adverse Event Dates 
For an adverse event (AE) with a partial start or end date, if it can be determined that the 
event occurred prior to the date of first dose of study treatment, the partial date will not be 
imputed; Otherwise, the partial date will be imputed using the rules described below. AE 
start dates should be imputed before imputation of AE condition end date in all cases.  
Incomplete AE Start Date  
AE day only is missing 
If the month/year is the same as the month/year of first dose of any study treatment: 
AE start date will be imputed as the first dose date of any study treatment 
If the month/year is after the month/year of first dose of any study treatment: 
AE start date will be imputed as the first day of the month 
AE day and month are missing, or month only is missing 
If the year is the same as the year of first dose of any study treatment: 
AE start date will be imputed as the first dose date of any study treatment 
If the year is after the year of first dose of any study treatment: 
AE start date will be imputed as January 1st 
AE day, month and year are missing, or year only is missing 
AE start date will be imputed as the first dose date of any study treatment 
If AE condition end date* is not missing, and the imputed start date is after the end date, the 
start date will be set to the AE condition end date. 
* only use condition end date if known and full end date is available. 
Incomplete AE End Date  
If AE outcome is “not recovered/resolved”, “unknown”, or blank: AE condition end date will 
not be imputed. 
If AE outcome is “recovering/resolving”, “recovered/resolved”, “recovered/resolved with 
sequelae”, or “fatal” apply the following:  
AE day only is missing 
AE condition end date will be imputed as the minimum of (death date, data extraction 
date, last day of the end date month/year, EOS date) 


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AE day and month are missing, or month only is missing 
If the year is equal to the year of the last dose date: 
AE condition end date will be imputed as the minimum of (last dose date + 30, death 
date, data extraction date, December 31st of the end date year, EOS date) 
If the year is not equal to the year of the last dose date: 
AE condition end date will be imputed as the minimum of (death date, data extraction 
date, December 31st of the end date year, EOS date) 
AE day, month and year are missing, or year only is missing 
AE condition end date will not be imputed 
Within a single record, if the imputed stop date is before the start date, then the imputed stop 
date will be equal to the start date.  
Example 
AE Number 4: Condition/Event NAUSEA 
First dose date 02APR2012 
Prior to imputation 
Log Line 
Start date 
Condition end date 
Severity 
Outcome 
1 
25APR2012 
UNAPR2012 
2 
recovering/resolving 
2 
UNAPR2012 
04MAY2012 
1 
recovered/resolved 
 
Post imputation 
Log Line 
Start date 
Condition end date 
Severity 
Outcome 
1 
25APR2012 
30APR2012 
2 
recovering/resolving 
2 
02APR2012 
04MAY2012 
1 
recovered/resolved 
 


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Appendix B 
Definition of the Term “Treatment-Emergent” with Respect to 
AE Classification  
The algorithm below should be used to determine whether an AE is classified as a treatment-
emergent adverse event TEAE. A TEAE is defined as any AE which worsens in severity 
during the safety reporting period or is newly occurring at any time, where newly occurring 
means that the AE was not present at baseline. For ease of reading, both pre-existing 
conditions and AEs will be referred to as AEs for the remainder of this document. AE dates 
should be imputed in accordance with the algorithm detailed in Appendix A prior to 
determination of TEAE classification. Details of the TEAE classification are as follows:  
1. For each patient, determine the first dose date, which is the earliest date the patient 
receives any amount of study drug.  
2. Baseline AEs: classify an AE record as baseline AE if it satisfies both criteria a and b 
below: 
a. AE onset satisfies either of i, ii or iii below:  
i. 
Onset date is prior to the first dose date 
ii. 
Onset date is the same as the first dose date, and Onset Period is “started after 
consent but before the first dose of any study treatment” or Onset Time Relative 
to Study Treatment is “started before first infusion or before infusion on any 
dosing day” 
iii. 
Onset Period is “started before the signing of consent” or “started after consent 
but before the first dose of any study treatment” 
b. AE end date satisfies either of i or ii below:  
i. 
End date is the same as or after the first dose date  
ii. 
End date is missing with outcome equal to  
● recovering/resolving, or 
● not recovered/not resolved, or  
● unknown or missing 
 
3. Post-baseline AEs: classify an AE record as post-baseline AE if it meets either of criteria 
a, b or c below: 
a. Onset date is after the first dose date 
b. Onset date is the same as the first dose date, and Onset Period is “started after the first 
dose of any study treatment” or Onset Time Relative to Study Treatment is not 
“started before first infusion or before infusion on any dosing day” 
c. Onset Period is “started after the first dose of any study treatment”  
 


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4. TEAE flag will be derived as follows: 
a. For all AE records that have an end date prior to the first dose date, assign TEAE flag 
to ‘N’ 
b. For all baseline AEs, assign TEAE flag to ‘N’ 
c. For post-baseline AEs: 
• If the post-baseline AE is a continuing event of a baseline AE (i.e., events with 
the same AE identifier, where AE identifier is the number before the colon in 
SDTM AE.AESPID), then compare the post-baseline AE to the most recent 
baseline AE with the same AE identifier (to be referred to as “baseline AE” 
below). Assign TEAE flag to ‘Y’ for the applicable post-baseline AE records if a 
post-baseline AE record meets any of the following worsening criteria based on 
relatedness, seriousness or CTCAE grade: 
o If the post-baseline AE is related to treatment, or 
o If the post-baseline AE meets the criteria for an SAE and the most recent 
baseline AE was not an SAE, or 
o If the post-baseline AE has a higher CTCAE grade 
 
All subsequent episodes of the same AE should have TEAE flag = ‘Y’. 
• Otherwise, assign TEAE flag to ‘N’ 
• If the post-baseline AE is not a continuing event of a baseline AE, then assign 
TEAE flag to ‘Y’ 
 
NOTE: For summaries which include only treatment emergent AEs, include all AEs 
which have at least one record classified as a TEAE as well as those AEs for which 
TEAE status could not be determined (e.g., the value of the TEAE variable may be 
missing if the event cannot be identified as baseline or post-baseline – missing 
information on the AE CRF should be queried). Only exclude those AEs which were 
determined to not be treatment emergent for all records. 


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Appendix C 
Integrated PET and CT Response According to Modified 
Lugano Criteria and Original Lugano Criteria 
The primary determination of antitumor efficacy will be ORR according to the Lugano 
Classification Revised Staging System for nodal non-Hodgkin and Hodgkin lymphomas 
modified to take into account CT response in the event of a PET PR (modified Lugano 
criteria). The disease assessment on the basis of PET and CT response according to modified 
Lugano criteria is summarized in the table below: 
PET Response 
CT Response 
Integrated Response 
CR 
Any 
CR 
PR 
CR, PR 
PR 
 
Non-CR, Non-PR 
SD 
SD 
Any 
SD 
PD 
Any 
PD 
 
Prior PET responsea 
CT Response 
 
Not done or  
CR 
Non-PD 
CRb 
Not evaluable 
non-CR 
Non-PD 
NE 
 
Any 
PD 
PD 
No FDG-avid disease  
at baseline c 
No disease present (NE) 
NE 
PD 
PD 
NE=not evaluable. 
a 
"Prior PET response" refers to the latest prior PET assessment that was evaluable. PET responses may be carried 
forward over multiple CT assessments. 
b 
A CR according to PET will be carried forward irrespective of CT response, until CT shows PD or is assessed as NE. 
c 
Per protocol all patients must have FDG-avid disease at baseline. 
 
Assessment of response, according to the original (unmodified) Lugano criteria 
(Cheson 2014), will be undertaken in the same manner as for modified Lugano, with the 
exception that if the PET response is PR the integrated response will be PR, irrespective of 
CT response.  
 



Prot_000.pdf: 
 
 
 
Protocol Number: 
SGN35-028 
Version: 
Amendment 3; 28-Apr-2020 
Protocol Title: 
A phase 2, multicenter, single-arm study of retreatment with 
brentuximab vedotin in subjects with relapsed or refractory 
classic Hodgkin lymphoma (cHL) or CD30-expressing 
peripheral T cell lymphoma (PTCL) 
Investigational Product: 
Brentuximab vedotin 
Brief Title: 
A phase 2 study of retreatment with brentuximab vedotin in 
subjects with classic Hodgkin lymphoma or CD30-expressing 
peripheral T cell lymphoma  
Phase: 
Phase 2  
IND Number: 
071634 
NCT Number: 
NCT03947255 
EudraCT Number: 
2019-003983-28 
Sponsor: 
Seattle Genetics, Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
Medical Monitor: 
 
Seattle Genetics, Inc.  
Tel: 
 
E-mail: 
 
SAE Email or Fax: 
See email or fax number specified on the SAE report form 
 
 


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PROTOCOL SYNOPSIS 
Protocol Number 
SGN35-028 
Version 
Amendment 3; 28-Apr-2020 
Phase 
2 
Product Name 
Brentuximab vedotin 
Sponsor 
Seattle Genetics, Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
Protocol Title 
A phase 2, multicenter, single-arm study of retreatment with brentuximab vedotin in subjects with relapsed or 
refractory classic Hodgkin lymphoma (cHL) or CD30-expressing peripheral T cell lymphoma (PTCL) 
Study Objectives 
To assess the following with brentuximab vedotin retreatment in subjects with cHL, systemic anaplastic large 
cell lymphoma (sALCL), or other CD30-expressing peripheral T cell lymphoma (PTCL). 
Primary 
● Objective response rate (ORR) per blinded independent central review (BICR) (modified Lugano) 
● Safety and tolerability 
Secondary 
● Duration of tumor control, including duration of response (DOR) per BICR (modified Lugano) 
● Progression-free survival (PFS) per BICR (modified Lugano) 
● Complete response (CR) rate per BICR (modified Lugano) 
● Overall survival (OS) 
● ORR per investigator (modified Lugano) 
● DOR rate per investigator (modified Lugano) 
● PFS per investigator (modified Lugano) 
● CR rate per investigator (modified Lugano) 
● ORR per BICR (Lugano) 
Additional 
● To assess the pharmacokinetic (PK) and immunogenicity with brentuximab vedotin retreatment 
● To assess ORR per BICR (RECIL) 
Study Population 
Key eligibility criteria include subjects with relapsed or refractory cHL and sALCL or other CD30-expressing 
PTCL (age ≥18 years) who were previously treated with a brentuximab vedotin-containing regimen, had 
evidence of objective response, and subsequently had disease progression or relapse after discontinuing 
treatment. 
Number of Planned Subjects 
Approximately 80 subjects are planned for this study: approximately 40 subjects with cHL and approximately 
40 subjects with CD30-expressing PTCL. In the PTCL cohort, sALCL will have an estimated enrollment cap of 
approximately 50%, and other CD30-expressing PTCL will have an estimated enrollment cap of approximately 
50%. 
Study Design 
This is a phase 2, multicenter, single-arm study to determine the safety and efficacy of brentuximab vedotin in 
subjects with cHL and sALCL or other CD30-expressing PTCL who experienced CR or partial response (PR) 
with a brentuximab vedotin-containing regimen and subsequently experienced disease progression or relapse. It 


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is anticipated that approximately 80 subjects will enroll in this study. Subjects will be administered 1.8 mg/kg 
brentuximab vedotin intravenously (IV), up to a maximum of 180 mg, over 30 minutes once per 21-day cycle. 
Subjects who previously required a dose reduction due to adverse events (AE) will be administered 
brentuximab vedotin at 1.2 mg/kg and will not escalate to 1.8 mg/kg. Safety will be monitored throughout the 
trial via laboratory values and AE collection. 
Investigational Product, Dose, and Mode of Administration 
Brentuximab vedotin 1.8 or 1.2 mg/kg up to a maximum of 180 mg, administered IV over 30 minutes every 
3 weeks. 
Control Product, Dose, and Mode of Administration 
Not applicable 
Duration of Treatment 
Subjects may continue on treatment until disease progression, unacceptable toxicity, or study closure occurs. 
Efficacy Assessments 
For subjects with cHL and sALCL or CD30-expressing PTCL, treatment response will be assessed by BICR 
and the investigator and based on objective response according to the modified Lugano Response Assessment 
Criteria for Malignant Lymphoma (Cheson 2014). 
Pharmacokinetic, Pharmacodynamic, and Immunogenicity Assessments 
Samples for serum antibody-drug conjugate (ADC) and plasma monomethyl auristatin E (MMAE) 
concentration will be analyzed using a validated enzyme-linked immunosorbent assay (ELISA), and a validated 
LC-MS/MS assay. A validated electrochemiluminescence (ECL) assay will be used to detect binding and 
neutralizing antibodies. 
Safety Assessments 
Safety assessments will include the surveillance and recording of AEs, physical examination findings, and 
laboratory tests. 
Statistical Methods 
Summaries of subject disposition, demographics, disease characteristics, and dosing of study drug will be 
provided. 
The objective response rates and their two-sided 95% exact confidence intervals (CI) will be calculated 
(Clopper 1934). The CR rates will be analyzed using the same methodology. Time-to-event endpoints, such as 
DOR, PFS, and OS, will be estimated using Kaplan-Meier methodology. The median durations of response, 
PFS, OS, and their two-sided 95% CI will be calculated. 
Approximately 40 cHL and 40 CD30-expressing PTCL subjects will be enrolled in this study. This sample size 
was chosen to allow adequate precision of estimates of response rates. 
For the cHL cohort, if 24 responses are observed, the estimated ORR would be 60%, and the associated 2-sided 
95% CI using the Clopper-Pearson method would be (43.3%, 75.1%). 
For the CD30-expressing PTCL cohort, if 20 responses are observed, the estimated ORR would be 50%, and the 
associated 2-sided 95% CI using the Clopper-Pearson method would be (33.8%, 66.2%). The 50% ORR for the 
PTCL cohort was calculated based on a weighted average of subjects with sALCL and other CD30-expressing 
PTCL, where sALCL subjects have an ORR of 60% and an estimated enrollment cap of approximately 50%, 
and the other CD30-expressing PTCL subjects have an ORR of 40% and an estimated enrollment cap of 
approximately 50%. 
Descriptive statistics will be provided for the safety data based on all subjects in the full analysis set. 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ....................................................................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................................................... 7 
1 
INTRODUCTION ........................................................................................................................................... 9 
1.1 
Clinical Experience with brentuximab vedotin..................................................................................... 9 
1.2 
CD30 Expression in cHL and PTCL .................................................................................................. 10 
1.3 
Study Rationale .................................................................................................................................. 10 
2 
OBJECTIVES ............................................................................................................................................... 11 
3 
INVESTIGATIONAL PLAN ....................................................................................................................... 12 
3.1 
Summary of Study Design .................................................................................................................. 12 
3.2 
Discussion and Rationale for Study Design........................................................................................ 13 
3.2.1 
Method of Assigning Subjects to Treatment Groups ........................................................... 13 
3.2.2 
Rationale for Selection of Doses .......................................................................................... 13 
3.2.3 
Blinding and Unblinding ...................................................................................................... 13 
3.3 
End of Study ....................................................................................................................................... 13 
4 
STUDY POPULATION................................................................................................................................ 13 
4.1 
Inclusion Criteria ................................................................................................................................ 14 
4.2 
Exclusion Criteria ............................................................................................................................... 15 
4.3 
Removal of Subjects from Therapy or Assessment ............................................................................ 16 
4.3.1 
Discontinuation of Study Treatment .................................................................................... 16 
4.3.2 
Subject Withdrawal from Study ........................................................................................... 16 
5 
TREATMENTS ............................................................................................................................................ 17 
5.1 
Treatments Administered.................................................................................................................... 17 
5.2 
Investigational Product ....................................................................................................................... 17 
5.2.1 
Description ........................................................................................................................... 17 
5.2.2 
Dose and Administration ...................................................................................................... 17 
5.2.3 
Dose Modifications .............................................................................................................. 17 
5.2.4 
Storage and Handling ........................................................................................................... 18 
5.2.5 
Packaging and Labeling ....................................................................................................... 18 
5.2.6 
Preparation ........................................................................................................................... 19 
5.3 
Required Premedication and Post medication .................................................................................... 19 
5.4 
Concomitant Therapy ......................................................................................................................... 19 
5.4.1 
Required Concomitant Therapy for HIV-Positive Subjects ................................................. 19 
5.4.2 
Allowed Concomitant Therapy ............................................................................................ 21 
5.4.3 
Prohibited Concomitant Therapy ......................................................................................... 21 
5.5 
Management of Adverse Reactions .................................................................................................... 21 
5.5.1 
Management of Infusion Reactions ...................................................................................... 21 
5.5.2 
Management of Suspected PML .......................................................................................... 22 
5.5.3 
Management of Overdose .................................................................................................... 22 
5.6 
Treatment Compliance ....................................................................................................................... 22 
6 
STUDY ACTIVITIES ................................................................................................................................... 23 
6.1 
Schedule of Events ............................................................................................................................. 23 
6.2 
Screening Visit (Day –28 to Day 1).................................................................................................... 23 
6.2.1 
Baseline Visit (Day –7 to Day 1) ......................................................................................... 23 
6.3 
Treatment Period (Day 1 to Day 21) .................................................................................................. 24 
6.3.1 
All Cycles, Day 1 ................................................................................................................. 24 
6.3.2 
Cycle 2 and Every 4 Cycles Thereafter: Day 15-21 Until Progression or Initiation of 
Subsequent Therapy ............................................................................................................. 24 
6.4 
End of Treatment Visit (30 to 37 days after last dose of study drug) ................................................. 25 
6.5 
Follow-up: Every 4 Months From the Last Scan Performed Until Date of Progression/Subsequent 
Therapy ............................................................................................................................................... 25 
6.6 
Subject End of Study/End of Follow-up ............................................................................................. 25 


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7 
STUDY ASSESSMENTS ............................................................................................................................. 26 
7.1 
Screening/Baseline Assessments ........................................................................................................ 26 
7.1.1 
Histological Diagnosis ......................................................................................................... 26 
7.2 
Response/Efficacy Assessments ......................................................................................................... 26 
7.2.1 
Modified Lugano Criteria ..................................................................................................... 27 
7.2.2 
Lugano Criteria .................................................................................................................... 28 
7.2.3 
International Working Group Consensus Response Evaluation Criteria in Lymphoma ...... 29 
7.3 
Pharmacokinetic and Immunogenicity Assessments .......................................................................... 29 
7.4 
Biospecimen Repository ..................................................................................................................... 29 
7.5 
Other Study Assessments ................................................................................................................... 30 
7.5.1 
Additional Monitoring for Post-Allogeneic Transplant Subjects ......................................... 30 
7.5.2 
Additional Monitoring for HIV-Positive and Hepatitis C-Positive Subjects ........................ 30 
7.6 
Safety Assessments............................................................................................................................. 30 
7.6.1 
Adverse Events ..................................................................................................................... 31 
7.6.2 
Clinical Laboratory Tests ..................................................................................................... 37 
7.6.3 
Physical Examination ........................................................................................................... 37 
7.7 
Appropriateness of Measurements...................................................................................................... 37 
8 
DATA QUALITY CONTROL AND QUALITY ASSURANCE ................................................................ 38 
8.1 
Site Training and Monitoring Procedures ........................................................................................... 38 
8.2 
Data Management Procedures ............................................................................................................ 39 
8.3 
Access to Source Data ........................................................................................................................ 39 
8.4 
Accuracy and Reliability of Data........................................................................................................ 39 
8.5 
Quality Assurance Procedures ............................................................................................................ 39 
8.6 
Data Handling and Record Keeping ................................................................................................... 40 
8.6.1 
Data Handling ...................................................................................................................... 40 
8.6.2 
Investigator Record Retention .............................................................................................. 40 
9 
DATA ANALYSIS METHODS ................................................................................................................... 40 
9.1 
Determination of Sample Size ............................................................................................................ 40 
9.2 
Study Endpoint Definitions ................................................................................................................ 41 
9.2.1 
Objective Response Rate ...................................................................................................... 41 
9.2.2 
Duration of Response ........................................................................................................... 41 
9.2.3 
Progression-Free Survival .................................................................................................... 41 
9.2.4 
Overall Survival ................................................................................................................... 41 
9.2.5 
Complete Response Rate ...................................................................................................... 41 
9.3 
Statistical and Analytical Plans .......................................................................................................... 42 
9.3.1 
General Considerations ........................................................................................................ 42 
9.3.2 
Subject Disposition .............................................................................................................. 43 
9.3.3 
Subject Characteristics ......................................................................................................... 43 
9.3.4 
Treatment Compliance ......................................................................................................... 43 
9.3.5 
Efficacy Analyses ................................................................................................................. 43 
9.3.6 
Pharmacokinetic and Immunogenicity Analyses.................................................................. 44 
9.3.7 
Safety Analyses .................................................................................................................... 44 
9.3.8 
Interim Analyses .................................................................................................................. 45 
10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY CONSIDERATIONS ................. 46 
10.1 Informed Consent ............................................................................................................................... 46 
10.2 Ethical Review .................................................................................................................................... 46 
10.3 Regulatory Considerations.................................................................................................................. 47 
10.3.1 
Investigator Information ....................................................................................................... 47 
10.3.2 
Protocol Amendments and Study Termination .................................................................... 47 
10.4 Study Documentation, Privacy and Records Retention ...................................................................... 47 
10.5 Clinical Trial Agreement .................................................................................................................... 47 
11 REFERENCES .............................................................................................................................................. 48 
APPENDIX A: SCHEDULE OF EVENTS ......................................................................................................... 51 


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APPENDIX B: PERFORMANCE STATUS SCALES CONVERSION ............................................................. 53 
APPENDIX C: NEW YORK HEART ASSOCIATION CLASSIFICATION .................................................... 54 
APPENDIX D: GUIDANCE ON CONTRACEPTION ....................................................................................... 55 
APPENDIX E: INVESTIGATOR SIGNATURE PAGE ..................................................................................... 56 
APPENDIX F: DOCUMENT HISTORY ............................................................................................................ 57 
 
LIST OF IN-TEXT TABLES 
Table 1:  
Objectives and corresponding endpoints ....................................................................................... 11 
Table 2: 
Recommended dose modifications for brentuximab vedotin-associated toxicity .......................... 18 
Table 3: 
Integrated PET and CT response according to modified Lugano criteria ...................................... 28 
Table 4: 
Integrated PET and CT response according to Lugano criteria per BICR ..................................... 28 
Table 5: 
Pharmacokinetic, pharmacodynamic, and immunogenicity sampling time points ........................ 29 
 
LIST OF IN-TEXT FIGURES 
Figure 1: 
Study design .................................................................................................................................. 12 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADC 
antibody-drug conjugate 
AE 
adverse event 
ALK 
Anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ATA 
antitherapeutic antibodies 
ATLL 
adult T cell leukemia/lymphoma 
auto-HSCT 
autologous hematopoietic stem cell transplantation 
BICR 
blinded independent central review 
Ceoi 
concentration at the end of infusion 
Ctrough 
trough concentration 
CBC 
complete blood count 
cHL 
classic Hodgkin lymphoma 
CI 
confidence interval 
CR 
complete response 
CT 
computed tomography  
CRF 
case report form 
CMV 
cytomegalovirus 
DILI 
drug-induced liver injury 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
end of treatment 
EU 
European Union 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose  
GFR 
glomerular filtration rate 
GvHD 
graft-versus-host disease 
HAART 
highly active antiretroviral therapy 
HIV 
human immunodeficiency virus 
HL 
Hodgkin lymphoma 
HTLV-1 
human T cell leukemia virus-1 
ICH 
International Council for Harmonisation  
IEC 
independent ethics committee 
IND 
investigational new drug 
IRB 
institutional review board 
IV 
intravenous 
JCV 
John Cunningham virus 
MDRD 
Modification of Diet in Renal Disease [study] 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMAE 
monomethyl auristatin E 
MRI 
magnetic resonance imaging 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NHL 
non-Hodgkin Lymphoma 
OS 
overall survival  


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ORR 
objective response rate 
PCR 
polymerase chain reaction  
PD 
progressive disease 
PET 
Positron emission tomography 
PFS 
progression-free survival 
P-gp 
p-glycoprotein 
PK 
pharmacokinetic(s) 
PML 
progressive multifocal leukoencephalopathy 
PR 
partial response 
PTCL 
peripheral T cell lymphoma 
RECIL 
Response Evaluation Criteria in Lymphoma 
SAE 
serious adverse event 
sALCL 
Systemic anaplastic large cell lymphoma 
SAP 
statistical analysis plan 
Scr 
serum creatinine 
SD 
stable disease 
SLD 
sum of the longest diameters 
SPD 
sum of the products of the longest perpendicular diameters 
SUSAR 
suspected unexpected serious adverse reaction 
ULN  
upper limit of normal 
USAN 
United States adopted name 
USP 
United States Pharmacopeia 
USPI 
United States Prescribing Information 


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1 
INTRODUCTION 
Brentuximab vedotin is a CD30-directed antibody-drug conjugate (ADC) consisting of 
3 components: 1) the chimeric IgG1 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. Targeted delivery of MMAE to 
CD30-expressing tumor cells is the primary mechanism of action of brentuximab vedotin 
(Sutherland 2006). Binding of MMAE to tubulin disrupts the microtubule network within the 
cell, subsequently inducing cell cycle arrest and apoptotic death of the cell. Other nonclinical 
studies suggest additional contributory mechanisms of action, including antibody-dependent 
cellular phagocytosis (ADCP); bystander effects on nearby cells in the tumor 
microenvironment due to released MMAE; and immunogenic cell death due to endoplasmic 
reticulum stress which drives exposure of immune activating molecules that can promote a 
T cell response (Cao 2016; Gardai 2016; Kim 2015; Li 2014; Muller 2014; Oflazoglu 2007). 
A complete summary of the clinical and nonclinical data relevant to the investigational 
product and its study in human subjects is provided in the Investigator’s Brochure. 
1.1 Clinical Experience with brentuximab vedotin 
The safety and efficacy of brentuximab vedotin has been evaluated in more than 
2700 subjects in company-sponsored clinical trials, and approved by the Food and Drug 
Administration (FDA) for 6 indications: 
● 
Classic Hodgkin lymphoma (cHL) after failure of autologous hematopoietic stem cell 
transplantation (auto-HSCT) or after failure of at least 2 prior multi-agent 
chemotherapy regimens in subjects who are not auto-HSCT candidates. 
● 
Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 prior 
multi-agent chemotherapy regimen. 
● 
cHL at high risk of relapse or progression as post auto-HSCT consolidation. 
● 
Previously untreated Stage III or IV classic cHL, in combination with doxorubicin, 
vinblastine, and dacarbazine. 
● 
Previously untreated sALCL or other CD30-expressing peripheral T cell lymphomas 
(PTCL), including angioimmunoblastic T cell lymphoma and PTCL not otherwise 
specified, in combination with cyclophosphamide, doxorubicin, and prednisone. 
● 
Primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing 
mycosis fungoides (MF) who have received prior systemic therapy. 
The pivotal clinical trials leading to these approvals included a phase 2 study of brentuximab 
vedotin monotherapy in relapsed or refractory HL after autologous stem cell transplant 
(SG035-0003), a phase 2 study of brentuximab vedotin monotherapy in relapsed or refractory 
sALCL (SG035-0004), a phase 3 study of brentuximab vedotin plus best supportive care 
versus placebo plus best supportive care in the treatment of subjects at high risk of residual 
HL following autologous stem cell transplant (SGN35-005), a phase 3 study of brentuximab 


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vedotin + doxorubicin, vinblastine, and dacarbazine (A+AVD) vs. doxorubicin, bleomycin, 
vinblastine, and dacarbazine (ABVD) as frontline therapy for newly diagnosed Stage III or 
IV cHL subjects (C25003), a phase 3 study of brentuximab vedotin + cyclophosphamide, 
doxorubicin, and prednisone (A+CHP) vs cyclophosphamide, doxorubicin, vincristine, and 
prednisone (CHOP) as frontline therapy for newly diagnosed CD30-expressing PTCL 
(SGN35-014), and a phase 3 study of brentuximab vedotin versus methotrexate or bexarotene 
in CD30-positive cutaneous T-cell lymphoma (C25001). 
1.2 CD30 Expression in cHL and PTCL 
CD30 is uniformly expressed and is pathognomonic in cHL and sALCL. Among non-sALCL 
PTCL subtypes, CD30 expression is more variable (Bossard 2014; Federico 2015; Sabattini 
2013).  
1.3 Study Rationale 
There is precedent for effective retreatment with an antibody-based therapy in lymphoma. 
Rituximab (Rituxan®; Genentech and Biogen Idec) is a genetically engineered chimeric 
mouse/human monoclonal antibody directed against the antigen CD20 and approved for the 
treatment of non-Hodgkin lymphoma (NHL). As a retreatment therapy, rituximab has been 
evaluated in subjects with relapsed/refractory low-grade or follicular B-cell NHL who 
achieved objective clinical response to initial rituximab therapy (Davis 2000; Kahl 2014). 
Study SGN35-006 demonstrated effective retreatment with brentuximab vedotin 
monotherapy in subjects who had previously achieved an objective response with 
brentuximab vedotin monotherapy as a treatment for relapsed or refractory cHL or sALCL. 
In that study the objective response rate (ORR) for retreatment of cHL was 60% (12 of 20 
evaluable subjects) with a complete response (CR) rate of 30% (6 of 20 evaluable subjects). 
For retreated sALCL, the ORR was 88% (7 of 8 subjects) with a CR rate of 63% (5 of 8 
subjects). The estimated median duration of response (DOR) for subjects with an objective 
response was 9.5 months and for subjects with a CR the estimated median DOR was 
12.3 months (Bartlett 2014). However, this prior study did not enroll any subjects who 
received brentuximab vedotin as part of frontline treatment or in subjects with non-sALCL 
PTCL. The ECHELON-2 study compared brentuximab vedotin in combination with 
cyclophosphamide, doxorubicin, and prednisone (A+CHP) to cyclophosphamide, 
doxorubicin, vincristine, and prednisone (CHOP) in previously untreated CD30-expressing 
PTCL. Of the 23 A+CHP patients who progressed and received treatment with a subsequent 
brentuximab vedotin containing therapy, 13 (57%) demonstrated an objective response, 
including patients with non-sALCL PTCL (reference is the SGN35-14 CSR). 


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2 
OBJECTIVES 
This study will evaluate the efficacy, safety, and pharmacokinetics (PK) of retreatment with 
brentuximab vedotin in subjects with cHL, sALCL, and CD30-expressing PTCL. Specific 
objectives and corresponding endpoints for the study are summarized below (Table 1). 
Table 1:  
Objectives and corresponding endpoints 
Primary Objective 
Corresponding Primary Endpoint 
• To assess the antitumor response by blinded 
independent central review (BICR) of brentuximab 
vedotin retreatment 
• BICR reporting of objective response rate (ORR) 
per modified Lugano response criteria (Cheson 
2014) 
• To assess the safety of retreatment with brentuximab 
vedotin 
• Type, incident, severity, seriousness, and 
relatedness of adverse events (AEs) 
• Type, incidence, and severity of laboratory 
abnormalities 
Secondary Objectives 
Corresponding Secondary Endpoints 
• To assess duration of tumor control, including 
duration of response (DOR) as determined by BICR 
• To assess progression-free survival (PFS) of 
retreatment with brentuximab vedotin as determined 
by BICR 
• BICR reporting of DOR per modified Lugano 
response criteria  (Cheson 2014) 
• BICR reporting of PFS per modified Lugano 
response criteria  (Cheson 2014) 
• To assess overall survival (OS)  
• OS 
• To assess complete response (CR) rate per BICR 
 
• To assess the antitumor response per investigator of 
brentuximab vedotin retreatment 
• To assess DOR rate per investigator assessment 
 
• To assess PFS per investigator assessment 
 
• To assess CR rate per investigator assessment 
• Rate of CR per BICR per modified Lugano 
response criteria (Cheson 2014) 
• Investigator reporting of ORR per modified 
Lugano response criteria (Cheson 2014) 
• Investigator reporting of DOR per modified 
Lugano response criteria (Cheson 2014) 
• Investigator reporting of PFS per modified Lugano 
response criteria (Cheson 2014) 
• Rate of CR per investigator per modified Lugano 
response criteria (Cheson 2014) 
• To assess ORR as determined by BICR 
• BICR reporting of ORR per Lugano response 
criteria (Cheson 2014) 
Additional Objectives 
Corresponding Additional Endpoints 
• To assess the PK and immunogenicity of 
brentuximab vedotin 
• To assess ORR as determined by BICR 
• Brentuximab vedotin PK concentrations and 
incidence of ATA to brentuximab vedotin 
• BICR reporting of ORR per RECIL (Younes 2017) 
 


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3 
INVESTIGATIONAL PLAN 
3.1 Summary of Study Design 
This is a phase 2, multicenter, single-arm study to determine the safety and efficacy of 
brentuximab vedotin in subjects with cHL, sALCL, or other CD30-expressing PTCL who 
demonstrated an objective response to a prior brentuximab vedotin-containing treatment 
regimen and subsequently experienced disease progression or relapse. It is anticipated that 
approximately 80 subjects will enroll in this study: approximately 40 subjects with cHL and 
approximately 40 subjects with CD30-expressing PTCL. In the PTCL cohort, subjects with 
systemic anaplastic large cell lymphoma (sALCL) will have an estimated enrollment cap of 
approximately 50%, and subjects with other CD30-expressing PTCL will have an estimated 
enrollment cap of approximately 50%. Subjects will be administered 1.8 mg/kg brentuximab 
vedotin intravenously (IV), up to a maximum of 180 mg, over 30 minutes once per 21-day 
cycle. Subjects who previously required a dose reduction due to adverse events (AE) will 
start brentuximab vedotin at a dose of 1.2 mg/kg and will not escalate to 1.8 mg/kg. Safety of 
treatment will be monitored throughout the trial via laboratory values and AE collection. 
Figure 1: 
Study design 
 
 


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3.2 Discussion and Rationale for Study Design 
The endpoints of the study are appropriate for evaluating the safety and efficacy of SGN-35 
in the retreatment setting. The primary efficacy endpoint of this study, ORR, is a direct 
measure of antitumor activity and is one of the surrogate endpoints recommended by FDA 
for approval of anti-cancer drugs (FDA Guidance for Industry “Clinical Trial Endpoints for 
the Approval of Cancer Drugs and Biologics”). To further assess the significance of ORR in 
this study, durability, CR rate, overall survival (OS), and progression-free survival (PFS) will 
be evaluated as secondary endpoints. 
This study will enroll subjects with relapsed or refractory cHL, sALCL, or CD30 expressing 
PTCL who have previously had an objective response to a regimen containing brentuximab 
vedotin, but have experienced subsequent disease progression or relapse at least 6 months or 
longer from their last dose. Given that these subjects are not refractory to brentuximab 
vedotin, it is clinically reasonable to evaluate retreatment in this setting. 
3.2.1 Method of Assigning Subjects to Treatment Groups 
This is single-arm study. 
3.2.2 Rationale for Selection of Doses 
The recommended dose for brentuximab vedotin per its prescribing information is 1.8 mg/kg 
via IV infusion administered every 3 weeks. This dose and schedule were evaluated in two 
pivotal phase 2 studies (SG035-0003 and SG035-0004) in subjects with CD30-positive 
hematologic malignancies. 
3.2.3 Blinding and Unblinding 
This study will not be blinded. 
3.3 End of Study 
The study will be closed 2 years after the last subject receives their last dose or when the last 
subject completes the last visit, last contact, discontinues from the study, or when no subjects 
remain in follow-up, whichever occurs first. In addition, the sponsor may terminate the study 
at any time (see Section 10.3.2). 
4 
STUDY POPULATION 
All relevant medical and non-medical conditions should be taken into consideration when 
deciding whether this protocol is suitable for a particular subject. Eligibility criteria may not 
be waived by the investigator and are subject to review in the event of Good Clinical Practice 
(GCP) or Health Regulatory Authority (HRA) inspection. Any questions regarding a 
subject’s eligibility should be discussed with the Sponsor’s study management group prior to 
enrollment. 
In order to be enrolled in this study, subjects must meet all the inclusion and exclusion 
criteria outlined below. Following informed consent and satisfaction of eligibility criteria, 


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enrollment in the study will be documented in the case report form (CRF). Subjects who 
undergo screening and are found to be ineligible will not be enrolled. 
4.1 Inclusion Criteria 
1. Histologically confirmed cHL, sALCL, or other CD30-expressing PTCL. 
CD30-expressing PTCL is defined as a tumor having a CD30 expression level ≥1% by 
local testing. 
2. Previously treated with brentuximab vedotin containing regimen, with evidence of 
objective response, and subsequent disease progression or relapse after discontinuing 
treatment. 
3. Documentation of disease relapse or progression ≥6 months after the last dose of 
brentuximab vedotin based on the Lugano Response Assessment Criteria for Malignant 
Lymphoma (Cheson 2014). 
4. Fluorodeoxyglucose positron emission tomography- (FDG-PET) avid and bidimensional 
measurable disease of at least 1.5 cm in longest axis as documented by radiographic 
technique (spiral computed tomography [CT] preferred) 
5. An Eastern Cooperative Oncology Group (ECOG) performance status ≤2 
6. The following required baseline laboratory data: 
● 
absolute neutrophil count (ANC) ≥750 cells/μL (unless documented bone marrow 
involvement with lymphoma) 
● 
platelets ≥50,000/μL (unless documented bone marrow involvement with lymphoma) 
● 
serum bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN for subjects with 
Gilbert’s disease 
● 
serum creatinine (Scr) ≤1.5 x ULN 
● 
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x ULN for 
subjects with documented hepatic involvement with lymphoma 
● 
estimated glomerular filtration rate (GFR) ≥30 mL/min/1.73m2 using the 
Modification of Diet in Renal Disease (MDRD) study equation as applicable 
7. Subjects of childbearing potential must have a negative serum or urine beta human 
chorionic gonadotropin (β-hCG) pregnancy test result within 7 days prior to the first dose 
of brentuximab vedotin. Subjects with false positive results and documented verification 
that the subject is not pregnant are eligible for participation. 
8. Subjects of non-childbearing potential are those who are postmenopausal >1 year or who 
have had a bilateral oophorectomy or hysterectomy. 
9. If sexually active in a way that could result in pregnancy, subjects of childbearing 
potential and subjects who can father children and have partners of childbearing potential 
must agree to use 2 effective contraception methods during the study and for 6 months 
following the last dose of study drug. 


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10. The following requirements for subjects who are human immunodeficiency virus 
(HIV)-positive: 
● 
CD4+ T cell counts ≥350 cell/µL 
● 
No AIDS-defining opportunistic infection within the past 12 months 
● 
On established highly active antiretroviral therapy (HAART) for at least 4 weeks with 
an HIV viral load less than 400 copies/mL 
11. Age 18 or older. 
12. The subject or subject’s legally acceptable representative must provide written informed 
consent. 
4.2 Exclusion Criteria 
1. Subjects who previously discontinued brentuximab vedotin due to any Grade 3 or higher 
toxicity. 
2. Subjects with existing Grade 2 or higher peripheral neuropathy. 
3.  Subjects who were previously refractory to treatment with brentuximab vedotin. 
4. Documented history of a cerebral vascular event (stroke or transient ischemic attack), 
unstable angina, myocardial infarction, or cardiac symptoms consistent with New York 
Heart Association Class III to IV (see Appendix C) within 6 months prior to their first 
dose of brentuximab vedotin. 
5. History of another malignancy within 3 years before the first dose of study drug or any 
evidence of residual disease from a previously diagnosed malignancy. Exceptions are 
malignancies with a negligible risk of metastasis or death (e.g., 5-year (OS) ≥90%), such 
as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, 
localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer. 
6. Subjects with acute or chronic graft-versus-host-disease (GvHD) or receiving 
immunosuppressive therapy as treatment for or prophylaxis agent against GvHD. 
7. Active cerebral/meningeal disease, including history of progressive multifocal 
leukoencephalopathy (PML). Subjects with a history of cerebral/meningeal disease 
related to the underlying malignancy are allowed if prior CNS disease has been treated. 
8. History of PML. 
9. Any active uncontrolled Grade 3 or higher (per the National Cancer Institute’s Common 
Terminology Criteria for AEs, NCI CTCAE Version 5.0) viral, bacterial, or fungal 
infection requiring treatment with antimicrobial therapy within 2 weeks prior to the first 
dose of brentuximab vedotin in this study. Routine antimicrobial prophylaxis is 
acceptable. 


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10. Chemotherapy, radiotherapy, biologics, and/or other antitumor treatment with 
immunotherapy that is not completed 4 weeks prior to first dose of study drug, unless 
underlying disease has progressed on treatment. 
11. Subjects who are pregnant or breastfeeding. 
12. Subjects with known hypersensitivity to any excipient contained in the drug formulation. 
13. Subjects <100 days from allogeneic transplant. 
14. Post-allogeneic transplant subjects with any detectable level of cytomegalovirus (CMV) 
by polymerase chain reaction (PCR). Prior PCR positivity that was successfully treated is 
acceptable provided the baseline PCR result is negative prior to first dose of study drug. 
15. Prior donor lymphocyte infusion <8 weeks prior to first dose of study drug. 
16. Other serious underlying medical condition that, in the opinion of the investigator, would 
impair the subject’s ability to receive or tolerate the planned treatment and follow-up. 
17. Subjects enrolled and treated in this study cannot enroll in this study again. 
4.3 Removal of Subjects from Therapy or Assessment 
Seattle Genetics or their designee must be notified if a subject is withdrawn from study 
treatment or from the study. The reason(s) for withdrawal must be documented in the 
subject’s medical records and CRF. 
4.3.1 Discontinuation of Study Treatment 
Subjects may continue on treatment for unlimited cycles until any of the following occur: 
● 
Progressive disease (PD) 
● 
AE with unacceptable toxicity 
● 
Pregnancy 
● 
Investigator decision 
● 
Subject decision, non-AE 
● 
Study termination by sponsor 
● 
Other, non-AE 
 
Subjects who discontinue from study treatment will remain on study for follow-up unless 
they withdraw consent. 
4.3.2 Subject Withdrawal from Study 
Any subject may be discontinued from the study for any of the following reasons: 
● 
Subject withdrawal of consent 
● 
Study termination by sponsor 
● 
Lost to follow-up 


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● 
Death 
● 
Other 
5 
TREATMENTS 
5.1 Treatments Administered 
Brentuximab vedotin, the investigational agent under study in this protocol, is an ADC 
consisting of the antibody cAC10, specific for human CD30; the microtubule-disrupting 
agent MMAE; and a protease-cleavable linker that covalently attaches MMAE to cAC10. 
5.2 Investigational Product 
Detailed information describing the preparation, administration, and storage of brentuximab 
vedotin is located in the Pharmacy Instructions. 
5.2.1 Description 
Brentuximab vedotin is a sterile, preservative free, white to off-white lyophilized cake or 
powder supplied by Seattle Genetics in single-use vials for reconstitution for IV 
administration. Each vial of the product contains brentuximab vedotin, trehalose, sodium 
citrate, and polysorbate 80. See the Pharmacy Instructions for further information. 
5.2.2 Dose and Administration 
Brentuximab vedotin will be administered by IV infusion given over approximately 
30 minutes. The starting dose of brentuximab vedotin will be 1.8 mg/kg every 21 days. 
Subjects who had required a previous dose reduction due to AEs will start at 1.2 mg/kg and 
will not escalate to 1.8 mg/kg. In the absence of infusion-related reactions, the infusion rate 
for all subjects should be calculated in order to achieve a 30-minute infusion period. 
Brentuximab vedotin must not be administered as an IV push or bolus. Brentuximab vedotin 
should not be mixed with other medications. 
Weight-based dosing is based on subject actual body weight. Doses must be adjusted for 
subjects who experience a ≥10% change in weight from baseline. Subject weight must be 
measured during all relevant assessment windows as described in the schedule of events. 
Other dose adjustments for changes in body weight are permitted per institutional standard. 
Rounding is permissible within 5% of the nominal dose. An exception to weight-based 
dosing is made for subjects weighing greater than 100 kg; doses will be based on 100 kg 
for these individuals. The maximum dose calculated per cycle in this study is 180 mg for 
subjects receiving the 1.8 mg/kg dose level, and 120 mg for subjects receiving 1.2 mg/kg 
dose level. 
5.2.3 Dose Modifications 
For post-allogeneic transplant subjects, any post baseline instances of detectable levels of 
CMV must be discussed with the Medical Monitor prior to continued dosing of brentuximab 
vedotin. Table 2 describes the recommended dose modifications for study 
treatment-associated toxicity. 


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Doses reduced for treatment-related toxicity should not be re-escalated without discussion 
with the sponsor. 
Table 2: 
Recommended dose modifications for brentuximab vedotin-associated toxicity 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Peripheral 
Neuropathy 
Continue at 
same dose 
level 
Withhold until toxicity resolves to Grade 1 
or baseline, then resume treatment at 
1.2 mg/kga 
Discontinue treatment 
Non-
hematologic 
(except 
peripheral 
neuropathy) 
Continue at 
same dose 
level 
Continue at same 
dose level 
Withhold dose until 
toxicity is ≤ Grade 2 or 
has returned to 
baseline, then resume 
treatment at the same 
dose levelb. 
Withhold dose until 
toxicity is ≤ Grade 2 or 
has returned to baseline, 
then reduce dose to 
1.2 mg/kg and resume 
treatment, or discontinue 
at the discretion of the 
investigator a,b,c. 
Hematologicd 
Continue at 
same dose 
level 
Continue at same 
dose level 
Withhold until toxicity resolves to ≤ Grade 2 or 
baseline, then resume treatment at the same dose 
levele. For Grade 3 or 4 neutropenia, growth factor 
support (G-CSF or GM-CSF) should be considered 
for subsequent cycles. If Grade 4 neutropenia 
recurs despite growth factor support, consider 
discontinuation or dose reduction to 1.2 mg/kg. 
a 
Dose reductions below 1.2 mg/kg are not allowed, and toxicities should be managed with dose delays. 
b 
Subjects who develop Grade 3 or 4 electrolyte laboratory abnormalities may continue study treatment without 
interruption. 
c 
Treatment should be discontinued for subjects who experience Grade 4 infusion-related reactions. 
d 
Support with blood product transfusions allowed per institutional standard of care. 
e 
Subjects who develop Grade 3 or 4 lymphopenia may continue study treatment without interruption. 
5.2.4 Storage and Handling 
Refrigeration should be set at 2 to 8°C for storage of vials and solutions containing 
brentuximab vedotin. The controlled location must be accessible only to the pharmacist, the 
investigator, or a duly designated person. 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 the time of use. Reconstituted vials and solutions must not be 
shaken. 
Drug accountability instructions are provided in the Pharmacy Binder. 
5.2.5 Packaging and Labeling 
Drug product vials may be labeled as brentuximab vedotin, the United States adopted name 
(USAN) and the International Nonproprietary Name (INN), or as SGN-35, the compound 
code; the 2 names can be used interchangeably. 


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5.2.6 Preparation 
Brentuximab vedotin vials are provided via single-use containers. Any partially used vials or 
diluted dosing solutions should be discarded using appropriate institutional drug disposal 
procedures. 
Brentuximab vedotin should be reconstituted with the appropriate amount of Sterile Water 
for Injection, United States Pharmacopeia (USP) or equivalent (see Pharmacy Instructions for 
details). The vial should be gently swirled until the contents are completely dissolved. The 
vial must not be shaken. The reconstituted drug product should be inspected visually for any 
particulate matter and discoloration. 
The required volume of reconstituted drug product should be diluted into an infusion bag. 
The bag should be gently inverted to mix the solution. The bag must not be shaken. Prior to 
administration, the reconstituted and diluted drug product should be inspected visually for 
any particulate matter and discoloration. 
Detailed drug preparation instructions are provided in the Pharmacy Instructions. 
5.3 Required Premedication and Post medication 
Routine premedication 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 5.5.1. Subjects who experience a 
Grade 3 or Grade 4 infusion-related reaction may potentially receive additional treatment 
with brentuximab vedotin at the discretion of the investigator after discussion with the 
sponsor. 
Subjects should be individually evaluated to assess the need for tumor lysis prophylaxis prior 
to the first dose of brentuximab vedotin. Subjects should receive prophylaxis as appropriate 
per the institutional standards. 
5.4 Concomitant Therapy 
All concomitant medications, blood products, and radiotherapy administered will be recorded 
from Day 1 (predose) through the safety reporting period. Any concomitant medication given 
for a study protocol-related AE should be recorded from the time of informed consent. 
5.4.1 Required Concomitant Therapy for HIV-Positive Subjects 
HIV-positive subjects must be managed in conjunction with an HIV specialist. The following 
measures are recommended. 


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5.4.1.1 HAART 
Highly Active Antiretroviral Therapy (HAART) is a requirement for the duration of the 
study. Participants must be on HAART therapy for at least 7 days before therapy. The 
specific agents are at the discretion of the Investigator and use of agents currently available 
on an expanded access basis is allowed. Use of experimental antiretroviral agents or those 
containing zidovudine (including Combivir® and Trizivir®), ritonavir (including Kaletra®), 
Cobicistat (Stribild®), or another potent CYP3 inhibitor are prohibited. Participants taking 
zidovudine- or ritonavir-based HAART must change to a different regimen 7 days prior to 
therapy initiation (see Section 5.4.3). Changes to HAART therapy may be made if medically 
necessary (toxicity, failure of regimen, etc.). 
5.4.1.2 Pneumocystis Prophylaxis 
Trimethoprim sulfamethoxazole (Bactrim) must be given at the onset of therapy for 
Pneumocystis and Toxoplasmosis prophylaxis, according to current NIH Guidelines for the 
Prevention of Opportunistic Infections in HIV-Infected Adults and Adolescents. 
Alternatively, dapsone (50 mg PO twice daily), atovaquone, or aerosolized pentamidine may 
be substituted for Pneumocystis prophylaxis in participants allergic to sulfonamides. 
Pneumocystis prophylaxis will be continued once therapy has been discontinued. 
5.4.1.3 Mycobacterium avium complex (MAC) Prophylaxis 
Azithromycin 1,200 mg PO once weekly must be initiated for prophylaxis if the CD4 count 
falls below 50 cells/µL or is expected to drop below 50 cells/L while on chemotherapy. 
Prophylaxis may be discontinued once the CD4 count is deemed reliably above 50 cells/µL 
by the treating investigator. 
Due to the glycoprotein P inhibition properties of azithromycin, this may increase the drug 
exposure and contribute to increased toxicity. Careful monitoring for brentuximab 
vedotin-related toxicities should be instituted in subjects receiving Azithromycin. 
Based on the PK of azithromycin and brentuximab vedotin, the study team recommends 
giving the azithromycin on Days 5, 12, 19, and 21 of each cycle. 
5.4.1.4 Effect of Other Drugs on Brentuximab Vedotin  
CYP3A4 Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A4. 
Co-administration of brentuximab with strong CYP3A4 inhibitors may increase exposure to 
MMAE. Subjects who are receiving strong CYP3A4 inhibitors concomitantly with 
brentuximab vedotin should be closely monitored for adverse reactions. Additionally, 
co-administration of brentuximab vedotin with potent CYP3A4 inducers may reduce 
exposure to MMAE. 
P-glycoprotein (P-gp) Inhibitors: Co-administration of brentuximab vedotin with P-gp 
inhibitors may increase exposure to MMAE. Subjects who are receiving P-gp inhibitors 
concomitantly with brentuximab vedotin should be closely monitored for adverse reactions. 


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5.4.2 Allowed Concomitant Therapy 
The use of platelet and/or red blood cell supportive growth factors or transfusions when 
applicable is allowed. The use of colony stimulating factors for the treatment of neutropenia 
per institutional practice is permitted during therapy. Concomitant prednisone (or equivalent) 
may be used at a dose of ≤20 mg/day. 
Routine premedication for infusion reactions should not be administered prior to the first 
dose of brentuximab vedotin. However, subjects who experience a Grade 1 or Grade 2 
infusion-related reaction may receive subsequent treatment with premedication as described 
in Section 5.5.1. 
Subjects who are receiving strong CYP3A4 inhibitors concomitantly with brentuximab 
vedotin should be closely monitored for adverse reactions. 
Routine prophylaxis with vaccines is permitted; it is recommended that vaccines used do not 
contain live micro-organisms. 
5.4.2.1 
Post-Allogeneic Transplant Therapy Recommendations 
For subjects who are post-allogeneic transplant, if a post baseline sample is positive for CMV 
by PCR, initiation of pre-emptive therapy with ganciclovir or valganciclovir per institutional 
guidelines is recommended until CMV PCR becomes negative (Tomblyn 2009). Granulocyte 
colony-stimulating factor support is recommended to maintain ANC ≥750 cells/µL. 
5.4.3 Prohibited Concomitant Therapy 
Subjects may not receive other investigational drugs, immunosuppressive medications, 
radiotherapy (except for palliative radiotherapy), or systemic anti-neoplastic therapy during 
the study. Use of experimental antiretroviral agents or those containing zidovudine (including 
Combivir® and Trizivir®), ritonavir (including Kaletra®), Cobicistat (Stribild®), or another 
potent CYP3 inhibitor are prohibited. In order to be eligible, participants taking zidovudine- 
or ritonavir-based HAART must change to a different regimen 7 days prior to therapy 
initiation. 
5.5 Management of Adverse Reactions 
5.5.1 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 
extending the infusion time and/or administering medications for infusion-related reactions. 
Subjects who have experienced a Grade 1 or Grade 2 infusion-related reaction to 
brentuximab vedotin may be premedicated for subsequent infusions. Premedication may 
include acetaminophen, an antihistamine, and a corticosteroid administered 30 to 60 minutes 
prior to each brentuximab vedotin infusion or according to institutional standards. If 


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anaphylaxis occurs, administration of brentuximab vedotin should be immediately and 
permanently discontinued. 
5.5.2 Management of Suspected PML 
Signs and symptoms of PML may include altered mental status, motor deficits such as 
hemiparesis or ataxia, visual disturbances, or higher cortical dysfunction such as dysphasia or 
agnosia. See the Investigator’s Brochure for further details. 
If PML is suspected, hold further brentuximab vedotin dosing and undertake a diagnostic 
work-up including (but not limited to): 
● 
Neurologic examinations, as warranted 
● 
Brain radiologic features by magnetic resonance imaging (MRI) 
● 
PCR analysis: John Cunningham virus (JCV) DNA detectable in cerebrospinal fluid 
 
If PML is confirmed, permanently discontinue treatment with brentuximab vedotin. 
5.5.3 Management of Overdose 
Weight-based dosing for brentuximab vedotin is based on subject actual body weight (see 
Section 5.2.2), with the exception of subjects weighing greater than 100 kg; doses will be 
based on 100 kg for these individuals. The maximum dose calculated per cycle in this 
study is 180 mg for subjects receiving the 1.8 mg/kg dose level, and 120 mg for subjects 
receiving 1.2 mg/kg dose level. 
In the event of an overdose of brentuximab vedotin ≥10%, study personnel should: 
● 
Care for and medically stabilize the subject until there is no immediate risk of 
complications or death, if applicable. There is currently no known antidote for an 
overdose of brentuximab vedotin. 
● 
Notify the Medical Monitor as soon as they become aware of the overdose, to discuss 
details of the overdose (e.g., exact amount of brentuximab vedotin administered, 
subject weight) and AEs, if any. 
5.6 Treatment Compliance 
Study drug administration will be performed by study site staff and documented in source 
documents and the CRF. 


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6 
STUDY ACTIVITIES 
6.1 Schedule of Events 
AEs and concomitant medications will be recorded from Day 1 (predose) through the safety 
reporting period (see Section 7.6.1.3). Any study protocol-related AE, as well as any 
concomitant medications given for treatment of the AE, should be recorded from the time of 
informed consent. 
Clinical laboratory assessments (serum chemistry panel, complete blood count [CBC] with 
differential [manual differential if clinically indicated], as well as physical exam, weight, and 
ECOG performance status) may be performed within 1 day prior to administration of study 
drug. The results from all relevant clinical laboratory assessments must be reviewed prior to 
dosing. 
A schedule of events is provided in Appendix A. Study activities are listed by visit in this 
section and descriptions of study assessments are presented in Section 7. 
6.2 Screening Visit (Day –28 to Day 1) 
● 
Informed consent  
● 
Study eligibility per inclusion/exclusion criteria (see Section 4) 
● 
Medical history 
● 
CD30-expression and histological confirmation of cHL and PTCL performed by the 
local laboratory 
○ 
Confirmation of human T cell leukemia virus-1 (HTLV-1) positivity for adult 
T cell leukemia/lymphoma (ATLL) subjects 
● 
Contrast enhanced CT of neck, chest, abdomen, pelvis 
● 
PET scan  
● 
Prior disease therapies 
● 
A biopsy within 60 days prior to study start to confirm CD30 expression is required, 
but may be omitted if, in the opinion of the Investigator, obtaining the biopsy would 
place the subject at undue risk. 
● 
Bone marrow biopsy for sALCL or other CD30-expressing PTCL subjects (Day –14 
to Day 1) 
6.2.1 Baseline Visit (Day –7 to Day 1) 
● 
Height and weight 
● 
Electrocardiogram (ECG) 
● 
Urine and/or serum pregnancy test for subjects of childbearing potential 
● 
Physical exam 
● 
ECOG performance status 
● 
Serum chemistry panel (fasting glucose required at baseline only) (submit results to 
central laboratory) 


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● 
CBC with differential (submit results to central laboratory) 
● 
Hemoglobin (Hgb) A1c (submit results to central laboratory) 
● 
CMV PCR (post-allogeneic stem cell transplant subjects only). Results must be ready 
prior to C1D1 (see Section 7.5.1) (submit results to central laboratory) 
● 
CD4 count for HIV positive subjects only (see Sections 5.4.1 and 7.5.2) (submit 
results to central laboratory) 
6.3 Treatment Period (Day 1 to Day 21) 
6.3.1 All Cycles, Day 1 
● 
Cycle 1 only, prior to dosing, confirm subject eligibility per inclusion/exclusion 
criteria 
● 
If the following activities occur within 1 day prior to Cycle 1, Day 1 (or occur within 
2 days prior to Day 1 of all other cycles), they do not need to be repeated on Day 1: 
○ 
ECOG performance status 
○ 
Serum chemistry panel (submit results to central laboratory) 
○ 
CBC with differential (submit results to central laboratory) 
● 
Results from clinical laboratory assessments must be reviewed and must confirm 
eligibility prior to study drug administration 
● 
Physical examination, including weight 
● 
B symptom assessment 
● 
Blood samples for PK assessment (Cycles 1–4 only) 
● 
Blood sample for antitherapeutic antibodies (ATA) assessment (Cycles 1–4 only) 
● 
CMV PCR (post-allogeneic stem cell transplant subjects only) (not required at 
Cycle 1 if done at baseline) (submit results to central laboratory) 
● 
CD4 count for HIV positive subjects only (not required at Cycle 1 if done at baseline. 
Required at Cycle 2 and every 4 cycles thereafter) (submit results to central 
laboratory) 
● 
brentuximab vedotin administration 
6.3.2 Cycle 2 and Every 4 Cycles Thereafter: Day 15-21 Until Progression or 
Initiation of Subsequent Therapy 
● 
CT of neck, chest, abdomen, pelvis 
● 
PET scan if not found to be negative at a prior restage 
● 
Bone marrow biopsy to confirm CR for sALCL or other CD30-expressing PTCL 
subjects (if not found to be negative at screening and the post baseline PET/CT shows 
a CR; D15-D21 or D1-D2 of Cycle 3 and every 4 cycles thereafter) 


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6.4 End of Treatment Visit (30 to 37 days after last dose of study drug) 
End of Treatment (EOT) visits should occur 30 to 37 days after the last dose of study drug 
unless delayed due to an AE. However, EOT evaluations must be performed before initiation 
of a new therapy. If EOT evaluations are completed before 30 days after the last study 
treatment, the subject will be contacted 30 to 37 days following the last treatment to assess 
for AEs. 
● 
ECOG performance status (Appendix B) 
● 
Physical examination 
● 
B symptom assessment 
● 
Serum chemistry panel (submit results to central laboratory) 
● 
CBC with differential (submit results to central laboratory) 
● 
Urine and/or serum pregnancy test for subjects of childbearing potential 
● 
Blood sample for PK and ATA assessment 
● 
CMV PCR (post-allogeneic stem cell transplant subjects only) (submit results to 
central laboratory) 
● 
If not done in the previous 6 weeks and/or the subject came off treatment for reasons 
other than progression: 
○ 
CT of neck, chest, abdomen, pelvis 
○ 
PET scan if not found to be negative at a prior restage 
○ 
Bone marrow biopsy to confirm CR for sALCL or other CD30-expressing PTCL 
subjects ( if not found to be negative at screening and the post baseline PET/CT 
shows a CR) 
6.5 Follow-up: Every 4 Months From the Last Scan Performed Until Date of 
Progression/Subsequent Therapy 
For subjects who are off treatment but have not progressed and have not started a subsequent 
therapy: 
● 
CT of neck, chest, abdomen, pelvis 
● 
PET scan if not found to be negative at a prior restage 
● 
Bone marrow biopsy to confirm CR for sALCL or other CD30-expressing PTCL 
subjects (if not found to be negative at a prior restage) 
● 
After 24 months, scanning schedule may be determined by institutional standard of 
care 
For subjects who have progressed and/or have started a subsequent therapy 
● 
Survival status and subsequent anticancer therapies received – every 
4 months (±1 week) after disease progression or new therapy 
6.6 Subject End of Study/End of Follow-up 
The date the subject met criteria for study discontinuation and the reason for study 
discontinuation will be recorded. 


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7 
STUDY ASSESSMENTS 
For blood sampling planning purposes, see Clinical Operations blood draw volumes 
reference spreadsheet. 
7.1 Screening/Baseline Assessments 
Only subjects who meet all inclusion and exclusion criteria specified in Section 4 will be 
enrolled in this study. 
Subject medical history includes a thorough review of significant past medical history, 
current conditions, any treatment for prior malignancies and response to prior treatment, and 
any concomitant medications. HTLV-1 status must be obtained by local laboratory 
assessment to inform the diagnosis. 
7.1.1 Histological Diagnosis 
A histological diagnosis for cHL or CD30-expressing PTCL and PTCL subtype must be 
determined by local pathology assessment. Local pathology will also assess anaplastic 
lymphoma kinase (ALK) status for subjects with a diagnosis of sALCL. CD30 expression 
level ≥1% will be considered positive. Submission of the tumor block, or freshly cut, 
unstained slides (with medical monitor approval) from a diagnostic biopsy will be required 
for subsequent central confirmation of CD30 expression; central confirmation is not required 
prior to the first dose of the study drug. The diagnostic specimen must be from a malignant 
lymph node or extranodal tissue obtained by core or excisional/incisional biopsy. Cutaneous, 
bone, or bone marrow samples alone are unacceptable. Fine needle aspirate and cytology 
samples are also unacceptable. Details and shipping instructions are provided in the 
Laboratory Manual. 
7.2 Response/Efficacy Assessments 
Radiographic assessments (contrast enhanced CT of chest, neck, abdomen, and pelvis) will 
be performed at protocol-specified time points or if disease progression is suspected. 
Assessment of lymphoma progression will be made according to the modified Lugano 
Criteria for Response Assessment (Cheson 2014). Treatment decisions by the investigator 
will be based on these assessments. CT and PET scans are required per protocol as directed 
in Section 6.3.2 and Appendix A. 
A combined CT/PET may be obtained to satisfy the requirements for CT and PET scanning 
when both are required per protocol, as long as the CT scan is of diagnostic quality. CT 
and/or PET scans may also be obtained throughout the study if clinically indicated; if scans 
are performed at non-protocol specified time points, results will be collected in the subject’s 
CRF and images will be submitted for central review. 
PET and CT scanning of diagnostic quality will be required until disease is PET negative; 
responses will then be assessed by CT scan of diagnostic quality only. A bone marrow biopsy 
is required at screening for sALCL and other CD30-expressing PTCL subjects. Post baseline 
biopsies are also required to confirm a complete radiographic response for sALCL and other 


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CD30-expressing PTCL subjects; this confirmation is to be obtained within 4 weeks of 
documentation of response by radiographic assessment. However, repeat bone marrow 
biopsies are not required if bone marrow is found to be negative at screening or post baseline. 
All subjects’ clinical data and tumor images must be available for CRF source verification. 
Copies of all imaging studies must be made available for review by the Sponsor (or its 
designee) and the third-party imaging core laboratory. 
7.2.1 Modified Lugano Criteria 
The primary determination of antitumor efficacy will be ORR according to the Lugano 
Classification Revised Staging System for nodal non-Hodgkin and Hodgkin lymphomas 
modified to take into account CT response in the event of a PET partial response (PR) 
(modified Lugano criteria). Treatment decisions by the Investigator will be based on local 
disease assessments according to modified Lugano criteria. Disease response of PD, stable 
disease (SD), PR, CR, or not evaluable (NE) will be determined at each assessment by BICR 
and the Investigator. Selection of up to 6 of the largest dominant nodes or other tumor lesions 
to follow for response assessment must be PET FDG-avid at baseline. Investigator evaluation 
of baseline radiographic assessment will enable study enrollment per Inclusion Criterion 4. In 
addition, per Lugano criteria, these nodes or masses should be selected according to all of the 
following: they should be clearly measurable in at least two perpendicular dimensions; if 
possible, they should be from disparate regions of the body; and they should include 
mediastinal and retroperitoneal areas of disease whenever these sites are involved. The nodes 
or masses should have bidimensional measurements with at least 1.5 cm in the longest axis. 
For PET scans, Deauville scores of 1, 2, and 3 will be regarded as “negative” while scores of 
4 and 5 with uptake greater than background liver uptake will be regarded as positive. 
As detailed in the Independent Review Charter, the integrated response at each disease 
assessment will be determined on the basis of PET and CT responses according to modified 
Lugano criteria, as summarized in Table 3. 
For time points where both PET and CT disease assessments are available, the response 
assessment will in general default to the PET assessment; however, when a PR is determined 
by PET but the CT response in neither CR nor PR, the integrated response will be SD. Once 
a CR has been determined by PET assessment, the integrated response will continue to be CR 
until PD is detected by PET or CT, even if there are no further PET assessments. When the 
CT response is PD and PET was not evaluated the integrated response will be PD. 


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Table 3: 
Integrated PET and CT response according to modified Lugano criteria 
PET Response 
CT Response 
Integrated Response 
CR 
Any 
CR 
PR 
CR, PR 
PR 
 
Non-CR, Non-PR 
SD 
SD 
Any 
SD 
PD 
Any 
PD 
 
Prior PET responsea 
CT Response 
 
Not done or  
CR 
Non-PD 
CRb 
Not evaluable 
non-CR 
Non-PD 
NE 
 
Any 
PD 
PD 
No FDG-avid disease  
at baselinec 
No disease present (NE) 
NE 
PD 
PD 
NE=not evaluable. 
a 
"Prior PET response" refers to the latest prior PET assessment that was evaluable. PET responses may be carried 
forward over multiple CT assessments. 
b 
A CR according to PET will be carried forward irrespective of CT response, until CT shows PD or is assessed as NE. 
c 
Per protocol all subjects must have FDG-avid disease at baseline. 
7.2.2 Lugano Criteria 
Response will also be assessed, by the BICR, according to the unmodified Lugano criteria 
(Cheson 2014). Assessment of response will be undertaken in the same manner as for 
modified Lugano criteria (Section 7.2.1), with the exception that if the PET response is PR 
the integrated response will be PR, irrespective of CT response (Table 4). 
Table 4: 
Integrated PET and CT response according to Lugano criteria per BICR 
PET Response 
CT Response 
Integrated Response 
CR 
Any 
CR 
PR 
Any 
PR 
SD 
Any 
SD 
PD 
Any 
PD 
 
Prior PET responsea 
CT Response 
 
Not done or  
CR 
Non-PD 
CRb 
Not evaluable 
non-CR 
Non-PD 
NE 
 
Any 
PD 
PD 
No FDG-avid disease 
No disease present (NE) 
NE 
at baselinec 
PD 
PD 
NE=not evaluable. 
a 
"Prior PET response" refers to the latest prior PET assessment that was evaluable. PET responses may be carried 
forward over multiple CT assessments. 
b 
A CR according to PET will be carried forward irrespective of CT response, until CT shows PD or is assessed as NE. 
c 
Per protocol all subjects must have FDG-avid disease at baseline. 


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7.2.3 International Working Group Consensus Response Evaluation Criteria 
in Lymphoma 
ORR according to RECIL (Younes 2017) per BICR assessment will be evaluated as an 
additional efficacy endpoint. 
7.3 Pharmacokinetic and Immunogenicity Assessments 
Sensitive, qualified assays will be used to measure drug analytes including brentuximab 
vedotin ADC and MMAE concentrations in serum or plasma. These assays will include 
enzyme linked immunosorbent assays (ELISA) and liquid chromatography/tandem mass 
spectrometry (LC-MS/MS) assays, as well as other assays if further characterization is 
required. 
Blood samples for PK testing will be collected at predose in Cycles 1 through 4, at end of 
infusion in Cycles 1 and 2 and at EOT (see Table 5). ATA to brentuximab vedotin will also 
be measured predose at Cycles 1 through 4 and at EOT using an appropriate qualified assay. 
Selected PK parameters to be estimated include trough concentration (Ctrough), and 
concentration at the end of infusion for brentuximab vedotin (Ceoi). The incidence of ATA to 
brentuximab vedotin will also be assessed. 
Table 5: 
Pharmacokinetic, pharmacodynamic, and immunogenicity sampling time 
points 
Cycle 
Study 
Day 
Time 
Window 
Relative Timea 
PK 
ATA 
1 and 2 
Day 1 
Pre-dose 
Within prior 24 hr 
Start of infusion 
X 
X 
End of infusion 
(30 min) 
Within 30 min 
post  
end of infusion 
End of infusion 
X 
 
3 and 4 
Day 1 
Pre-dose 
Within prior 24 hr 
Start of infusion 
X 
X 
EOT 
 
X 
X 
a 
Relative to infusion of brentuximab vedotin 
7.4 Biospecimen Repository 
In the US only, for subjects who provide additional consent, remaining de-identified unused 
blood may be retained by Seattle Genetics and used for future research, including but not 
limited to the evaluation of targets for novel therapeutic agents, the biology of ADC 
sensitivity and resistance mechanisms, and the identification of pharmacodynamic 
biomarkers of ADCs. Blood samples donated for future research may be retained for a period 
of up to 25 years. If additional consent is not provided, any remaining biological samples will 
be destroyed after the study has been completed and all applicable regulatory obligations 
have been met. 


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7.5 Other Study Assessments 
7.5.1 
Additional Monitoring for Post-Allogeneic Transplant Subjects 
Subjects who have previously received an allogeneic transplant are at greater risk of 
developing opportunistic infections than subjects who have not received an allogeneic 
transplant. While risk of infection may be greatest in the first 100 days post-transplant, late 
infections (>100 days post-transplant) occur with some subjects remaining 
immunocompromised >2 years post-transplant (Tomblyn 2009). Consequently, 
post-allogeneic transplant subjects should be monitored by the investigator for signs or 
symptoms of potential opportunistic infections during the subject observation visits. 
In addition, all post-allogeneic transplant subjects must participate in CMV surveillance 
during treatment with brentuximab vedotin. At the time of enrollment, the investigator needs 
to discuss the surveillance schedule with the medical monitor and have it approved before 
initiating treatment. For subjects who are <1-year post-transplant and considered at high risk 
for reactivation, blood samples for CMV surveillance should be drawn at least weekly while 
on therapy and at EOT. For subjects who are ≥1-year post-transplant, or <1-year post 
transplant and not considered at high risk for reactivation, blood samples for surveillance 
should be drawn at least Day 1 of every treatment cycle and at EOT. Local laboratory will 
assess levels of CMV DNA using PCR. 
If at any time CMV level is detectable (defined as >0 copies/mL), initiation of pre-emptive 
therapy with ganciclovir or valganciclovir is recommended until CMV PCR becomes 
negative. Once CMV is no longer detectable by PCR, assessments will be conducted at least 
weekly during subsequent treatment on study. 
Any post baseline instances of detectable levels of CMV must be discussed with the Medical 
Monitor prior to continued dosing of brentuximab vedotin. 
7.5.2 
Additional Monitoring for HIV-Positive and Hepatitis C-Positive 
Subjects 
HIV-positive subjects must be co-managed with an HIV specialist; monitoring of CD4 
counts will be done at baseline, Cycle 2 and every 4 cycles thereafter, at EOT, and should be 
performed according to institutional standard of care. Hepatitis C-positive subjects should be 
monitored for viral reactivation according to institutional standards. 
7.6 Safety Assessments 
The assessment of safety during the course of this study will consist of the surveillance and 
recording of AEs including serious adverse events (SAEs), recording of concomitant 
medication, and measurements of protocol-specified physical examination findings and 
laboratory tests. 


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7.6.1 Adverse Events 
7.6.1.1 Definitions 
Adverse Event 
According to the International Council for Harmonisation (ICH) E2A guideline Definitions 
and Standards for Expedited Reporting, and 21 CFR 312.32, Investigational New Drug 
(IND) Safety Reporting, an AE is any untoward medical occurrence in a subject 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 AEs and Pre-existing Conditions CRF: 
● 
From the time of informed consent through the day prior to study Day 1, only study 
protocol-related AEs should be recorded. A protocol-related AE is defined as an 
untoward medical event occurring as a result of a protocol mandated procedure. 
● 
All medical conditions present or ongoing predose on study Day 1 should be 
recorded. 
● 
All AEs (regardless of relationship to study drug) should be recorded from study 
Day 1 (during and post-dose) through the end of the safety reporting period (see 
Section 7.6.1.3). Complications that occur in association with any procedure 
(e.g., biopsy) should be recorded as AEs whether or not the procedure was protocol 
mandated. 
● 
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 
(e.g., record “anemia” rather than “low hemoglobin”). 


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Serious Adverse Events 
An AE should be classified as an SAE if it meets one of the following criteria: 
Fatal: 
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 resulted in hospitalization or prolonged an existing in subject 
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 underlying cancer or study target 
disease need not be captured as SAEs. 
Disabling/ 
incapacitating: 
An AE that 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: 
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. Potential drug-induced liver injury (DILI) also is 
considered a medically significant event (see Section 7.6.1.2 for the definition of 
potential DILI.) 
Adverse Event Severity 
AE severity should be graded using the NCI CTCAE, Version 5.0. These criteria are 
provided in the study manual. 
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 SAEs, above). 
Relationship of the Adverse Event to Study Treatment 
The relationship of each AE to each study treatment (brentuximab vedotin) should be 
evaluated by the investigator using the following criteria: 
Related: 
There is evidence to suggest a causal relationship between the drug and the AE, such as: 
• 
A single occurrence of an event that is uncommon and known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome) 
• 
One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug 
(e.g., tendon rupture) 
Unrelated: 
Another cause of the AE is more plausible (e.g., 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 treatment, or a causal relationship is 
considered biologically implausible 


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7.6.1.2 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 non-directed 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 AEs and Pre-existing Conditions CRF: 
● 
Description including onset and resolution dates 
● 
Whether it met SAE criteria 
● 
Severity 
● 
Relationship to study treatment or other causality 
● 
Outcome 
Diagnosis vs. 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 
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. 


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Progression of the Underlying Cancer 
Since progression of underlying malignancy is being assessed as an efficacy variable, it 
should not be reported as an AE or SAE. The terms “Disease Progression,” “Progression of 
Disease,” or “Malignant disease progression” and other similar terms should not be used to 
describe an AE or SAE. However, clinical symptoms of progression may be reported as AEs 
or SAEs if the symptom cannot be determined as exclusively due to progression of the 
underlying malignancy or does not fit the expected pattern of progression for the disease 
under study. In addition, complications from progression of the underlying malignancy 
should be reported as AEs or SAEs. 
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. Email or 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 30 days of the last dose of study 
drug(s), will also be recorded on the AEs 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 Section 7.6.1.1) should be reported as SAEs. 
Potential Drug-Induced Liver Injury 
The observation of the critical importance of altered liver function has been referred to 
informally as Hy’s Law (Reuben 2004). Hy’s Law can be used to estimate severity and the 
likelihood that a study drug may cause an increased incidence of severe hepatotoxicity. 
The absence of hepatotoxicity in clinical trials provides a limited predictive value for 
potential hepatotoxicity in the clinical setting(s) being studied. However, finding 1 Hy’s Law 
case in clinical trials is ominous; finding 2 cases is highly predictive of a potential for severe 
drug-induced liver injury (DILI). 


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Definition 
Briefly, potential Hy’s Law cases include the following 3 components: 
1. Aminotransferase (ALT and/or AST) elevation >3 x ULN 
AND 
2. Total bilirubin >2 x ULN, without initial findings of cholestasis (i.e., elevated serum 
alkaline phosphatase), 
AND 
3. No other immediately apparent possible causes of aminotransferase elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or 
acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
Reporting Requirements 
Any potential Hy’s Law case should be handled as a suspected unexpected serious 
adverse reaction (SUSAR) associated with the use of the drug and reported promptly to 
the Sponsor. 
Reporting should include all available information and should initiate close follow-up until 
complete resolution of the problem and completion of all attempts to obtain supplementary 
data. 
Follow-up for Abnormal Laboratory Results Suggesting Potential DILI 
In general, an increase of serum ALT or AST to >3 x ULN should be followed by repeat 
testing within 48 to 72 hours of serum ALT, AST, alkaline phosphatase, and total bilirubin, 
to confirm the abnormalities and to determine whether they are worsening. 
Appropriate medical assessment should be initiated to investigate potential confounding 
factors and alternative causes of hepatotoxicity. Consider withholding study drug during the 
investigation. 
7.6.1.3 Reporting Periods for Adverse Events and Serious Adverse Events 
The safety reporting period for all AEs and SAEs is from study Day 1 (predose) through the 
EOT visit or 30 days after the last study treatment, whichever is later. However, all study 
protocol-related AEs are to be recorded from the time of informed consent. 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. 
SAEs 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 non-serious AEs will be followed through the 
safety reporting period. Certain non-serious AEs of interest may be followed until resolution, 
return to baseline, or study closure. 


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7.6.1.4 Serious Adverse Events Require Immediate Reporting 
Within 24 hours of observing or learning of an SAE, investigators are to report the event to 
the sponsor, regardless of the relationship of the event to the study treatment regimen. 
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 
● 
Study treatment, if known 
 
The completed SAE form and SAE Fax Cover Sheet are to be emailed or faxed to the 
sponsor’s Drug Safety Department within 24 hours (see email address or fax number 
specified on the SAE report form)  
Relevant follow-up information is to be submitted to the sponsor as soon as it becomes 
available. 
7.6.1.5 Sponsor Safety Reporting to Regulatory Authorities 
Investigators are required to report all SAEs, including anticipated SAEs, to the sponsor (see 
Section 7.6.1.4). 
The sponsor will report all SAEs to regulatory authorities as required per local regulatory 
reporting requirements. In the United States, endpoints that assess disease-related mortality 
or major morbidity, as well as other SAEs that are not study endpoints but are known 
consequences of the underlying disease or condition that are anticipated to occur in the study 
population, should not be reported to the FDA as individual IND safety reports per the final 
rule amending the IND safety reporting requirements under 21 CFR 312.32 and the FDA’s 
guidance Safety Assessment for IND Safety Reporting Guidance for Industry (draft guidance 
December 2015). 
In this study, progression of underlying malignancy is not reported as AEs or SAEs. No 
individual IND safety reports will be submitted for progression of underlying malignancy. 
Progression of underlying malignancy will be evaluated as an efficacy endpoint. 


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7.6.2 Clinical Laboratory Tests 
Samples will be drawn for local labs. The following laboratory assessments will be 
performed by the local lab to evaluate safety at scheduled time points (see Appendix A) 
during the course of the study and the results (no blood) will be sent to central lab: 
● 
The chemistry panel is to include the following tests: albumin, alkaline phosphatase, 
ALT, AST, blood urea nitrogen, calcium, creatinine, chloride, glucose, lactate 
dehydrogenase, phosphorus, potassium, sodium, total bilirubin, amylase, lipase, and 
uric acid. 
● 
The CBC with differential is to include the following tests: white blood cell count 
with five-part differential (neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils), platelet count, hemoglobin, and hematocrit. 
● 
The estimated GFR should be calculated using the MDRD equation as applicable, 
with Scr reported in mg/dL. 
○ 
GFR (mL/min/1.73 m2) =175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x 
(1.212 if African American) 
● 
A serum or urine β-hCG pregnancy test for subjects of childbearing potential at 
screening/baseline and EOT. 
7.6.3 Physical Examination 
Physical examinations should include assessments of the following body parts/systems: 
abdomen, extremities, head, heart, lungs, neck, and neurological. Measurements of height 
obtained within the prior 12 months may be utilized. 
7.7 Appropriateness of Measurements 
The safety measures that will be used in this trial are considered standard procedures for 
evaluating the potential adverse effects of study medications. 
Response will be assessed according to Lugano Criteria for Response Assessment (Cheson 
2014) which are standardized criteria for evaluating response in cHL, PTCL, and sALCL. 
The intervals of evaluation in this protocol are considered appropriate for disease 
management. 
Immunogenicity is commonly assessed for biologics; therefore, standard tests will be 
performed to detect the possible presence of specific antibodies to brentuximab vedotin. PK 
assessments are also common in clinical studies to help characterize dose-exposure-response 
relationships. 


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8 
DATA QUALITY CONTROL AND QUALITY ASSURANCE 
8.1 Site Training and Monitoring Procedures 
A study manual with instructions for study compliance and CRF completion will be 
provided. Prior to the enrollment of subjects at the site, Seattle Genetics or its designated 
clinical and medical personnel will review the following items with the investigator and 
clinic staff: 
● 
The protocol, study objectives, eligibility requirements, study procedures, 
registration, and withdrawal processes 
● 
Current Investigator’s Brochure/package insert 
● 
Recording and reporting AEs and SAEs 
● 
Enrollment goals and study timelines 
● 
The CRF completion process and source documentation requirements 
● 
Monitoring requirements 
● 
Institutional review board/independent ethics committee (IRB/IEC) review and 
approval process 
● 
Informed consent process 
● 
Good clinical practice guidelines and related regulatory documentation requirements 
● 
Key study team roles and responsibilities 
● 
Investigational product storage, accountability, labeling, dispensing and record 
keeping 
● 
Subject coding and randomization (if applicable) 
● 
Study samples/specimen collection, handling and shipping 
● 
Protocol compliance 
● 
Clinical study record keeping, document retention, and administrative requirements 
Monitoring visits will occur periodically, with frequency dependent on the rate of enrollment 
and workload at each site. During monitoring visits, the Seattle Genetics representative will 
typically review regulatory documentation, CRFs, source documentation, and investigational 
product storage, preparation, and accountability. The CRFs will be reviewed for 
completeness, adherence to the provided guidelines, and accuracy compared to the source 
documents. The investigators must ensure that the monitor is allowed to inspect all source 
documents pertinent to study subjects, and must cooperate with the monitor to ensure that 
any problems noted in the course of the trial are resolved. The investigator must maintain a 
comprehensive and centralized filing system of all study-related documentation that is 


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suitable for inspection by Seattle Genetics or its designated monitors and by quality 
assurance auditors, or representatives of regulatory authorities. 
8.2 Data Management Procedures 
Seattle Genetics will provide CRF Completion Guidelines for electronic CRF (eCRF) data 
entry. Study specific data management procedures will be maintained in the data 
management plan. Queries resulting from edit checks and/or data verification procedures will 
be posted electronically in the eCRF. 
8.3 Access to Source Data 
The investigator will permit the sponsor’s representatives to monitor the study as frequently 
as the sponsor deems necessary to determine that protocol adherence and data recording are 
satisfactory. Appropriate measures to protect subject confidentiality are to be employed 
during monitoring. The CRFs and related source documents will typically be reviewed by the 
monitor at each site visit to ensure data quality. Original source documents or certified copies 
are needed for review. Other study records, such as correspondence with the sponsor and the 
IRB/IEC and screening and drug accountability logs will also be inspected. All source data 
and study records must also be available for inspection by representatives of regulatory 
authorities and the IRB/IEC. 
8.4 Accuracy and Reliability of Data 
Steps to be taken to assure the accuracy and reliability of data include: 
● 
The selection of qualified investigators and appropriate study centers. 
● 
Review of protocol procedures with the investigators and associated personnel prior 
to the study. 
● 
Periodic monitoring visits by the designated monitor(s). 
● 
CRFs will be reviewed for accuracy and completeness during monitoring visits to the 
study centers and/or by centralized monitoring. Any discrepancies will be resolved 
with the investigator or designees as appropriate. 
8.5 Quality Assurance Procedures 
The Research and Development Quality group or its designee may conduct audits at the 
clinical site or other study-related facilities and organizations. Audit reports will be retained 
by the Research and Development Quality group of Seattle Genetics as part of the written 
record. 


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8.6 Data Handling and Record Keeping 
8.6.1 Data Handling 
It is the investigator’s responsibility to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported to the sponsor in the CRFs and in all required reports. Data 
reported on the CRF that is derived from source documents should be consistent with the 
source documents or the discrepancies should be explained. 
Any change or correction to a CRF will be maintained in an audit trail within the electronic 
data capture system. Data changes may only be made by those individuals so authorized. The 
investigator should retain records of the changes and corrections, written and/or electronic. 
8.6.2 Investigator Record Retention 
The investigator shall retain study drug disposition records and all source documentation 
(such as original ECG tracings, laboratory reports, insubject or office subject records) for the 
maximum period required by the country and Institution in which the study will be 
conducted, or for the period specified by Seattle Genetics, whichever is longer. The 
investigator must contact Seattle Genetics prior to destroying any records associated with the 
study. If the investigator withdraws from the study (due to relocation, retirement, etc.), the 
records shall be transferred to a mutually agreed upon designee, such as another investigator 
or IRB/IEC. Notice of such transfer will be provided in writing to Seattle Genetics. 
9 
DATA ANALYSIS METHODS 
9.1 Determination of Sample Size 
It is anticipated that approximately 40 cHL and 40 CD30-expressing PTCL subjects will be 
enrolled in this study. This sample size was chosen to allow adequate precision of estimates 
of response rates. 
For the cHL cohort, if 24 responses are observed, the estimated ORR would be 60%, and the 
associated 2-sided 95% confidence interval (CI) using the Clopper-Pearson method would be 
(43.3%, 75.1%). 
For the CD30-expressing PTCL cohort, if 20 responses are observed, the estimated ORR 
would be 50%, and the associated 2-sided 95% CI using the Clopper-Pearson method would 
be (33.8%, 66.2%). The 50% ORR for the PTCL cohort was calculated based on a weighted 
average of subjects with sALCL and other CD30-expressing PTCL, where subjects with 
sALCL have an ORR of 60% and an estimated enrollment cap of approximately 50%, and 
subjects with other CD30-expressing PTCL have an ORR of 40% and an estimated 
enrollment cap of approximately 50%. 


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9.2 Study Endpoint Definitions 
9.2.1 Objective Response Rate 
Objective Response Rate (ORR) is defined as the portion of subjects with CR or PR 
according to the modified Lugano Criteria for Response Assessment (Cheson 2014) based on 
BICR or investigator as specified in Section 2. The ORR according to Lugano Criteria for 
response Assessment (Cheson 2014) per BICR, and the ORR according to RECIL (Younes 
2017) per BICR will be evaluated as a secondary endpoint and an additional endpoint, 
respectively. 
9.2.2 Duration of Response 
DOR is defined as the time from start of the first documentation of objective tumor response 
(CR or PR) based on BICR or investigator to the first documentation of objective tumor 
progression or to death due to any cause, whichever comes first. DOR data will be censored 
on the day following the date of the last radiological assessment of measured lesions 
documenting absence of PD for subjects who do not have objective tumor progression and 
are still on study at the time of an analysis, are given antitumor treatment other than the study 
treatment or stem cell transplant (includes donor lymphocyte infusion), or are removed from 
study prior to documentation of objective tumor progression. DOR will only be calculated for 
the subgroup of subjects with OR. Duration of CR will also be analyzed in the subset of 
subjects who achieve a CR. 
9.2.3 Progression-Free Survival 
PFS is defined as the time from start of study treatment to first documentation of objective 
tumor progression based on BICR or investigator or to death due to any cause, whichever 
comes first. PFS data will be censored on the date of the last radiological assessment of 
measured lesions documenting absence of PD for subjects who do not have objective tumor 
progression and are still on study at the time of an analysis, are given antitumor treatment 
other than the study treatment or stem cell transplant (includes donor lymphocyte infusion), 
or are removed from study prior to documentation of objective tumor progression. Subjects 
lacking an evaluation of tumor response after their first dose will have their event time 
censored at 1 day. 
9.2.4 Overall Survival 
OS is defined as the time from start of study treatment to date of death due to any cause. In 
the absence of confirmation of death, survival time will be censored at the last date the 
subject is known to be alive. Subjects lacking data beyond the day of first dose will have 
their survival time censored at 1 day. The start of study treatment is defined as the first dose 
of brentuximab vedotin on the current study. 
9.2.5 Complete Response Rate 
CR rate is defined as the portion of subjects with CR according to the modified Lugano 
Criteria for Response Assessment (Cheson 2014) based on BICR or investigator. 


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9.3 Statistical and Analytical Plans 
The statistical and analytical plans presented below summarize the more complete plans to be 
detailed in the statistical analysis plan (SAP). A change to the data analysis methods 
described in the protocol will require a protocol amendment only if it alters site conduct 
(e.g., adding baseline assessments to define a subgroup). The SAP will be finalized prior to 
database lock. Any changes to the methods described in the final SAP will be described and 
justified in the clinical study report. 
9.3.1 General Considerations 
9.3.1.1 Randomization and Blinding 
Randomization and blinding will not be performed. 
9.3.1.2 Adjustments for Covariates 
Covariates are not considered for adjustment in the analyses. 
9.3.1.3 Handling of Dropouts and Missing Data 
With the exception of time-related endpoints, no imputation will be conducted for missing 
data unless otherwise specified in the SAP. 
For time-related endpoints, e.g., DOR, OS, and PFS, etc., subjects who have no specified 
event will be censored at the time of the last valid assessment of the endpoint(s). 
9.3.1.4 Multicenter Studies 
Site-to-site variation will not be adjusted in the analyses. 
9.3.1.5 Multiple Comparisons and Multiplicity 
No multiple comparisons are planned, and no alpha adjustment is needed because no formal 
hypotheses are being tested. 
9.3.1.6 Data Transformations and Derivations 
Baseline values used in all statistical analyses will be the most recent non-missing 
measurement prior to the first dose of brentuximab vedotin unless otherwise specified in the 
analysis plan. 
9.3.1.7 Analysis Sets 
Full Analysis Set 
The full analysis set includes all subjects who receive at least 1 dose of brentuximab vedotin 
on this study. The full analysis set will be used for efficacy analyses and all safety analyses. 
Demographics and baseline disease characteristics will be summarized based on full analysis 
set. 
Additional analysis sets of subjects may be defined in the SAP. 


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9.3.1.8 Examination of Subgroups 
As exploratory analyses, subgroup analyses may be conducted for selected endpoints. 
Detailed methodology will be provided in the SAP. 
9.3.1.9 Timing of Analyses 
The primary analysis will be conducted when all treated subjects have been followed for at 
least 6 months, discontinued from study, or had 30 days of safety follow-up after PD, 
whichever comes first.  
9.3.2 Subject Disposition 
An accounting of study subjects by disposition will be tabulated and the number of subjects 
will be summarized. All enrolled subjects who discontinue study treatment and subjects who 
withdraw from the study will be summarized with reason for discontinuation or withdrawal. 
9.3.3 Subject Characteristics 
Demographics and other baseline characteristics will be summarized. Details will be 
provided in the SAP. 
9.3.4 Treatment Compliance 
The dose (mg/kg) administered at each cycle will be assessed and dose intensity will be 
summarized. Details will be provided in the SAP. 
9.3.5 Efficacy Analyses 
9.3.5.1 Primary Efficacy Analyses 
The ORR by BICR and its two-sided 95% exact CI will be calculated using the Clopper-
Pearson method (Clopper 1934). The maximum percent reduction in the sum of the products 
of the largest diameters (SPD) per the modified Lugano Response Assessment Criteria for 
Malignant Lymphoma (Cheson 2014) will be graphically displayed. Detailed methodology 
will be provided in the SAP. 
9.3.5.2 Secondary Efficacy Analyses 
The CR rate will be derived and its two sided 95% exact confidence interval will be 
calculated using the Clopper-Pearson method (Clopper 1934). DOR and PFS in the FAS will 
be estimated using Kaplan-Meier methodology and Kaplan-Meier plots will be provided. The 
median DOR, PFS, and OS and their two sided 95% CI by Brookmeyer and Crowley 
(Brookmeyer 1982) will be calculated. The ORR by investigator per the modified Lugano 
Response Assessment Criteria for Malignant Lymphoma (Cheson 2014) and its two-sided 
95% exact CI will be calculated using the Clopper-Pearson method (Clopper 1934). The 
ORR by BICR per the Response Assessment Criteria for Malignant Lymphoma (Cheson 
2014) will be analyzed similarly. The maximum percent reduction in the sum of the products 
of the longest perpendicular diameters (SPD) per the modified Lugano Response Assessment 


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Criteria for Malignant Lymphoma (Cheson 2014) will be graphically displayed. Detailed 
methodology will be provided in the SAP. 
9.3.5.3 Additional Efficacy Analyses 
The ORR by BICR and its two-sided 95% exact CI will be calculated using the 
Clopper-Pearson method (Clopper 1934). The maximum percent reduction in the sum of the 
longest diameters (SLD) per the RECIL Criteria (Younes 2017) will be graphically 
displayed. 
9.3.6 Pharmacokinetic and Immunogenicity Analyses 
Antibody drug-conjugate (brentuximab vedotin) and unconjugated drug (MMAE) levels in 
serum or plasma will be summarized with descriptive statistics at each PK sampling time 
point. Any additional PK and PK/PD analyses may be described in a separate analysis plan 
and presented in a separate report. 
9.3.7 Safety Analyses 
9.3.7.1 Extent of Exposure 
Total dose, duration of treatment, number of cycles and dose intensity will be summarized 
and listed. Dose modifications will also be summarized and listed. Details will be provided in 
the SAP.  
9.3.7.2 Adverse Events 
An overview of AEs will provide a tabulation of the incidence of all AEs, treatment-
emergent AEs, treatment-related AEs, Grade 3 and higher AEs, SAEs, treatment-related 
SAEs, deaths, and AEs leading to study treatment discontinuation. AEs will be defined as 
treatment emergent if they are newly occurring or worsen following study treatment. 
AEs will be listed and summarized by Medical Dictionary for Regulatory Activities 
(MedDRA) preferred term, severity, and relationship to study drug. In the event of multiple 
occurrences of the same AE with the same preferred term in 1 subject, the AE will be 
counted once as the occurrence for that subject. The incidence of AEs will be tabulated by 
preferred term. AEs leading to premature discontinuation of study drug will be summarized 
and listed in the same manner. 
9.3.7.3 Deaths and Serious Adverse Events 
SAEs will be listed and summarized in the same manner as all AEs. Events with a fatal 
outcome will be listed. 


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9.3.7.4 Clinical Laboratory Results 
For laboratory results, summary statistics for actual values and for change from baseline may 
be tabulated as appropriate by scheduled visit. Laboratory values will be listed with grade per 
NCI CTCAE version 5.0 and flagged when values are outside the normal reference range. 
9.3.8 Interim Analyses 
No formal interim analyses are planned. 


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10 INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS 
This study will be conducted in accordance with the Note for Guidance on Good Clinical 
Practice (ICH Harmonised Tripartite Guideline E6 (R2); FDA CFR [21 CFR § 50, 56, 312]), 
Declaration of Helsinki (Brazil 2013), and all applicable regulatory requirements. 
10.1 Informed Consent 
The investigator is responsible for presenting the risks and benefits of study participation to 
the subject in simple terms using the IRB/IEC approved informed consent document and for 
ensuring subjects are re-consented when the informed consent document is updated during 
the study, if required. The investigator will ensure that written informed consent is obtained 
from each subject, or legally acceptable representative, if applicable to this study, by 
obtaining the signature and date on the informed consent document prior to the performance 
of protocol evaluations or procedures. 
For phase 1 studies, it is preferable for a subject to provide consent themselves. If informed 
consent is obtained from a legally acceptable representative for a subject who is unable to 
provide informed consent at study entry (if applicable), but the subject is later able to provide 
informed consent, the investigator must obtain written informed consent from the subject. 
10.2 Ethical Review 
The investigator will provide the sponsor or its designee with documentation of the IRB/IEC 
approval of the protocol and the informed consent document before the study may begin at 
the investigative site(s). The name and address of the reviewing ethics committee are 
provided in the investigator file. 
The investigator will supply the following to the investigative site’s IRB/IEC: 
● 
Protocol and amendments 
● 
Informed consent document and updates 
● 
Clinical Investigator’s Brochure and updates 
● 
Relevant curricula vitae, if required 
● 
Required safety and SAE reports 
● 
Any additional submissions required by the site’s IRB/IEC 
 
The investigator must provide the following documentation to the sponsor or its designee: 
● 
The IRB/IEC periodic (e.g., quarterly, annual) re-approval of the protocol. 
● 
The IRB/IEC approvals of any amendments to the protocol or revisions to the 
informed consent document. 
● 
The IRB/IEC receipt of safety and SAE reports, as appropriate. 


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10.3 Regulatory Considerations 
This study will be conducted in accordance with the protocol and ethical principles stated in 
the applicable guidelines on good clinical practice, and all applicable local and/or regional 
laws, rules, and regulations. 
10.3.1 Investigator Information 
The contact information and qualifications of the principal investigator and sub investigators 
and name and address of the research facilities are included in the investigator file. 
10.3.2 Protocol Amendments and Study Termination 
Protocol amendments will be submitted to the IRB/IEC prior to implementing. The 
investigator is responsible for enrolling subjects who have met protocol eligibility criteria. 
Protocol deviations must be reported to the sponsor and the local IRB/IEC in accordance 
with IRB/IEC policies. 
The sponsor may terminate the study at any time. The IRB/IEC must be advised in writing of 
study completion or early termination. 
10.4 Study Documentation, Privacy and Records Retention 
To protect the safety of participants in the study and to ensure accurate, complete, and 
reliable data, the investigator will keep records of laboratory tests, clinical notes, and subject 
medical records in the subject files as original source documents for the study. If requested, 
the investigator will provide the sponsor, its licensees and collaborators, applicable 
regulatory agencies, and applicable IRB/IEC with direct access to original source documents 
or certified copies. 
Records containing subject medical information must be handled in accordance with local 
and national laws, rules, and regulations and consistent with the terms of the subject 
authorization contained in the informed consent document for the study (the Authorization). 
Care should be taken to ensure that such records are not shared with any person or for any 
purpose not contemplated by the Authorization. Furthermore, CRFs and other documents to 
be transferred to the sponsor should be completed in strict accordance with the instructions 
provided by the sponsor, including the instructions regarding the coding of subject identities. 
In compliance with local and/or regional regulations, this trial may be registered and trial 
results may be posted on public registries, such as ClinicalTrials.gov. 
10.5 Clinical Trial Agreement 
Payments by the sponsor to investigators and institutions conducting the trial, requirements 
for investigators’ insurance, the publication policy for clinical trial data, and other 
requirements are specified in the clinical trial agreement. 


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11 REFERENCES 
Bartlett NL, Chen R, Fanale MA, Brice P, Gopal A, Smith SE, Advani R, Matous JV, 
Ramchandren R, Rosenblatt JD, Huebner D, Levine P, Grove L, Forero-Torres A 
(2014). Retreatment with brentuximab vedotin in patients with CD30-positive 
hematologic malignancies. J Hematol Oncol 7(1): 24. 
 
Bossard C, Dobay MP, Parrens M, Lamant L, Missiaglia E, Haioun C, Martin A, Fabiani B, 
Delarue R, Tournilhac O, Delorenzi M, Gaulard P, de Leval L (2014). 
Immunohistochemistry as a valuable tool to assess CD30 expression in peripheral T-
cell lymphomas: high correlation with mRNA levels. Blood 124(19): 2983-6. 
 
Brookmeyer R, Crowley J (1982). A confidence interval for the median survival time. 
Biometrics 38(1 (March)): 29-41. 
 
Cao A, Heiser R, Law CL, Gardai SJ (2016). Auristatin-based antibody drug conjugates 
activate multiple ER stress response pathways resulting in immunogenic cell death 
and amplified T-cell responses. Cancer Res 76(14 Suppl): Abstract 4914. 
 
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA, Alliance 
Australasian Leukaemia Lymphoma Group, Eastern Cooperative Oncology Group, 
European Mantle Cell Lymphoma Consortium, Italian Lymphoma Foundation, 
European Organisation for Research, Treatment of Cancer/Dutch Hemato-Oncology 
Group, Grupo Espanol de Medula Osea, German High-Grade Lymphoma Study 
Group, German Hodgkin's Study Group, Japanese Lymphorra Study Group, 
Lymphoma Study Association, NCIC Clinical Trials Group, Nordic Lymphoma 
Study Group, Southwest Oncology Group, United Kingdom National Cancer 
Research Institute (2014). Recommendations for initial evaluation, staging, and 
response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano 
classification. J Clin Oncol 32(27): 3059-68. 
 
Clopper CJ, Pearson ES (1934). The use of confidence or fiducial limits illustrated in the 
case of the binomial. Biometrika 26(4): 404-13. 
 
Davis TA, Grillo-Lopez AJ, White CA, McLaughlin P, Czuczman MS, Link BK, Maloney 
DG, Weaver RL, Rosenberg J, Levy R (2000). Rituximab anti-CD20 monoclonal 
antibody therapy in non-Hodgkin's lymphoma: safety and efficacy of re-treatment. J 
Clin Oncol 18(17): 3135-43. 
 
Federico M, Bellei M, Luminari S, Horwitz SM, Montoto S, Zucca E, Pileri SA, Ko YH, 
Zinzani PL, Connors JM, Foss FM, Polliack A, Cabrera ME, Kim WS, Spina M, De 
Souza CA, Varela SB, Dlouhy I, Advani RH, Vose J (2015). CD30+ expression in 
peripheral T-cell lymphomas (PTCLs): a subset analysis from the international, 
prospective T-Cell Project. J Clin Oncol 33(15 Suppl): Abstract 855s. 
 
Gardai SJ, Heiser R, Cao A, Li F, Leung-Law C (2016). Immune systems engagement results 
in non-classical antibody-drug conjugate antitumor activity of brentuximab vedotin. 
Haematologica 101(Suppl 5): 53. 


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Kahl BS, Hong F, Williams ME, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, 
Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann 
WC, Horning SJ (2014). Rituximab extended schedule or re-treatment trial for low-
tumor burden follicular lymphoma: eastern cooperative oncology group protocol 
E4402. J Clin Oncol 32(28): 3096-102. 
 
Kim YH, Tavallaee M, Sundram U, Salva KA, Wood GS, Li S, Rozati S, Nagpal S, Krathen 
M, Reddy S, Hoppe RT, Nguyen-Lin A, Weng WK, Armstrong R, Pulitzer M, 
Advani RH, Horwitz SM (2015). Phase II investigator-initiated study of brentuximab 
vedotin in mycosis fungoides and Sezary syndrome with variable CD30 expression 
level: a multi-institution collaborative project. J Clin Oncol 33(32): 3750-8. 
 
Li F, Zhang X, Emmerton K, Jonas M, Setter J, Arthur B, Okeley N, Lyon R, Benjamin D, 
Law CL (2014). Relationship between in vivo antitumor activity of ADC and payload 
release in preclinical models. Cancer Res 74(Suppl 19): Abstract 3694. 
 
Muller P, Martin K, Theurich S, Schreiner J, Savic S, Terszowski G, Lardinois D, 
Heinzelmann-Schwarz VA, Schlaak M, Kvasnicka HM, Spagnoli G, Dirnhofer S, 
Speiser DE, von Bergwelt-Baildon M, Zippelius A (2014). Microtubule-
depolymerizing agents used in antibody-drug conjugates induce antitumor immunity 
by stimulation of dendritic cells. Cancer Immunol Res 2(8): 741-55. 
 
Oflazoglu E, Stone IJ, Gordon KA, Grewal IS, van Rooijen N, Law CL, Gerber HP (2007). 
Macrophages contribute to the antitumor activity of the anti-CD30 antibody SGN-30. 
Blood 110(13): 4370-2. 
 
Reuben A (2004). Hy's law. Hepatology 39(2): 574-8. 
 
Sabattini E, Pizzi M, Tabanelli V, Baldin P, Sacchetti CS, Agostinelli C, Zinzani PL, Pileri 
SA (2013). CD30 expression in peripheral T-cell lymphomas. Haematologica 98(8): 
e81-2. 
 
Sutherland MS, Sanderson RJ, Gordon KA, Andreyka J, Cerveny CG, Yu C, Lewis TS, 
Meyer DL, Zabinski RF, Doronina SO, Senter PD, Law CL, Wahl AF (2006). 
Lysosomal trafficking and cysteine protease metabolism confer target-specific 
cytotoxicity by peptide-linked anti-CD30-auristatin conjugates. J Biol Chem 281(15): 
10540-7. 
 
Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, Wingard JR, Young JA, 
Boeckh MA (2009). Guidelines for preventing infectious complications among 
hematopoietic cell transplantation recipients: a global perspective. Biol Blood 
Marrow Transplant 15(10): 1143-238. 
 


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Younes A, Hilden P, Coiffier B, Hagenbeek A, Salles G, Wilson W, Seymour JF, Kelly K, 
Gribben J, Pfreunschuh M, Morschhauser F, Schoder H, Zelenetz AD, Rademaker J, 
Advani R, Valente N, Fortpied C, Witzig TE, Sehn LH, Engert A, Fisher RI, Zinzani 
PL, Federico M, Hutchings M, Bollard C, Trneny M, Elsayed YA, Tobinai K, 
Abramson JS, Fowler N, Goy A, Smith M, Ansell S, Kuruvilla J, Dreyling M, 
Thieblemont C, Little RF, Aurer I, Van Oers MHJ, Takeshita K, Gopal A, Rule S, de 
Vos S, Kloos I, Kaminski MS, Meignan M, Schwartz LH, Leonard JP, Schuster SJ, 
Seshan VE (2017). International Working Group consensus response evaluation 
criteria in lymphoma (RECIL 2017). Ann Oncol 28(7): 1436-47. 


 
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APPENDIX A: SCHEDULE OF EVENTS 
 
 
 
Screening/ Baseline 
Enrollment 
Every 21-
day cycle 
Cycle 2 and 
every 4 cycles 
thereafter 
Cycle 2 and 
every 4 cycles 
thereafter 
EOT 
Long-term 
follow-up (Every 
4 months since 
last scan) 
 
Day 
D –28 to 
1 
D –7 to 
1 
Within 7D 
of 1st dose 
D1 
D1 
D15-21 (or D1-2 
of Cycle 3 and 
every 4 cycles 
thereafter)N 
Within  
30–37D of last 
doseA 
Every 4 months 
 
Visit window 
 
 
 
2d 
–2d 
 
 
2 wk 
Screening/ Baseline 
Assessments  
Informed consent 
X 
 
Submit eligibility confirmation to  
Sponsor prior to treatment 
 
 
 
 
 
Inclusion/Exclusion, medical history  
X 
 
XK 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
CD30/histology 
X 
 
 
 
 
 
 
HTLV-1 status for ATLL subjects/ALK status for 
sALCL subjects 
X 
 
 
 
 
 
 
Prior disease therapies 
X 
 
 
 
 
 
 
ECG 
 
X 
 
 
 
 
 
Pregnancy test – urine and/or serum (subjects of 
childbearing potential) 
 
X 
 
 
 
X 
 
Height  
 
X 
 
 
 
 
 
Weight 
 
X 
XB 
 
 
 
 
 
Biopsy to confirm CD30 expressionL 
X 
 
 
 
 
 
 
Safety Assessments 
Physical exam 
 
X 
XB 
 
 
X 
X 
ECOG performance status 
 
X 
XB 
 
 
X 
 
CBC with differential 
 
X 
XB 
 
 
X 
 
Chemistry panel 
 
X 
XB 
 
 
X 
 
Hgb A1c 
 
X 
 
 
 
 
 
B symptom assessment 
 
 
X 
 
 
X 
 
CMV PCR for post-allogeneic subjects 
 
X 
See Section 7.5.1 
X 
 
CD4 count for HIV positive subjects 
 
X 
 
 
X 
 
X 
 
Monitoring for Hep C positive subjects   
Monitor for viral reactivation per institutional standards 
Concomitant medications 
Related to study proceduresE 
Collect from Day 1 predose through safety reporting period of study drug 
Adverse event collection 
Treatment 
Study drug administration 
 
 
 
X 
 
 
 
 
PK/Immunogenicity 
Blood sample collection 
See Table 5 for sample collection details 
Response Assessment 
CT of neck, chest, abdomen, pelvis 
X 
 
 
 
 
XC 
XD 
XI 
PETF 
X 
 
 
 
 
XG 
XD,G 
XG, I 
Bone marrow biopsy 
XM 
 
 
 
 
XH 
XD 
XH 
Survival Status 
 
 
 
 
 
 
 
XJ 


 
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A. 
EOT evaluations should be obtained before the initiation of non-protocol therapy. If EOT evaluations are completed before 30 days following the last study treatment, conduct a phone screen 30–37 days 
following the subject’s last study treatment to ensure that no changes in AE profile have occurred. 
B. 
Does not need to be repeated if done within 1 day prior to C1D1 or 2 days prior to any other cycle. 
C. 
Window Day 15–21 
D. 
Not required if conducted 6 weeks prior to EOT. 
E. 
From time of informed consent. 
F. 
A combined CT/PET may be obtained to satisfy the requirements for CT and PET scanning, as long as a diagnostic quality CT scan is obtained; PET scans may also be obtained any time during the study if 
clinically indicated. 
G. 
Once disease is determined to be PET negative, only CT scans are required. 
H. 
Bone marrow biopsy is required only to confirm complete response for sALCL and other CD30-expressing PTCL subjects and should be obtained within 4 weeks after documentation of response; does not 
need to be repeated once bone marrow is negative. 
I. 
Required every 4 months for 24 months for subjects that came off treatment but have not progressed or initiated a new therapy. Obtain until subject experiences PD per investigator assessment, initiation of new 
therapy, death, or analysis of the primary endpoint, whichever comes first. After 24 months, scanning schedule may be per institutional standard of care. 
J. 
Once a subject experiences PD per investigator assessment or initiates a new therapy, survival status is required every 4 months (±1 week) until death or study closure, whichever comes first. Collect 
information regarding subsequent anticancer therapies. 
K. 
Cycle 1 only. 
L. 
A biopsy within 60 days prior to study start to confirm CD30 expression is required, but may be omitted if, in the opinion of the Investigator, obtaining the biopsy would place the subject at undue risk. 
M. 
Window Day -14 to Day 1; for sALCL and other CD30-expressing PTCL subjects only. 
N. 
Study drug may only be administered after the response assessment is confirmed to show lack of PD. 
 


 
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APPENDIX B: PERFORMANCE STATUS SCALES CONVERSION 
Karnofsky 
Lansky 
ECOG 
Percent 
Description 
Percent 
Description 
Score 
Description 
100 
Normal, no complaints, no evidence 
of disease. 
100 
Fully active, normal. 
0 
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
90 
Minor restrictions in physically 
strenuous activity. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
80 
Active, but tires more quickly. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
70 
Both greater restriction of, and less time 
spent in, play activity. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
60 
Up and around, but minimal active 
play; keeps busy with quieter activities. 
2 
In bed <50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
50 
Requires considerable assistance 
and frequent medical care. 
50 
Gets dressed, but lies around much of 
the day; no active play; able to 
participate in all quiet active play and 
activities. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed, participates in quiet 
activities. 
3 
In bed >50% of the time. Capable of 
only limited self-care, confined to 
bed or chair more than 50% of 
waking hours. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
30 
In bed, needs assistance even for quiet 
play. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
20 
Often sleeping, play entirely limited to 
very passive activities. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
10 
Moribund, fatal processes 
progressing rapidly. 
10 
No play, does not get out of bed. 
0 
Dead. 
0 
Dead. 
5 
Dead. 


 
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APPENDIX C: NEW YORK HEART ASSOCIATION CLASSIFICATION 
A Functional and Therapeutic Classification for Prescription of Physical Activity for 
Cardiac Subjects 
Class I:  
subjects with no limitation of activities; they suffer no symptoms from ordinary activities. 
Class II:  
subjects with slight, mild limitation of activity; they are comfortable with rest or with mild 
exertion. 
Class III:  
subjects with marked limitation of activity; they are comfortable only at rest. 
Class IV:  
subjects who should be at complete rest, confined to bed or chair; any physical activity brings 
on discomfort and symptoms occur at rest. 
Online source: http://www heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-Heart-
Failure_UCM_306328_Article.jsp 
 




 
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APPENDIX E: INVESTIGATOR SIGNATURE PAGE 
 
Investigator Statement and Signature 
 
I have read the attached protocol titled “A phase 2, multicenter, single-arm study of treatment 
with brentuximab vedotin in subjects with relapsed or refractory classic Hodgkin lymphoma 
(cHL) or CD30-expressing peripheral T cell lymphoma (PTCL).”  
I understand and agree to the provisions of the protocol, and I accept the responsibilities 
listed above in my role as principal investigator for the study. 
 
 
 
Investigator Signature 
 
Date 
 
 
 
 
 
 
 
 
 
Investigator Name, Printed 
 
 
 


 
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APPENDIX F: DOCUMENT HISTORY 
Version 
Date 
Original 
16-Apr-2019 
Amendment 1 
26-Aug-2019 
Amendment 2 
20-Nov-2019 
Amendment 3 
28-Apr-2020 
 


 
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Summary of Changes in Amendment 1 
Section(s) 
Change 
Rationale 
Title page 
Change of medical monitor to Julie Lisano 
Change in medical monitor. 
3.1, 5.2.2, and 
Synopsis 
Clarified that subjects who start at a dose of 1.2 mg/kg 
because of prior dose reduction due to AEs will not 
escalate to 1.8 mg/kg. 
Subjects who previously required a 
dose reduction due to AEs may 
potentially have a repeat of the AEs at 
the higher dose. 
3.2 
Modified inclusion criterion 3 by changing 
documentation of disease or relapse progression from 
3 months to 6 months and removing language about 
brentuximab vedotin treatment in frontline and second 
line or beyond setting. Criterion now reads: 
Documentation of disease relapse or progression ≥6 
months after the last dose of brentuximab vedotin 
based on the Lugano Response Assessment Criteria 
for Malignant Lymphoma (Cheson 2014). 
Lengthened requirement for duration 
of brentuximab vedotin treatment 
from 3 months to 6 months. 
4.1 
Modified inclusion criterion 6:  
Bullet 1: Changed ANC count from ≥1000 cells/μL to 
≥750 cells/μL and added “unless documented bone 
marrow involvement with lymphoma.” 
Bullet 2: Added “unless documented bone marrow 
involvement with lymphoma”  
Bullet 5: Added “for subjects with documented 
hepatic involvement with lymphoma.” 
Clarification 
4.2 
Removal of the following exclusion criterion: 
“Subjects with dementia or altered mental state that 
would preclude the understanding and rendering of 
informed consent.” 
 
Added: Subjects who were previously refractory to 
treatment with brentuximab vedotin. 
Conflicted with inclusion criterion. 
 
 
 
Clarification.  
5.4.1.4 
Added new section to include the effects of other 
drugs (CYP3A4 and P-gp inhibitors/inducers) on 
brentuximab vedotin 
Included to keep the protocol 
language consistent with the USPI 
label.  
5.4.2.1 
Changed ANC from ≥1000 cells/μL to ≥750 cells/μL 
To harmonize with change made in 
Section 4.1 
6.2 and 
Appendix A 
Included biopsy requirement. 
For confirmation for CD30 expression 
7.1.1 
Added language for CD30 expression and biopsy 
requirements. 
Clarification 
7.2 
Added Table 3 (Integrated PET and CT Response) to 
expand on the response assessment.  
Clarification 
7.3 
Clarified that blood samples for PK will be collected 
at predose Cycles 1 through 4. Deleted PK collection 
at 48 hours.  
Clarification  
7.6.2 
Change made from central to local labs and clarified 
that only results will be sent to central lab.  
Clarification  


 
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Section(s) 
Change 
Rationale 
3.1, 9.1 and 
synopsis 
Changed sample size and ORR rates for cHL and 
CD30-expressing PTCL 
Changed from a previous 
heterogeneous population with a 
sample size of approximately 50 to 
two distinct samples sizes: 
approximately 40 subjects each for 
cHL and other CD30-expressing 
PTCL 
Throughout 
Minor administrative edits and corrections. 
Corrections 
 


 
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Summary of Changes in Amendment 2 
Section(s) 
Change 
Rationale 
2 (Table 1), 9 
(Table 5) and 
Synopsis 
Changed primary endpoint to ORR per modified Lugano 
criteria, added a secondary endpoint for ORR per 
unmodified Lugano criteria, and added an additional 
endpoint for ORR per Response Evaluation Criteria in 
Lymphoma (RECIL). 
Regulatory feedback indicated 
that Lugano criteria should be 
modified in the trial. 
7.2.1 and 
7.2.2 
Added new sections that include text and tables to specify 
how PET and CT response assessments are integrated for 
modified Lugano criteria and unmodified Lugano criteria. 
Clarification 
9.3.5.1 
Added response criteria to “modified” Lugano. 
Clarification 
9.3.5.2 
Added language to reflect addition of secondary objective 
of ORR by investigator. 
Clarification 
9.3.5.3 
Added language to include ORR per RECIL as determined 
by BICR. 
Clarification 
Throughout 
protocol 
Minor administrative changes, corrections, renumbering of 
sections, and rearrangement of text. 
Clarity and consistency 
 


 
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Summary of Changes in Amendment 3 
Section(s) 
Change 
Rationale 
Title Page 
Addition of NCT and EudraCT numbers and change in 
medical monitor. 
Administrative update 
3.3 
New section to define end of study. 
Updated to meet EU regulatory 
requirements 
4.1 and 7.1.1 
Added language to inclusion criterion 1 to include CD30 
expression threshold for eligibility 
Clarification to correct 
inconsistency  
5.4.3 
Added exception of palliative radiotherapy. 
Clarification 
6.2 
Specified window for bone marrow biopsy.  
To align with existing practice 
6.3.2, 6.4, and 
7.2 
Added language to clarify requirement to confirm CR for 
sALCL or other CD30-expressing PTCL subjects 
To align with existing practice 
6.6 
Modified section header to distinguish it from Section 3.3 
header. 
Clarification 
7.2.1 and 
Table 4 
Added language to clarify that disease response will be 
assessed by BICR and the Investigator. 
Clarification 
Table 6 
Table removed 
To streamline the protocol and 
avoid redundancy 
Appendix A 
Added bone marrow biopsy specific to PTCL subjects 
during screening. 
 
Added language and footnote to expand screening window. 
To align with existing practice 
 
Expanded scanning window due 
to COVID-19 pandemic 
Appendix D 
Added appendix for Guidance on Contraception.  
Guidance to the investigator that 
encompasses US and EU 
contraception requirements 
Throughout 
protocol 
Minor administrative changes, corrections, clarifications, 
and rearrangements of text. 
Clarity and consistency